DK3025_half-series-title.qxd

7/11/05

3:09 PM

Page A

Handbook of Pharmaceutical
Granulation Technology© 2005 by Taylor & Francis Group, LLC

DK3025_half-series-title.qxd

7/11/05

3:09 PM

Page BDRUGS AND THE PHARMACEUTICAL SCIENCES
Executive Editor

James Swarbrick
PharmaceuTech, Inc.
Pinehurst, North Carolina

Advisory Board
Larry L. Augsburger

Harry G. Brittain

University of Maryland
Baltimore, Maryland

Center for Pharmaceutical Physics
Milford, New Jersey

Jennifer B. Dressman
Johann Wolfgang Goethe University
Frankfurt, Germany

Anthony J. Hickey
University of North Carolina School of
Pharmacy
Chapel Hill, North Carolina

Jeffrey A. Hughes
University of Florida College of
Pharmacy
Gainesville, Florida

Trevor M. Jones
The Association of the
British Pharmaceutical Industry
London, United Kingdom

Vincent H. L. Lee

Ajaz Hussain
U.S. Food and Drug Administration
Frederick, Maryland

Hans E. Junginger
Leiden/Amsterdam Center
for Drug Research
Leiden, The Netherlands

Stephen G. Schulman

University of Southern California
Los Angeles, California

University of Florida
Gainesville, Florida

Jerome P. Skelly

Elizabeth M. Topp

Alexandria, Virginia

University of Kansas School of
Pharmacy
Lawrence, Kansas

Geoffrey T. Tucker
University of Sheffield
Royal Hallamshire Hospital
Sheffield, United Kingdom© 2005 by Taylor & Francis Group, LLC

Peter York
University of Bradford School of
Pharmacy
Bradford, United Kingdom

DK3025_half-series-title.qxd

7/11/05

3:09 PM

Page CDRUGS AND THE PHARMACEUTICAL SCIENCES
A Series of Textbooks and Monographs

1. Pharmacokinetics, Milo Gibaldi and Donald Perrier
2. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total
Quality Control, Sidney H. Willig, Murray M. Tuckerman,
and William S. Hitchings IV
3. Microencapsulation, edited by J. R. Nixon
4. Drug Metabolism: Chemical and Biochemical Aspects, Bernard Testa
and Peter Jenner
5. New Drugs: Discovery and Development, edited by Alan A. Rubin
6. Sustained and Controlled Release Drug Delivery Systems,
edited by Joseph R. Robinson
7. Modern Pharmaceutics, edited by Gilbert S. Banker
and Christopher T. Rhodes
8. Prescription Drugs in Short Supply: Case Histories, Michael A. Schwartz
9. Activated Charcoal: Antidotal and Other Medical Uses, David O. Cooney
10. Concepts in Drug Metabolism (in two parts), edited by Peter Jenner
and Bernard Testa
11. Pharmaceutical Analysis: Modern Methods (in two parts),
edited by James W. Munson
12. Techniques of Solubilization of Drugs, edited by Samuel H. Yalkowsky
13. Orphan Drugs, edited by Fred E. Karch
14. Novel Drug Delivery Systems: Fundamentals, Developmental Concepts,
Biomedical Assessments, Yie W. Chien
15. Pharmacokinetics: Second Edition, Revised and Expanded, Milo Gibaldi
and Donald Perrier
16. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total
Quality Control, Second Edition, Revised and Expanded, Sidney H. Willig,
Murray M. Tuckerman, and William S. Hitchings IV
17. Formulation of Veterinary Dosage Forms, edited by Jack Blodinger
18. Dermatological Formulations: Percutaneous Absorption, Brian W. Barry
19. The Clinical Research Process in the Pharmaceutical Industry,edited by Gary M. Matoren
20. Microencapsulation and Related Drug Processes, Patrick B. Deasy
21. Drugs and Nutrients: The Interactive Effects, edited by Daphne A. Roe
and T. Colin Campbell
22. Biotechnology of Industrial Antibiotics, Erick J. Vandamme
23. Pharmaceutical Process Validation, edited by Bernard T. Loftus
and Robert A. Nash

© 2005 by Taylor & Francis Group, LLC

DK3025_half-series-title.qxd

7/11/05

3:09 PM

Page D

24. Anticancer and Interferon Agents: Synthesis and Properties,edited by Raphael M. Ottenbrite and George B. Butler
25. Pharmaceutical Statistics: Practical and Clinical Applications,
Sanford Bolton
26. Drug Dynamics for Analytical, Clinical, and Biological Chemists,
Benjamin J. Gudzinowicz, Burrows T. Younkin, Jr.,and Michael J. Gudzinowicz
27. Modern Analysis of Antibiotics, edited by Adjoran Aszalos
28. Solubility and Related Properties, Kenneth C. James
29. Controlled Drug Delivery: Fundamentals and Applications,
Second Edition, Revised and Expanded, edited by Joseph R. Robinson
and Vincent H. Lee
30. New Drug Approval Process: Clinical and Regulatory Management,edited by Richard A. Guarino
31. Transdermal Controlled Systemic Medications, edited by Yie W. Chien
32. Drug Delivery Devices: Fundamentals and Applications,edited by Praveen Tyle
33. Pharmacokinetics: Regulatory • Industrial • Academic Perspectives,edited by Peter G. Welling and Francis L. S. Tse
34. Clinical Drug Trials and Tribulations, edited by Allen E. Cato
35. Transdermal Drug Delivery: Developmental Issues and Research
Initiatives, edited by Jonathan Hadgraft and Richard H. Guy
36. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms,edited by James W. McGinity
37. Pharmaceutical Pelletization Technology, edited by
Isaac Ghebre-Sellassie
38. Good Laboratory Practice Regulations, edited by Allen F. Hirsch
39. Nasal Systemic Drug Delivery, Yie W. Chien, Kenneth S. E. Su,
and Shyi-Feu Chang
40. Modern Pharmaceutics: Second Edition, Revised and Expanded,edited by Gilbert S. Banker and Christopher T. Rhodes
41. Specialized Drug Delivery Systems: Manufacturing and Production
Technology, edited by Praveen Tyle
42. Topical Drug Delivery Formulations, edited by David W. Osborne
and Anton H. Amann
43. Drug Stability: Principles and Practices, Jens T. Carstensen
44. Pharmaceutical Statistics: Practical and Clinical Applications,
Second Edition, Revised and Expanded, Sanford Bolton
45. Biodegradable Polymers as Drug Delivery Systems,
edited by Mark Chasin and Robert Langer
46. Preclinical Drug Disposition: A Laboratory Handbook, Francis L. S. Tseand James J. Jaffe© 2005 by Taylor & Francis Group, LLC

DK3025_half-series-title.qxd

7/11/05

3:09 PM

Page E

47. HPLC in the Pharmaceutical Industry, edited by Godwin W. Fongand Stanley K. Lam
48. Pharmaceutical Bioequivalence, edited by Peter G. Welling,
Francis L. S. Tse, and Shrikant V. Dinghe
49. Pharmaceutical Dissolution Testing, Umesh V. Banakar
50. Novel Drug Delivery Systems: Second Edition, Revised and Expanded,
Yie W. Chien
51. Managing the Clinical Drug Development Process, David M. Cocchetto
and Ronald V. Nardi
52. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total
Quality Control, Third Edition, edited by Sidney H. Willig and James R.
Stoker
53. Prodrugs: Topical and Ocular Drug Delivery, edited by Kenneth B. Sloan
54. Pharmaceutical Inhalation Aerosol Technology, edited by
Anthony J. Hickey
55. Radiopharmaceuticals: Chemistry and Pharmacology, edited byAdrian D. Nunn
56. New Drug Approval Process: Second Edition, Revised and Expanded,edited by Richard A. Guarino
57. Pharmaceutical Process Validation: Second Edition, Revisedand Expanded, edited by Ira R. Berry and Robert A. Nash
58. Ophthalmic Drug Delivery Systems, edited by Ashim K. Mitra
59. Pharmaceutical Skin Penetration Enhancement, edited by
Kenneth A. Walters and Jonathan Hadgraft
60. Colonic Drug Absorption and Metabolism, edited by Peter R. Bieck
61. Pharmaceutical Particulate Carriers: Therapeutic Applications,edited by Alain Rolland
62. Drug Permeation Enhancement: Theory and Applications,edited by Dean S. Hsieh
63. Glycopeptide Antibiotics, edited by Ramakrishnan Nagarajan
64. Achieving Sterility in Medical and Pharmaceutical Products, Nigel A. Halls
65. Multiparticulate Oral Drug Delivery, edited by Isaac Ghebre-Sellassie
66. Colloidal Drug Delivery Systems, edited by Jörg Kreuter
67. Pharmacokinetics: Regulatory • Industrial • Academic Perspectives,
Second Edition, edited by Peter G. Welling and Francis L. S. Tse
68. Drug Stability: Principles and Practices, Second Edition, Revisedand Expanded, Jens T. Carstensen
69. Good Laboratory Practice Regulations: Second Edition, Revisedand Expanded, edited by Sandy Weinberg
70. Physical Characterization of Pharmaceutical Solids, edited byHarry G. Brittain© 2005 by Taylor & Francis Group, LLC

DK3025_half-series-title.qxd

7/11/05

3:09 PM

Page F

71. Pharmaceutical Powder Compaction Technology, edited by
Göran Alderborn and Christer Nyström
72. Modern Pharmaceutics: Third Edition, Revised and Expanded,edited by Gilbert S. Banker and Christopher T. Rhodes
73. Microencapsulation: Methods and Industrial Applications,edited by Simon Benita
74. Oral Mucosal Drug Delivery, edited by Michael J. Rathbone
75. Clinical Research in Pharmaceutical Development, edited by Barry Bleidt
and Michael Montagne
76. The Drug Development Process: Increasing Efficiency and Cost
Effectiveness, edited by Peter G. Welling, Louis Lasagna,
and Umesh V. Banakar
77. Microparticulate Systems for the Delivery of Proteins and Vaccines,
edited by Smadar Cohen and Howard Bernstein
78. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total
Quality Control, Fourth Edition, Revised and Expanded, Sidney H. Willig
and James R. Stoker
79. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms:
Second Edition, Revised and Expanded, edited by James W. McGinity
80. Pharmaceutical Statistics: Practical and Clinical Applications,Third Edition, Sanford Bolton
81. Handbook of Pharmaceutical Granulation Technology, edited by
Dilip M. Parikh
82. Biotechnology of Antibiotics: Second Edition, Revised and Expanded,edited by William R. Strohl
83. Mechanisms of Transdermal Drug Delivery, edited by Russell O. Potts
and Richard H. Guy
84. Pharmaceutical Enzymes, edited by Albert Lauwers and Simon Scharpé
85. Development of Biopharmaceutical Parenteral Dosage Forms,edited by John A. Bontempo
86. Pharmaceutical Project Management, edited by Tony Kennedy
87. Drug Products for Clinical Trials: An International Guide to Formulation •Production • Quality Control, edited by Donald C. Monkhouseand Christopher T. Rhodes
88. Development and Formulation of Veterinary Dosage Forms: Second
Edition, Revised and Expanded, edited by Gregory E. Hardee
and J. Desmond Baggot
89. Receptor-Based Drug Design, edited by Paul Leff
90. Automation and Validation of Information in Pharmaceutical Processing,edited by Joseph F. deSpautz
91. Dermal Absorption and Toxicity Assessment, edited by Michael S. Roberts
and Kenneth A. Walters© 2005 by Taylor & Francis Group, LLC

DK3025_half-series-title.qxd

7/11/05

3:09 PM

Page G

92. Pharmaceutical Experimental Design, Gareth A. Lewis, Didier Mathieu,
and Roger Phan-Tan-Luu
93. Preparing for FDA Pre-Approval Inspections, edited by Martin D. Hynes III
94. Pharmaceutical Excipients: Characterization by IR, Raman, and NMR
Spectroscopy, David E. Bugay and W. Paul Findlay
95. Polymorphism in Pharmaceutical Solids, edited by Harry G. Brittain
96. Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products,edited by Louis Rey and Joan C. May
97. Percutaneous Absorption: Drugs–Cosmetics–Mechanisms–Methodology,
Third Edition, Revised and Expanded, edited by Robert L. Bronaugh
and Howard I. Maibach
98. Bioadhesive Drug Delivery Systems: Fundamentals, Novel Approaches,
and Development, edited by Edith Mathiowitz, Donald E. Chickering III,and Claus-Michael Lehr
99. Protein Formulation and Delivery, edited by Eugene J. McNally
100. New Drug Approval Process: Third Edition, The Global Challenge,edited by Richard A. Guarino
101. Peptide and Protein Drug Analysis, edited by Ronald E. Reid
102. Transport Processes in Pharmaceutical Systems, edited byGordon L. Amidon, Ping I. Lee, and Elizabeth M. Topp
103. Excipient Toxicity and Safety, edited by Myra L. Weinerand Lois A. Kotkoskie
104. The Clinical Audit in Pharmaceutical Development, edited byMichael R. Hamrell105. Pharmaceutical Emulsions and Suspensions, edited by
Francoise Nielloud and Gilberte Marti-Mestres106. Oral Drug Absorption: Prediction and Assessment, edited by
Jennifer B. Dressman and Hans Lennernäs
107. Drug Stability: Principles and Practices, Third Edition, Revisedand Expanded, edited by Jens T. Carstensen and C. T. Rhodes
108. Containment in the Pharmaceutical Industry, edited by James P. Wood
109. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total
Quality Control from Manufacturer to Consumer, Fifth Edition, Revisedand Expanded, Sidney H. Willig
110. Advanced Pharmaceutical Solids, Jens T. Carstensen
111. Endotoxins: Pyrogens, LAL Testing, and Depyrogenation, Second Edition,
Revised and Expanded, Kevin L. Williams
112. Pharmaceutical Process Engineering, Anthony J. Hickeyand David Ganderton
113. Pharmacogenomics, edited by Werner Kalow, Urs A. Meyer,
and Rachel F. Tyndale
114. Handbook of Drug Screening, edited by Ramakrishna Seethalaand Prabhavathi B. Fernandes© 2005 by Taylor & Francis Group, LLC

DK3025_half-series-title.qxd

7/11/05

3:09 PM

Page H

115. Drug Targeting Technology: Physical • Chemical • Biological Methods,edited by Hans Schreier116. Drug–Drug Interactions, edited by A. David Rodrigues
117. Handbook of Pharmaceutical Analysis, edited by Lena Ohannesianand Anthony J. Streeter
118. Pharmaceutical Process Scale-Up, edited by Michael Levin
119. Dermatological and Transdermal Formulations, edited by
Kenneth A. Walters
120. Clinical Drug Trials and Tribulations: Second Edition, Revised andExpanded, edited by Allen Cato, Lynda Sutton, and Allen Cato III
121. Modern Pharmaceutics: Fourth Edition, Revised and Expanded,edited by Gilbert S. Banker and Christopher T. Rhodes
122. Surfactants and Polymers in Drug Delivery, Martin Malmsten
123. Transdermal Drug Delivery: Second Edition, Revised and Expanded,edited by Richard H. Guy and Jonathan Hadgraft124. Good Laboratory Practice Regulations: Second Edition,
Revised and Expanded, edited by Sandy Weinberg
125. Parenteral Quality Control: Sterility, Pyrogen, Particulate, and Package
Integrity Testing: Third Edition, Revised and Expanded, Michael J. Akers,
Daniel S. Larrimore, and Dana Morton Guazzo
126. Modified-Release Drug Delivery Technology, edited byMichael J. Rathbone, Jonathan Hadgraft, and Michael S. Roberts
127. Simulation for Designing Clinical Trials: A PharmacokineticPharmacodynamic Modeling Perspective, edited by Hui C. Kimko
and Stephen B. Duffull
128. Affinity Capillary Electrophoresis in Pharmaceutics and Biopharmaceutics,
edited by Reinhard H. H. Neubert and Hans-Hermann Rüttinger
129. Pharmaceutical Process Validation: An International Third Edition,
Revised and Expanded, edited by Robert A. Nash and Alfred H. Wachter
130. Ophthalmic Drug Delivery Systems: Second Edition, Revisedand Expanded, edited by Ashim K. Mitra
131. Pharmaceutical Gene Delivery Systems, edited by Alain Rolland
and Sean M. Sullivan
132. Biomarkers in Clinical Drug Development, edited by John C. Bloom
and Robert A. Dean
133. Pharmaceutical Extrusion Technology, edited by Isaac Ghebre-Sellassie
and Charles Martin
134. Pharmaceutical Inhalation Aerosol Technology: Second Edition,
Revised and Expanded, edited by Anthony J. Hickey
135. Pharmaceutical Statistics: Practical and Clinical Applications,
Fourth Edition, Sanford Bolton and Charles Bon
136. Compliance Handbook for Pharmaceuticals, Medical Devices,and Biologics, edited by Carmen Medina© 2005 by Taylor & Francis Group, LLC

DK3025_half-series-title.qxd

7/11/05

3:09 PM

Page I

137. Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products:
Second Edition, Revised and Expanded, edited by Louis Rey
and Joan C. May
138. Supercritical Fluid Technology for Drug Product Development,edited by Peter York, Uday B. Kompella, and Boris Y. Shekunov
139. New Drug Approval Process: Fourth Edition, Accelerating Global
Registrations, edited by Richard A. Guarino
140. Microbial Contamination Control in Parenteral Manufacturing,edited by Kevin L. Williams
141. New Drug Development: Regulatory Paradigms for Clinical Pharmacology
and Biopharmaceutics, edited by Chandrahas G. Sahajwalla
142. Microbial Contamination Control in the Pharmaceutical Industry,edited by Luis Jimenez
143. Generic Drug Product Development: Solid Oral Dosage Forms,edited by Leon Shargel and Izzy Kanfer
144. Introduction to the Pharmaceutical Regulatory Process,edited by Ira R. Berry
145. Drug Delivery to the Oral Cavity: Molecules to Market, edited by
Tapash K. Ghosh and William R. Pfister146. Good Design Practices for GMP Pharmaceutical Facilities,edited by Andrew Signore and Terry Jacobs
147. Drug Products for Clinical Trials, Second Edition, edited by Donald
Monkhouse, Charles Carney, and Jim Clark
148. Polymeric Drug Delivery Systems, edited by Glen S. Kwon
149. Injectable Dispersed Systems: Formulation, Processing, and Performance,
edited by Diane J. Burgess
150. Laboratory Auditing for Quality and Regulatory Compliance,
Donald Singer, Raluca-Ioana Stefan, and Jacobus van Staden
151. Active Pharmaceutical Ingredients: Development, Manufacturing, andRegulation, edited by Stanley H. Nusim
152. Preclinical Drug Development, edited by Mark C. Rogge and David Taft
153. Pharmaceutical Stress Testing: Predicting Drug Degradation, edited by
Steven W. Baertschi
154. Handbook of Pharmaceutical Granulation Technology: Second Edition,edited by Dilip M. Parikh© 2005 by Taylor & Francis Group, LLC

DK3025_half-series-title.qxd

7/11/05

3:09 PM

Page iHandbook of Pharmaceutical
Granulation Technology
Second Edition

edited by

Dilip M. Parikh
Synthon Pharmaceuticals Inc.
Research Triangle Park, North Carolina, U.S.A.

Boca Raton London New York Singapore© 2005 by Taylor & Francis Group, LLC

DK3025_Discl.fm Page 1 Tuesday, April 12, 2005 2:45 PM

Published in 2005 by
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742© 2005 by Taylor & Francis Group, LLC
No claim to original U.S. Government works
Printed in the United States of America on acid-free paper
10 9 8 7 6 5 4 3 2 1International Standard Book Number-10: 0-8247-2647-2 (Hardcover)
International Standard Book Number-13: 978-0-8247-2647-8 (Hardcover)This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted withpermission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish
reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials
or for the consequences of their use.
No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, orother means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information
storage or retrieval system, without written permission from the publishers.
For permission to photocopy or use material electronically from this work, please access www.copyright.com(http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA
01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For
organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged.
Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for
identification and explanation without intent to infringe.
Library of Congress Cataloging-in-Publication Data
Catalog record is available from the Library of Congress

Taylor & Francis Groupis the Academic Division of T&F Informa plc.

© 2005 by Taylor & Francis Group, LLC

Visit the Taylor & Francis Web site at
http://www.taylorandfrancis.com

Do not follow where the path may lead. Go instead where there isno path and leave a trail.
— Ralph Waldo Emerson© 2005 by Taylor & Francis Group, LLC

To
My wife, Leena Parikh, M.D. andmy son, Neehar Parikh, M.D.
for your support during this project
andAll of the co-workers at various companies andfriends from whom I have learned
over the last thirty years.
Thank you.

© 2005 by Taylor & Francis Group, LLC

Preface

It has been over eight years since the ﬁrst edition of the Handbook of Pharmaceutical
Granulation Technology was published. The enthusiastic reception afforded by thescientiﬁc community was heartwarming.
The basic science of granulation has not changed much over the last few years;
however, a better understanding of the theory of granulation and the proliferation ofdifferent dosage forms has. The second edition seeks to improve and update the content of the ﬁrst edition, as well as to enlarge the coverage by addition of new chaptersthat reﬂect the current state of the technology and the regulatory environment.
The pharmaceutical industry has seen several waves of consolidation with eachsuccessive year. The economic pressures on the industry have been increasing due topolitical policies and dwindling supply of new chemical entities. The surge in expiration of patents has given opportunities to the generic drug industry as never seen
before and the trend will continue for some time to come. The emergence ofbiotechnology as the new resource for new drug candidates is exciting. To maintainmarket share and remain in the forefront of technological advances, a number of different dosage forms utilizing different granulation technologies have been explored.
The technologies of interest include techniques for producing rapid release dosage
forms, the use of various meltable materials for melt pelletizations and the manufacture of controlled release dosage forms. Thus, a new chapter on the rapid release
granulation techniques is included in this edition. A chapter on melt granulationand pelletization is added together with another on effervescent granulation. These
additions provide pharmaceutical scientists a spectrum of granulation techniques
reﬂecting the current state of the art. Additionally, the chapter on spray drying isrevised to include the spray congealing technique, which is also becoming popular.
Regulatory requirements in the pharmaceutical industry have created the needfor an understanding of this unit operation at an early stage of product formulation,
method selection, and process development. Because the process and speciﬁcations
for the pivotal batches and full-scale production batches ‘‘must be equivalent,’’ theneed for reliable control of the manufacturing process used to produce the test
and clinical batches cannot be overemphasized.
The FDA’s Process Analytical Technology (PAT) initiative is an effort tofacilitate the introduction of new manufacturing technologies in the pharmaceuticalvii© 2005 by Taylor & Francis Group, LLC

viii

Prefaceindustry for achieving more efﬁcient processes. PATs are systems that enhance
process understanding and assist in identifying and controlling critical points in aprocess. These include appropriate measurement devices, which can be placed in- or
on-line, statistical and information technology tools, and a scientiﬁc systems approachfor data analysis to control processes that will ensure production of in-process materials and ﬁnal products of the desired quality. A separate chapter on PAT covers thisimportant topic.
Every chapter in this edition is updated to reﬂect new developments in thetechnologies and how these technologies are used to produce the desired granulation
end product.
This book is designed to give readers comprehensive knowledge of the subject.
As in the earlier edition, chapters include an appropriate level of theory on the fundamentals of powder characterization, granulation, and state-of-the-art technology.
However, the emphasis is on the application of these basic principles to the industrial
practice of producing pharmaceutical granulation for subsequent processing into
dosage forms. The new regulatory requirements along with the new technologies
employed in the industry and contemporary approaches to producing pharmaceutical granulation are important areas covered in this second edition.
Pharmaceutical professionals, such as research and development scientists,
process engineers, validation specialists, process specialists, quality assurance andquality control professionals, and graduate students in industrial pharmacy programs will ﬁnd the level of theory appropriate and the wealth of practical information from renowned pharmaceutical professionals invaluable. The knowledge
provided will be invaluable for selecting the appropriate granulation technology,
while keeping in mind regulatory requirements and cost effectiveness.
I would like to acknowledge the support and cooperation of all the contributing authors throughout this process; to them I offer a most sincere thank you.
Without their dedication and timely submission of material, this book would nothave gone to print. I would also like to give special mention to Dr. Paul Heng
(National University of Singapore) and Dr. Gurvinder Singh Rekhi (Elan Drug
Delivery, Inc.) for their invaluable support during this project.
A special recognition goes to Ms. Sandra Beberman, Vice President of Taylor& Francis Books. It was with her encouragement that I was driven to revise andupdate the second edition of this book. I am overwhelmed by the wide acceptanceof the ﬁrst edition throughout the worldwide pharmaceutical industry and academias. It is my hope that this second edition will continue to serve as a reference tool
and will provide useful knowledge in this important unit operation.
Dilip M. Parikh© 2005 by Taylor & Francis Group, LLC

Contents

Preface . . . . vii
Contributors . . . . xv
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Dilip M. Parikh
References . . . . 6
2. Theory of Granulation: An Engineering Perspective . . . . . . . . . . . . . 7
Bryan J. Ennis
1. Introduction . . . . 7
2. Wetting . . . . 19
3. Granule Growth and Consolidation . . . . 34
4. Granule Strength and Breakage . . . . 55
5. Controlling Granulation Processes . . . . 60
References . . . . 77
3. Drug Substance and Excipient Characterization . . . . . . . . . . . . . . 79
L. W. Chan and P. W. S. Heng
1. Introduction . . . . 79
2. Particle Shape, Size, and Surface Area . . . . 80
3. Solubility . . . . 89
4. Crystal Properties and Polymorphism . . . . 95
5. Other Physical Properties . . . . 100
6. Commonly Used Excipients in Granulation . . . . 102
7. Compatibility of Drug and Excipient . . . . 103
8. Conclusion . . . . 105
References . . . . 106
4. Binders and Solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Ehab Hamed, Derek Moe, Raj Khankari, and John Hontz
1. Introduction . . . . 109
2. Types of Binders . . . . 109
3. Factors Inﬂuencing Binder Efﬁciency . . . . 115
ix© 2005 by Taylor & Francis Group, LLC

xContents

4. Processing Parameters for Commonly Used Binders . . . . 119
References . . . . 125
5. Spray Drying and Pharmaceutical Applications . . . . . . . . . . . . . . 129
Metin Çelik and Susan C. Wendel
1. Introduction . . . . 129
2. Spray Drying Process Stages . . . . 130
3. Process Layouts . . . . 138
4. Theory of Spray Drying Fundamentals . . . . 139
5. Spray Drying Applications . . . . 146
6. Conclusion . . . . 154
References . . . . 155
6. Roller Compaction Technology . . . . . . . . . . . . . . . . . . . . . . . . . 159
Ronald W. Miller
1. Introduction . . . . 159
2. Powder Granulation and Compaction . . . . 159
3. Background . . . . 160
4. Beneﬁts of Roller Compaction . . . . 161
5. Compaction Theory . . . . 162
6. Design Features of Roller Compactors . . . . 166
7. Roll Conﬁguration . . . . 167
8. Feed Screw Design . . . . 170
9. Future Trends in Granulation Technology . . . . 172
10. New Findings . . . . 173
11. Deaeration Theory . . . . 178
12. Roller Compaction and Near-Infrared
Spectroscopy . . . . 182
13. Roller Compaction and PAT . . . . 185
References . . . . 188
7. High-Shear Granulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
Rajeev Gokhale, Yichun Sun, and Atul J. Shukla
1. Introduction . . . . 191
2. High-Shear Granulators . . . . 192
3. High-Shear Granulation Process . . . . 195
4. Mechanism of High Shear Wet Granulation . . . . 200
5. Factors Affecting the Granulation Process
and Granule Properties . . . . 204
6. Granulation End-Point Determination . . . . 212
7. Formulation Development (Optimization) . . . . 217
8. Process Scale-Up . . . . 219
9. Conclusion . . . . 224
References . . . . 224© 2005 by Taylor & Francis Group, LLC

Contentsxi

8. Low-Shear Granulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
Tom Chirkot and Cecil Propst
1. Introduction . . . . 229
2. Mechanical Agitator Granulators . . . . 231
3. Rotating Shape Granulators . . . . 235
4. Scale-Up . . . . 240
5. End-Point Determination and Control . . . . 243
6. Conclusions . . . . 244
References . . . . 244
9. Batch Fluid Bed Granulation . . . . . . . . . . . . . . . . . . . . . . . . . . 247
Dilip M. Parikh and Martin Mogavero
1. Introduction . . . . 247
2. Fluidization Theory . . . . 248
3. System Description . . . . 251
4. Particle Agglomeration and Granule Growth . . . . 261
5. Fluid Bed Drying . . . . 265
6. Process and Variables in Granulation . . . . 268
7. Process Controls and Automation . . . . 276
8. Process Scale-Up . . . . 282
9. Safety in Fluid Bed . . . . 286
10. Material Handling Options . . . . 291
11. Fluid Bed Technology Progress . . . . 294
References . . . . 304
10. Single-Pot Processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
Harald Stahl and Griet Van Vaerenbergh
1. Introduction . . . . 311
2. Typical Single-Pot Process . . . . 313
3. Drying Methods for Single-Pot Processors . . . . 315
4. Other Processes and Applications . . . . 321
5. Scale-Up of Drying Processes . . . . 324
6. Cleaning . . . . 326
7. Product Stability . . . . 326
8. Regulatory Considerations . . . . 326
9. Validation of Single-Pot Processors . . . . 327
10. Control Systems and Data Acquisition Systems . . . . 328
11. Safety . . . . 328
12. Conclusion . . . . 330
References . . . . 330
11. Extrusion/Spheronization as a Granulation Technique . . . . . . . . . 333
Ketan A. Mehta, Gurvinder Singh Rekhi, and Dilip M. Parikh
1. Introduction . . . . 333
2. Applications . . . . 335
3. General Process Description . . . . 336© 2005 by Taylor & Francis Group, LLC

xiiContents

4. Equipment Description and Process Parameters . . . . 337
5. Formulation Variables . . . . 352
6. Compression of Pellets . . . . 357
7. Conclusions . . . . 359
References . . . . 360
12. Effervescent Granulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
Guia Bertuzzi
1. Introduction . . . . 365
2. The Effervescent Reaction . . . . 366
3. Formulation . . . . 366
4. Raw Materials . . . . 367
5. Manufacturing of Effervescent Forms . . . . 371
References . . . . 382
13. Melt Granulation and Pelletization . . . . . . . . . . . . . . . . . . . . . . 385
T. W. Wong, W. S. Cheong, and P. W. S. Heng
1. Introduction . . . . 385
2. Mechanism of Melt Agglomeration . . . . 389
3. Factors Affecting Melt Agglomeration . . . . 393
4. Control of Melt Agglomeration . . . . 395
5. Conclusions . . . . 400
References . . . . 401
14. Rapid Release Granulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
P. W. S. Heng, Anthony Yolande, and Lee Chin Chiat
1. Introduction . . . . 407
2. Formulation-Related Factors . . . . 409
3. Granulation-Related Factors . . . . 417
4. Solid Dispersion . . . . 419
5. Conclusions . . . . 423
References . . . . 424
15. Continuous Granulation Technologies . . . . . . . . . . . . . . . . . . . . . 431
Rudolf Schroeder and Klaus-Jürgen Steffens
1. Introduction . . . . 431
2. Comparison of Different Modes of Processing . . . . 431
3. Fluid Bed Systems . . . . 433
4. Mechanical Wet Granulation Systems . . . . 437
5. Roller Extrusion System . . . . 441
References . . . . 456
16. Scale-Up Considerations in Granulation . . . . . . . . . . . . . . . . . . . 459
Y. He, L. X. Liu, and J. D. Litster
1. Introduction . . . . 459
2. General Considerations in Process Scale-Up: Dimensional Analysis
and the Principle of Similarity . . . . 460© 2005 by Taylor & Francis Group, LLC

Contents

xiii

3. Analysis of Granulation Rate Processes
and Implications for Scale-Up . . . . 462
4. Scale-Down, Formulation Characterization, and Formulation Designin Pharmaceutical Granulation . . . . 473
5. Scale-Up of Fluidized Bed Granulators . . . . 475
6. Scale-Up of High-Shear Mixer Granulators . . . . 480
7. Concluding Remarks . . . . 487
Nomenclature . . . . 487
References . . . . 488
17. Sizing of Granulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491
Gurvinder Singh Rekhi and Richard Sidwell
1. Introduction . . . . 491
2. Theory of Comminution or Size Reduction . . . . 492
3. Properties of Feed Materials Affecting
the Sizing Process . . . . 493
4. Criteria for Selection of a Mill . . . . 494
5. Classiﬁcation of Mills . . . . 495
6. Wet Milling . . . . 499
7. Variables Affecting the Sizing Process . . . . 502
8. Scale-Up . . . . 507
9. Case Studies . . . . 509
10. List of Equipment Suppliers . . . . 510
References . . . . 511
18. Granulation Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . 513
Raj Birudaraj, Sanjay Goskonda, and Poonam G. Pande
1. Introduction . . . . 513
2. Physical and Chemical Characterizationof Granules . . . . 513
3. Conclusion . . . . 531
References . . . . 531
19. Bioavailability and Granule Properties . . . . . . . . . . . . . . . . . . . . 535
Sunil S. Jambhekar
1. Introduction . . . . 535
2. Bioavailability Parameters . . . . 536
3. Conclusion . . . . 541
References . . . . 542
Recommended Reading . . . . 543
20. Process Analytical Technology . . . . . . . . . . . . . . . . . . . . . . . . . 545
D. Christopher Watts and Ajaz S. Hussain
1. Introduction . . . . 545
2. Background . . . . 546
3. PAT and Process Understanding . . . . 548© 2005 by Taylor & Francis Group, LLC

xiv

Contents

4. PAT Tools and Their Application . . . . 549
5. Conclusion . . . . 552
References . . . . 552
21. Granulation Process Modeling . . . . . . . . . . . . . . . . . . . . . . . . . 555
I. T. Cameron and F. Y. Wang
1. Modeling of Granulation Systems . . . . 555
2. Key Factors in Granulation Modeling . . . . 560
3. Representing Granulation Processes ThroughPopulation Balances . . . . 562
4. Solving and Using Population Balances . . . . 570
5. Application of Modeling Techniques . . . . 577
6. Conclusion . . . . 590
References . . . . 591
22. Regulatory Issues in Granulation . . . . . . . . . . . . . . . . . . . . . . . . 595
Prasad Kanneganti
1. Introduction . . . . 595
2. Pharmaceutical Quality Management . . . . 595
3. Postapproval Change Considerations . . . . 597
4. Validation of Granulation Processes . . . . 609
5. Conclusion . . . . 613
References . . . . 613© 2005 by Taylor & Francis Group, LLC

Contributors

Guia Bertuzzi IMA S.p.A., Solid Dose Division, Bologna, Italy
Raj Birudaraj Roche Palo Alto, Palo Alto, California, U.S.A.
I. T. Cameron Particle and Systems Design Centre, School of Engineering,
The University of Queensland, Queensland, Australia
L. W. ChanNational University of Singapore, Singapore

W. S. Cheong National University of Singapore, Singapore
Lee Chin Chiat
Singapore

International Specialty Products (ISP) Asia Paciﬁc Pte. Ltd.,Patterson-Kelly Co., East Stroudsburg, Pennsylvania, U.S.A.

Tom Chirkot

Metin Çelik Pharmaceutical Technologies International, Inc., Belle Mead,
New Jersey, U.S.A.
Bryan J. Ennis

E&G Associates, Inc., Nashville, Tennessee, U.S.A.

Rajeev Gokhale Incyte Corporation, Wilmington, Delaware, U.S.A.
Sanjay Goskonda Durect Corp., Cupertino, California, U.S.A.
Ehab Hamed CIMA Labs Inc., Eden Prairie, Minnesota, U.S.A.
Y. He Particle and Systems Design Centre, Division of Chemical Engineering,
School of Engineering, The University of Queensland, Queensland, Australia
P. W. S. Heng
John Hontz



National University of Singapore, Singapore

Biovail, Chantilly, Virginia, U.S.A.

Present Address: Merck Research Laboratories, West Point, Pennsylvania, U.S.A.
xv© 2005 by Taylor & Francis Group, LLC

xvi

Contributors

Ajaz S. Hussain Ofﬁce of Pharmaceutical Science, Center for Drug Evaluation andResearch, Food and Drug Administration, Bethesda, Maryland, U.S.A.
Sunil S. Jambhekar
Georgia, U.S.A.

South University School of Pharmacy, Savannah,

Prasad Kanneganti Quality Operations, Pﬁzer Global Manufacturing,Pﬁzer Asia Paciﬁc Pte. Ltd., Singapore
CIMA Labs Inc., Eden Prairie, Minnesota, U.S.A.

Raj Khankari

J. D. Litster Particle and Systems Design Centre, Division of Chemical
Engineering, School of Engineering, The University of Queensland,
Queensland, Australia
L. X. Liu Particle and Systems Design Centre, Division of Chemical Engineering,
School of Engineering, The University of Queensland, Queensland, Australia
Ketan A. Mehta

RÖHM Pharma, Degussa Corp., Piscataway, New Jersey, U.S.A.

Ronald W. Miller Bristol-Myers Squibb Company, New Brunswick,
New Jersey, U.S.A.
Derek Moe CIMA Labs Inc., Eden Prairie, Minnesota, U.S.A.
Martin Mogavero

Niro Pharma Systems, Columbia, Maryland, U.S.A.

Poonam G. Pande Synthon Pharmaceuticals Inc., Research Triangle Park,
North Carolina, U.S.A.
Dilip M. Parikh Synthon Pharmaceuticals Inc., Research Triangle Park,
North Carolina, U.S.A.
Cecil Propst

SPI Pharma, Norton Shores, Michigan, U.S.A.

Gurvinder Singh Rekhi

Elan Drug Delivery Inc., Gainesville, Georgia, U.S.A.

Rudolf Schroeder L.B. Bohle Maschinen und Verfahren GmbH, Ennigerloh,
Germany
Atul J. Shukla College of Pharmacy, University of Tennessee, Memphis,
Tennessee, U.S.A.
Richard Sidwell
Harald Stahl

Elan Drug Delivery Inc., Gainesville, Georgia, U.S.A.

Niro Pharma Systems, Muellheim, Germany

Present Address: Abbott GmbH & Co. KG, Ludwigshafen, Germany.

© 2005 by Taylor & Francis Group, LLC

MeU.SContributors

xvii

Klaus-Jürgen Steffens Department of Pharmaceutical Technology,
University of Bonn, Bonn, Germany
Yichun Sun College of Pharmacy, University of Tennessee, Memphis,
Tennessee, U.S.A.
Griet Van VaerenberghCollette N.V., Wommelgren, Belgium

F. Y. Wang Particle and Systems Design Centre, School of Engineering,
The University of Queensland, Queensland, Australia
D. Christopher Watts Ofﬁce of Pharmaceutical Science, Center for Drug
Evaluation and Research, Food and Drug Administration, Bethesda, Maryland,
U.S.A.
Susan C. Wendel
T. W. Wong
Malaysia

Elan NanoSystems, King of Prussia, Pennsylvania, U.S.A.

Faculty of Pharmacy, University of Technology MARA, Selangor,

Anthony Yolande International Specialty Products (ISP) Asia Paciﬁc Pte. Ltd.,Singapore© 2005 by Taylor & Francis Group, LLC

1Introduction
Dilip M. Parikh
Synthon Pharmaceuticals Inc., Research Triangle Park, North Carolina, U.S.A.

Perry’s Chemical Engineer’s Handbook (1) deﬁnes the granulation process as ‘‘any
process whereby small particles are gathered into larger, permanent masses in which
the original particles can still be identiﬁed.’’ This deﬁnition is of course particularly
appropriate to a pharmaceutical granulation where the rapid breakdown of agglomerates is important to maximize the available surface area and aid in solution of theactive drug. The granulation process of size enlargement used within the pharmaceutical industry has its roots in ancient times. The practice of delivering medicinal powder by hand rolling into a pill by using honey or sugar has been used for centuries.
It is still the practice to deliver the botanical and herbal extract in homeopathic andayurvedic branches of medicine, which are still practiced in India along with allopathic medicine. The term ‘‘granulated’’ material is derived from the Latin word‘‘granulatum,’’ meaning grained. The granulated material can be obtained by direct
size enlargement of primary particles, or size reduction from dry compacted material. In modern times, granulation technology has been widely used by a wide range
of industries, such as coal, mining, and agrochemical. These industries employ
agglomeration techniques to reduce dust, provide ease of handling, and enhance
the material’s ultimate utility.
The development of pharmaceutical granulation was driven by the invention of
the tablet press by W. Brockedon in 1843. Subsequent improvements in the tablet
machinery were patented in the United States by J. A. McFerran (1874), T. J. Young(1874), and J. Dunton (1876). The demands on the granulation properties were further
enhanced in the 1970s as high-speed tablet and capsule ﬁlling machines with automated controls were introduced. The continuous reﬁnements in the regulatory requirements such as low-dose products requiring blend uniformity/content uniformity
necessitated knowledge and technology to produce the required granule characteristics. The high-speed compression and capsule ﬁlling machines require a uniform ﬂow
of material to the dies or ﬁlling stations that produce pharmaceutical dosage form.
Granulation is an example of particle design. The desired attributes of the
granule are controlled by a combination of the formulation and the process.
Granulation methods can be divided into two major types: wet methods which
utilize some form of liquid to bind the primary particles, and dry methods which do
not utilize any liquid (Fig. 1).
1© 2005 by Taylor & Francis Group, LLC

2

ParikhFigure 1 Various granulation techniques.

Application of spray dryer to produce granulated product suitable for directcompression is now possible.
A new approach in the 1990s was to use supercritical ﬂuid technology to produce uniform particles to replace crystallization. Even though super critical ﬂuids
were discovered over 100 years ago, and the commercial plant was built over 20 years
ago in the United States, it is only now that the technology is used for a number ofpharmaceutical applications (2–5), so as to produce aspirin, caffeine, ibuprofen,
acetaminophen, etc. One of the major areas on which the research and developmentof supercritical ﬂuids is focused is particle design. There are different concepts suchas ‘‘rapid expansion of supercritical solution,’’ ‘‘gas antisolvent recrystallization,’’and ‘‘supercritical antisolvent’’ to generate particles, microspheres, microcapsules,
liposomes, or other dispersed materials.
When the supercritical ﬂuid and drug solution make contact, a volume expansion occurs leading to a reduction in solvent capacity, increase in solute saturation,and then supersaturation with associated nucleation and particle formation. A number of advantages are claimed by using this platform technology (6), such as particle
formation from nanometers to tens of micrometers, low residual solvent levels in
products, preparation of polymorphic forms of drug, etc.
The classical granulation process using either wet or dry methods is employedin the process industries. Pharmaceutical granulation process is used for tablet andsometimes capsule dosage forms; however, in some applications the process is used
to produce spherical granules for the modiﬁed release indications or to prepare granules as sprinkles to be used by pediatric patients. In some countries like Japan, having granulated product in a ‘‘sachet’’ is acceptable where a large dose of the drug
product is not suitable for swallowing. The reasons for granulating a pharmaceuticalcompound are listed as follows:
1.
2.
3.
4.

To increase the uniformity of drug distribution in the productTo densify the material
To enhance the ﬂow rates and rate uniformity
To facilitate metering or volumetric dispensing© 2005 by Taylor & Francis Group, LLC

Introduction

3

5. To reduce dust
6. To improve the appearance of the product.
Five primary methods exist to form an agglomerated granule. They are formation of solid bridges, sintering, chemical reaction, crystallization, or deposition ofcolloidal particles. Binding can also be achieved through adhesion and cohesion
forces in highly viscous binders.
Successful processing for the agglomeration of primary particles depends onproper control of the adhesional forces between particles, which encourage agglomerate formation and growth and provide adequate mechanical strength in the
product. Furthermore, the rheology of the particulate system can be critical to
the rearrangement of particles necessary to permit densiﬁcation of the agglomerate and the development of an agglomerate structure appropriate for the end-use
requirements. If the particles are close enough then the surface forces such as vander Waals forces (short-range) and electrostatic forces can interact to bond particles.
Decreasing particle size increases surface–mass ratio and favors the bonding. van der
Waals forces are sevenfold stronger than electrostatic forces and increase substantially when the distance between them is reduced, which can be achieved by applying
pressure as in dry granulation method.
The cohesive forces that operate during the moist agglomerates are mainly due
to the liquid bridges that develop between the solid particles. Electrostatic forces
keep particles in contact long enough for another mechanism to govern the agglomeration process.
The processing of drug substance with the excipients can be achieved without
going through the granulation steps. By simply mixing in a blender, a directly compressible formulation can be processed and compressed in tablets or ﬁlled in the hardgelatin capsules. In the 1970s, microcrystalline cellulose as a directly compressible
vehicle was introduced. The compressible formulation containing microcrystalline
cellulose is suitable for a number of products. This has several obvious advantages,
such as lower equipment cost, faster process time, and efﬁcient operation involving
only two process steps. Sometimes excipient costs may have to be compared against
the savings in the processing steps and equipment by using alternate methods.
There are, however, a number of products that require low dose of drug
substance, where the blend uniformity and the content uniformity in the drug
product are critical. Traditionally, the assessment of the blend uniformity is done
after the blending process is complete. This required considerable delays in obtaining results, and the sampling techniques and product discharge from the blender
required consistency to obtain satisfactory results. However, with the current interestin process analytical technology (PAT) on-line measurement of ingredients is possible. The U.S. Food and Drug Administration (FDA) has recently released guidance
for industry detailing the current thinking on PAT (7).
Other than content uniformity of a low-dose drug substance there are a numberof reasons why direct compression may not be suitable for a wide array of products.
These include the required ﬂow properties; the amount of drug substance in a dosage
form may require it to be densiﬁed to reduce the size of the drug product, obtain therequired hardness, friability, disintegration/dissolution, and other attributes.
Another approach which is becoming popular is to use traditional spray-drying
process to produce drum to hopper granulation by-passing the conventional granulation process. This process may be suitable for large-volume products such as overthe-counter tablets or capsules.
© 2005 by Taylor & Francis Group, LLC

4ParikhDry compaction technique like roller compaction is experiencing renewedinterest in the industry. There are a number of drug substances which are moisturesensitive and cannot be directly compressed. The roller compaction provides suitable
alternative technology for processing these products.
Early stages of wet granulation technology development, employed low-shear
mixers or the mixers/blenders normally used for dry blending such as ribbon mixers.
There are a number of products currently manufactured using these low-shear granulators. The process control and efﬁciency has increased over the years; however, theindustry has embraced high-shear granulators for wet granulation because of its
efﬁcient and reproducible process and modern process control capabilities. The
high-shear mixers have also facilitated new technologies, such as one-pot processing,that use the mixer to granulate and then dry using vacuum, gas stripping/vacuum, or
microwave assist in the same vessel.
Fluid-bed processors have been used in the pharmaceutical industry for the last
35 years, initially only as a dryer, and now as a multiprocessor to granulate, dry,pelletize, and coat particles. The most preferred method of granulation is to use
the high-shear mixer to granulate and use the ﬂuid bed as a dryer in an integrated
equipment setup. This provides the best of both technologies: efﬁcient controllable
dense wet granules and a fast drying cycle using ﬂuid-bed dryer. Here again, thechoice of this approach will be dependent on the product being processed, and its
desired properties at the end of the granulation process. Extrusion/spheronization
is used to produce granulation for the tableting or pelletizing, which involves mixing,
extruding, spheronizing, and drying unit operations. These pellets can be produced
as matrix pellets with the appropriate polymer or are coated in ﬂuid-bed unit to produce modiﬁed release dosage forms. Table 1 illustrates various options to granulate apharmaceutical compound.
Many researchers studied the inﬂuence of material properties of the granulating powder and process conditions on the granulation process in a rather empiricalway. In the 1990s a fundamental approach to research was started on various topics
in the granulation research, looking into more detailed aspects of particle wetting,
Table 1 Frequently Used Granulation Techniques and Subsequent Processing
Process
Wet granulation

Dry granulation

Low-shear mixer
High-shear mixer
High-shear mixer
Fluid-bed granulator/dryer
Spray dryer
Extrusion/spheronization
Continuous mixer granulator(mechanical)
Continuous ﬂuid-bed granulator
Process
Direct compression
Slugging
Roller compactor© 2005 by Taylor & Francis Group, LLC

Drying techniqueTray or ﬂuid-bed dryer
Tray or ﬂuid-bed dryer
Vacuum/gas stripping/microwave
assist—one-pot
Fluid-bed granulator/dryer
Spray dryer
Tray or ﬂuid-bed dryer
Fluid bed—continuous or batch
Fluid bed (continuous)
Further processing
Blend and process further
Mill slugged tablets/blend/
recompress/process further
Compacts milled/blend/processfurther

Introduction

5

mechanism of granulation, material properties, and inﬂuence of mixing apparatus on
the product. The overall hypothesis suggested that the granulation can be predictedfrom the raw material properties and the processing conditions of the granulation
process. One of the major difﬁculties encountered in granulation technology is theincomplete description of the behavior of powders in general. The ongoingfundamental research on mixing, segregation mechanisms of powder, surface chemistry, and material science are necessary to develop the theoretical framework of
granulation technology. An excellent review of the wet granulation process waspresented by Iveson and coauthors (8). The authors have advanced the understanding of the granulation process by stating that there are three fundamental sets of rate
processes which are important in determining wet granulation behavior. These arewetting and nucleation, consolidation and growth; and breakage and attrition. Oncethese processes are sufﬁciently understood, then it will be possible to predict theeffect of formulation properties, equipment type, and operating conditions of granulation behavior, provided these can be adequately characterized according to thereviewers.
Efﬁcient and cost-effective manufacturing of pharmaceutical products is being
evaluated by the scientists, engineers, and operational managers of pharmaceuticalcompanies worldwide. In the United States, where 49% of the world pharmaceuticalmarket is, pharmaceutical companies are under tremendous pressure from the managed care organizations, politicians, and consumers. The pharmaceutical industry,
worldwide in general and in the United States in particular, faces a unique paradox—
drive future innovation through substantial R&D investments and return competitive
margin to shareholders, while providing access to pharmaceutical products at low orno cost. The industry has reached a critical juncture in its 100-year history. The industry
is impacted simultaneously by growing competition, declining market performance,increasing regulation, escalating pricing pressures, and rapidly evolving innovations
for improving people’s health and quality of life. A new report (9) into pharmaceutical
R&D has identiﬁed an emerging trend favoring outsourcing of discovery, research,clinical trials, and manufacturing of dosage forms, providing relief from the consistent,
high-growth ﬁnancial return faced by the majority of pharmaceutical companies. Outsourcing allows these companies to pursue potential new revenue streams outside of
their core focus areas, and to beneﬁt from improved productivity, emerging technologies, inlicensing opportunities, and increased growth. Consumers and local governments in the United States are pressuring the FDA authorities and politicians toallow importation of the drugs from other countries like Mexico and Canada wherecosts are generally lower than in the United States. Demands for price control also
extend to Europe; government-backed pharmaceutical payment plans in Germany
and Italy, for example, have cut back reimbursements. Other European countries havecontrols on the drug prices. As a result of these pricing pressures and to enhance thedrugs in the pipeline, mergers and acquisitions have accelerated. Acquisitions remain
the preferred route to quickly enhance a product portfolio. This trend of merging
of equals or takeover of the signiﬁcant technological companies will continue. Thishas created emergence of small niche technology companies as well. Major pharmaceutical companies are witnessing the end of traditional research and development.
Drug delivery companies are becoming potential targets for mergers or strategic alliances. During all of the upheaval that the industry is going through, it is becoming
obvious that the cost of development and production, and cost of goods, must be
controlled. Recently released draft guidance by the U.S. FDA for quality systems
approach for the current good manufacturing practices may help to streamline the© 2005 by Taylor & Francis Group, LLC

6

Parikhcompliance programs in the industry (10). The efﬁciencies in the research, development, and manufacturing, which were not necessarily sought after, are becoming
the ﬁrst priority of the pharmaceutical companies however small they may be in comparison to the ﬁnal cost of the product to consumer. The manufacturing of solid
dosage product is no exception.
The signiﬁcant advances that have taken place in the pharmaceutical granulation technology are presented in this book to provide the readers with choices thatare available. There is no substitute for good science. The characterization of the
drug substance along with the knowledge of granulation theory, process modelingcapability, in-line or on-line (PAT) tools, process scale-up approaches, and a gooddeﬁnition of the end product required will prepare the reader to explore the various
options presented in this book. Each drug substance poses a unique challenge thatmust be taken into consideration at the process selection stage by the scientists.
The various techniques presented in this book will further help the scientists in theirunderstanding and selection of the granulation process most appropriate for the
drug substance. For production engineering, validation, and quality professionals
in the industry, this book is intended to provide the fundamental understanding of
the technique of granulation, and the rationale behind the selection of each particulartechnique. This will further enhance the ability to design the production plant, carryout the technology transfer, scale-up, troubleshoot, and maintain the pharmaceutical
granulation operation, in accordance with regulatory compliance.

REFERENCES
1. Ennis BJ, Litster JD. Particle enlargement. Perry RH, Greens D, eds. Perry’s Chemical
Engineer’s Handbook. 7th ed. New York: McGraw Hill, 1997:20-56–20-89.
2. Charoenchaitrakool M, Dehghani F, Foster NR. Micronization by RESS to enhance thedissolution rates of poorly water soluble pharmaceuticals. Proceedings of the 5th International Symposium on Supercritical Fluids, Atlanta, GA, April 8–12, 2000.
3. Matson DW, Fulton JL, Petersen RC, Smith RD. Rapid expansion of supercritical ﬂuid
solutions: solute formation of powders, thin ﬁlms, and ﬁbers. Ind Eng Chem Res 1987;
26:2298–2306.
4. Subra P, Boissinot P, Benzaghou S. Precipitation of pure and mixed caffeine and anthracene by rapid expansion of supercritical solutions. Proceedings of the 5th Meeting on
Supercritical Fluids, Tome I, Nice, France, March 23–25, 1998.
5. Gilbert DJ, Palakodaty S, Sloan R, York V. Particle engineering for pharmaceuticalapplications—a process scale up. Proceedings of the 5th International Symposium on
Supercritical Fluids, Atlanta, GA, April 8–12, 2000.
6. York P, et al. Supercritical ﬂuids ease drug delivery. Manuf Chemist 2000; 26–29.
7. Food and Drug Administration. Guidance for Industry PAT—A Framework for
Innovative Pharmaceutical Development, Manufacturing and Quality Assurance.
FDA, September 2004.
8. Iveson SM, Litster JD, Hopgood K, Ennis B. Nucleation, growth, and breakage phenomenon in agitated wet granulation process: a review. Powder Technol 2001; 117:3–39.
9. Cambridge Healthcare Advisors (CHA) Report. Report identiﬁes increasing outsourcing
by pharma–Inpharma.com, September 29, 2004.
10. Guidance for Industry. Quality Systems Approach to Pharmaceutical Current Good
Manufacturing Practice Regulations, Draft Guidance, September 2004.

© 2005 by Taylor & Francis Group, LLC

2
Theory of Granulation: An Engineering
Perspective
Bryan J. Ennis
E&G Associates, Inc., Nashville, Tennessee, U.S.A.

1. INTRODUCTION
1.1. Overview
Wet granulation is a subset of size enlargement (1–5), which involves any process
whereby small particles are agglomerated, compacted, or otherwise brought together
into larger, relatively permanent structures in which the original particles can still be
distinguished. Granulation technology and size-enlargement processes have beenused by a wide range of industries, from the pharmaceutical industry to fertilizer
or detergent production to the mineral processing industries. Size enlargement generally encompasses a variety of unit operations or processing techniques dedicated toparticle agglomeration. These processes can be loosely broken down into agitationand compression methods.
Although terminology is industry speciﬁc, agglomeration by agitation will bereferred to as granulation. As depicted in Figure 1, a particulate feed is introduced
to a process vessel and is agglomerated, either batchwise or continuously, to forma granulated product. Agitative processes include ﬂuid bed, pan (or disk), drum,
and mixer granulators. Such processes are also used as coating operations forcontrolled release, taste masking, and cases where solid cores may act as a carrier
for a drug coating. The feed typically consists of a mixture of solid ingredients,
referred to as a formulation, which includes an active or key ingredient, binders,diluents, ﬂow aids, surfactants, wetting agents, lubricants, ﬁllers, or end-use aids
(e.g., sintering aids, colors or dyes, taste modiﬁers). A closely related process of spraydrying is also included here, but is discussed more fully elsewhere [Refs. 6,7 andChapter 5]. Product forms generally include agglomerated or layered granules, coatedcarrier cores, or spray dried product consisting of agglomerated solidiﬁed drops.
An alternative approach to size enlargement is agglomeration by compression,or compaction, where the mixture of particulate matter is fed to a compression device
which promotes agglomeration due to pressure, as depicted in Figure 2. Either
continuous sheets of solid material or solid forms such as briquettes or tablets areproduced. Compaction processes range from conﬁned compression devices such astableting to continuous devices such as roll presses (Chapter 6), briqueting machines,
7© 2005 by Taylor & Francis Group, LLC

8

Ennis

Figure 1 The unit operation of agitative agglomeration or granulation. (From Refs. 1–5.)

and extrusion (Chapter 11). Some processes operate in a semicontinuous fashionsuch as ram extrusion. Capsule ﬁlling operations would be considered as low-pressurecompaction processes.
At the level of a manufacturing plant, the size-enlargement process involves
several peripheral, unit operations such as milling, blending, drying, or cooling,
and classiﬁcation, referred to generically as an agglomeration circuit (Fig. 3). In
addition, more than one agglomeration step may be present as in the case of a pharmaceutical process. In the case of pharmaceutical granulation, granulated material isalmost exclusively an intermediate product form, which is then followed by tableting.
In the context of granulation, therefore, it is important to understand compaction
processes to establish desirable granule properties for tableting performance.
Numerous beneﬁts result from size-enlargement processes as summarized inTable 1. A wide variety of size-enlargement methods are available; a classiﬁcation ofthese is given in Table 2 with key process attributes. A primary purpose of wet granulation in the case of pharmaceutical processing is to create free-ﬂowing, nonsegregating
blends of ingredients of controlled strength, which may be reproducibly metered in

Figure 2 The unit operation of compressive agglomeration or compaction. (From Refs. 1–5.)© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

9

Figure 3 A typical agglomeration circuit utilized in the processing of pharmaceuticals
involving both granulation and compression techniques. (From Refs. 1–5.)

subsequent tableting or for vial or capsule ﬁlling operations. The wet granulation
process must generally achieve the desired granule properties within some prescribedrange. These attributes clearly depend on the application at hand. However, common
to most processes is a speciﬁc granule size distribution and granule voidage. Size
distribution affects ﬂow and segregation properties, as well as compaction behavior.
Granule voidage controls strength, and impacts capsule and tablet dissolution
behavior, as well as compaction behavior and tablet hardness.
Control of granule size and voidage will be discussed in detail throughout thischapter. The approach taken here relies heavily on attempting to understand interactions at a particle level, and scaling this understanding to bulk effects. Developing
an understanding of these microlevel processes of agglomeration allows a rational
approach to the design, scale-up, and control of agglomeration processes. Although
Table 1 Objectives of Size Enlargement
Production of a useful structural form
Provision of a deﬁned quantity for dispensing, with improved ﬂow properties for metering
Improved product appearance
Reduced propensity to caking
Increased bulk density for storage
Creation of nonsegregating blends of powder ingredientsControl of solubility
Control of porosity, hardness, and surface-to-volume ratio and particle size
Source: From Refs. 1–5.
© 2005 by Taylor & Francis Group, LLC

10Table 2 Size-Enlargement Methods and Application
MethodProduct size(mm)Granule density

Scale ofoperation

Additional comments

Typical applications

Very spherical granules

Fertilizers, iron ore,
nonferrous ore,
agricultural chemicals

Tumbling granulators:
Drums
Disks
Mixer granulators
Continuous high shear(e.g., Shugi mixer)

0.5–20Moderate

0.5–800
tons/hr

0.1–2

Low

Up to 50
ton/hrBatch high shear(e.g., paddle mixer)

0.1–2

High

Up to 500 kg,
batch

0.1–2

Low (agglomerated),
moderate (layered)Continuous: fertilizers,
100–900 kg, batch; Flexible, relatively easy toinorganic salts, detergents;
50 ton/hr,
scale, difﬁcult for cohesivebatch: pharmaceuticals,
continuous
powders, good for coating
agricultural chemicals,
applications
nuclear wastes

Fluidized granulators:
Fluidized beds
Spouted beds
Wurster coaters

Chemicals, detergents, clays,
carbon black
Pharmaceuticals, ceramics

Ennis© 2005 by Taylor & Francis Group, LLC

Handles very cohesivematerials well, both batchand continuous

0.3–3Moderate to highSpray methods
Spray drying

0.05–0.5

Low

0.7–2

Moderate

Prilling
Pressure compaction
Extrusion
Roll press
Tablet press
Molding press
Pellet mill

>0.5
>1
10

High to very highUp to 200 kg,
batch

Powder layering and coating Pharmaceuticals, agricultural
applications
chemicalsMorphology of spray dried
powders can vary widely

Instant foods, dyes,
detergents, ceramics,
pharmaceuticals
Urea, ammonium nitrate0

Up to 5 ton/hr
Up to 50 ton/hr
Up to 1 ton/hr

Very narrow size
distributions, very sensitive
to powder ﬂow andmechanical properties

Theory of Granulation

Centrifugal granulators

Pharmaceuticals, catalysts,
inorganic chemicals,organic chemicals, plastic
preforms, metal parts,
ceramics, clays, minerals,
animal feeds

Source: From Refs. 1–5.

11

© 2005 by Taylor & Francis Group, LLC

12

Ennis

the approach is difﬁcult, qualitative trends are uncovered along the way, which aid informulation development and process optimization, and which emphasize powder
characterization as an integral part of product development and process designwork.

1.2. Granulation Mechanisms
Four key mechanisms or rate processes contribute to granulation, as originally outlined by Ennis (3,4), and later developed further by Ennis and Litster (1,5). These
include wetting and nucleation, coalescence or growth, consolidation, and attritionor breakage (Fig. 4). Initial wetting of the feed powder and existing granules by
the binding ﬂuid is strongly inﬂuenced by spray rate or ﬂuid distribution as well
as feed formulation properties, in comparison with mechanical mixing. Wetting promotes nucleation of ﬁne powders, or coating in the case of feed particle size in excess
of drop size. Often wetting agents such as surfactants are carefully chosen to enhance
poorly wetting feeds. In the coalescence or growth stage, partially wetted primaryparticles and larger nuclei coalesce to form granules composed of several particles.
The term nucleation is typically applied to the initial coalescence of primary particles
in the immediate vicinity of the larger wetting drop whereas the more general term of

Figure 4 The rate processes of agitative agglomeration, or granulation, which include
powder wetting, granule growth, granule consolidation, and granule breakage. These processes combine to control granule size and porosity, and they may be inﬂuenced by formulation or process design changes.
© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

13

coalescence refers to the successful collision of two granules to form a new, larger
granule. In addition, the term of layering is applied to the coalescence of granules
with primary feed powder. Nucleation is promoted from some initial distributionof moisture, such as a drop, or from the homogenization of a ﬂuid feed to thebed, as with high-shear mixing. The nucleation process is strongly linked with thewetting stage. As granules grow, they are consolidated by compaction forces due
to bed agitation. This consolidation stage controls internal granule voidage or granule porosity, and therefore end-use properties such as granule strength, hardness, ordissolution. Formed granules may be particularly susceptible to attrition if they are
inherently weak or if ﬂaws develop during drying.
These mechanisms or rate processes can occur simultaneously in all granulation
units, ranging from spray drying to ﬂuidized beds to high-shear mixers. However,certain mechanisms may dominate in a particular manufacturing process. For example, ﬂuidized bed granulators are strongly inﬂuenced by the wetting process, whereas
mechanical redispersion of binding ﬂuid by impellers and particularly high-intensity
choppers diminishes the wetting contributions to granule size in high-shear mixing.
On the other hand, granule consolidation is far more pronounced in high-shear
mixing than in ﬂuidized-bed granulation. These simultaneous rate processes taken
as a whole—and sometimes competing against one another—determine the ﬁnal granule size distribution and granule structure and voidage resulting from a process, andtherefore the ﬁnal end-use or product quality attributes of the granulated product.
1.3. Compaction Mechanisms
Compaction is a forming process controlled by mechanical properties of the feed inrelationship to applied stresses and strains. Microlevel processes are controlled byparticle properties such as friction, hardness, size, shape, surface energy, and elastic
modulus.
Key steps in any compaction process include (1) powder ﬁlling, (2) stress application and removal, and (3) compact ejection. Powder ﬁlling and compact weightvariability is strongly inﬂuenced by bulk density and powder ﬂowability (1,2), as wellas any contributing segregation tendencies of the feed. The steps of stress application
and removal consist of several competing mechanisms, as depicted in Figure 5.
Powders do not transmit stress uniformly. Wall friction impedes the applied load,causing a drop in stress as one moves away from the point of the applied load(e.g., a punch face in tableting or roll surface in roll pressing.) Therefore, the applied
load and resulting density are not uniform throughout the compact, and powder frictional properties control the stress transmission and distribution in the compact (8).
The general area of study relating compaction and stress transmission is referred toas powder mechanics (1,2,8,9). For a local level of applied stress, particles deform attheir point contacts, including plastic deformation for forces in excess of the particle
surface hardness. This allows intimate contact at surface point contacts, allowing
cohesion/adhesion to develop between particles, and therefore interfacial bonding,which is a function of their interfacial surface energy. During the short time scaleof the applied load, any entrapped air must escape, which is a function of feed
permeability, and a portion of the elastic strain energy is converted into permanent
plastic deformation. Upon stress removal, the compact expands due to the remaining
elastic recovery of the matrix, which is a function of elastic modulus, as well as any
expansion of the remaining entrapped air. This can result in loss of particle bonding,and ﬂaw development, and this is exacerbated for cases of wide distributions in© 2005 by Taylor & Francis Group, LLC

14

Ennis

Figure 5 The microlevel processes of compressive agglomeration, or compaction. These
processes combined control compact strength, hardness, and porosity.

compact stress due to poor stress transmission. The ﬁnal step of stress removal
involves compact ejection, where any remaining radial elastic stresses are removed.
If recovery is substantial, it can lead to capping or delamination of the compact.
These microlevel processes of compaction control the ﬁnal ﬂaw and density
distribution throughout the compact, whether it is a roll pressed, extruded, or tableted product, and as such, control compact strength, hardness, and dissolution
behavior. Compaction processes will not be discussed further here, with the remainder of the chapter focusing on wet granulation, agitative processes. For further
discussion regarding compaction, see Chapter 6 and Refs. 1, 2, and 10.
1.4. Formulation vs. Process Design
The end-use properties of granulated material are controlled by granule size andinternal granule voidage or porosity. Internal granule voidage egranule and bed
voidage ebed, or voidage between granules, are related byrbulk ¼ rgranule ð1  ebed Þ ¼ rs ð1  ebed Þð1  egranule Þð1:1Þ

where rbulk, rgranule, and rs are bulk, granule, and skeletal primary particle density,
respectively. Here, granule voidage and granule porosity will be used interchangeably. Granule structure may also inﬂuence properties. To achieve the desired productquality as deﬁned by metrics of end-use properties, granule size and voidage may be
manipulated by changes in either process operating variables or product material
variables (Figs. 4 and 5) as initially outlined by Ennis (3,4), and later developed
further by Ennis and Litster (1,2,5). The ﬁrst approach is the realm of traditional
process engineering, whereas the second is product engineering. Both approaches
are critical and must be integrated to achieve the desired end point in productquality. Operating variables are deﬁned by the chosen granulation technique and© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

15

Figure 6 Typical operating variable for pharmaceutical granulation processes. (From Ref. 4.)

peripheral processing equipment, as illustrated for a ﬂuidized-bed and mixer granulator in Figure 6. In addition, the choice of agglomeration technique dictates the
mixing pattern of the vessel. Material variables include parameters such as binderviscosity, surface tension, feed particle size distribution, powder friction, and theadhesive properties of the solidiﬁed binder. Material variables are speciﬁed by the
choice of ingredients, or product formulation. Both operating and material variables
together deﬁne the kinetic mechanisms and rate constants of wetting, growth,
consolidation, and attrition. Overcoming a given size-enlargement problem often
requires changes in both processing conditions and product formulation.
The importance of granule voidage to ﬁnal product quality is illustrated in
Figures 7–9 for a variety of formulations. Here, bulk density is observed to decrease,
granule attrition to increase, and dissolution rate to increase with an increase in
granule voidage. Bulk density is clearly a function of both granule size distribution,
which controls bed voidage or porosity between granules, and the voidage within the
granule itself. The data of Figure 7 are normalized with respect to its zero intercept,
or its effective bulk density at zero granule voidage. The granule attrition results of
Figure 8 are based on a CIPAC test method, which is effectively the percentage ofﬁnes passing a ﬁne mesh size following attrition in a tumbling apparatus. Granules
weaken with increased voidage. The dissolution results of Figure 9 measure thelength required for granule dissolution in a long tube, or disintegration length (alsobased on the CIPAC test method). Increased granule voidage results in increased
dissolution rate and shorter disintegration length. All industries have their own
speciﬁc quality and in-process evaluation tests. However, what they have in common
are the important contributing effects of granule size and granule voidage.
An example of the importance of distinguishing the effects of process andformulation changes can be illustrated with the help of Figures 8 and 9. Let us
assume that the particular formulation and current process conditions produce a
granulated material with a given attrition resistance and dissolution behavior(indicted as ‘‘current product’’). If one desires instead to reach a given ‘‘target,’’either the formulation or the process variable may be changed. Changes to theprocess, or operating variables, generally readily alter granule voidage. Examples
to decrease voidage might include increased bed height, increased processing time,© 2005 by Taylor & Francis Group, LLC

16

Ennis

Figure 7 Impact of granule density on bulk density: Normalized bulk density as a functionof granule voidage. (From Ref. 4.)

or increased peak bed moisture. However, only a range of such changes in voidage,
and therefore attrition resistance and dissolution, is possible and is illustrated bymoving along the given formulation curve. The various curves in Figures 8 and 9
are due instead to changes in formulation properties. Therefore, it may not be

Figure 8 Impact of granule density on strength and attrition: Illustration of process changes
vs. formulation changes. Kc is the fracture toughness. (From Ref. 4.)© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

17

Figure 9 Impact of granule density on disintegration: Gc is the strain energy release rate.
(From Ref. 4.)

possible to reach a target change in dissolution without changes in formulation ormaterial variables. Examples of key material variables affecting voidage would
include feed primary particle size, inherent formulation bond strength, and binder
solution viscosity, as discussed in detail in the following sections. Understanding thiscrucial interaction between operating and material variables is critical for successful
formulation, and requires substantial collaboration between processing and formulation groups, and a clear knowledge of the effect of scale-up on this interaction.
1.5. Key Historical Investigations
A range of historical investigations has been undertaken involving the impact ofoperating variables on granulation behavior. As a review, see Refs. 3–5,11–13. Typical variables have included the effects of bed hydrodynamics and agitation intensity,
pan angle and speed, ﬂuid-bed excess gas velocity, mixer impeller and chopper
speeds, drum rotation speed, spray method, drop size, nozzle location, and binderand solvent feed rates. While such studies are important, their general application
and utility to studies beyond the cited formulations and process conditions can beseverely limited. Often the state of mixing, moisture distribution and rates, and material properties such as formulation size distribution, powder frictional properties,
and solution viscosity are insufﬁciently deﬁned. As such, these results should be usedjudiciously and with care. Often even the directions of the impact of operating variables on granule properties are altered by formulation changes.
Two key pieces of historical investigation require mention, as the approachdeveloped here stems heavily from this work. The ﬁrst involves growth and breakage
mechanisms, which control the evolution of the granule size distribution (14), as© 2005 by Taylor & Francis Group, LLC

18

Ennis

Figure 10 Growth and breakage mechanisms in granulation processes. (From Ref. 14.)

illustrated in Fig. 10. These include the nucleation of ﬁne powder to form initial
primary granules, the coalescence of existing granules, and the layering of raw material onto previously formed nuclei or granules. Granules may simultaneously becompacted by consolidation and reduced in size by breakage. There are strong interactions between these rate processes. In addition, these mechanisms in various forms
have been incorporated into population-balance modeling to predict granule size inthe work of Kapur and Sastry (14–19) (Chapter 23 for details). Given the progress
made in connecting rate constants to formulation properties, the utility of population-balance modeling has increased substantially.
The second important area of contribution involves the work of Rumpf (20,21)
and Ausburger and Vuppala (22), which studied the impact of interparticle force H
on granule static tensile strength, or





9 1e H1  e g cos y
A ¼ 9=4 for pendular state
with
¼A
sT ¼
A¼6
for capillary state
8
e
a2
e
a
ð1:2Þ
Forces of a variety of forms were studied, including viscous, semisolid, solid,
electrostatic, and van der Waals forces. Of particular importance was the contribution of pendular bridge force arising from surface tension to granule tensile strength.
Capillary pressure deﬁciency due to the curvature of the pendular bridge in addition
to a contact line force results in an interparticle force, as highlighted in Figure 11(here, interparticle velocity U ¼ 0). This force summed over the granule area results
in a granule static strength, which is a function of pore saturation S as experimentally plotted. The states of pore ﬁlling have been deﬁned as pendular (single bridges),© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

19

Figure 11 Static yield strength of wet agglomerates vs. pore saturation. (See Section 3.5 fornomenclature.) (From Refs. 20–22.)

funicular (partially complete ﬁlling and single bridges), capillary (nearly complete
ﬁlling S  80–100%) followed by drop formation, and loss of static strength. Thisapproach will be extended in subsequent sections to include viscous forces anddynamic strength behavior (U 6¼ 0).
The approach taken, in this chapter, follows this same vein of research as originally established by Rumpf and Kapur, namely, relating granule and particle levelinteractions to bulk behavior through the development of the rate processes ofwetting and nucleation, granule growth and consolidation, and granule breakage
and attrition. Each of these will now be dealt with in turn in the following sections.

2. WETTING
2.1. Overview
The initial distribution of binding ﬂuid can have a pronounced inﬂuence on the size
distribution of seed granules, or nuclei, which are formed from ﬁne powder. Both theﬁnal extent of and the rate at which the ﬂuid wets the particulate phase areimportant. Poor wetting results in drop coalescence, and in fewer, larger nuclei with
ungranulated powder and overwetted masses, leading to broad nuclei distributions.
Granulation can retain a memory, with nuclei size distribution impacting ﬁnal granule size distribution. Therefore, initial wetting can be critical to uniform nuclei formation and often a narrow, uniform product. Wide nuclei distributions can lead to awide granule size distribution. When the size of a particulate feed material is larger
than drop size, wetting dynamics controls the distribution of coating material which
has a strong inﬂuence on the later stages of growth. Wetting phenomena also inﬂuence redistribution of individual ingredients within a granule, drying processes, andredispersion of granules in a ﬂuid phase. Other granule properties such as voidage,© 2005 by Taylor & Francis Group, LLC

20

Ennis

strength, and attrition resistance may be inﬂuenced as well. Preferential wetting ofcertain formulation ingredients can cause component segregation with granule size.
An extensive review of wetting research may be found in Litster and Ennis (5), Parﬁtt(23), and Hapgood (24), with a summary of references given in Table 3.

2.2. Mechanics of the Wetting Rate Process
As outlined previously, wetting is the ﬁrst stage in wet granulation involving liquidbinder distribution to the feed powder. There are two extremes: (1) liquid drop size islarge compared to unit or primary particle size of the feed and (2) particle size islarge compared to the drop size.
As depicted in Figure 12 for the ﬁrst case of ﬁne feeds compared to drop size,
the wetting process consists of several important steps. First, droplets are formed
related to spray distribution, or spray ﬂux deﬁned as the wetting area of the bed
per unit time. Important operating variables include nozzle position, spray area,
spray rate, and drop size. Second, droplets impact and coalesce on the powder
bed surface if mixing or wet-in time is slow. Third, droplets spread and penetrate into
the moving powder bed to form loose nuclei, again coalescing if wet-in is slow. In thecase of high-shear processes, shear forces break down overwet clumps, also producing nuclei.
For the second case of small drop size compared to the primary particle size,
the liquid will coat the particles as depicted in Figure 13. Coating is produced bycollisions between the drop and the particle followed by spreading of the liquid overthe particle surface. If the particle is porous, then liquid will also be sucked into thepores by capillary action. The wetting dynamics control the distribution of coating
material, which has a strong inﬂuence on the later stages of growth as well as coating
quality.

2.3. Methods of Measurement
Methods of characterizing the rate process of wetting include four approaches as
illustrated in Table 4. The ﬁrst considers the ability of a drop to spread across thepowder. This approach involves the measurement of a contact angle of a drop on
a powder compact, given by the Young–Dupré equation, or
gsv  gsl ¼ glv cos y
sv

sl

lv

ð2:1Þ

where g , g , g are the solid–vapor, solid–liquid, and liquid–vapor interfacial energies, respectively, and y is measured through the liquid. In the limit of gsv  gsl  glv,
the contact angle equals 0 and the ﬂuid spreads on the solid. The extent of wetting iscontrolled by the group glv cosy, which is referred to as adhesion tension. Sessile drop
studies of contact angle can be performed on powder compacts in the same way as
on planar surfaces. Methods involve the (1) direct measurement of the contact angle
from the tangent to the air–binder interface, (2) solution of the Laplace–Youngequation involving the contact angle as a boundary condition, or (3) indirect calculations of the contact angle from measurements of, e.g., drop height. The compact caneither be saturated with the ﬂuid for static measurements, or dynamic measurements
may be made through a computer imaging goniometer, as depicted in Figure 14. For
granulation processes, the dynamics of wetting are often crucial, requiring that
powders be compared on the basis of a short time scale, dynamic contact angle.
© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

21

Table 3 Summary of Wetting Research Contributions
Workers (Year)

Materials

Equipment

InvestigatedSchaefer and Wørts(1978)

Lactose and maize
starch powder withgelatine, PVP, and
MCC binders
Lactose powder withwater and 3–8%
PVP solution
binders
Lactose and ballotini
powders with waterand 5% PVP
solution
Lactose andcornstarch withwater

Fluid bed

Drop size

Packed bed
inpetri dishDrop size

Fluid bed

Drop size

Hybrid ﬂuid
bed
withagitator
High–shear
mixer

Drop size, binder
distribution

Fluid bedContact angle

Drum

Contact angle

Fluid bedContact angle

Fluid bed

Spreading coefﬁcients

Mixer
granulator

Spreading coefﬁcients

Fluid bed

Drum

Binder addition rate,
powder ﬂux, sprayzone
Binder addition rate

Fluid bed

Binder addition rate

High shear

Viscosity, binder
dispersion, shear
forcesSchaafsma et al.
(1999)

Waldie (1991)

Watano et al. (1994)

Holm et al. (1983,
1984)

Aulton and Banks(1979)
Gluba et al. (1990)

Jaiyeoba and Spring(1980)

Krycer and Pope
(1983)
Zajic and Buckton(1990)

Rankell et al. (1964)

Heim and Antkowiak(1989)
Crooks and Schade(1978)
Kristensen and
Schaefer (1994)

Lactose and calcium
hydrogen phosphatewith water and 10–
15% PVP solution
Lactose and salicylic
acid powder withwater
Talcum, chalk, andkaolin powder
combinations withwater
Lactose, boric acid,kaolin,suphanilamide, andsalicylic acidpowders with water.
Paracetamol powder
with HPMC, PVP,
and water
Methycellulose
powder with
HPMC, PVP, andwater
Aluminium hydroxideand sucrose powder
with water
Talc powder andwater
5% Phenylbutazone inlactose powder mix
with 10% solution
Lactose powder with
PEG300 and
PEG6000

Drop size, binder
distribution, andshear forces(Continued)© 2005 by Taylor & Francis Group, LLC

22

Ennis

Table 3

Summary of Wetting Research Contributions (Continued )Workers (Year)

Materials

Equipment

InvestigatedSchaefer et al. (1992)

Lactose powder with
PEG300 and
PEG6000
Lactose, sucrose, andstarch powder
mixed with water
Lactose–cornstarch–
MCC with HPMC
3cp
Lactose, comstarch,magnesium stearate,
gelatin, and benzene
powder with gelatinsolutionHigh shear

Viscosity, binder
dispersion, shear
forces, powder ﬂux
Binder dispersion

Cartensen et al. (1976)

Kokubo et al. (1996)

Davies and Gloor(1971)High shear

High–speed
mixer

Powder ﬂux

Fluid bed

Spray zone

Source: From Ref. 5.

Important factors are the physical nature of the powder surface (particle size, poresize, porosity, environment, roughness, pretreatment). The dynamic wetting process
is therefore inﬂuenced by the rates of ingredient dissolution and surfactant adsorption and desorption kinetics (25).
The second approach to characterize wetting considers the ability of the ﬂuid
to penetrate a powder bed, as illustrated in Figure 15. It involves the measurementof the extent and rate of ﬂuid rise by capillary suction into a column of powder, better known as the Washburn test. Considering the powder to consist of capillaries ofradius R, the equilibrium height of rise he is determined by equating capillary andgravimetric pressures, or
he ¼

2glv cos y
DrgR

Figure 12 Stages of wetting for ﬁne powder compared to drop size. (From Ref. 5.)© 2005 by Taylor & Francis Group, LLC

ð2:2Þ

Theory of Granulation

23

Figure 13 Stages of wetting for coarse powder compared to drop size. (From Ref. 5.)

where is Dr the ﬂuid density with respect to air, g is gravity, and glv cos y is the adhesion tension as before.
In addition to the equilibrium height of rise, the dynamics of penetration are
particularly important. Ignoring gravity and equating viscous losses with the capillary pressure, the rate (dh/dt) and dynamic height of rise h are given bysﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃ
 lvdh Rglv cos y
Rg cos y¼
or h ¼
t
ð2:3Þ
dt
4mh
2m
where t is time and m is binder ﬂuid viscosity (23). The grouping of terms in brackets
involve the material properties which control the dynamics of ﬂuid penetration,
namely, average pore radius, or tortuosity R (related to particle size and void distribution of the powder), adhesion tension, and binder viscosity. The rate of capillary
ﬂuid rise, or the rate of binding ﬂuid penetration in wet granulation, increases withincreasing pore radius (generally coarser powders with larger surface–volume average particle size), increasing adhesion tension (increased surface tension anddecreased contact angle), and decreased binder viscosity.
The contact angle of a binder–particle system is not itself a primary thermodynamic quantity, but rather a reﬂection of individual interfacial energies (Eq. 2.1),
which are a function of the molecular interactions of each phase with respect toone another. An interfacial energy may be broken down into its dispersion and polar
components. These components reﬂect the chemical character of the interface, withthe polar component due to hydrogen bonding and other polar interactions and thedispersion component due to van der Waals interactions. These components may be
determined by the wetting tests described here, where a variety of solvents are chosen
as the wetting ﬂuids to probe speciﬁc molecular interactions (26). Interfacial energy
is strongly inﬂuenced by trace impurities which arise in crystallization of the active
ingredient, or other forms of processing such as grinding. It may be modiﬁed by judicious selection of surfactants (27). Charges may also exist at interfaces, as characterized by electrokinetic studies (28). The total solid–ﬂuid interfacial energy (i.e., bothdispersion and polar components) is also referred to as the critical solid surface
energy of the particulate phase. It is equal to the surface tension of a ﬂuid which justwets the solid with zero contact angle. This property of the particle feed may be
determined by a third approach to characterize wetting, involving the penetrationof particles into a series of ﬂuids of varying surface tension (27,29), or by the variation of sediment height (30).
The last approach to characterizing wetting involves chemical probing of properties which control surface energy. As an example, inverse gas chromatography(IGC) uses the same principles and equipment as standard gas chromatography.
In IGC, however, the mobile phase is composed of probe gas molecules that move© 2005 by Taylor & Francis Group, LLC

24

Ennis

Table 4 Methods of Characterizing Wetting Dynamics of Particulate Systems
Mechanism of wetting

Characterization method

Spreading drops on powder surface

Contact angle goniometer:
Contact angle
Drop height or volume
Spreading velocity
References:
Kossen, Heertjes. Chem Eng Sci 1965;
20:593Pan et al. Dynamic Properties of Interfaces
and Association Structure. New York:
American Oil Chem Soc Press, 1995

Penetration of drops into powder bed

Washburn test:
Rate of penetration by height or volume
Bartell cell:
Capillary pressure difference
References:Parﬁtt, ed. Dispersion of Powders in
Liquids. Washburn: Elsevier Applied
Science Publishers Ltd., 1986, and Phys Rev
1921; 17:273
Bartell, Osterhof. Ind Eng Chem 1927;
19:1277

Penetration of particles into ﬂuid

Flotation tests:
Penetration time
Sediment height
Critical solid surface energy distribution
References:
Ayala R. Ph.D.Thesis, Chem. Eng.,
Carnegie Mellon University, 1985
Fuerstaneau et al. Coll Surf 1991; 60:127
Vargha-Butler. In: Botsaris, Glazman, eds.
Interfacial Phenomena in Coal Technology,
Chap. 2, 1994

Chemical probing of powder

Inverse gas chromatography:
Preferential adsorption with probe gases
Electrokinetics:
Zeta potential and charge
Surfactant adsorption:
Preferential adsorption with probesurfactants
References:
Lloyd et al., eds. ACS Symposium Series.
Vol. 391. Washington, DC: ACS, 1989
Aveyard, Haydon. An Introduction to the
Principles of Surface Chemistry. Cambridge
University Press, 1973
Shaw. Introduction to Colloid & Surface
Chemistry. London: Butterworths & Co.
Ltd., 1983

Source: From Refs. 1,2,5.
© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

25

Figure 14 Characterizing wetting by dynamic contact angle goniometry. (From Refs. 4,25.)

through a column packed with the powder of interest, which is the stationary phase.
As the probe molecules travel through the packed column, they adsorb to and desorb
from the powder. The rate and degree of this interaction is determined by the surface
chemistry of the powder and the probe molecules. Since the surface chemistry of theprobe molecules is known, this allows calculation of the surface chemistry (surface

Figure 15 Characterizing wetting by Washburn test and capillary rise. (From Refs. 4,23.)© 2005 by Taylor & Francis Group, LLC

26

Ennis

Figure 16 IGC retention times for glass powder. (From Refs. 4,5.)

energies) of the powder with the help of a series of plots of both alkane and various
polar probes. A distinct advantage of IGC is the reproducible measurements of physical chemical surface properties which control adhesion tension.
The strength of the solid/liquid interactions determines the average retention
time of a probe. Retention time data for each probe is converted into net retention
volumes, VN. The free energy of desorption is given byqﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃ qﬃﬃﬃﬃﬃﬃﬃﬃﬃ
DgPS gPL þ c
ð2:4Þ
gD
DG ¼ RT ln VN þ c ¼ 2Na
S gL þ
where R is the universal gas constant, T is the column temperature, c is a system constant, N is Avagadro’s number, and a is the surfacepﬃﬃﬃﬃﬃarea of a probe molecule. As illustrated in Figure 16, a plot of RT ln VN vs. a gD
L should give a straight line for aseries of alkanes, the slope of which allows
determinationof the solid’s dispersivepﬃﬃﬃﬃﬃ
D for the polar probes will give a point
surface energy gD.
Plotting
RT
ln
V
vs.
a
g
N
L
S
that is generally somewhere above the alkane reference line. The polar solid energygPS is then found from a plot of these deviations.

2.4. Granulation Examples of the Impact of Wetting
Wetting dynamics has a pronounced inﬂuence on initial nuclei distribution formed
from ﬁne powder. As an example, the inﬂuence of contact angle on the average granule size formed in ﬂuid-bed granulation is illustrated in Figure 17. Water contact
angle was varied by changing the percentages of hydrophilic lactose and hydrophobic salicylic acid (31). Note that granule size in this study is actually nuclei size, sincelittle growth has taken place in the process. Nuclei size is seen to improve with contact angle. In addition, the x-coordinate would more appropriately be replaced withadhesion tension. Aulton et al. (32) also demonstrated the inﬂuence of surfactant
concentration on shifting nuclei size due to changes in adhesion tension.
Figure 18(A) illustrates an example of dynamic wetting, where a time series ofdrop proﬁles are imaged as a drop wets in to a formulation tablet. Note that the time© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

27

Figure 17 The inﬂuence of contact angle on nuclei size formed in ﬂuid-bed granulation of
lactose/salicylic acid mixtures. Powder contact angle determined by goniometry and percent
lactose of each formulation are given in parentheses. (From Ref. 31.)

scale of wetting in this case is 2 sec, with nearly complete wet-in occurring in 1 sec.
This particular formulation was granulated on a continuous pan system in excess
of 2 tons/hr. Figure 18(B) compares differences in lots of the formulation. Note thata second lot—referred to as problem technical—experiences signiﬁcantly degradedgranule strength and requires production rates to be substantially reduced. This isassociated with nearly twice the initial contact angle (120 ) and slower spreading
velocity when compared with the good technical. Poor wetting in practice can translate into reduced production rates to compensate for increased time for drops towork into the powder bed surface. Weaker granules are also often observed, sincepoor wet phase interfacial behavior translates in part to poor solid bond strengthand high granule voidage. Note that differences in the lots are only observed overthe ﬁrst 0.25–0.5 sec, illustrating the importance of comparing dynamic behavior
of formulations, after which time surfactant adsorption/desorption reduces thecontact angle.
As an example of Washburn approaches as illustrated in Figure 19, the effectof ﬂuid penetration rate and the extent of penetration on granule size distribution for
drum granulation was shown by Gluba et al. (Powder Hand. & Proc 1990; 2:323).
Increasing penetration rate, as reﬂected by Eq. 2.3 increased granule size anddecreased asymmetry of the granule size distribution.

2.5. Regimes of Nucleation and Wetting
As previously depicted in Figure 12, the wetting and nucleation process for ﬁne powders consists of several important steps. First, droplets are formed related to spray
distribution, or spray ﬂux deﬁned as the wetted area of the bed per unit time.
© 2005 by Taylor & Francis Group, LLC

28

Ennis

Figure 18 Dynamic imaging of drop wetting, and its impact on continuous pan granulation:(A) Dynamic image of a drop wetting into a formulation, with good active ingredient.
(B) Comparison of surface spreading velocity and dynamic contact angle vs. time for goodand bad active ingredients or technical. Bad technical required reduced production rates.
(From Ref. 4.)© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

29

Second, droplets impact and coalesce on the powder bed surface if mixing or wet-intime is slow. Third, droplets spread and penetrate into the moving powder bed toform loose nuclei, again coalescing, if wet-in is slow. In the case of high-shear processes, shear forces break down overwet clumps, also producing nuclei.
Two key features control this wetting and nucleation process. One is the timerequired for a drop to wet-in to the moving powder bed, in comparison to some circulation time of the process. As discussed previously, this wet-in time is strongly
inﬂuenced by formulation properties (e.g., Eq. 2.3). The second is the actual sprayrate or spray ﬂux, in comparison to solids ﬂux, or mixing rates. Spray ﬂux is strongly
inﬂuenced by manufacturing and process design.
One can envision that drop penetration time and spray ﬂux deﬁne regimes ofnucleation and wetting. If the wet-in is rapid and spray ﬂuxes are low, individual
drops will form discrete nuclei somewhat larger than the drop size, deﬁning a droplet
controlled regime. At the other extreme, if drop penetration is slow and spray ﬂux islarge, drop coalescence and pooling of binder material will occur throughout thepowder bed, which must be broken down by mechanical dispersion. In the mechanical dispersion regime of nucleation, shear forces control the breakdown of wetting
clumps, independent of drop distribution.
Falling between these two extreme regimes, drop overlap and coalescenceoccur to varying extent deﬁning an intermediate regime of nucleation, being a function of penetration time and spray ﬂux. To better deﬁne wetting, particularly in thesense of process engineering and scale-up, we will consider drop penetration or wet-intime and spray ﬂux in greater detail.
Beginning with penetration time, Eq. 2.3 deﬁnes key formulation properties
controlling capillary rise in powder beds. From considering a distribution of macroand micropores in the moving powder bed, as shown in Figure 20, Hapgood (24)determined a total drop penetration time tp of
2=3 V
tp ¼ 1:35 2deeffmReff g cos y


ð2:5Þ

As shown previously, drop wet-in time decreases with increasing pore radius
Reff, decreasing binder viscosity and increasing adhesion tension. In addition, drop
penetration time decreases with decreasing drop size Vd and increasing bed porosity
eeff. Effective pore radius Reff is related to the surface-volume average particle size
d32, particle shape, and effective porosity of packing eeff by


j d32
eeff
Reff ¼
ð2:6Þ
3
1  eeff
To remain with a droplet controlled regime of nucleation, the penetration time
given by Eq. 2.5 should be less than some characteristic circulation time tc of the
granulator in question. Circulation time is a function of mixing and bed weight,
and can change with scale-up.
Now turning our attention to spray ﬂux, consider Figure 21 where an idealized
powder bed of width B moves past a ﬂat spray of spray rate (dV/dt) at a solids velocity of w. For a given spray rate, the number of drops is determined by drop volume,
which in turn deﬁnes the drop area a per unit time which will be covered by thespray, giving a spray ﬂux of:© 2005 by Taylor & Francis Group, LLC

30

Ennis

Figure 19 Inﬂuence of capillary penetration on drum granule size: Increasing penetration
rate, as reﬂected by Eq. 2.3 increases granule size and decreases asymmetry of the granule size
distribution.

Figure 20 Drop penetration in a moving powder bed. (From Ref. 5.)© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

31

Figure 21 Idealized ﬂat spray zone in a spinning rifﬂe granulator. (From Ref. 5.)
da dV =dt pdd2
3 ðdV =dtÞ
¼
¼
dt
Vd
2 dd
4

ð2:7Þ

As droplets contact the powder bed at a certain rate, the powder moves past
the spray zone at its own velocity, or at solids ﬂux given for this simple example by
dA
¼ Bw
dt

ð2:8Þ

The ratio of the droplet spray ﬂux to the solids ﬂux deﬁnes a dimensionlessspray ﬂux given byca ¼

ðda=dtÞ 3 ðdV =dtÞ¼
ðdA=dtÞ 2 dd ðdA=dtÞ

ð2:9Þ

The dimensionless spray ﬂux is the ratio of the rate at which wetted area is covered by droplets to the area of ﬂux of powder through the spray zone, and is a measure of the density of drops falling on the powder surface. As with drop penetration
time, it plays a role in deﬁning the regimes of nucleation as illustrated in Figure 22(5,23). For small spray ﬂux (ca  1), drops will not overlap on contact and will form
separate discrete nuclei for fast penetration time. For large spray ﬂux (ca  1), however, signiﬁcant drop overlap occurs, forming nuclei much larger than drop size, andin the limit, independent of drop size.

Figure 22 Monte-Carlo simulations of drop coverage. (From Ref. 5.)© 2005 by Taylor & Francis Group, LLC

32

Ennis

Figure 23 Effect of spray drop distribution (low spray ﬂux) on nuclei distribution: Lactose
feed powder in spinning granulator. (From Ref. 33.)

For the case of random drop deposition as described by a Poisson distribution,
Hapgood (23) showed the fraction of surface covered by spray was given by
fsingle ¼ 1  expðca Þ

ð2:10Þ

In addition, the fraction of single drops forming individual nuclei (assuming
rapid drop penetration) vs. the number of agglomerates formed was given by
fsingle ¼ expð4ca Þð2:11Þ

fagglom ¼ 1  expð4ca Þð2:12Þ

Examples of the above as applied to nucleation are depicted in Figures 23 and24 and described by Litster et al. (33). Here, nuclei distribution was studied as a function of drop size and spray ﬂux. Lactose was sprayed with a ﬂat spray in a spinning
rifﬂe granulator, mimicking the geometry of Figure 21. For a moderate, intermediate
spray ﬂux of , ca ¼ 0.22, a clear relationship is seen between nuclei size and spray
distribution, with nuclei formed somewhat larger than drop size as shown in Figure
23. However, as the speed of the rifﬂes is slowed down (i.e., solids velocity and solids
ﬂux are decreased, and dimensionless spray ﬂux increased), the nuclei distribution
widens with the formation of agglomerates as depicted in Figure 24.
The spray ﬂux captures the impact of equipment operating variables on nucleation, and as such is very useful for scale-up if nucleation rates and nuclei sizes are to
be maintained constant. The overall impact of dimensionless spray ﬂux on nucleation and agglomerate formation is illustrated in Figure 25, with agglomerates
increasing with increased spray ﬂux as clearly governed by Eq. 2.12 for the case of
rapid drop penetration.
© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

33

Figure 24 Effect of powder velocity (variable spray ﬂux—water) on nuclei distribution:
Lactose feed powder in spinning granulator. (From Ref. 33.)

The regimes of nucleation may now be deﬁned, as depicted in Figure 26 withthe help of dimensionless drop penetration time tp and spray ﬂux ca, or
tp ¼

tp penetration time¼
circulation time
tc

and

ca ¼

ðda=dtÞ spray flux¼
ðdA=dtÞ solids flux

ð2:13Þ

A droplet controlled nucleation regime occurs when there is both low sprayﬂux—relatively few drops overlap—and fast droplet penetration—drops wet into

Figure 25 Agglomerate formation vs. spray ﬂux: Lactose powder with water and HPLC
solutions. (From Ref. 5.)© 2005 by Taylor & Francis Group, LLC

34

Ennis

Figure 26 A possible regime map of nucleation, relating spray ﬂux, solids mixing (solids ﬂux
and circulation time), and formulation properties. (From Refs. 5,24.)

the bed completely before bed mixing allows further drop contact. Nuclei will beformed of the order of drop size.
A mechanical dispersion regime occurs at the other extreme of high spray ﬂux—
giving large drop overlap and coalescence, and large drop penetration times, promoted by poor wet-in rates and slow circulation times and poor mixing. In thisregime, nucleation and binder dispersion occur by mechanical agitation. Viscous,
poorly wetting binders are slow to ﬂow through pores in the powder bed in the caseof poor penetration time. Drop coalescence on the powder surface occurs (alsoknown as ‘‘pooling’’) creating very broad nuclei size distributions. Binder solutiondelivery method (drop size, nozzle height) typically has minimal effect on the nuclei
size distribution, though interfacial properties may affect nuclei and ﬁnal granulestrength.
An intermediate regime exists for moderate drop penetration times and moderate spray ﬂux, with the resulting nuclei regime narrowing with decreases in both.
There are several implications with regard to the nucleation regime map ofFigure 26 with regard to trouble shooting of wetting and nucleation problems. If
drop penetration times are large, making adjustments to spray may not be sufﬁciently narrow granule size distributions if remaining in the mechanical regime. Signiﬁcant changes to wetting and nucleation only occur if changes take the system
across a regime boundary. This can occur in an undesirable way if processes are
not scaled, with due attention to remaining in the drop controlled regime.

3. GRANULE GROWTH AND CONSOLIDATION
3.1. Overview
As previously outlined in Figures 4 and 10, the evolution of the granule size distribution of a particulate feed in a granulation process is controlled by several mechanisms, including wetting, nucleation, and coating; granule coalescence andconsolidation; and granule breakage. Nucleation of ﬁne powders and coating ofexisting granules by the ﬂuid phase have been discussed in the previous section.
© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

35

Figure 27 Granule porosity and mean (pellet) size: Typical regimes of granule growth andconsolidation. (Adapted from Refs. 15–19.)

Breakage mechanisms will be treated in the following section. Here, we focus particularly on growth and consolidation mechanisms.
Granule growth includes the coalescence of existing granules as well as thelayering of ﬁne powder onto previously formed nuclei or granules. The breakdownof wet clumps into a stable nuclei distribution can also be included among coalescence mechanisms. As granules grow by coalescence, they are simultaneously compacted by consolidation mechanisms, which reduce internal granule voidage orporosity.
There are strong interactions between these rate processes, as illustrated in
Figure 27 for the case of drum granulation of ﬁne feed. Here, granule size is illustrated to progress through three stages of growth, including rapid, exponential
growth in the initial nucleation stage, followed by linear growth in the transition
stage, ﬁnishing with very slow growth in a ﬁnal balling stage. Simultaneously withgrowth, granule porosity or voidage is seen to decrease with time as the granules
are compacted. Granule growth and consolidation are intimately connected;
increases in granule size are shown here to be associated with a decrease in granuleporosity. This is a dominant theme in wet granulation.
As originally outlined in Ennis (3), these growth patterns are common throughout ﬂuidized-bed, drum, pan, and high-shear mixer processes for a variety of formulations. Speciﬁc mechanisms of growth may dominate for a process—sometimes tothe exclusion of others (4,5,11,12). However, what all processes have in common
is that the prevailing mechanisms are dictated by a balance of critical particle levelproperties, which control formulation deformability, and operating variables which
control the local level of shear, or bed agitation intensity.
3.2. Mechanics of the Growth Rate Process
In order for two colliding granules to coalesce rather than break up, the collisional
kinetic energy must ﬁrst be dissipated to prevent rebound as illustrated in Figure 28.
© 2005 by Taylor & Francis Group, LLC

36

Ennis

Figure 28 Mechanisms of granule coalescence for low- and high-deformability systems:
Rebound occurs for average granule sizes greater than the critical granule size Dc.
K ¼ deformability. (From Refs. 1,2.)

In addition, the strength of the bond must resist any subsequent breakup forces in
the process. The ability of the granules to deform during processing may be referred
to as the formulation’s deformability, and deformability has a large effect on growthrate. Increases in deformability increase the bonding or contact area thereby dissipating and resisting breakup forces. From a balance of binding and separating forces
and torque acting within the area of granule contact, Ouchiyama and Tanaka (34)derived a critical limit of size above which coalescence becomes impossible, or a maximum growth limit given by
Dc ¼ ðAQ3B=2 K 3=2 sT Þ1=ð4ð3=2ÞZÞ

ð3:1Þ

Here, K is deformability, a proportionality constant relating the maximum
compressive force Q to the deformed contact area, A is a constant with units of[L3/F], which relates granule volume to impact compression force, and sT is the tensile strength of the granule bond. Granules are compacted as they collide. This expels
pore ﬂuid to the granule surface thereby increasing local liquid saturation in the contact area of colliding granules. This surface ﬂuid (1) increases the tensile strength ofthe liquid bond sT and (2) increases surface plasticity and deformability K.
Dc represents the largest granule that may be grown in a granulation process,and it is a harmonic average granule size. Therefore, it is possible for the collision of
two large granules to be unsuccessful, their average being beyond this critical size,
whereas the collision of a large and small granule leads to successful coalescence.
The growth limit Dc is seen to increase with increased formulation deformability(which will be shown to be a strong function of moisture and primary particle size
distribution), increased compressive forces (which are related to local shear levelsin the process), and increased tensile forces (which are related to the interparticle
forces previously discussed.) The parameters z and Z depend on the deformation
mechanism within the contact area. For plastic deformation, z ¼ 1, Z ¼ 0, and K /1/H where H is hardness. For elastic, Hertzian deformation, z ¼ 2/3, Z ¼ 2/3, andK / (1/E)2/3 where E is the reduced elastic modulus. Granule deformation is initially dominated by inelastic behavior of contacts during collision (35).
© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

37

3.3. Types of Granule Growth
The importance of deformability to the growth process depends on bed agitation
intensity. If little deformation takes place during granule collisions, the system isreferred to as a low deformability or low agitation intensity process. This generally
includes ﬂuid bed, drum, and pan granulators. Growth is largely controlled by theextent of any surface ﬂuid layer and surface deformability, with surface ﬂuid playing
a large role in dissipating collisional kinetic energy. Growth generally occurs at a faster time scale than overall granule deformation and consolidation. This is depicted in
Figure 29, where smaller granules can still be distinguished as part of a larger granule
structure, or a ‘‘pop-corn’’-type appearance as often occurs in ﬂuid-bed granulation.
(Note that such a structure may not be observed if layering and nucleation alone
dominate with little coalescence of large granules.) In this case, granule coalescenceand consolidation have less interaction than they do with high deformability systems, making low deformability–low agitation systems easier to scale and model.
For high shear rates or bed agitation intensity, large granule deformation
occurs during granule collisions, and granule growth and consolidation occur on
the same time scale. Such a system is referred to as a deformable or high agitation
intensity process, and it generally includes continuous pin and plow shear-type mixers, as well as batch high-shear pharmaceutical mixers. In these cases, substantial
collisional kinetic energy is dissipated with deformation of the wet mass composing
the granule. Rather than a ‘‘sticking’’ together process as often occurs in the low
deformability process of ﬂuid beds, granules are ‘‘smashed’’ together as with a highshear mixer, and smaller granules are not distinguishable with the granule structure,
as depicted in Figure 29. High-agitation, high-deformable processes generally produce
denser granules than those with low deformablity and low agitation intensity. In addition, the combined and competing effects of granule coalescence and consolidation
make high-agitation processes difﬁcult to model and scale. Both coalescence andconsolidation increase with increase in shear and deformability, whereas as granules
densify, they become less deformable, which works to lower coalescence in the laterstages of growth.

Figure 29 Granule structures resulting from (A) low- and (B) high-deformability systems,
typical for ﬂuid-bed and high-shear mixer granulators, respectively. (From Ref. 4.)© 2005 by Taylor & Francis Group, LLC

38

Ennis

Figure 30 Classiﬁcation of agglomeration processes by agitation intensity and compaction
pressure. (From Refs. 1,2,5.)

Bed agitation intensity is controlled by mechanical variables of the process such as
ﬂuid-bed excess gas velocity, or mixer impeller and chopper speed. Agitation intensity
controls the relative collisional and shear velocities of granules within the process andtherefore growth, breakage, consolidation, and ﬁnal product density. Figure 30 summarizes typical characteristic velocities, agitation intensities, and compaction pressures,and product relative densities achieved for a variety of size-enlargement processes.
Last, it should be noted that the process or formulation itself cannot deﬁne
whether it falls into a low- or high-agitation intensity process. As discussed more
fully in the following sections, it is a function of both the level of shear as well as
the formulation deformability. A very stiff formulation with low deformability may
behave as a low deformability system in a high-shear mixer, or a very pliable formulation may act as a high-deformable system in a ﬂuid-bed granulator.

3.4. Granule Deformability
Granule deformability—and hence Dc—is a strong function of moisture, as illustrated in Figure 31 by the marked increase in average granule size. Deformability
K is related to both the yield strength of the material sy, i.e., the ability of the material to resist stresses, and the ability of the surface to be strained without degradation
or rupture of the granule, with this maximum allowable critical deformation strain
denoted by (DL/L)c. Figure 32 illustrates the low shear rate stress–strain behaviorof agglomerates during compression as a function of liquid saturation, with strain
denoted by DL/L. In general, high deformability K requires low yield strength sy
and high critical strain (DL/L)c. For this formulation, increasing moisture increases
deformability by lowering interparticle frictional resistance, which also increases
mean granule size (Fig. 31).
In most cases, granule deformability increases with increasing moisture,
decreasing binder viscosity, decreasing surface tension, decreasing interparticle© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

39

Figure 31 Effect of granule saturation on mean granule diameter, indicating the marked
increase in granule deformability. Mean granule diameter is a measure of the critical limitof size Dc. Granulation of calcium hydrogen phosphate–aqueous binder solutions. Fielder
PMAT 25 VG mixer. (From Ref. 36.)

friction, and increasing average particle size (speciﬁcally dsv, or the surface–volume
mean size), as well as increasing bed agitation intensity. The important contributionsof binder viscosity and friction to granule deformability and growth are illustrated
by fractions of energy dissipated during a granule collision as depicted in Figure 33.
Note that 60% of the energy is dissipated through viscous losses, with the majority of
the remainder through interparticle friction. Very little is loss due to capillary forces
controlled by surface tension. Therefore, modern approaches to granule coalescence
rest in understanding the impact of granule deformability on growth, rather than theoriginal capillary framework alone, as put forth by Rumpf (20,21) regarding pendular and funicular forces due to interparticle liquid bridges.

3.5. Interparticle Forces Due to Pendular Bridges
Interstitial ﬂuid and the resulting pendular bridges play a large role in both granule
growth and granule deformability. Pendular bridges between particles of which a
granule is composed, give rise to capillary and viscous interparticle forces. These
forces develop interparticle pressure, which also allows friction to act between point
contacts (Fig. 34). Interparticle forces due to pendular bridges, and their impact on
deformability, warrant further attention. Note that capillary forces for small contact© 2005 by Taylor & Francis Group, LLC

40

Ennis

Figure 32 The inﬂuence of sample saturation S on granule deformability: Deformation
strain (DL/L) is measured as a function of applied stress, with the peak stress and strain
denoted by tensile strength sy and critical strain (DL/L)c of the material. Dicalcium phosphatewith 15 wt% binding solution of PVP/PVA KollidonÕ VA64. Fifty percent compact porosity.
(From Ref. 37.)

angle attract particles (but repel for y > 90 ), whereas viscous and frictional forces
act to resist the direction of motion.
As shown in Figures 11 and 34, consider two spherical particles of radius aseparated by a gap distance 2ho approaching one another at a velocity U. The twoparticles may represent two primary particles within the granule, in which case weare concerned about the contribution of interparticle forces to granule strengthand deformability. Or they may represent two colliding granules, in which case weare concerned with the ability of the pendular bridge to dissipate granule kinetic
energy and resist breakup forces in the granulation process. The two spheres arebound by a pendular bridge of viscosity m, density r, and surface tension g. The
pendular bridge consists of the binding ﬂuid in the process, which includes the added
solvent and any solubilized components. In some cases, it may also be desirable toinclude very ﬁne solid components within the deﬁnition of the binding ﬂuid, and,
therefore, consider instead a suspension viscosity and surface tension. These material
parameters vary on a local level throughout the process, and are also time dependentand a function of drying conditions.
For the case of a static liquid bridge (i.e., U ¼ 0) with perfect wetting, surface
tension induces an attractive capillary force between the two particles due to a threephase contact line force and a pressure deﬁciency arising from interfacial curvature.
The impact of this static pendular bridge force on static granule strength has beenstudied and reported extensively (3,20–22). It is important to recognize that in mostprocesses, however, the particles are moving relative to one another and, therefore,
the bridge liquid is in motion. This gives rise to viscous resistance forces which cancontribute signiﬁcantly to the total bridge strength. The strength of both Newtonian© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

41

Figure 33 Distribution of energy dissipation during agglomerate collisions, with granularsimulations of wall impact for 128 ms duration for invisicid and viscous binder agglomerates.
(From Ref. 11.)and non-Newtonian pendular bridges have been studied extensively (3,39,40). For
Newtonian ﬂuids (39), the dynamic strength was shown to be given byF¼ Fcap þ Fvis ¼ Fo þ 3Ca=epga

8< Fcap ¼ ð2  2Ho Þ sin2 j
whereFvis ¼ 3Ca=e:
Ca ¼ mU=g

ð3:2Þ

Here, all forces have been made dimensionless with respect to a measure of thecapillary force, or pga. Note that the bridge strength consists of two components.
Fcap is the strength of a static capillary bridge, and is a function of curvature of

Figure 34 Interparticle forces and granule deformability: Interparticle forces include
capillary forces, viscous lubrication forces, and frictional forces. (From Ref. 4.)© 2005 by Taylor & Francis Group, LLC

42

Ennis

Figure 35 Maximum strength of a liquid bridge between two axial moving particles asa function of Ca for Newtonian and shear thinning ﬂuids. (From Ref. 3.)

the interface Ho and the ﬁlling angle. In dimensional form, it is given byFcap¼ pgað2  2Ho Þ sin2 jð3:3Þ

Fvis is the strength of a viscous, dynamic bridge, and is equivalent to the force
between two spheres approaching one another in an inﬁnite ﬂuid. This force is afunction of binder viscosity m, and the collision velocity U. Here, e ¼ 2ho/a is gap distance, and not granule voidage. In dimensional form, the viscous force is given byFvis¼ 6pmUa=eð3:4Þ

From Eq. 3.2, one ﬁnds that the dynamic bridge force begins with the static
bridge strength—which is a constant independent of velocity (or Ca), and thenincreases linearly with Ca, which is a capillary number representing the ratio of viscous (pmUa) to capillary (pga) forces, and is proportional to velocity. This is conﬁrmed experimentally as illustrated in Figure 35 for the case of two spheres
approaching axially. Extensions of the theory have also been conducted for
non-Newtonian ﬂuids (shear thinning), shearing motions, particle roughness, wettability, and time-dependent drying binders. The reader is referred to Ennis (3,39)
for additional details. Curves for non-Newtonian ﬂuids are also included in
Figure 35.
For small velocities, small binder viscosity, and large gap distances, thestrength of the bridge will approximate a static pendular bridge, or Fcap, which is
proportional to and increases with increases in surface tension. This force is equivalent to the static pendular force H previously given in Eq. 1.2 as studied by Rumpf(20,21) and Augsburger and Vuppala (22). On the other hand, for large binder viscosities and velocities, or small gap distances, the bridge strength will approximately
be equal to Fvis, which is proportional to and increases with increases in binder viscosity and velocity. This viscous force is singular in the gap distance and increases
dramatically for small separation of the particles. It is important to note that as© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

43

granules are consolidated, resulting in decreases in effective interparticle gap distance, and as binders dry, resulting in large increases in binder viscosity, the dynamic
bridge strength can exceed the static strength by orders of magnitude.
3.6. Dynamic Wet Mass Rheology and Deformability Revisited
The yield stress of powder compacts has previously been reported in Figure 32 forthe case of slow yielding. However, the dependence of interparticle forces on shear
rate clearly impacts wet mass rheology and therefore deformability. Figure 36 illustrates the stress–strain response of compacts, demonstrating that the peak ﬂow or
yield stress increases proportionally with compression velocity (41). In fact, in a similar fashion to dynamic liquid bridge forces, the peak ﬂow stress of wet unsaturated
compacts (initially pendular state) can be seen to also increase with Ca as follows(Fig. 37):8
so ¼ 5:0  5:3
<
sPeak
B
y
¼ so þ A Ca
where A ¼ 280  320; B ¼ 0:58  0:64
ð3:5Þ
:
g=a
Ca ¼ m_ea=g
There are several important issues worth noting with regard to these results.
First is the similarity between the strength of the assembly or compact given by
Eq. 3.5 and the strength of the individual dynamic pendular bridge given by Eq.
3.2; both curves are similar in shape with a capillary number dependency. As withthe pendular bridge, two regions may be deﬁned. In region 1, for a bulk capillary
number of Ca < 104 , the strength or yield stress of the compact depends on the static pendular bridge, and therefore on surface tension, particle size, and liquid load-

Figure 36 Typical compact stress response for fast compression vs. crosshead compression
velocity for glass ballotini (d32 ¼ 35 mm) and compact diameter 20 mm, length 25 mm. (FromRef. 41.)© 2005 by Taylor & Francis Group, LLC

44

Ennis

Figure 37 Dimensionless peak ﬂow stress of Fig. 36 vs. bulk capillary number, for various
binder solutions. (From Ref. 41.)

ing. In region 2, for Ca > 104 , the strength depends on the dynamic pendular
bridge, and therefore on binder viscosity and strain rate, in addition to particle size.
Second, the results of Figure 37 do not clearly depict the role of saturation andcompact porosity, though these properties are known to affect strength. Decreases
in compact porosity generally increases compact strength through increases in interparticle friction, whereas increases in saturation lower strength (e.g., Figure 32)(36,37,42). Hence, the curve of Figure 37 should be expected to shift with these variables, particularly since the viscous force for axial approach is singular in the interparticle gap distance (Eqs. 3.4).
Third, the static granule or assembly strength (Eq. 1.2), as originally developedby Rumpf (20,21) and Augsburger and Vuppala (22), is captured by the constant,
low Ca value of the yield stress or
9 1  e H 9 1  e g cos y
Peakfor Ca < 104
ð3:6Þsy  so ðg=aÞ 
8
e
a2 4
e
a
Fourth, the mechanism of compact failure also depends on strain rate.
Figure 38 illustrates schematically the crack behavior observed in compacts as afunction of capillary number. At low Ca, compacts fail by brittle fracture withmacroscopic crack propagation, whereas at high Ca, compacts fail by plastic ﬂow.
Within the context of granulation, small yield stresses at low Ca may result in
unsuccessful growth when these stresses are compared with large breakup forces.
With increased yield stress comes stronger granules but also decreased deformability.
Therefore, high strength might imply a low-deformability growth mechanism forlow-shear processes such as a ﬂuid bed. On the other hand, it might imply smaller
growth rates for high-shear processes which are able to overcome this yield stressand bring about kneading action and plastic ﬂow in the process. Therefore, it isimportant to bear in mind that increased liquid saturation may initially lower yieldstress, allowing more plastic deformation during granule collisions. However, as
granules grow and consolidate and decrease in voidage, they also strengthen and rise© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

45

Figure 38 Collisions between surface wet granules, beginning with approach, and ending
with separation. (From Refs. 3,5,43,44.) Note that no deformation takes place in the original
Stokes model.

in yield stress, becoming less deformable with time and withstanding shear forces in
the granulator. Hence, the desired granule strength and deformability is linked in
a complex way to granulator shear forces and consolidation behavior.

3.7. Low-Agitation Intensity–Low-Deformability Growth
For those low-agitation processes or formulations which allow little granule deformation during granule collisions, consolidation of the granules occurs at a muchslower rate than growth, and granule deformation can be ignored to a ﬁrst approximation. The growth process can be modeled by the collision of two nearly stiff granules each coated by a liquid layer of thickness h. A pictorial depiction of a granulecollision is illustrated in Figure 38. For the case of zero plastic deformation, theprobability of successful coalescence as developed by Ennis and coworkers (3,43)
is governed by a dimensionless energy, or Stokes number St given by
St ¼

4ru0 a9m

ð3:7Þ

where u0 is the relative collisional velocity of the granules, r is granule density, a isthe harmonic average of granule diameter, and m is the solution phase binder viscosity.
The Stokes number represents the ratio of initial collisional kinetic energy to theenergy dissipated by viscous lubrication forces, and it is one measure of normalized
bed agitation energy. Successful growth by coalescence or layering requires that


1


St < St where St ¼ 1 þ
ð3:8Þ
lnðh=ha Þ
erwhere St is a critical Stokes number representing the energy required for rebound.
The binder layer thickness h is related to liquid loading, er is the coefﬁcient of restitution of the granules, and ha is a measure of surface roughness or asperities. The
critical condition given by Eq. 3.8 controls the growth of low deformability systems. This criteria has also been extended to capillary coalescence (3) and for casesof plastic deformation (44).
Binder viscosity is a function of local temperature, collisional strain rate (fornon-Newtonian binders), and binder concentration dictated by drying rate and local© 2005 by Taylor & Francis Group, LLC

46

Ennis

Figure 39 Median granule diameter for ﬂuid-bed granulation of ballotini with binders of different viscosity indicating regimes of growth. (From Refs. 3,43.)

mass transfer and local bed moisture. It can be controlled through judicious selectionof binding and surfactant agents and measured by standard rheological techniques(45). The collisional velocity is a function of process design and operating variables,
and is related to bed agitation intensity and mixing. Possible choices of u0 are summarized in Figure 30, and discussed more fully regarding scale-up in Chapter 18.
Note that u0 is an interparticle collisional velocity, which is not necessarily the local
average granular ﬂow velocity.
Three regimes of granule growth may be identiﬁed for low-agitation intensity–
low-deformability processes (3,43), as depicted for ﬂuid-bed granulation in Figure 39,
and outlined as follows:
Noninertial regime: For small granules or high binder viscosity lying within anoninertial regime of granulation, all values of St will lie below the critical value St and therefore all granule collisions result in successful
growth provided binder is present. Growth rate is independent of granulekinetic energy, particle size, and binder viscosity (provided other rate
processes are constant). Distribution of binding ﬂuid and degree of mixing then control growth and, and this is strongly coupled with the rate
process of wetting (see previous section). As shown in Figure 39, bothbinders have the same initial growth rate for similar spray rates, independent of binder viscosity. Increases in bed moisture (e.g., spray rate, droprate) and increases in granule collisions in the presence of binder will
increase the overall rate of growth. It must be borne in mind, however,that there is a 100% success of these collisions, since dissipation of energy
far exceeds collisional kinetic energy.
Inertial regime: As granules grow in size, their collisional momentum increases,
leading to localized regions in the process where St exceeds the criticalvalue St. In this inertial regime of granulation, granule size, binder© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

47

Figure 40 (A) Exponential growth in drum granulation reaching a growth limit dmax, or
maximum extent of growth (kt)max, which are functions of moisture saturation (15–19). (B)Maximum extent of noninertial growth (kt)max as a linear function of saturation of the powder
feed and binder viscosity. (C) Maximum extent normalized for differences in binder viscosity,
drum speed, granule density by Stokes number. (From Ref. 46.)

viscosity, and collision velocity determine the proportion of the bed inwhich granule rebound is possible. Increases in binder viscosity anddecreases in agitation intensity increase the extent of granule growth—i.e., the largest granule that may be grown [e.g., Dc of Eq. 3.1]. This is
conﬁrmed in Figure 39 with the CMC binder continuing to grow,whereas the PVP system with lower viscosity slows down in growth. Notethat the rate of growth, however, is controlled by binder distribution andmixing, and not binder viscosity. For example, increasing binder viscosity will not affect growth rate, or initial granule size, but it will result in
an increased growth limit.
Coating regime: When the spatial average of St exceeds St, growth is balanced
by granule disruption or breakup, leading to the coating regime of granulation. Growth continues by coating of granules by binding ﬂuid alone.
The PVP system with lower viscosity is seen to reach its growth limit andtherefore coating regime in Figure 39.
Transitions between granulation regimes depend on bed hydrodynamics. As
demonstrated by Ennis et al. (3,4,43), granulation of an initially ﬁne powder may
exhibit characteristics of all three granulation regimes as time progresses, since St
increases with increasing granule size. Implications and additional examples regarding the regime analysis are highlighted by Ennis (3,4,43). In particular, increases in
ﬂuid-bed excess gas velocity exhibit a similar but opposite effect on growth rate
to binder viscosity; namely, it is observed to not affect growth rate in the initial
Noninertial regime of growth, but instead lowers the growth limit in the inertial
regime.
© 2005 by Taylor & Francis Group, LLC

48

Ennis

3.8. Example: Extent of Noninertial Growth
Growth by coalescence in granulation processes may be modeled by population
balances (Chapter 21). It is necessary to determine both the mechanism and the kernel which describe growth. For ﬁne powders within the noninertial regime of growth,
all collisions result in successful coalescence provided binder is present. Coalescenceoccurs via a random, size independent kernel which is only a function of liquid loading y, as well as mixing, orbðu; vÞ ¼ k ¼ k f ðyÞ

ð3:9Þ

For random growth and in the presence of sufﬁcient binding ﬂuid, it may berigorously proven that the average granule size increases exponentially with time, ord ¼ d0 ekt

ð3:10Þ

This exponential increase in size with time is conﬁrmed experimentally in
Figure 40, where increases in liquid loading f(y) increase growth rate. (Note that
granule saturation S is connected to liquid loading y and porosity.) Based on theregime analysis work above, growth will continue in a process while the conditionsof Eq. 3.8 are met, i.e., dissipation exceeds collisional kinetic energy. Examples ofthese growth limits are seen in the drum granulation work of Kapur (15–19) in
Figure 40, as well as ﬂuid beds (Fig. 39) and mixers (Fig. 41). It may be shown thatthe maximum extent of granulation (kt)max occurring within the noninertial regime isgiven byFigure 41 Granule diameter as a function of time for high-shear mixer granulation, illustrating the inﬂuence of deformability on growth behavior. Directions of increasing viscosity and
impeller speed indicated by arrows. (A) Ten-liter melt granulation of lactose with 15 wt% binder and impeller speed of 1400 rpm for two different viscosity grades of polyethylene gylcol
binders. (B) Ten-liter vertical high-shear mixer granulation of dicalcium phosphate with
15 wt% binder solution of PVP/PVA KollidonÕ VA64, liquid loading of 16.8 wt%, and chopper speed of 1000 rpm for varying impeller speed. (From Refs. 47,48.)© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

49



m
ðktÞmax ¼ 6 lnðSt =St0 Þ f ðyÞ / ln
ru0 d0ð3:11Þ

St0 is the Stokes number based on initial nuclear diameter d0 (46). Extent(kt) max is taken as the logarithm of the growth limit in the ﬁrst random stage of
growth, or dmax. The growth limits dmax of Figure 40(A) are replotted as extents
in Figure 40(B). Here, (kt)max is observed to depend linearly on liquid loading y.
Therefore, the maximum granule size depends exponentially on liquid loading, as
observed experimentally (Fig. 31).
From Eq. 3.11, it is possible to scale or normalize a variety of drum granulation data to a common drum speed and binder viscosity. Maximum granule size dmax
and extent (kt)max depend linearly and logarithmically, respectively, on binderviscosity and the inverse of agitation velocity. This is illustrated in Figure 40(B),where the slope of each formulation line depends linearly on binder viscosity.
Figure 40 illustrates the normalization of extent (kt)max for the drum granulationof limestone and fertilizers, correcting for differences in binder viscosity, granuledensity, and drum rotation speed, with the data collapsing onto a common line
following normalization.

3.9. High-Agitation Intensity–Deformable Growth
For high-agitation processes involving high-shear mixing or for readily deformableformulations, granule deformability, plastic deformation, and granule consolidation
can no longer be neglected as they occur at the same rate as granule growth. Typical
growth proﬁles for high-shear mixers are illustrated in Figure 41. Two stages ofgrowth are evident, which reveal the possible effects of binder viscosity and impeller
speed, as shown for data replotted vs. impeller speed in Figure 42. The initial, nonequilibrium stage of growth is controlled by granule deformability, and is of mostFigure 42 Granule diameter as a function of impeller speed for both initial nonequilibrium
and ﬁnal equilibrium growth limit for high-shear mixer granulation (From Ref. 10,48.)© 2005 by Taylor & Francis Group, LLC

50

Ennis

practical signiﬁcance in manufacturing for high-shear mixers. Increases in St due tolower viscosity or higher impeller speed increase the rate of growth, since the system
becomes more deformable and easier to knead into larger granule structures (e.g.,
Fig. 29). These effects are contrary to what is predicted from the Stokes analysis
based on rigid, low-deformability granules, where high viscosity and low velocity
increase the growth limit.
Growth continues until disruptive and growth forces are balanced in the process. This last equilibrium stage of growth represents a balance between dissipationand collisional kinetic energy, and so increases in St decrease the ﬁnal granule size, as
expected from the Stokes analysis. Note that the equilibrium granule diameterdecreases with the inverse square root of the impeller speed, as it should based on
St ¼ St, with u0 ¼ a(du/dx) ¼ oa.
The Stokes analysis is used to determine the effect of operating variables andbinder viscosity on equilibrium growth, where disruptive and growth forces arebalanced. In the early stages of growth for high-shear mixers, the Stokes analysis
in its present form is inapplicable. Freshly formed, uncompacted granules are easily
deformed, and as growth proceeds and consolidation of granules occur, they will
surface harden and become more resistant to deformation. This increases the importance of the elasticity of the granule assembly. Therefore, in later stages of growth,older granules approach the ideal Stokes model of rigid collisions. In addition, theStokes number controls in part the degree of deformation occurring during a collision since it represents the importance of collision kinetic energy in relation to viscous dissipation, although the exact dependence of deformation on St is presently
unknown.
The Stokes coalescence criteria of Eq. 3.8 developed by Ennis must be generalized to account for substantial plastic deformation in order to treat the initial nonequilibrium stages of growth in high-agitation systems such as high-shear mixers. In
this case, granule growth and deformation are controlled by a generalization of St,
or a deformation Stokes number Stdef, as originally deﬁned by Tardos et al. (49,50):
.
2 2
2
rðdu
o dxÞ druo¼
ð3:12Þ
Stdef ¼sysy
Viscosity has been replaced by a generalized form of plastic deformation controlled by the yield stress sy, which may be determined by compression experiments.
As shown previously, yield stress is related to deformability of the wet mass, and is afunction of shear rate, binder viscosity, and surface tension, primary particle size andfriction, and saturation and voidage as previously given by Eq. 3.5 and Figures 32
and 37.
Critical conditions required for granule coalescence may be deﬁned in terms ofthe viscous and deformation Stokes number, or St and Stdef, respectively. These
represent a complex generalization of the critical Stokes number given by Eq. 3.9,
and are discussed in detail elsewhere (5,44).
An overall view of the impact of deformability on growth behavior may begained from Figure 43, where types of granule growth are plotted vs. deformability
in a regime map, and yield stress has been measured by compression experiments(51). Growth mechanism depends on the competing effects of high-shear promoting
growth by deformation on the one hand and the breakup of granules giving a growth
limit on the other. For high velocities, growth is not possible by deformation due tohigh shear, and the material remains in a crumb state. For low pore saturation,© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

51

Figure 43 Regime map of growth mechanisms, based on moisture level and deformabilty of
formulations. (From Ref. 51.)

growth is only possible by initial wetting and nucleation, with the surrounding
powder remaining ungranulated. At intermediate levels of moisture, growth occurs
at a steady rate for moderate deformability, but has a delay in growth for low
deformability. This delay, or induction time, is related to the time required towork moisture to the surface to promote growth. For high moisture, very rapid
and potentially unstable growth occurs.
The currrent regime map as presented requires considerable development.
Overall growth depends on the mechanics of local growth, as well as the overall mixing pattern and local/overall moisture distribution. Levels of shear are poorly understood in high-shear processes. In addition, growth by both deformation and the rigid
growth model is possible. Lastly, deformability is intimately linked to both voidage
and moisture. They are not a constant for a formulation, but depend on time and thegrowth process itself through the interplay of growth and consolidation. Nevertheless, the map provides a starting point, and is discussed in additional detail in
Chapter 18.
3.10. Determination of St
The extent of growth is controlled by some limit of granule size, either reﬂected by
the critical Stokes number St or by the critical limit of granule size Dc. There areseveral possible methods to determine this critical limit. The ﬁrst involves measuring
the critical rotation speed for the survival of a series of liquid binder drops during
drum granulation (3). A second reﬁned version involves measuring the survival of
granules in a couette-ﬂuidized shear device (49,50). Both the onset of granule deformation and the complete granule rupture are determined from the dependence ofgranule shape and the number of surviving granules, respectively, on shear rate.
The critical shear rate describing complete granule rupture deﬁnes St, whereas
the onset of deformation and the beginning of granule breakdown deﬁnes an© 2005 by Taylor & Francis Group, LLC

52

Ennis

Figure 44 Determination of the onset of granule deformation and complete granule breakdown with the ﬂuidized couette constant shear device. Y is a yield number, Fsur is the fractionof surviving granules, and Ddef is the average degree of granule deformation. (From Refs. 49,50.)

additional critical value (Fig. 44). The third approach is to measure the deviation in
the growth rate curve from random exponential growth (52). The deviation fromrandom growth indicates a value of w, or the critical granule diameter at which
noninertial growth ends. This value is related to Dc (Fig. 45). (See Chapter 21 regarding

Figure 45 Determination of critical granule diameter, or growth limit, from the evolution of
the granule size distribution. (From Ref. 51.)
© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

53

modeling for further discussion.) The last approach is through the direct measurement of the yield stress through compression experiments.

3.11. Example: High-Shear Mixer Growth
An important case study for high-deformability growth was conducted by Holm et al.
(42) for high-shear mixer granulation. Lactose, dicalcium phosphate, and dicalcium
phosphate/starch mixtures (15% and 45% starch) were granulated in a Fielder
PMAT 25 VG laboratory scale mixer. Granule size, porosity, power level, temperature rise, and ﬁnes disappearance were monitored during liquid addition and wet
massing phases. Impeller and chopper speeds were kept constant at 250 and 3500
rpm, respectively, with 7.0–7.5 kg starting material. Liquid ﬂow rates and amountof binder added were varied according to the formulation.
Figure 46 illustrates typical power proﬁles during granulation, whereas
Figure 47 illustrates the resulting granule size and voidage (or porosity). Note that
wet massing time (as opposed to total process time) is deﬁned as the amount of time
following the end of liquid addition, and the beginning of massing time is indicatedin Figure 47.
Clear connections may be drawn between granule growth, consolidation,
power consumption, and granule deformability. From comparing Figures 46 and47 for the case of lactose, one may note that there is no further rise in power following the end of water addition (beginning of wet massing), and this corresponds to nofurther changes in granule size and porosity. In contrast, dicalcium phosphate continues to grow through the wet massing stage, with corresponding continual
increases in granule size and porosity. Last, the starch formulations are noted tohave power increase for approximately 2 min into the wet massing stage, corresponding to 2 min of growth; however, growth ceases when power consumption levels off.
Therefore, power clearly tracks growth and consolidation behavior.
Further results connecting power and growth to compact deformability areprovided in Holm (42). The deformability of lactose compacts, as a function ofsaturation and porosity, is shown to increase with moisture in a stable fashion.

Figure 46 Power consumption for lactose, dicalcium phosphate, and dicalcium phosphate/starch mixtures (15% and 45% starch) granulated in a Fielder PMAT 25 VG. (From Ref. 42.)
© 2005 by Taylor & Francis Group, LLC

54

Ennis

Figure 47 Granule size and porosity vs. wet massing time for lactose, dicalcium phosphate,and dicalcium phosphate/starch mixtures (15% and 45% starch) granulated in a Fielder
PMAT 25 VG. (From Ref. 42.)

Therefore, growth rates and power rise do not lag behind spray addition, and growthceases with the end of spraying. Dicalcium phosphate compacts, on the other hand,remain undeformable until a critical moisture is reached, after which they become
extremely deformable and plastic. This unstable behavior is reﬂected by an inductive
lag in growth and power after the end of spray addition, ending with unstable growthand bowl sticking as moisture is ﬁnally worked to the surface.
In closing, a comment should be made with regard to using power for control
and scale-up. While it is true the power is reﬂective of the growth process, it is adependent variable in many respects. Different lots of an identical formulation,e.g., may have different yield properties and deformability, and a different dependence on moisture. This may be due to minute particle property changes controlling
the rate processes. Therefore, there is no unique relationship between power andgrowth. However, power measurements might be useful to indicate a shift in formation properties.
Lastly, speciﬁc power is required for scale-up, where power is normalized by
the active portion of the powder bed. The impact of scale-up on mixing and distribution of power in a wet mass, however, is only partly understood at this point.
3.12. Granule Consolidation
Consolidation of granules determines granule porosity or voidage, and hence granuledensity. Granules may consolidate over extended times and achieve high densities if
there is no simultaneous drying to stop the consolidation process. The extent andrate of consolidation are determined by the balance between the collision energy
and the granule resistance to deformation. The voidage e may be shown to dependon time as follows:e  emin¼ expðbtÞe0  eminwhere b ¼ fnðy; St; Stdef Þð3:13Þ

Here, y is liquid loading, e0 and emin are the beginning and ﬁnal minimum porosity, respectively (53). The effect of binder viscosity and liquid content are complex
and interrelated. For low-viscosity binders, consolidation increases with liquid© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

55

Figure 48 Effect of binder liquid content and primary feed particle size on granule porosity
for the drum granulation of glass ballotini: Decreasing granule porosity corresponds toincreasing extent of granule consolidation. (From Ref. 53.)

content as shown in Figure 48 (53). This is the predominant effect for the majority of
granulation systems, with liquid content related to peak bed moisture on average.
Increased drop size and spray ﬂux are also known to increase consolidation. Drying
effects peak bed moisture and consolidation as well through varying both moisturelevel as well as binder viscosity. For very viscous binders, consolidation decreases
with increasing liquid content. As a second important effect, decreasing feed particle
size decreases the rate of consolidation due to the high speciﬁc surface area and low
permeability of ﬁne powders, thereby decreasing granule voidage. Last, increasing
agitation intensity and process residence time increases the degree of consolidation
by increasing the energy of collision and compaction. The exact combined effectof formulation properties is determined by the balance between viscous dissipationand particle frictional losses, and therefore the rate is expected to depend on theviscous and deformation Stokes numbers (53).

4. GRANULE STRENGTH AND BREAKAGE
4.1. Overview
Dry granule strength impacts three key areas of pharmaceutical processing. These
include the physical attrition or breakage of granules during the granulation anddrying processes, the breakage of granules in subsequent material handling steps
such as conveying or feeding, and last, the deformation and breakdown of granules
in compaction processes such as tableting. Modern approaches to granule strength
rely on fracture mechanics (54). In this context, a granule is viewed as a nonuniform
physical composite possessing certain macroscopic mechanical properties, such as a
generally anisotropic yield stress, as well as an inherent ﬂaw distribution. Hard materials may fail in tension, with the breaking strength being much less than the inherent
tensile strength of bonds because of the existence of ﬂaws. Flaws act to concentratestress, as depicted in Figure 49 for commercial metamucil tablets. Here, razor scores
or notches have been added to the tablets, which were subsequently broken under
three-point bend loading (see later). In all cases, the tablets break at the razor
score—which acts as a sharp ﬂaw to concentrate stress—rather than at the tableted
original indentation notch.
© 2005 by Taylor & Francis Group, LLC

56

Ennis

Figure 49 Breakage of metamucil tablets by under three-point loading with razor scoring.
(A) Upper left: unscored; upper right: notched scored; bottom: scored 90 to notch. (B) Breakage results. (From Ref. 4.)

Bulk breakage tests of granule strength measure both inherent bond strengthand granule ﬂaw distribution and voidage (3,4). Figure 8 presented previously illustrates granule attrition results for a variety of formulations. Granule attrition clearly
increases with increasing voidage; note that this voidage is a function of granule consolidation discussed previously. Different formulations fall on different curves, due
to inherently differing interparticle bond strengths. It is often important to separate
the impact of bond strength vs. voidage on attrition and granule strength. Processing
inﬂuences ﬂaw distribution and granule voidage, whereas inherent bond strength iscontrolled by formulation properties.
The mechanism of granule breakage is a strong function of material propertiesof the granule itself as well as the type of loading imposed by the test conditions (55).
Ranking of product breakage resistance by ad hoc tests may be test speciﬁc, and in
the worst case differ from actual process conditions. Instead, material properties
should be measured by standardized mechanical property tests which minimize theeffect of ﬂaws and loading conditions under well-deﬁned geometries of internal
stress, as described in the following section.
4.2. Mechanics of the Breakage Rate Process
Fracture toughness Kc deﬁnes the stress distribution in the body just before fracture
and is given by
pﬃﬃﬃﬃﬃ
Kc ¼ Y sf pc
ð4:1Þ
where sf is the applied fracture stress, c is the length of the crack in the body, and Y
is a calibration factor introduced to account for different body geometries (Fig. 50).
The elastic stress is increased dramatically as the crack tip is approached. In practice,
however, the elastic stress cannot exceed the yield stress of the material, implying a
region of local yielding at the crack tip. Irwin (57) proposed that this process zone
size rp be treated as an effective increase in crack length dc. Fracture toughness isthen given by
pﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃ
ð4:2Þ
Kc ¼ Y sf pðc þ dcÞ with d c  rp
The process zone is a measure of the yield stress or plasticity of the material incomparison to its brittleness. Yielding within the process zone may take place either
plastically or by diffuse microcracking, depending on the brittleness of the material.
© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

57

Figure 50 Fracture of a brittle material by crack propagation. (From Ref. 56.)

For plastic yielding, rp is also referred to as the plastic zone size. The critical strainenergy release rate Gc is the energy equivalent to fracture toughness, ﬁrst proposedby Grifﬁth (58). They are related by
Gc ¼ Kc2 =E

ð4:3Þ

4.3. Fracture Measurements
In order to ascertain fracture properties in any reproducible fashion, very speciﬁc
test geometry must be used since it is necessary to know the stress distribution atpredeﬁned, induced cracks of known length. Three traditional methods are: (1) the
three-point bend test, (2) indentation fracture testing, and (3) Hertzian contact
compression between two spheres of the material. Figures 51 and 52 illustrate a typical geometry and force response for the case of a three-point bend test. By breaking aseries of dried formulation bars under three-point bend loading of varying crack

Figure 51 Three-point bend and indentation testing for fracture properties. (From Ref. 56.)
© 2005 by Taylor & Francis Group, LLC

58

Ennis

Figure 52 Typical force–displacement curve for three-point bend semistable failure. (FromRef. 56.)

length, fracture toughness is determined from the variance of fracture stress on crack
length, as given by Eq. 4.2. (For details, see Ref. 56.)
In the case of indentation fracture, one determines hardness H from the area ofthe residual plastic impression, and fracture toughness from the lengths of cracks
propagating from the indent as a function of indentation load F (59). Hardness isa measure of the yield strength of the material. Toughness and hardness in the caseof indentation are given byrﬃﬃﬃﬃﬃ
EF
F
Kc ¼ b
ð4:4Þ
and H H c3
A
Table 5 compares typical fracture properties of agglomerated materials. Fracture toughness Kc is seen to range from 0.01 to 0.06 MPa m1/2, less than that typicalfor polymers and ceramics, presumably due to the high agglomerate voidage. Criticalstrain energy release rates Gc are from 1 to 200 J/m2, typical for ceramics but lessthan that for polymers. Process zone sizes dc are seen to be large and of the orderof 0.1–1 mm, values typical for polymers. Ceramics on the other hand typically haveprocess zone sizes less than 1 m m. Critical displacements required for fracture may
be estimated by the ratio Gc/E, which is an indication of the brittleness of the material. This value was of the order of 107–108 mm for polymer–glass agglomerates,
similar to polymers, and of the order of 109 mm for herbicide bars, similar to ceramics. In summary, granulated materials behave not only similar to brittle ceramics,
which have small critical displacements and yield strains, but also similar to ductile
polymers, which have large process or plastic zone sizes.
4.4. Mechanisms of Breakage
The process zone plays a large role in determining the mechanism of granulebreakage (56), with mechanisms such as those previously presented in Table 1.
© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

Table 5 Fracture Properties of Agglomerated Materials
Material
Bladex 60Õ a
Bladex 90Õ aGleanÕ a
GleanÕ Ageda
CMC-Na (M)b
Klucel GFb
PVP 360Kb
CMC 2% 1kNb
CMC 2% 5kNb
CMC 5% 1kNb

Id

Kc
(MPa-m1/2)

Gc(Jsolm2)

dc
(mm)

E
(MPa)

Gc/E
(m)

B60
B90
G
GA
CMC
KGF
PVP
C2/1
C2/5
C5/1

0.070
0.014
0.035
0.045
0.157
0.106
0.585
0.097
0.087
0.068

3.0
0.96
2.9
3.2
117.0
59.6
199.0
16.8
21.1
15.9

340
82.7
787
3510
614
703
1450
1360
1260
231

567
191
261
465
266
441
1201
410
399
317

5.29  1095.00  109
1.10  108
6.98  109
4.39  107
1.35  107
1.66  107
4.10  108
5.28  108
5.02  108aDuPont corn herbicides.
Fifty-micrometer glass beads with polymer binder.
Source: From Ref. 56.
b59© 2005 by Taylor & Francis Group, LLC

60

Ennis

Agglomerates with process zones small in comparison to granule size break by a brittle fracture mechanism into smaller fragments, called fragmentation or fracture. On
the other hand, for agglomerates with process zones of the order of their size, there isinsufﬁcient volume of agglomerate to concentrate enough elastic energy to propagate
gross fracture during a collision. The mechanism of breakage for these materials is
one of wear, erosion, or attrition brought about by diffuse microcracking. In thelimit of very weak bonds, agglomerates may also shatter into small fragments or primary particles.
Each mechanism of breakage implies a different functional dependence of
breakage rate on material properties. Granules generally have been found to havelarge process zones, which suggests granule wear as a dominant mechanism of breakage or attrition. For the case of abrasive wear of ceramics due to surface scratchingby loaded indentors, Evans and Wilshaw (60) determined a volumetric wear rate V of
1=2

V¼

di

3=4

A1=4 Kc H 1=2

P5=4 lð4:5Þ

where di is indentor diameter, P is applied load, l is wear displacement of the indentor, and A is apparent area of contact of the indentor with the surface. Therefore,
wear rate depends inversely on fracture toughness. For the case of fragmentation,
Yuregir et al. (61) have shown that the fragmentation rate of organic and inorganic
crystals is given by
V

H 2
ru a
Kc2

ð4:6Þ

where a is crystal length, r is crystal density, and u is impact velocity. Note that hardness plays an opposite role for fragmentation than for wear, since it acts to concentratestress for fracture. Fragmentation rate is a stronger function of toughness as well.
Drawing on analogies with this work, the breakage rates by wear Bw and fragmentation Bf for the case of ﬂuid-bed granulation and drying processes should be of
the forms:
1=2

Bw ¼

Bf 

d0

3=4
Kc H 1=2

5=4

hb ðU  Umf ÞHrðU  Umf Þ2 a
Kc2

ð4:7Þ

ð4:8Þ

where d is granule diameter, d0 is primary particle diameter, (U  Umf) is ﬂuid-bed
excess gas velocity, and hb is bed height. Figure 53 illustrates the dependence of erosion rate on material properties for bars and granules undergoing a wear mechanismof breakage, as governed by Eqs. 4.5 and 4.7.

5. CONTROLLING GRANULATION PROCESSES
5.1. An Engineering Approach to Granulation Processes
Future advances in our understanding of granulation phenomena rest heavily inengineering process design. A change in granule size or voidage is akin to a change© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

61

Figure 53 Bar wear rate and ﬂuid-bed erosion rate as a function of granule material
properties. Kc is fracture toughness and H is hardness. (From Ref. 56.)

in chemical species, and so analogies exist between granulation growth kinetics andchemical kinetics and the unit operations of size enlargement and chemical reaction.
These analogies are highlighted in Figure 54, where several scales of analysis must be
considered for successful process design. Let us begin by considering a small-volume
element of material A within a mixing process as shown in Fig. 55, and consider
either the molecular or the primary particle/single-granule scale. On the granule scaleof scrutiny, the design of chemical reactors and granulation processes differs conceptually in that the former deals with chemical transformations, whereas the latter
deals primarily with physical transformations controlled by mechanical processing[Refs. 62–64]. Here, the rate processes of granulation are controlled by a setof key physicochemical interactions. These rate processes have been deﬁned in theproceeding sections, including wetting and nucleation, granule growth and consolidation, and granule attrition and breakage.
We now consider a granule volume scale of scrutiny, returning to our smallvolume element of material A of Figure 54. Within this small volume for the caseof chemical kinetics, we generally are concerned with the rate at which one or morechemical species is converted into a product. This is generally dictated by a reaction
rate constant or kinetic constant, which is in turn a local function of temperature,pressure, and the concentration of feed species, as was established from previous
physicochemical considerations. These local variables are in turn a function of overall heat, mass, and momentum transfer of the vessel controlled by mixing andheating/cooling. The chemical conversion occurring within a local volume element
may be integrated over the entire vessel to determine the chemical yield or extent
of conversion for the reactor vessel; the impact of mixing and heat transfer is generally considered in this step at the process volume scale of scrutiny. In the case of a
granulation process, an identical mechanistic approach exists for design, whereThis approach was pioneered by Hans Rumpf (62) and others in the early 1960s at the Universität Karlsruhe, leading to development of mechanical process technology within chemicalengineering in Germany, or Mechanische Verfahrenstechnik. This was key to the founding of
powder technology, an area in which the United States has traditionally lagged behind Europe
and Japan in the areas of chemical engineering and pharmaceutical processing (61–63).

© 2005 by Taylor & Francis Group, LLC

62

Ennis

Figure 54 Changes in state as applied to granulator kinetics and design.

chemical kinetics is replaced by granulation kinetics. The performance of a granulator
may be described by the extent of granulation of a species. Let (x1, x2, . . . , xn) represent a list of attributes such as average granule size, porosity, strength, and any othergeneric quality metric and associated variances. Alternatively, (x1, x2, . . . , xn) might
represent the concentrations or numbers of certain granule size or density classes, justas in the case of chemical reactors. The proper design of a chemical reactor or a granulator then relies on understanding and controlling the evolution (both time and spatial) of the feed vector X to the desired product vector Y. Inevitably, the reactor or
granulator is contained within a larger plant scale process chain, or manufacturing circuit, with overall plant performance being dictated by the interaction between individual unit operations. At the plant scale of scrutiny, understanding interactions
between unit operations can be critical to plant performance and product quality.
These interactions are far more substantial with solids processing, than with liquid–gas processing. Ignoring these interactions often leads processing personnel to misdiagnose sources of poor plant performance. Tableting is often affected by segregation orpoor mixing. Segregation becomes vital for preferential wetting and drug assay© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

63

Figure 55 Granulation within a local volume element, as a subvolume of a process
granulator volume, which controls local size distribution.

variation per size class. This is often effected by trace impurites in the production of
drug or excipients (1,2,64).
There are several important points worth noting with regard to this approach.
First, the engineering approach to the design of chemical reactors is well developed
and an integral part of traditional chemical engineering education [e.g. (65)]. At
present, only the most rudimentary elements of reaction kinetics have been applied
to granulator design (1,2,5). Much more is expected to be gleaned from this approachover the coming decade.
Examples might include staged addition of ingredients, micronization of processes, and tailored process designs based on speciﬁc formulation properties. Second,an appreciation of this engineering approach is absolutely vital to properly scale-up
granulation processes for difﬁcult formulations. Last, this perspective provides alogical framework to approach and unravel complex processing problems, which
often involve several competing phenomena. Signiﬁcant progress has been madewith this approach in crystallization (66) and grinding (67).
© 2005 by Taylor & Francis Group, LLC

64

Ennis

Many complexities arise when applying the results of the previous sections
detailing granulation mechanisms to granulation processing. The purpose of this section is to summarize approaches to control these rate processes by placing themwithin the context of actual granulation systems and granulator design. Additional
details of modeling and granulator design can be found in Chapters 16 and 21.
5.2. Scale: Granule Size and Primary Feed Particles
When considering a scale of scrutiny of the order of granules, we ask what controls
the rate processes, as presented in detail in the previous sections. This key step links
formulation on material variables to the process operating variables, and successful
granulator design hinges on this understanding. Two key local variables of thevolume element A include the local bed moisture and the local level of shear (bothshear rate and shear forces). These variables play an analogous role of species concentration and temperature in controlling kinetics in chemical reaction. In the caseof chemical reaction, increased temperature or concentration of a feed species generally increases reaction rate. For the case of granulation considered here, increases
in shear rate and moisture result in increased granule/powder collisions in the presence of binding ﬂuid, resulting in an increased frequency of successful growth eventsand increases in granule growth rate. Increases in shear forces also increase the granule consolidation rate, and aid growth for deformable formulations. In the limit ofvery high shear (e.g., due to choppers), they promote wet and dry granule breakage,or limit the growth at the least. Last, in the case of simultaneous drying, bed and gas
phase moisture and temperature control heat and mass transfer and the resulting
drying kinetics.
5.3. Scale: Granule Volume Element
Next, consider a scale of scrutiny of the level of a small bulk volume of granules, orvolume element of material A in Figure 55. This volume element has a particular
granule size distribution controlled by the local granulation rate processes as shown
pictorially in Figure 56. In the wetting and nucleation rate process, droplets interact
with ﬁne powder to form initial nuclei, either directly or through mechanical breakdown of pooled overwetted regions. It is generally useful to consider the initial powder phase and drop phases as independent feed phases to the granule phase. In
addition, the granule phase can be broken down into separate species, each species
corresponding to a particular granule mesh size cut. Nucleation therefore results
in a loss of powder and drop phases, and the birth of granules. Granules and initial
nuclei collide within this volume element with each other and with the surrounding
powder phase, resulting in both granule growth, and consolidation due to compaction forces. Granule growth by coalescence results in the discrete birth of granules toa new granule size class or species, as well as loss or death of granules from theoriginating size classes. On the other hand, granule growth by layering and granuleconsolidation result in a slow differential increase and decrease in granule size,
respectively. Granule breakage by fracture and attrition (or wear) act in a similar,
but opposite fashion to granule coalescence and layering, increasing the powder
phase and species of smaller granules. Last, this volume element of granules interacts
with the surrounding material of the bed, as granulated, powder, and drop
phases ﬂow to and from the surrounding volume elements. The rate processes of
granulation and the ﬂows or exchanges with the surrounding elements combine to© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

65

Figure 56 The population balance over a sieve class, over speciﬁc granule size class.

control the local granule size distribution and growth rate within this small-volume
element.
As illustrated in Figure 56, conducting an inventory of all granules enteringand leaving a given size class n(x) by all possible granulation mechanisms leads toa microlevel population balance over the volume element given by@na@þðna ui Þ ¼ Ga ¼ Ba  Da
@xi
@t

ð5:1Þ

where n(x,t) is the instantaneous granule size distribution, which varies with time andposition. G, B, and D are growth, birth, and death rates due to granule coalescenceand granule fracture. The second left-hand side term reﬂects contributions to the
distribution from layering and wear, as well as interchanges of granules from thesurrounding volume elements. Nucleation rate would be considered a boundary
condition of Eq. 5.1, providing a source of initial granules. Eq. 5.1 governs the local
granule growth of volume element A.
Solutions to this population balance are described in greater detail in Chapter
21, as well as (5,46,52). Analytical solutions are only possible in the simplest of cases.
Although actual processes would require speciﬁc examination, some general comments are warranted. Beginning with nucleation, in the case of fast drop penetration
into ﬁne powders, and for small spray ﬂux, new granules will be formed of the orderof the drop size distribution, and contribute to those particular size cuts or granulespecies. If spray is stopped at low moisture levels, one will obtain a bimodel distribution of nuclei size superimposed on the original feed distribution. Very little growth
may occur for these low moisture levels. This should not be confused with induction
type growth, which is a result of low overall formulation deformability. In fact, themoisture level of the nuclei themselves will be found to be high and nearly saturated.
Moisture, however, is locked up within these nuclei, surrounded by large amounts of© 2005 by Taylor & Francis Group, LLC

66

Ennis

ﬁne powder. Therefore, it is important not to confuse granule moisture, local moisture, and the overall average peak bed moisture of the process; they are very much
not the same and are inﬂuenced by proper vessel design and operation. As moisturelevels increase, and the concentration of the ungranulated powder phase decreases,
the portion of the granule phase increases. As granules begin to interact more fully
due to decreased surrounding powder and greater chances of achieved wet granuleinteraction, granule coalescence begins to occur. This in turn results in a decreasein granule number, and a rapid often exponential increase in granule size, as previously demonstrated. Coalescence generally leads to an initial widening of the granule size distribution until the granule growth limit is reached. As larger granules
begin to exceed this growth limit, they can no longer coalesce with granules of similar
size. Their growth rate drops substantially as they can only continue to grow by coalescence with ﬁne granules, or by layering with any remaining ﬁne powder. At thispoint, the granule size distribution generally narrows with time. Note that this provides a local description of growth, whereas the overall growth rate of the processdepends greatly on mixing described next, as controlled by process design.
5.4. Scale: Granulator Vessel
The local variables of moisture and shear level vary with volume element, or positionin the granulator, which leads to the kinetics of nucleation, growth, consolidation,and breakage being dependent on position in the vessel, leading to a scale of scrutinyof the vessel size. As shown in Figure 55, moisture levels, drop phase concentration,and nucleation will be high at position D. Signiﬁcant growth will occur at position B
due to increased shear forces and granule deformation, as well as increased contacting. Signiﬁcant breakage can occur at position C in the vicinity of choppers. Each ofthese positions or volume elements will have their own speciﬁc granule size distribution.
Solids mixing (2,68) impacts overall granulation in several ways. First, it
controls the local shear. Local shear rates and forces are functions of shear stresstransfer through the powder bed, which is in turn a function of mixer design andbed bulk density, granule size distribution, and frictional properties. Local shear
rates determine granule collisional velocities. This ﬁrst area is possibly one of theleast understood areas of powder processing, and requires additional research toestablish the connection between operating variables and local shear rates andforces. It is also a very important scale-up consideration, as discussed in Chapter 18.
Second, solids mixing controls the interchange of moisture, powder phase, anddroplet phases among the local volume elements. Third, it controls the interchangeof the granulated phase. Within the context of reaction kinetics (65), one generally
considers extremes of mixing between well-mixed continuous and plug ﬂow continuous, or well-mixed batch processes. The impact of mixing on reaction kinetics iswell understood, and similar implications exist for the impact of mixing on granulation
growth kinetics. In particular, well-mixed continuous processes would be expected toprovide the widest granule size distribution (deep continuous ﬂuidized beds are an
example), whereas plug ﬂow or well-mixed batch processes should result in narrower
distributions.y In addition, it is possible to narrow the distribution further byyAll else being equal, plug ﬂow continuous and batch well mixed processes should produce
identical size distributions. It is very difﬁcult to achieve uniform mixing in practice, withproperly operating ﬂuidized beds possibly coming the closest.

© 2005 by Taylor & Francis Group, LLC

Theory of Granulation67

purposely segregating the bed by granule size,z or staging the addition of ingredients,
though this is a less explored area of granulator design. Last, it should be possible topredict the effects of dispersion, backmixing, and dead/stagnant zones on granule size
distribution, based on previous work regarding chemical reaction kinetics.
Equation 5.1 reﬂects the evolution of granule size distribution for a particularvolume element. When integrating this equation over the entire vessel, one is able topredict the granule size distribution vs. time and position within the granulator. Last,
it is important to understand the complexities of scaling rate processes on a local
level to overall growth rate of the granulator. If such considerations are not made,misleading conclusions with regard to granulation behavior may be drawn. Wide distributions in moisture and shear level, as well as granule size, and how this interacts
with scale-up must be kept in mind when applying the detailed description of rate
processes discussed in the previous sections. With this phenomenological descriptionof granulation in place, we will now discuss controlling wetting, growth and consolidation, and breakage in practice, as well as the implications for two of the morecommon pharmaceutical granulation processes, namely ﬂuid-bed and high-shear
mixer granulation.
5.5. Controlling Processing in PracticeTable 6 summarizes operating variables and their impact on ﬂuid-bed and high-shear
mixer granulation. From a processing perspective, we begin with the uniformity ofthe process in terms of solids mixing. Approaching a uniform state of mixing as previously described will ensure equal moisture and shear levels and, therefore, uniform
granulation kinetics throughout the bed; on the other hand, poor mixing will lead todifferences in local kinetics. If not accounted for in design, these local differences willlead to a wider distribution in granule size distribution and properties than is necessary, and often in an unpredictable fashion—particularly with scale-up.
Increasing ﬂuid-bed excess gas velocity (U  Umf) will increase solids ﬂux anddecrease circulation time. This can potentially narrow nuclei distribution for intermediate drop penetration times. Growth rates will be minimally affected due toincreased contacting; however, the growth limit will decrease. There will be someincrease in granule consolidation, and potentially a large increase in attrition. Lastly,
initial drying kinetics will increase. Impeller speed in mixers will play a similar role inincreasing solids ﬂux. However, initial growth rates and granule consolidation arelikely to increase substantially with an increase in impeller speed. The growth limit
will decrease, partly controlled by chopper speed.
Fluidized beds can be one of the most uniform processes in terms of mixing
and temperature. Powder frictional forces are overcome as drag forces of the ﬂuidizing gas support bed weight, and gas bubbles promote rapid and intensive mixing. In
the case of mixers, impeller speed in comparison to bed mass promotes mixing, withchoppers eliminating any gross maldistribution of moisture and over growth.
With regard to bed weight, forces in ﬂuid beds, and therefore consolidation andgranule density, generally scale with bed height. As a gross rule of thumb, ideally, thepower input per unit mass should be maintained with mixer scale-up, related in partz

Pan granulation is a speciﬁc process promoting segregation by granule size. Since large granules interact less with smaller granule size classes, layering can be promoted at the expense of
coalescence, thereby narrowing the granule size distribution.

© 2005 by Taylor & Francis Group, LLC

68

Ennis

Table 6 Impact of Key Operating Variables in Pharmaceutical Granulation
Effect of changing key
process variables

Fluidized beds (including
coating and drying)

Increasing solids mixing,
solids ﬂux, and bed
agitation

Increasing excess gas velocity:
Improves bed uniformity
Increases solids ﬂux
Decreases solids circulation time
Potentially improves nucleation
No effect on noninertial growth
rate
Lowers growth limit
Some increase in granuleconsolidation
Increases granule attrition
Increases initial drying kinetics
Distributor design: Impacts
attrition and deﬂuidization

Increasing impeller/
chopper speed:
Improves bed
uniformity
Increases solids ﬂux
Decreases solids
circulation time
Potentially improves
nucleation
Increases growth rate
Lowers growth limit
Increase granuleconsolidation
Impeller/chopper
design:Improvements needed
to improve shear
transmission
for cohesive
powders

Increasing bed weight

Increasing bed height:
Increases granule consolidation,
density and strength

Increasing bed weight:
Generally lowers power
per unit mass in mostmixers, lowering
growth rate
Also increases
nonuniformity ofcohesive powders, andlowers solids ﬂux andincreases circulation
time

Increasing bed moisture(Note: Increasing bed
temperature normallyacts to lower bed
moisture due to drying)

Increases rates of nucleation,
growth, and consolidation
giving larger, denser granules
with generally a wider
distribution

Increases rates ofnucleation, growth, andconsolidation giving
larger, denser granules
with generally a wider
distribution
Granule size anddistribution generally
increase until limit
Distribution cannarrow if growth
limit is reached
Increases chances ofovermassing and bowl
buildup

Increasing residence time

Granule size and distribution
generally increase until limit
Distribution can narrow if
growth limit is reached
Increases chances ofdeﬂuidization

High-shear mixers(Continued)© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

Table 669

Impact of Key Operating Variables in Pharmaceutical Granulation (Continued )Effect of changing key
process variables
Increasing spray
distribution:
Lower liquid feed orspray rate
Lower drop size
Increase number ofnozzles
Increase air pressure(two-ﬂuid nozzles)
Increase solids mixing(above)Fluidized beds (including
coating and drying)

High-shear mixers

Largely affected

Less affectedWettable powders and shortpenetration times generally
required
For fast penetration:
Decreases growth rate

Poorly wetting powders
and longer penetration
time possible
For fast penetration:
Decreases growth rate

Decreases spread of size
distribution
Decreases granule density
and strength
For slow penetration:
Poor process choice
Deﬂuidization likely

Decreases spread of size
distribution
Decreases granuledensity and strength
For slow penetration:
Mechanical dispersionof ﬂuid
Little effect of
distribution; however,slowing rate ofaddition minimizes lag
in growth rate

Increase in growth rate
Increasing feed particle size Requires increase in excess
Increase in granulegas velocity(Can be controlled byconsolidation and
Minimal effect of growth rate
milling)density
Increase in granule consolidationand density

to swept volume per unit time, as studied by Kristensen and coworkers. However,cohesive powders can be ineffective in transmitting stress, meaning that only a portion of the bed may be activated with shear at large scale, whereas the entire bowl
may be in motion at a laboratory scale. Therefore, mixing may not be as uniform
in mixers as it is in ﬂuidized beds. Equipment design also plays a large role, including
air distributor and impeller/chopper design for ﬂuid bed and mixers, respectively.
Increasing bed moisture and residence time increase overall growth and consolidation. However, it also increases the chances of bed deﬂuidization or overmassing/bowl buildup in ﬂuid beds and mixers, respectively. Increasing bed temperature normally acts to lower bed moisture due to drying. This acts to raise effective binder viscosity and lower granule consolidation and density, as well as initial growth rates for thecase of high-shear mixers. This effect of temperature and drying generally offsets theinverse relationship between viscosity and temperature.
Spray distribution generally has a large effect in ﬂuid beds, but in many cases, asmall effect in mixers. In fact, ﬂuid-bed granulation is only practical for wettablepowders with short drop penetration time, since otherwise deﬂuidization of the
bed would be promoted to local pooling of ﬂuid. Mechanical dispersion counteracts
this in mixers. There may be beneﬁt, however, to slowing spray rates in mixers forformulation with inductive growth behavior, as this will minimize the lag between
spray and growth, as discussed previously.
© 2005 by Taylor & Francis Group, LLC

70

Ennis

In summary, for the case of ﬂuid-bed granulation, growth rate is largely controlledby spray rate and distribution and consolidation rate by bed height and peak bed moisture. For the case of mixers, growth and consolidation are controlled by impeller andchopper speed. From a formulation perspective, we now turn to each rate process.
5.6. Controlling Wetting in PracticeTable 7 summarizes typical changes in material and operating variables which
improve wetting uniformity. Also listed are appropriate routes to achieve thesechanges in a given variable through changes in either the formulation or the processing. Improved wetting uniformity generally implies a tighter granule size distribution and improved product quality. Eqs. 2.5, 2.9, and 2.13 provide basic trends ofthe impact of material variables on wetting dynamics and extent, as described by
the dimensionless spray ﬂux and drop penetration time.
Since drying occurs simultaneously with wetting, the effect of drying can substantially modify the expected impact of a given process variable and this should not
be overlooked. In addition, simultaneous drying often implies that the dynamics ofwetting are far more important than the extent.
Adhesion tension should be maximized to increase the rate and extent of bothbinder spreading and binder penetration. Maximizing adhesion tension is achievedby minimizing contact angle and maximizing surface tension of the binding solution.
These two aspects work against one another as surfactant is added to a binding ﬂuid,
and in general, there is an optimum surfactant concentration for the formulation (27).
Surfactant type inﬂuences adsorption and desorption kinetics at the three-phase contact line. Inappropriate surfactants can lead to Marangoni interfacial stresses whichslow the dynamics of wetting (25). Additional variables which inﬂuence adhesion tension include (1) impurity proﬁle and particle habit/morphology typically controlled in
the particle formation stage such as crystallization, (2) temperature of granulation,and (3) technique of grinding, which is an additional source of impurity as well.
Decreases in binder viscosity enhance the rate of both binder spreading and binder penetration. The prime control over the viscosity of the binding solution is throughbinder concentration. Therefore, liquid loading and drying conditions strongly inﬂuencebinder viscosity. For processes without simultaneous drying, binder viscosity generally
decreases with increasing temperature. For processes with simultaneous drying, however, the dominant observed effect is that lowering temperature lowers binder viscosityand enhances wetting due to decreased rates of drying and increased liquid loading.
Changes in particle size distribution affect the pore distribution of the powder.
Large pores between particles enhance the rate of binder penetration, whereas they
decrease the ﬁnal extent. In addition, the particle size distribution affects the abilityof the particles to pack within the drop as well as the ﬁnal degree of saturation (69).
The drop distribution and spray rate of binder ﬂuid have a major inﬂuence on
wetting. Generally, ﬁner drops will enhance wetting as well as the distribution of binding ﬂuid. The more important question, however, is how large may the drops be or how
high a spray rate is possible. The answer depends on the wetting propensity of the feed.
If the liquid loading for a given spray rate exceeds the ability of the ﬂuid to penetrateand spread on the powder, maldistribution in binding ﬂuid will develop in the bed. Thismaldistribution increases with increasing spray rate, increasing drop size, and decreasing spray area (due to, e.g., bringing the nozzle closer to the bed or switching to fewer
nozzles). The maldistribution will lead to large granules on the one hand and ﬁne ungranulated powder on the other. In general, the width of the granule size distribution will
© 2005 by Taylor & Francis Group, LLC

Typical changes in material or operating
variables which improve wetting uniformity

Appropriate routes to alter variablethrough formulation changes

Appropriate routes to alter variablethrough process changes

Increase adhesion tension
Maximize surface tension
Minimize contact angle

Alter surfactant concentration or type to maximize
adhesion tension and minimize Marangoni effects
Precoat powder with wettable monolayers,e.g., coatings or steam

Control impurity levels in particle formation
Alter crystal habit in particle formation
Minimize surface roughness in milling

Decrease binder viscosity

Lower binder concentration
Change binder
Decrease any diluents and polymers which act
as thickeners

Raise temperature for processes without
simultaneous drying
Lower temperature for processes withsimultaneous drying since binderconcentration will decrease due toincreased liquid loading

Increase pore size to increase rate of
ﬂuid penetration
Decrease pore size to increase extent of
ﬂuid penetration

Modify particle size distribution of feed ingredients

Alter milling, classiﬁcation, or formation
conditions of feed if appropriate to modify
particle size distribution

Improve spray distribution (Related todimensionless spray ﬂux, given by ratioof spray to solid ﬂuxes)

Improve atomization by lowering binder ﬂuid viscosity

Increase wetted area of the bed per unit mass
per unit time by increasing the number ofspray nozzles, lowering spray rate,increasing air pressure or ﬂow rate of two
ﬂuid nozzles

Increase solids mixing (Related todimensionless spray ﬂux)

Improve powder ﬂowability of feed

Increase agitation intensity (e.g., impeller
speed, ﬂuidization gas velocity, or rotation
speed)

Minimize moisture buildup and losses

Avoid formulations which exhibit adhesive characteristics
with respect to process walls

Maintain spray nozzles to avoid caking andnozzle drip; avoid spray entrainment inprocess air streams, and spraying process
walls© 2005 by Taylor & Francis Group, LLC

71

Source: Refs. 1,2,5.

Theory of Granulation

Table 7 Controlling Wetting in Granulation Processes

72

Table 8 Controlling Growth and Consolidation in Granulation Processes
Typical changes in material or operating
variables which maximize growth andconsolidation
Rate of growth (low deformability):
Increase rate of nuclei formation
Increase collision frequency

Appropriate routes to alter variablethrough formulation changes
Improve wetting properties (see Wetting subsection);
Increase binder distribution

Increase spray rate and number of drops
Increase mixer impeller or drum rotation
speed or ﬂuid-bed gas velocity
Increase batch time or lower feed rate

Decrease binder concentration or change binder; decrease
any diluents and polymers which act as thickeners

Decrease operating temperature for systems
with simultaneous drying; otherwise
increase temperature

Increase residence time
Rate of growth (high deformability):
Decrease binder viscosity

Increase agitation intensity© 2005 by Taylor & Francis Group, LLC

Increase mixer impeller or drum rotation
speed or ﬂuid-bed gas velocity

Ennis

Increase particle density
Increase rate of nuclei formation,
collision frequency and residencetime, as above for lowdeformability systems

Approprziate routes to alter variablethrough process changes

Increase binder concentration, change binder, or add
diluents and polymers as thickeners

Increase operating temperature for systems
with simultaneous drying; otherwise
decrease temperature
Decrease mixer impeller or drum rotation
speed or ﬂuid-bed gas velocity
Extent observed to increase linearly withmoisture

As above for high deformability systems
Particle size and friction strongly interact with binderviscosity to control consolidation; feed particle size
may be increased and ﬁne tail of distribution
removedAs above for high deformability systems; inaddition, increase compaction forces by
increasing bed weight, or altering mixer
impeller or ﬂuid-bed distributor plate
designSize is controlled in milling and particle
formation

Decrease agitation intensity
Decrease particle density
Increase liquid loading
Rate of consolidation:
Decrease binder viscosity
Increase agitation intensity
Increase particle density
Increase particle size

Theory of Granulation

Extent of growth:
Increase binder viscosity

Source: From Refs. 1,2,5.

73© 2005 by Taylor & Francis Group, LLC

74

Table 9 Controlling Breakage in Granulation Processes
Typical changes in material or operating
variables which minimize breakage

Appropriate routes to alter variable throughformulation changes

Appropriate routes to alter variablethrough process changes

Increase binder concentration or change binder; bondstrength strongly inﬂuenced by formulation andcompatibility of binder with primary particles

Decrease binder viscosity to increase
agglomerate consolidation by altering
process temperatures (usually decrease forsystems with simultaneous drying)
Increase bed agitation intensity (e.g.,increase impeller speed, increase bedheight) to increase agglomerateconsolidation
Increase granulation residence time toincrease agglomerate consolidation, but
minimize drying time

Increase hardness to reduce wear
Minimize binder plasticity
Minimize agglomerate voidage
Decrease hardness to reduce fragmentation
Maximize binder plasticity
Maximize agglomerate voidage

Increase binder concentration or change binder; binder
plasticity strongly inﬂuenced by binder typeSee above effects which decrease
agglomerate voidage

Change binder; binder plasticity strongly inﬂuenced bybinder type

Reverse the above effects to increase
agglomerate voidage
Apply coating to alter surface hardness© 2005 by Taylor & Francis Group, LLC

Ennis

Increase fracture toughness
Maximize overall bond strength
Minimize agglomerate voidage

Lower formulation density

Decrease contacting by lowering mixing andcollision frequency (e.g., mixer impeller
speed, ﬂuid-bed excess gas velocity, drum
rotation speed)

Decrease contact displacement to reduce
wear

Decrease impact velocity to reducefragmentation

Decrease bed agitation and compaction
forces (e.g., mixer impeller speed, ﬂuid-bed
height, bed weight, ﬂuid-bed excess gas
velocity)

Lower formulation density

Theory of Granulation

Decrease load to reduce wear

Decrease bed agitation intensity (e.g., mixer
impeller speed, ﬂuid-bed excess gas
velocity, drum rotation speed)
Also strongly inﬂuenced by distributor plate
design in ﬂuid beds, or impeller andchopper design in mixers

Source: From Refs. 1,2,5.

75© 2005 by Taylor & Francis Group, LLC

76

Ennis

increase and generally the average size will decrease. Improved spray distribution can be
aided by increases in agitation intensity (e.g., mixer impeller or chopper speed, drum
rotation rate, or ﬂuidization gas velocity) and by minimizing moisture losses due tospray entrainment, dripping nozzles, or powder caking on process walls.
5.7. Controlling Growth and Consolidation in PracticeTable 8 summarizes typical changes in material and operating variables which maximize granule growth and consolidation. Also listed are appropriate routes toachieve these changes in a given variable through changes in either the formulationor the processing. Growth and consolidation of granules are strongly inﬂuenced byrigid (especially ﬂuid beds) and deformability (especially mixers) Stokes numbers.
Increasing St increases energy with respect to dissipation during deformation of
granules. Therefore, the rate of growth for deformable systems (e.g., deformable formulation or high-shear mixing) and the rate of consolidation of granules generally
increases with increasing St. St may be increased by decreasing binder viscosity or
increasing agitation intensity. Changes in binder viscosity may be accomplished byformulation changes (e.g., the type or concentration of binder) or by operating temperature changes. In addition, simultaneous drying strongly inﬂuences the effective
binder concentration and viscosity. The maximum extent of growth increases withdecreasing St and increased liquid loading, as reﬂected by Eqs. 3.11. Increasing
particle size also increases the rate of consolidation, and this can be modiﬁed by
upstream milling or crystallization conditions.
5.8. Controlling Breakage in PracticeTable 9 summarizes typical changes in material and operating variables necessary tominimize breakage. Also listed are appropriate routes to achieve these changes in agiven variable through changes in either the formulation or the processing. Bothfracture toughness and hardness are strongly inﬂuenced by the compatibility of thebinder with the primary particles, as well as the elastic/plastic properties of the binder.
In addition, hardness and toughness increase with decreasing voidage and are inﬂuenced by previous consolidation of the granules. While the direct effect of increasinggas velocity and bed height is to increase breakage of dried granules, increases in thesevariables may also act to increase consolidation of wet granules, lower voidage, andtherefore lower the ﬁnal breakage rate. Granule structure also inﬂuences breakage rate,e.g., a layered structure is less prone to breakage than a raspberry-shaped agglomerate.
However, it may be impossible to compensate for extremely low toughness by changes
in structure. Measurements of fracture properties help deﬁne expected breakage rates
for a product and aid product development of formulations.
ACKNOWLEDGMENTS
This chapter is the result of many collaborative efforts. Support for initial granulation research was provided by the International Fine Particle ResearchInstitute, G. Tardos and R. Pfeffer of The City College of the City University of
New York, and E.I Du Pont de Nemours & Company. Based on earlier versions
with A. Maraglou of Du Pont, the material was developed into a training course
by E&G Associates, and later reﬁned in collaboration with J. Litster of the Univer© 2005 by Taylor & Francis Group, LLC

Theory of Granulation

77

sity of Queensland. All of these collaborations, as well as discussions with P. Mort,
A. Adetayo, J. Seville, S. Pratsinis, S. Iveson, K. Hapgood, J. Green, P. C. Kapur, T.
Schaefer, and H. Kristensen are acknowledged with great appreciation. Last, to thecountless course participants over the last decade goes a special thank you.
REFERENCES
1. Ennis BJ, Litster J. Size enlargement and size reduction. In: Green D, Perry R, eds.
Perry’s Chemical Engineers’ Handbook. 7th ed. New York: McGraw-Hill, 1994:
Section 21.
2. Ennis BJ, ed. Solids-solids processing. In: Green D, Perry R, eds. Perry’s Chemical Engineers’ Handbook. 8th ed. New York: McGraw Hill, 2005:Section 19.
3. Ennis BJ. On the Mechanics of Granulation. Ph.D. thesis, The City College of the City
University of New York, University Microﬁlms International, 1990.
4. Ennis BJ. Design & Optimization of Granulation Processes for Enhanced Product
Performance. Nashville, TN: E&G Associates, 1990–2004.
5. Litster J, Ennis BJ. The Science & Engineering of Granulation Processes. Dordrecht, The
Netherlands: Kluwer Academic, 2004.
6. Masters K. Spray Drying Handbook 3rd ed. New York: Wiley & Sons, 2002.
7. Masters K. Spray Drying in Practice. ApS, Denmark: SprayDryConsult International,
1979.
8. Ennis BJ, Mehos G, Wu S, Patel P. Characterizing the impact of ﬂow aids on ﬂowabilityof pharmaceutical excipients by automated shear cell. AAPS Annual Meeting.
Baltimore: MD, 2004.
9. Brown RL, Richards. Principles of Powder Mechanics. Oxford: Pergamon Press, 1970.
10. Stanley-Wood N. Enlargement and Compaction of Particulate Solids. London: Butterworth & Co. Ltd, 1983.
11. Ennis BJ. Powder Technol 1996; 88:203.
12. Turton R, Tardos G, Ennis BJ. Fluidized Bed Coating and Granulation. In: Yang WC,
Fluidization, Solids Handling & Processing, New Jersey: Noyes Publications, Westword,
1999.
13. Pietsch W. Size Enlargement by Agglomeration. Chichester: John Wiley & Sons Ltd.,1992.
14. Sastry K, Fuerstenau D. In: Sastry, ed. Agglomeration ’77. New York: AIME, 1977:381.
15. Kapur PC. Adv Chem Eng 1978; 10:55.
16. Kapur PC. Chem Eng Sci 1971; 26:1093.
17. Kapur PC, Fuerstenau DW. Ind Eng Chem Eng (Proc Des Dec) 1966; 5:5.
18. Kapur PC. Chem Eng Sci 1971; 26:1863.
19. Kapur PC. Chem Eng Sci 1971; 26:1093.
20. Rumpf H. The strength of granules and agglomerates. In: Knepper WA, ed. Agglomeration. New York: Interscience, 1962: 379–414.
21. Rumpf H. Particle adhesion. In: Sastry KVS, ed. Agglomeration ‘77, New York: AIME,
1997: 97–129.
22. Augsburger L, Vuppala M. Chap. 2, In: Parikh D, Handbook of Pharmaceutical Granulation Technology. 1st ed., New York: Marcel-Dekker, 1999.
23. Parﬁtt G, ed. Dispersion of Powders in Liquids. Amsterdam: Elsevier Applied Science
Publishers Ltd., 1986.
24. Hapgood K. Nucleation and Binder Dispersion in Wet Granulation, Ph.D. Thesis,
University of Queensland, 2000.
25. Pan R, Green J, Ennis BJ, Maderelli C. Dynamic Properties of Interfaces & Association
Structure. New York: American Oil Chemical Society Press, 1995.
26. Zisman WA. Contact angle, wettability, and adhesion. Adv Chem Ser 1964; 43:1.
27. Ayala R. Ph.D. Thesis, Chem. Eng., Carnegie Mellon University, 1985.
© 2005 by Taylor & Francis Group, LLC

78

Ennis

28. Shaw R. Introduction to Colloid and Surface Chemistry. London: Butterworths & Co.
Ltd, 1983.
29. Fuerstaneau DW, Diao J, Williams MC. Coll Surf 1991; 60:127.
30. Vargha-Butler EI. In: Botsaris GD, Glazman YM, eds. Interfacial Phenomena in Coal
Technology. Chap. 2. New York: Marcel-Dekker, 1989.
31. Aulton ME, Banks M. Proceedings of Powder Technology in Pharmacy Conference:
Powder Advisory Centre, Basel, Switzerland, 1979.
32. Aulton ME et al. J Pharm Pharmacol 1977; 29:59.
33. Litster JD, Hapgood KP, Kamineni SK, Hsu T, Sims A, Roberts M, Michaels J. Powder
Technol 2001; 124:272.
34. Ouchiyama N, Tanaka T. I and EC. Proc Des Dev 1982; 21:29.
35. Johnson KL. Contact Mechanics. Cambridge University Press, 1985.
36. Ritala M, Holm P, Schaefer T, Kristensen HG. Drug Dev Ind Pharm 1988; 14(8):1041.
37. Holm P, Schaefer T, Kristensen HG. Powder Technol 1985; 43:213.
38. Adams M, Thornton C, Lian G. Agglomeration & size enlargement. In: Ennis BJ, ed.
Proceedings of the First International Particle Technology Forum. Vol. 1. Denver,
CO: AIChE, 1994:155–286.
39. Ennis BJ, Li J, Tardos G, Pfeffer R. Chem Eng Sci 1990; 45(10):3071.
40. Mazzone D, Tardos G, Pfeffer R. J Coll Interface Sci 1986; 113:544.
41. Iveson SM, Breathe JA, Page NW. Powder Technol 2002; 127:149.
42. Holm P, Schaefer T, Kristensen HG. Part V and VI. Powder Techol 1985; 43:213–233.
43. Ennis B, Tardos G, Pfeffer R. Powder Technol 1991; 65:257.
44. Liu LX, Litster JD, Iveson SM, Ennis BJ. AIChE J 2000; 46(3):529.
45. Bird RB, Armstrong R, Hassager O. Dynamics of Polymeric Liquids. Vol. 1. New York:John Wiley & Sons, Inc., 1977.
46. Adetayo AA, Lister JD, Pratsinis SE, Ennis BJ. Powder Technol 1995; 82:37.
47. Schaefer T, Holm P, Kristensen HG. Drug Dev Ind Pharm 1990; 16(8):1249.
48. Schaefer T, Holm P, Kristensen HG. Pharm Ind 1990; 52(9):1147.
49. Tardos G, Khan MI. AIChE Annual Meeting, Miami, 1995.
50. Tardos GI, Khan MI, Mort PR. Powder Technol 1997; 94:245.
51. Iveson SM, Wauters PAL, Forrest S, Litster JD, Meester GMH, Scarlett B, Ennis B.
Powder Technol 2001; 117:83.
52. Adetayo AA, Ennis B. AIChE J 1997; 43(4):927.
53. Iveson SM, Litster JD, Ennis BJ. Powder Techol 1996; 88:15.
54. Lawn B. Fracture of Brittle Solids. 2nd ed. Cambridge University Press, 1975.
55. Benbow JJ, Bridgwater J. Powder Technol 1987; 49:97.
56. Ennis BJ, Sunshine G. Tribology International 1993; 26:319.
57. Irwin J Appl Mech 1957; 24:361.
58. Grifﬁth AA. Philos Trans T Soc 1920; A221:163.
59. Johnsson L, Ennis BJ. In: Ennis BJ, ed. Proceedings of the First International Particle
Technology Forum. Vol. 2. Denver, CO: AIChE, 1994:178.
60. Evans AG, Wilshaw TR. Acta Metall 1976; 24:939.
61. Yuregir KR, Ghadiri M, Clift R. Chem Eng Sci 1987; 42:843.
62. Rumpf H. Translated FA Bulletin. Particle Technology. New York: Chapman & Hall, 1990.
63. Ennis BJ, Green J, Davies R. The US Legacy of Neglect. Chem Eng Prog 1994; 90(4):32.
64. Ennis BJ, Green J. Visualizing Pharmaceutical Manufacturing as an Integrated Series ofParticle Processes. New York: Interphex, 1995.
65. Levenspiel O. Chemical Reaction Engineering. 2nd ed. New York: Wiley, 1972.
66. Randolph AD, Larson MA. Theory of Particulate Processes. 2nd ed. San Diego: Academic Press Inc., 1991.
67. Prasher CL. Crushing and Grinding Process Handbook. New York: Wiley, 1987.
68. Weinekötter R, Gericke H. Mixing of Solids. Dordrecht, The Netherlands: Kluwer
Academic, 2000.
69. Waldie B. Chem Eng Sci 1991; 46:2781.
© 2005 by Taylor & Francis Group, LLC

3
Drug Substance and Excipient
Characterization
L. W. Chan and P. W. S. Heng
National University of Singapore, Singapore

1. INTRODUCTION
Characterization of drug substances and excipients is a very important step at the
preformulation phase of product development. Although testing will involve additional time and cost, failure to carry out the appropriate characterization tests canbe even more costly to manufacturers if the product made is not within speciﬁcations. Preformulation characterization of raw materials creates a body of information which is very useful in the development of products. The lack of suchinformation leaves the formulator with little leeway for remediation action whena problem arises from the production process or from the quality of the ﬁnishedproduct. It is important to eliminate the possible inﬂuences of the raw material characteristics before venturing into investigation of processing variables. The knowledge
derived from the characterization of raw materials can also serve to enable better
speciﬁcations to be drawn up for procuring materials with the aim of either reducing
cost or improving product quality. In addition, a review of material characterization
results can provide an excellent database for the assessment of suppliers who canprovide materials of consistent quality.
Materials from reputable companies may be supplied with detailed speciﬁcations and their methods of determination may be obtained, if requested. The
information on speciﬁcations such as purity or content is very often available.
Nevertheless, it is prudent to conﬁrm such information. The information provided
by different suppliers may vary. The type of tests carried out or the techniques used
for the characterization of a particular physical property, for example, the particle
size distribution, may be different. Comparison of materials from different suppliers
can therefore be difﬁcult. Sometimes, the analytical result supplied by the manufacturer is given as falling within a certain range and this gives virtually no information
about batch to batch variation of the material.
It is therefore important to have a system of in-house characterization of raw
materials alongside the stability and functional tests for the ﬁnished product. Whenever possible, tests carried out should yield quantitative results rather than a pass/
fail or present/absent assessment. Retrospective studies of the ﬁnished product test
79
© 2005 by Taylor & Francis Group, LLC

80

Chan and Heng

results together with well-documented production process validation and characterization tests of raw materials can provide directions for reﬁnement of the production
process and improve the speciﬁcations for raw materials.
The method of material characterization varies considerably as it depends on
the nature and form of material used as well as the process involved in the conversion of the raw materials to the ﬁnished products. The desirable characterization testfor each material depends on the material itself and the likely use or inﬂuence ofa particular material property on the process or product. For instance, detailed
information of the particle size distribution of a drug material may be less importantwhen the end product is a solution, more important when the material is to be granulated and very critical when preparing an inhalant. As unnecessary testing can betranslated into additional cost, careful consideration of the type and number of tests
to be carried out on the raw materials should be weighed against the usefulness oftests to give information on the identity and quality of raw materials, their effects
during processing and manufacturing and the functionality and esthetics of the
ﬁnished products.
The task of building up a body of information on materials is indeed difﬁcult
given the wide spectrum of drugs and excipients used in pharmaceutical granulation.
Many compendial tests are concerned with the chemical aspects of testing and rarely
address the physical characterization of excipient materials. The physical aspects of
raw materials are more likely than their chemical properties to exert a greaterinﬂuence on the granulation process as well as the quality and functionality of the
ﬁnished products. The ability to deﬁne excipients using the correct functionality tests
would undoubtedly beneﬁt the formulator greatly as better-deﬁned excipients could
help to eliminate many processing problems. It is obvious that some material
characterization tests such as determination of identity and purity are importantbut discussion on them is not included as they are better dealt separately.

2. PARTICLE SHAPE, SIZE, AND SURFACE AREA
2.1. Particle ShapeParticle shape is an important parameter which can have a signiﬁcant effect on thebulk properties of a powder. It is well known that spherical particles ﬂow better,
pack better, and have a lower surface to volume ratio. Despite the well-recognized
importance of particle shape, the method of shape determination has not beenclearly deﬁned owing to the complexity and variability of the three-dimensional
particles. In general, shape measurement methods are only able to deﬁne accurately
the shape if the shape of constituent particles can be correctly predicted based on a
two-dimensional model.
Shape of particles may be assessed descriptively by terms such as spherical,
elongated, acicular, angular, or a host of other terms. Although these are descriptive
terms, if accurately used, they can convey a general idea of the particle shape. However, they reveal little about the degree to which the particles take upon a particularshape. Without a comparable quantitative measure, it may be difﬁcult to assess theeffects of particle shape on a process or product.
From the linear dimensional description of breadth, length, and height, someshape data can be derived. Breadth is usually deﬁned as the minimum distance
between two parallel lines bracketing the particle while length is the maximum
distance between two parallel lines enclosing the particle and is perpendicular to© 2005 by Taylor & Francis Group, LLC

Drug Substance and Excipient Characterization

81

Figure 1 Image analysis system.

the breadth. The height is the thickness of the particle resting in its most stableorientation. The measurement of height is generally difﬁcult for small particles as
they are usually viewed through a microscope.
Direct microscopic measurement of particle dimensions is very tedious. The
particle dimension is obtained using a linear eyepiece graticule. A camera lucida
attachment may be used to trace out the outline of particles onto a paper. The perimeter of particle tracing may be obtained by using either a string or a planimeter.
Projected area can be obtained by using paper with grids or by cutting out tracingof particle and weighing. By determining the area per unit weight of the paper,
weight of tracing may be converted into an area measurement. The popularity ofthis laborious manual mode of dimensional measurement has declined signiﬁcantlywith the introduction of image analyzers. When a video camera is attached to a
microscope, the image obtained on a high-resolution monitor may be digitized
and analyzed using a computer as shown in Figure 1. Information on the breadth,length, perimeter, and area of particles can be determined very rapidly. The degreeof accuracy of such measurements depends on the clarity of image available andthe separation of particles from one another.
There are a large number of transformation models which can be used toanalyze the image dimensional parameters in the determination of particle shape.
Some methods require additional information of particle surface area, volume or
thickness to give better estimates of shape but for most purposes, a simple approach
is often preferred. The common treatment of data, namely, breadth, length, perimeter, and area to reﬂect the particle shape (1,2) is given as follows:

Aspect or elongation ratio ¼© 2005 by Taylor & Francis Group, LLC

LengthBreadth

ð2:1Þ

82

Chan and Heng

Bulkiness factor ¼

Formfactor ¼

AreaðLength þ BreadthÞ

4pðAreaÞ
ðPerimeterÞ2

ð2:2Þ

ð2:3Þ

The elongation ratio is very useful for assessing deviation from a sphericalshape to an elongated form. The formfactor, on the hand, gives a measure ofsphericity and a perfect sphere has a formfactor value of unity. The bulkiness factor
gives an indication of solidity and large indentations on the particles give rise to low
values (3).
For many users of image analyzers, a wider array of mathematical models
is usually available on the software. The problem that confronts many users is
not the mathematical treatment of image analysis data but rather the selection of an
appropriate transformation model. Procedures for Fourier shape analysis and fractal measurement (4–7) are also available to allow further treatment of image analysis
data. Indirect methods using two or more measurement techniques like sedimentation and sieving have also been used for particle shape determination (8). Vendors for image analysis systems include Data Translations, Malboro, MA; Edax,
Mahwah, NJ; and Synoptics, Cambridge, U.K.
2.2. Particle Size
There is much literature on the measurement of particle size and size distribution.
With the abundance of information on particle sizing and sizing methods, a lessexperienced operator can ﬁnd it daunting as to which method is the best. Uponcompletion of a measurement, the task of data interpretation and validation of
the accuracy and reliability of measurement can be difﬁcult. Often, standards areused for comparison and the information obtained from these standards are used
for calibration of the size measuring system. Standards used are very often ideal
particles with a high degree of sphericity and a narrow size distribution. The real
samples for size analysis are often not spherical and can have a considerably wide
size distribution. It is therefore important to regard all results with some suspicion
and in a comparative perspective, which depends on the standard calibrator used
and the method of measurement. Proper and stringent development of the method
for size measurement should be carried out to ensure reliability, reproducibility,
and sensitivity of measurement method.
The present discussion on the particle sizing methods does not attempt toestablish yet another theory and practice guide on particle sizing but to review the
popular methods of particle sizing, their problems and usefulness in providing
information valuable to a formulator. Little attempt will be made to explain the theories of various sizing methods as they are dealt with in many other comprehensive
publications on this subject (8–10).
2.2.1. Microscopy
Microscopy is a very old technique capable of sizing ﬁne powders accurately. It is
nowadays regarded as an unpopular method to use due mainly to the tedium in measurement and the availability of more sophisticated and easy-to-use particle sizers.
© 2005 by Taylor & Francis Group, LLC

Drug Substance and Excipient Characterization

83

Nevertheless, microscopy still presents as the most direct method of particle size
analysis. However, as a particle sizer, a minimum of at least 625 particles must be
measured for computation of reasonable size statistics (11). In a particle sizing
laboratory, the value of the microscope is usually not as a primary equipment forparticle sizing but rather for the preliminary examination of the size distributionof a powder sample prior to the use of a less direct particle size analyzer. The estimation of particle size characteristics obtainable from the microscope would certainly
provide a rough guide for the setting of an automated particle sizer to the correct
sizing range or checking if the size analysis data obtained are within an expected
range.
Unlike other particle sizers, the microscope gives the operator a clear visual
outline of each individual particle being measured. In addition, the material may
be presented in its normal form, dry or in a liquid medium. Particles that are aggregated can be identiﬁed and will not be measured as a single entity. Problems associated with microscopic sizing lie not only in the tedious nature of the technique
but also in the slide sample preparation, optical resolution, and operator bias.
Sample preparation for microscopy must ensure a representative distributionof particles on the slide to be used for sizing. When powder material is to be madeas a suspension, there should be neither loss of smaller particles through dissolution
nor loss of large particles due to sedimentation prior to transferring onto a slide. It isbest to wet a sample on the slide itself. Presentation of the area of slide specimen forsizing must be carried out in a systematic and orderly manner by moving the slide toview different areas of the sample. There is an intrinsic orientation problem as particles when presented always ﬁnd their most stable orientation. Microscopy involves
measuring a particle from only the top view and measurement is two dimensional.
Thus, ﬂakes or discoids will tend to be oversized. Decision on the dimension(s) tomeasure needs to be made should a linear eyepiece graticule be used. An area graticule may also be employed for projected area determination. Orientation problems
may be overcome by dispersing powders onto adhesive before viewing or setting particles in plastic or wax, which is then sectioned for viewing. These techniques willdeﬁnitely make an already tedious technique even more so.
Clarity is always a problem as sizes of particles approach the lower limits oflight microscope optics, which is about 1 mm. The quality of lenses may also playa part. There is often a tendency to oversize slightly due to fringe effects aroundparticles. Various microscope accessories and lighting techniques can improve theviewed image resolution to a varying extent. In some cases, the use of dyes can help
improve the contrast between particle and background.
An operator with good technique is necessary in order to obtain reliable resultswith minimal systematic errors. Operator technique can inﬂuence accuracy of microscopic determination of particle size. There is a natural tendency for an operator
to pay greater attention to large particles as he is less likely to miss them. Not only
do small particles tend to be missed, they also pose problems by being hidden by
the larger particles or appearing as clumps. However, in volumetric terms, small
particles have a lesser inﬂuence.
Automation of the microscopy technique began with an image shearing
technique (12) and progressed to image projection and measurement and, ﬁnally,
computer image digitization and image analysis (13). The preceding discussion on
particle shape has covered the use of image analysis. Information for particle sizeand size distribution is easily obtained from the set of data for deriving shape factorof the particles. An extension of light microscopy is scanning electron microscopy.
© 2005 by Taylor & Francis Group, LLC

84

Chan and Heng

Measurements may be made directly from the video image or via photomicrographs.
Attached image analysis systems may also be utilized for sizing. There have also been
improved methods to incorporate image processing systems to microscopic methods. By taking images at varying focal distances, a composite image with highly
sharpened edges can be digitally produced.
2.2.2. Sedimentation
Sedimentation technique for particle sizing and classiﬁcation has been in use fora long time. In recent years, however, the success of light scattering particle sizers
has effectively eroded away the market for sedimentation-based particle sizers.
Sedimentation technique for sizing is based on the settling of particles under gravity
described by Stokes’ law. For a particle of diameter, d, and density, r1, under theforce of gravity, g, in a ﬂuid of viscosity, Z, and density, r2, at its terminal velocity,n, the accelerating force due to gravity is balanced by the viscous drag andd 2 gðr1  r2 Þ
ð2:4Þ
18Z
The Andreasen pipette introduced in the 1920s is perhaps the most popularmanual apparatus for sampling from a sedimenting suspension. Determination of
the change in density of the sampled particle suspension with time enables the calculation of size distribution of the particles. As Stokes’ law applies only to sphericalparticles, the nonspherical particles give a mean diameter referred to as Stokes’
equivalent diameter. The size range measurable by this method is from 2 to
60 mm (8). The upper limit depends on the viscosity of liquid used while the lower
limit is due to the failure of very small particles to settle as these particles are kept
suspended by Brownian motion.
An improvement of the Andreasen pipette method is to use a pan attached to asensitive balance which records the changes in weight of the pan as an increasing
amount of suspending particles settle on it. Later, sedimentation techniques using
light extinction by changes in turbidity of the suspension and x-ray were introduced
for more sensitive and rapid measurements.
The introduction of centrifugal sedimentation makes the technique capable ofdetermining the distribution of particles below 5 mm. The lower limit depends on thecentrifugal velocity. The time of analysis is reduced drastically and multiple samples
in cells can be analyzed simultaneously.
n¼

2.2.3. Sieving
Sieving is probably the oldest method of sizing, used initially for particle classiﬁcation
rather thanpsize
ﬃﬃﬃ analysis. The introduction of high-quality standardized woven-wiresieves in a 2 progression, starting from 75 mm has helped to establish sieving as awidely used particle sizing method, especially for the larger particles. Conceptually,
particle sizing by sieving is easily understood as the different meshes classify the particles to different weight-based size fractions giving rise to the frequency distribution.
The process of sieving involves a nest of sieves, usually ﬁve to eight, arranged
from the largest apertures to the ﬁnest followed by a receiving pan. The sieves with a
lid and receiving pan are then placed on a sieve shaker, which may gyrate, oscillate,or vibrate the sieves. Most commonly used shakers are vibrators. It is important todetermine the time required for completion of sieving. This is commonly taken as thetime when there is no further change in the weight of material retained on each sieve© 2005 by Taylor & Francis Group, LLC

Drug Substance and Excipient Characterization

85

after additional sieving time is given. The load for sieve analysis should be sufﬁcientin order that the amount present after sieving on each mesh can be accurately
weighed.
In size analysis using sieves, it must be borne in mind that the aperture size of agiven sieve is not an absolute cutoff value for the size of particles permitted to passthrough. The permitted aperture tolerance is much wider and following the maximum tolerance allowed by the British Standard 410 (1976), particles from 55 to
95 mm may go through or be arrested by a 75 mm aperture size sieve. Particles tend
to pass through based on their narrower cross-sectional area. An elongated particle,
such as a rod-shaped particle, will pass through an aperture just larger than its minimum cross-sectional proﬁle. Woven sieves can be made down to about 30 mm. Finersieves of much higher precision from 100 mm down to a few micrometers can be madeusing etching methods and these sieves are often referred to as electroformed micromesh sieves. Sieves with bases that have accurately drilled or punched circular holes
instead of woven mesh are available for sizing larger particles, generally about
500 mm and larger.
Size analysis by sieving is a relatively slow process and there may be problems
with dust pollution. For many drugs, the safety of the operator needs to be considered. In addition, wire mesh stretches with repeated use. Apertures may be blanked
by improper or inadequate washing. For ﬁne powders, aggregation of powders due
to cohesive or electrostatic charges can give inaccurate results. Inadequate sieving
time will also produce unreliable data. It is also important to ensure that the sieving
process itself does not bring about size reduction.
As sieving ﬁne powder in a dry state may be a problem due to the cohesive nature of such a powder and a long sieving time is required, wet sieving by suspending
the powder in a suitable liquid can improve sieving efﬁciency. However, the procedure becomes more tedious. It now requires the additional drying of size fractions.
It is recommended that sieving starts with the ﬁnest mesh to remove the ﬁnes witha volume of liquid, followed by classifying the powder retained with the largest to
the smallest mesh.
Air-jet sieving is a much more popular method for sizing ﬁne powders below
75 mm than wet sieving. It involves the use of a vacuum pump to remove air fromthe underside of a sieve. Air current is also supplied from the underside of the sieve
through a rotating arm of jets, which helps to unclog the mesh. A collecting cyclone
may be attached in the vacuum line to collect the ﬁnes. In-line ﬁlters may also be used
to collect the ﬁnes. Air-jet sieving is usually used as a one-mesh sieving. For information of size distribution, composite size distribution may be obtained from separate
air-jet sieving operations using different meshes for samples of the same powder.
A common point of discontent with size analysis using sieves is that the process
requires quite a bit of preparatory work, weighing, and subsequent washing. Yet,a typical analysis would yield only seven to eight points on the size distribution
and this may not be sufﬁciently discriminating. Nevertheless, sieving is a straightforward and robust technique suitable for a wide variety of ﬁne to very coarse powders.
Material properties such as density, optical property, water solubility, or conductivity
are not required for computation of the particle size.
2.2.4. Electrical Sensing
The electrical sensing zone principle, which is more commonly known as the Coulter
principle, is based on a simple electrical property that the electrical resistance© 2005 by Taylor & Francis Group, LLC

86

Chan and Heng

Figure 2 The Coulter principle.

between two compartments containing an electrolyte and connected by an apertureis proportional to the electrical conducting area of the aperture. Figure 2 illustrates
the basic Coulter principle. By drawing electrolyte from one compartment to theother, particles streaming through will decrease the conducting area of the aperture.
By fast time-based tracing of the resistance, resistance pulses coinciding with the passage of particles through the aperture will be obtained. The amplitude of the pulse is
proportional to the volume of the particle. With a pulse analyzer, the Coulter counter can analyze a large number of particles within a short time.
Particle size range detectable depends on the aperture tube used. Each aperturetube is effective over a size range of about 2–40% of its nominal diameter. Aperturesof sizes from 15 to 4000 mm are available. Before use, it is necessary to calibrate theequipment with a standard latex containing monosize spherical particles of mean size
within 5–20% of the aperture diameter.
When working with small apertures, aperture blockage may be a problem.
With large apertures for sizing large particles, settling of the large particles may giverise to sizing errors. It is important that the material for sizing is nonconductive andnonporous. For porous particles, sizing values obtained may be much smaller thanthose derived by visual inspection. Prior to addition of the powder for sizing, it isnecessary to ensure a low background count. When dispersed in the electrolyte,
the powder particles must not be ﬂocculated and do not dissolve in the electrolyte
solution. Care must be taken to ensure proper dispersion of powder. The concentration of particles must be within the range acceptable. Higher concentration will resultin higher errors due to coincidence while low concentration will necessitate a longer
counting time.
2.2.5. Light Scattering
There has been a tremendous growth in the application of light scattering techniquefor particle sizing in recent years and light scattering particle sizers have taken a© 2005 by Taylor & Francis Group, LLC

Drug Substance and Excipient Characterization

87

lion share of the market for particle sizers. The large number of manufacturers of
instruments using light scattering technique has also a hand in convincing manylaboratories of their need for such a sizer. It is however unfair to ascribe the recent
popularity of light scattering sizing to just its marketing. Light scattering particle
sizers for both wet and dry samples are indeed much easier to use and are highly
efﬁcient. The measurement time is short and the method is able to produce detailed
and reproducible particle size information.
Without dwelling on the theories of light scattering, particle sizers using thisprinciple can be roughly divided into three groups, two for determining particle size
down to about 1 mm using light obscuration and laser diffraction and the third, forsubmicron particle size using photon correlation spectroscopy. A schematic diagramof the various techniques of light scattering is shown in Figure 3.
Light obscuration or blockage technique involves measuring particles singly.
The passage of a particle across the light beam produces a reduction in the amountof transmitted light which is detected by a sensor directly opposite the incident light.
The pulses are then classiﬁed, giving the frequency distribution. The degree of lightdiffraction, opacity, and orientation of the particle as it passes the light beam canaffect the extent of light blockage and may affect measurement accuracy.
As a small particle passes through a beam of light in a laser diffraction sizer, it
will scatter light, which will be directed onto a diode array detector directly opposite
the incident light. The detector has a series of photodiodes arranged outward froma central photodiode detector. Since the intensity of the light scattered decreases as
the scatter angle increases, photodiode elements are generally larger as they arefurther from the center. Calculations for particle size and size distribution involve
rather complex mathematics. Simply put, sizing of a particle is based on the angleof diffracted light, with small particles diffracting at wider angles than larger
particles. Thus, from the light scattering pattern, information on the size distributionof the particles can be obtained through a series of complex calculations.
Sample presentation for light obscuration sizer involves the dispersion of theparticles in a liquid medium like in the case of the electrical sensing sizer. The maindifference is that light obscuration sizer may operate in the absence of an electrolyte.

Figure 3 Schematic diagram for light-scattering particle sizing.
© 2005 by Taylor & Francis Group, LLC

88Chan and Heng

For laser diffraction, sizing may be carried out on both particles dispersed in liquid
as well as dry powders using dry powder feeders. Laser diffraction is also very usefulfor sizing aerosol particles and sprays. Increasingly, there has been an attempt to use
information from diffraction to elucidate shape parameters.
The possibility of measuring the particle size and size distribution of powders
in their dry state with an acceptable level of accuracy and in a very short timespanhas attracted many laboratories. For many users, the laser diffraction sizer is an efﬁcient equipment for producing detailed and accurate size distribution information of
the powder particles. However, the sizing of some powders using a dry powder feeder
with the laser diffraction sizer can be fraught with problems. Possible causes of nonreproducible results are the poor control of ambient humidity, cohesive nature of thepowder, powder particles that fragmentate easily, large size span of the particles,
variable rate of introduction of particles during measurement period, possible segregation of powders during introduction, and stray powder particles depositing on thelens. The sizing of a powder composed of very large and very small particles can beproblematic as a portion of the small particles will adhere onto their larger counterparts. The complete dislodging of the smaller particles can be an extremely difﬁculttask and with different feed rates of particles for sizing, different results may beobtained. In addition, humidity of the atomizing air can also affect sizing results.
2.2.6. Photon Correlation Spectroscopy
The measurement of submicrometer particles had been difﬁcult until the introduction of photon correlation spectroscopy for particle sizing. This technique enables
particles from a few nanometers to a few micrometers to be measured. The measurement principle involves the determination of ﬂuctuations in the scattered light intensity at an angle (Fig. 3). These ﬂuctuations are the result of Brownian motion ofsuspended particles in the liquid. Large particles will diffuse more slowly than smaller ones and therefore, the rate of decay in intensity of scattered light at a particularmeasuring point will depend on the size of the particle. The particle size distribution
is computed using complex calculations and approximations from the intensities ofscattered light (normally at 90 to the incident beam) and their rate of decay. Multiple angle measurements are sometimes applied to improve the quality of the size
parameters obtainable.
Although the photon correlation sizer represents a very interesting instrument
for the sizing technologist, powders for granulation do not generally fall into thesubmicrometer range. The few possible uses of this instrument are in the evaluationof polymeric materials employed for binding and coating. Suppliers for both laser
diffraction and scattering particle sizers include Beckman Coulter, Fullerton, CA,
USA; Hach Ultra Analytics, Grant Pass, OR, USA; Malvern Instruments, Worcs,
U.K.; and Horiba, Kyoto, Japan.
2.3. Particle Surface Area
Surface area measurement is usually carried out by either gas permeability or
adsorption. The technique of gas permeability depends on measuring the resistanceto gas ﬂow through a packed bed of particles. It is important that packing of the bed
is uniform and from the volumetric ﬂow rate of the gas through and pressure drop
across the bed, the speciﬁc surface area of the powder can be calculated. The measurement of speciﬁc surface area by gas permeability does not take into account© 2005 by Taylor & Francis Group, LLC

Drug Substance and Excipient Characterization89

the very small pores or ﬁssures since the ﬂow of gas is not hindered as it passes overthem. More accurate measurements can be made by measuring gas ﬂow under
reduced pressure but still, the accuracy cannot match that obtainable by gas adsorption if the total area to be determined includes those of the ﬁne pores. Although gas
permeability gives a lower speciﬁc area for a powder compared with gas adsorption,
the value obtained is sometimes more useful in explaining factors like lubricity andﬂow, which would not involve the micropores present in the particles.
Gas adsorption is carried out by placing a powder sample in a chamber andevacuating the air within. The latter process is commonly referred to as degassing.
Upon achieving a very high vacuum, known volumes of an adsorbing gas are introduced. From the knowledge of pressures and temperatures before and after introduction of the adsorbing gas, usually nitrogen, calculations of total sample surface area
can be made. The surface area determination by gas adsorption is based on a simple
principle. From Avogadro’s number, a known volume of air at a certain temperatureand pressure contains a determinable number of molecules. When varying volumesof gas are introduced to a degassed sample, the small pressure changes in the chamber are recorded and using a calculation technique known as the BET method, theinitial amount of gas molecules which are adsorbed onto the surface forminga monolayer can be calculated. Thus, the surface area covered by the gas molecules
can be determined by multiplying the number of molecules needed with the surface
area occupied per molecule. Samples are usually cooled to a low temperature using
liquid nitrogen. There are variations in the technique for gas adsorption by different
instrument manufacturers (14).
In addition to determining the speciﬁc surface area, pores below 50 nm
may also be characterized by gas adsorption. Distribution of larger pores, 0.003–
0.004 mm, can be determined by mercury intrusion porosimetry technique, wherethe volume of mercury intruded under pressure represents the volume of pores whose
entrant diameter can be calculated from the applied pressure (15). The main suppliers of equipment for surface and porosimetry include Quantachrome, Boynton, FL,
USA, and Micromeritics, Norcross, GA, USA.

3. SOLUBILITY
The solubilities of drugs and excipients are an important physicochemical property
as they affect the bioavailability of the drug, the rate of drug release into the dissolution medium, and consequently, the therapeutic efﬁcacy of the pharmaceutical product. It must be borne in mind that a drug must ﬁrst be in solution in order to beabsorbed into the blood circulation. If the solubility of the drug is less than desirable,
steps must be taken to improve its solubility or to use another more soluble drug
form. Excipients which are poorly soluble in water might retard the release of drug
into the dissolution medium. Hence, the determination of drug and excipient solubilities constitutes an important aspect of formulation study.
The solubility of a material is usually determined by the equilibrium solubility
method, which employs a saturated solution of the material. The saturated solution
is obtained by stirring an excess of the material in the solvent for a prolonged periodof time at a constant temperature until equilibrium is attained. As a guide, stirring
the mixture overnight is usually adequate for achieving equilibrium. The saturated
solution can also be obtained by warming the solvent with an excess of the material
and allowing the mixture to cool to the required temperature. This, however, may© 2005 by Taylor & Francis Group, LLC

90

Chan and Heng

produce a supersaturated solution for some materials and therefore, heating should
be applied with caution. A portion of the saturated solution obtained by either
method is then removed with the aid of a syringe through a membrane ﬁlter at different time intervals. The determination is completed only if at least two successive
samples have the same results, indicating that equilibrium is attained. The ﬁnal value
thus obtained is the solubility of the material. The material present in the sample ofsaturated solution may be assayed by a variety of methods such as UV spectrophotometry, electrical conductivity measurement, gravimetric or volumetric analysis,
and chromatographic methods.
The following precautions should be observed in order to obtain accurate andreproducible solubility values: The material and solvent must be pure
 The temperature must be properly controlled It is essential that some undissolved material is present in the solution toensure that the solution obtained is saturated
 The saturated solution used for assay must be free from undissolved
material The method of assay must be reliable
A good understanding of the factors affecting solubilities of materials is pertinent in explaining the changes in solubility under different conditions. These factors
can therefore be employed to improve the solubility and bioavailability of various
drugs.

3.1. Nature of Solvent
Some materials dissolve very readily in a solvent while others dissolve sparingly. The
solubility of the material in a given solvent depends on the ability of the solvent toovercome the forces that bind the atoms or molecules of the material. Studies haveshown a deﬁnite correlation between the solubility and the molecular structures ofthe material and solvent. It is noted that the greater the similarity in molecular structure, the higher would be the solubility of the material in the solvent. As a rule, polarmaterials dissolve readily in polar solvents and nonpolar materials in nonpolar
solvents. Materials with both polar and nonpolar groups in their molecules may
dissolve in polar solvents but their solubilities tend to decrease as the proportionof nonpolar groups in the molecule increases.
A large number of materials have poor solubilities in water and often posea problem in the formulation of pharmaceutical products. Addition of anothersolvent, in which these materials are more readily soluble, will increase the concentration of the materials in the solution. This additional solvent is known as acosolvent and common examples include glycerin, sorbitol, propylene glycol, andpolyethylene glycols. The proportion of cosolvent required varies from system tosystem.

3.2. Temperature
The solubilities of most materials increase with rising temperature due to theirendothermic dissolution process. Similarly, the solubilities of materials which exhibit
exothermic dissolution decrease with rising temperature. The relationship between© 2005 by Taylor & Francis Group, LLC

Drug Substance and Excipient Characterization

91

Figure 4 Typical solubility curves.

solubility and temperature is expressed by solubility curves. Three typical solubility
curves are shown in Figure 4.
A material whose solubility increases with rising temperature exhibits a continuous curve with a positive slope (Curve A) while that whose solubility decreases withrising temperature exhibits a negative slope (Curve B). Some solubility curves show
an abrupt change in slope at certain temperatures (Curve C). This phenomenon is
attributed to the change in nature of the material at the temperature where the slopechanges direction. For example, the solubility curve C is derived from a material
which can exist in two forms. The curve shows that Form I is converted toForm II at temperature t. The dissolution of Form I in water is endothermic, which
explains the increasing solubility of the material with rising temperature until t.
Above this temperature, Form I is converted to Form II, which exhibits exothermic
dissolution. The slope of the solubility curve therefore changes from positive tonegative as the temperature exceeds t.
3.3. Crystal Characteristics
Materials may exist as amorphous or crystalline substances. Some materials such as
cortisone, tetracycline, sulfathiazole, and chloramphenicol palmitate can exist in
more than one crystalline form and this property is described as polymorphism.
The different crystalline forms which are known as polymorphs exhibit different
degrees of stability. The lattice structure of the crystalline substances may be alteredby the incorporation of molecules of the solvent from which crystallization occurs.
The resultant crystals obtained are called solvates. If the solvent is water, the crystals
are said to be hydrated.
The different forms of a material have varying solubilities. The amorphous
substance is more soluble than the crystalline counterpart. Among the crystalline
forms, the metastable polymorphs are generally more soluble than the stable polymorphs. Hydrated crystals tend to exhibit a lower solubility in water compared with
their anhydrous form. On the contrary, the aqueous solubilities of the nonaqueous
solvates are often greater than those of the unsolvated forms.
© 2005 by Taylor & Francis Group, LLC

92

Chan and Heng

3.4. Particle Size
It is important to distinguish equilibrium solubility from intrinsic solubility ofa material. Unlike intrinsic solubility, equilibrium solubility is not affected by theparticle size of the material. The solubilities of materials reported in the literature
generally refer to the equilibrium solubilities. The method of determining equilibrium solubility is given in an earlier section.
The intrinsic solubility of a material is dependent on the particle size of thematerial. Smaller particles have a higher intrinsic solubility compared with their larger counterparts. This is aptly explained by the existence of a higher interfacial freeenergy on smaller particles resulting in a thermodynamically unstable system whichis corrected by greater dissolution of the particles and production of a supersaturated
solution. The increase in intrinsic solubility with decrease in particle size, however,ceases when the particles have a very small radius and any further decrease in particle
size causes a decrease in intrinsic solubility.

3.5. pHThe solubility of a material will be affected by the pH of the liquid medium if thematerial is acidic or basic. For example, a weakly acidic drug is more soluble inan alkaline solution while a weakly basic drug is more soluble in an acidic solution.
This phenomenon is due to the formation of more soluble salts as a result of acid–base reaction. Conversely, the weakly acidic drug will precipitate from the solution
if the pH is lowered by the addition of an acid while the weakly basic drug will
precipitate from the solution if the pH is raised by the addition of an alkali. The
precipitation is a result of the conversion of the drug in solution to the less soluble
unionized form.
The relationship between pH and solubility of a material is given by Eqs. 3.1
and 3.2. These equations which are modiﬁed from the Henderson–Hasselbalch
equation are useful in the estimation of the solubility of materials under different
pH conditions.
For acidic materials,
S  S0S0
For basic materials,

pH ¼ pKa þ log

pH ¼ pKa þ log

S0
S  S0

ð3:1Þ

ð3:2Þ

where S is the overall solubility of the drug and S0 is the solubility of its unionizedform.

3.6. Additives
Additives refer to other substances incorporated into the solvent in which the drug
is dissolved. The drug in the solution may exist as ionized or nonionized forms.
Drugs that dissociate in the solvent to form ions are described as ionizable while
those that do not dissociate are nonionizable. Like the drugs, some additives ionize
readily in the solvent while others do not. Among the additives that ionize, someproduce a similar ion to the drug. The effect of additives on the solubility of a
© 2005 by Taylor & Francis Group, LLC

Drug Substance and Excipient Characterization

93

drug depends on the nature of the drug as well as the additives. For ease of understanding, the additives will be classiﬁed as common ions, indifferent electrolytes, andnonelectrolytes.
3.6.1. Effect of Common Ions on the Solubility of Ionizable Drugs
The solubility of a sparingly soluble drug is decreased by an additive that possesses asimilar ion to the drug. This phenomenon which is a result of common ion effect canbe explained by the Law of Mass Action.
The equilibrium of a saturated solution in the presence of undissolved drug isrepresented as follows:
ABðsÞ

,

Undissolved
drug

AB

Aþ þ B

,

Undissociatedmolecule

Ions

ð3:3Þ

If the material is sparingly soluble, the concentration of dissolved drug is sufﬁciently
small to assume complete dissociation into ions. The overall equilibrium may therefore be expressed as:ABðsÞ , Aþ þ B

ð3:4ÞFrom the Law of Mass Action, the equilibrium constant (K) for this reversible reaction is given by the following equation:
K¼½Aþ ½B ½ABðsÞð3:5Þ

where the square brackets indicate the concentrations of the respective components.
Since the concentration of a solid may be regarded as being constant, Eq. 3.5 can be
rewritten as:
Ks0 ¼ ½Aþ ½B ð3:6Þ

where Ks0 is a constant which is known as the solubility product of the drug AB.
Some drugs have molecules which contain more than one ion of each type. The equilibrium and solubility product of these drugs are similarly expressed as:Ax By ðsÞ , xAþ þ yB

ð3:7Þ

Ks0 ¼ ½Aþ x ½B y

ð3:8Þ
þ



If the additive dissociates to produce either A or B , the concentrations of theseions in the solvent will increase. As a result, the product [Aþ][B] or [Aþ]x[B]y will
also increase. It should be recalled that Ks0 is a constant. Therefore, if Ks0 is exceededby the product of the concentrations of ions, the equilibrium will move toward theleft in order to restore the equilibrium and the drug will be precipitated. This
explains the decrease in the solubility of a drug by common ion effect.
3.6.2. Effect of Indifferent Electrolytes on the Solubility of Ionizable Drugs
Additives which dissociate to form ions different from those of the drug are known
as indifferent electrolytes. Unlike common ions, indifferent electrolytes may increase
the solubility of a sparingly soluble drug.
© 2005 by Taylor & Francis Group, LLC

94

Chan and Heng

The solubility product deﬁned by Eq. 3.6 is only an approximation from themore exact thermodynamic relationship expressed by the following equation:
Ks ¼ aAþ  aB

ð3:9Þ

where Ks is the solubility product of drug AB and aAþ and aB are the activities of therespective ions. The activity of an ion is deﬁned as the effective concentration of theion in solution. It generally has a lower value than the actual concentration becausesome of the ions are ‘‘taken out of play’’ by strong association with oppositely
charged ions.
At inﬁnite dilution, the wide separation of ions prevents interionic associationand the actual concentration and activity of the ion are equal. This situation isapplicable to a sparingly soluble drug where the concentrations of ions produced
are so small that the ions are completely unassociated. Therefore, the solubility product can be expressed by Eq. 3.6. However, if the concentration of ions increases, theeffects of interionic association are no longer negligible and the activity becomes lessthan the actual concentration. The activity coefﬁcient, which is the ratio of activity
to actual concentration (Eq. 3.10), indicates the extent of interionic association. An
activity coefﬁcient of unity shows that the ions are completely unassociated whilesmaller values show greater interionic association:aA þ¼ f Aþ
½Aþ or aAþ ¼ fAþ  ½Aþ 

ð3:10Þ

where fAþ is the activity coefﬁcient of ion A.
Eq. 3.9 can thus be expressed as:
Ks ¼ fAþ  ½Aþ   fB  ½B  ¼ fAþ  fB  ½Aþ   ½B ð3:11Þ

According to Eq. 3.6, the product of the concentrations is the constant Ks0 . The
product of the activity coefﬁcients of the respective ions may be equated to fA2þ B ,where fAþ B is the mean activity coefﬁcient of the drug. Hence,
Ks ¼ Ks0 fA2þ Bð3:12Þ

The value of the activity coefﬁcient decreases from unity as the overall concentrationof ions of the solution increases. Since Ks is a constant, it follows that Ks0 will increase
with the ionic strength and become larger than Ks. The increase in the solubility of adrug by the addition of indifferent electrolytes is attributed to the increase in theionic strength of the solution due to the indifferent electrolytes.
3.6.3. Effect of Nonelectrolytes on the Solubility of Ionizable Drugs
The solubility of an ionizable drug depends on the dissociation of the drug into ions.
The degree of dissociation is affected by the dielectric constant of the solvent. Solvents with a high dielectric constant, being polar in nature, are able to reduce theforces that attract the oppositely charged ions produced by dissociation of the drug.
Addition of a nonelectrolyte such as alcohol will lower the dielectric constant of thesolvent. This will decrease the dissociation and, subsequently, solubility of the drug.
3.6.4. Effect of Electrolytes on the Solubility of Nonionizable Drugs
Nonionizable drugs do not dissociate into ions in solution. They exist as single
molecules and their solubility in the solvent depends on the formation of weak
© 2005 by Taylor & Francis Group, LLC

Drug Substance and Excipient Characterization

95

intermolecular bonds with the molecules of the solvent. For example, the solubilityof the drug in water is dependent on the formation of hydrogen bonds between
the molecules of the drug and water. When an electrolyte is added, it will dissociate
to form ions which have a high afﬁnity for water. These ions will compete with themolecules of the drug for water and reduce the solubility of the drug in water.
3.6.5. Effect of Surfactants
Surfactants are solutes that cause a marked decrease in the surface tension of the solvent. These substances are commonly employed as solubilizing, wetting, and emulsifying agents. They are composed of a lipophilic group that has little afﬁnity for waterand a hydrophilic group that has strong afﬁnity for water. At a speciﬁc concentration known as the critical micellar concentration, the surfactant molecules exist as
large aggregates called micelles. In an aqueous system, the hydrophilic group isorientated on the exterior while the lipophilic groups are on the interior of themicelles. Drugs which are poorly soluble in water may be taken into the interiorof these micelles, resulting in more of the drug being able to go into solution. The
enhanced solubility obtained as a result of the solubilization phenomenon is known
as the apparent solubility of the drug.
3.6.6. Effect of Complex Formation
The amount of drug that can go into solution may be altered by the addition of a
substance which interacts with the drug to form a complex. The solubility of thecomplex will determine the apparent solubility of the drug. If the complex is moresoluble than the drug, a larger amount of the drug will dissolve to form the complex.
Thus, the drug will show a higher solubility in the solvent. Similarly, if the complex isless soluble, some of the drug will be precipitated in the form of the complex. The
drug will therefore show a lower solubility in the solvent. It should be borne in mind
that the modiﬁed solubility obtained is not the solubility but the apparent solubilityof the drug.

4. CRYSTAL PROPERTIES AND POLYMORPHISM
Materials may occur as amorphous substances without any deﬁnite structure or as
crystalline particles with a deﬁnite structure and shape. Some materials may exist
in more than one crystalline form (polymorph) and are described as exhibiting polymorphism. The type of crystal formed depends on the conditions, such as temperature and type of solvent, under which crystallization is induced. At a speciﬁc
temperature or pressure, more than one polymorph can exist but only one will bethermodynamically stable. The less stable or metastable forms will be converted tothe stable form with time. Studies show that it may take from minutes to years torevert to the stable lattice structure.
The different crystalline forms of a material generally differ in many physicalcharacteristics, such as solubility, melting point, optical and electrical properties,
density, hardness, and stability. The use of metastable polymorphs frequently resultsin higher solubility and dissolution rates while the stable polymorphs are often moreresistant to chemical degradation. It is obvious that any change in the crystalline
form will affect the therapeutic efﬁcacy of a pharmaceutical product. Therefore,© 2005 by Taylor & Francis Group, LLC

96

Chan and Heng

knowledge of the crystalline form of a drug in the formulation of pharmaceuticalproducts is very important and steps should be taken to ensure that the crystals
do not convert from one form to another during production and storage of the product. Some problems which may arise if the crystal properties of the drug are notproperly characterized are precipitation, low stability, and poor bioavailability of
drug. The signiﬁcance of polymorphism in pharmacy is discussed in detail by
Haleblian and McCrone (17).
A number of techniques may be used to identify the crystalline form of a material. It is advisable to employ more than one method in the analysis as the use of only
one method has been found to be unreliable at times.

4.1. Dissolution Study
An amount of the material in excess of its solubility is added to the dissolution
medium and aliquot samples are removed and assayed at appropriate time intervals.
The concentration of the material in solution as a function of time is then plotted.
The crystalline form which constitutes the material is reﬂected by the shape of the
dissolution curve. The typical dissolution proﬁle of metastable polymorph whichreadily reverts to the stable form is shown in Figure 5A.
The concentration of the metastable polymorph is noted to increase much
more rapidly at the initial period of the dissolution study and then drop to thatof the stable polymorph. For the stable polymorph, the dissolution proﬁle justincreases gradually to a plateau. The solubility of the metastable form is indicatedby the peak of its dissolution curve. In some cases, the metastable polymorph
does not revert readily to the stable form. The dissolution curve of such a metastable form lies above that of the stable form, indicating that the former is moresoluble (Fig. 5B). The plateau of each curve indicates the solubility of the respective
polymorph.

Figure 5 Typical dissolution proﬁles.
© 2005 by Taylor & Francis Group, LLC

Drug Substance and Excipient Characterization

97

4.2. X-Ray Diffraction
Crystalline materials in powder form exhibit characteristic X-ray diffraction patterns
with peaks of varying heights and in different positions. These diffraction patterns
are also known as X-ray diffractograms. A typical X-ray diffractogram is illustrated
in Figure 6.
The polymorphs of a material have different crystal packing arrangements andthus produce differences in their diffractograms from which the crystalline form of
the material is identiﬁed. This method of analysis is nondestructive and requires avery small sample of the material which can be examined without further processing.
X-ray diffraction studies are especially useful for investigations on the changes ofcrystal form during processing. In some cases, the extent of the conversion of a crystalline drug to the amorphous form can be determined.
Conventional X-ray diffraction method cannot distinguish polymorphs whichhave relatively small crystallites because of the low resolution of diffractometers.
Synchrotron sources have been employed to obtain high-resolution electron diffraction patterns which enable differentiation of such polymorphs (18). The developmentof very sensitive charge-coupled detectors (CCD) has allowed electron diffraction
patterns to be recorded in a few seconds using very low electron currents.

4.3. Infrared Analysis
As mentioned earlier, the polymorphs of a material show varying crystal packing
arrangements and produce different X-ray diffractograms. The crystal packing
arrangement also affects the energy of molecular bonds and results in different IR
spectra for the polymorphs of a material. Identiﬁcation of the crystalline form ofa material is based on the spectrum derived. Infrared (IR) analysis can be used forboth qualitative and quantitative identiﬁcation. It is important to use only materials
in the solid form as the polymorphs of a material in solution have identical IR
spectra.
In the area of substance identiﬁcation, near IR is increasingly being used
for conﬁrming the identity of a chemical substance. Chemometric methods using

Figure 6 Typical X-ray diffractogram.
© 2005 by Taylor & Francis Group, LLC

98

Chan and Hengnear IR have also been developed for source identiﬁcation of pharmaceuticalproducts.

4.4. Thermal Analysis
In this method, the polymorphs are identiﬁed by their thermal behaviors. The change
in energy of the polymorph as it undergoes transformation when it is heated isrecorded as a thermogram. An example of a thermogram is given in Figure 7. The
thermogram consists of characteristic peaks, including melting point (Tm) and glasstransition temperature (Tg). The peaks pointing downward indicate endothermicchanges such as melting, sublimation, and desolvation. The different polymorphsof a material will exhibit different thermograms which allow them to be identiﬁed.
Differential scanning calorimetry (DSC) and differential thermal analysis(DTA) are two methods of thermal analysis commonly used for these studies. In
DSC, the energy resulting from the crystalline transformation is recorded as a function of temperature. In DTA, the energy is expressed by differential temperature(sample vs. inert substance).
Conventional DSC has a major limitation: if a Tg occurs in the same temperature range as another transition, for example, water or solvent loss, the two events
cannot be separated. This limitation may be overcome by employing modulated temperature DSC (MTDSC), where the measurements are conducted using sine wave
temperature programs deﬁned by underlying heating rate, amplitude, and period.
The heat capacity change associated with the Tg can be separated from the heat ﬂow
changes caused by melting, drying, and solvent loss. By use of the phase angle curve
produced from the MTDSC data analysis, very small changes in speciﬁc heat can bedetected, thereby increasing the sensitivity of the method. Based on thermal behavior, MTDSC is able to differentiate the amorphous and polymorphic formsof a material with much greater clarity (19). One of the disadvantages of thisFigure 7 Example of a thermogram.
© 2005 by Taylor & Francis Group, LLC

Drug Substance and Excipient Characterization

99

method is that the data analysis and interpretation are more difﬁcult than for DSC.
In addition, the experiment process can be long as much lower heating rates
are used.
4.5. Hot Stage Microscopy
The polarizing microscope ﬁtted with a hot stage is very useful for identifying
the crystalline forms of a material. In this method, the polymorph is heated to atemperature at which it undergoes a change in birefringence and/or appearance
which is characteristic of the polymorph.
4.6. Raman Spectroscopy
Raman spectroscopy provides molecular information about the crystalline, as well as
the amorphous forms of a material. In this method, the material is subjected toa laser beam and a spectrum of the scattered light obtained. The spectrum shows
vibrational bands of the material at their characteristic frequencies. The amorphousand polymorphic forms of a material can be distinguished by their characteristic
spectra.
Raman spectroscopy and IR spectroscopy complement each other. The former
measures a change in polarization whereas the latter measures a change in dipole
moment. IR-inactive vibrations can be strong in Raman spectra and vice versa.
For example, vibrations in the region of 10–400 cm1 are more easily studied by
Raman than by IR spectroscopy.
One advantage of the Raman spectroscopy method is that no sample preparation is required, thus the likelihood of inducing phase changes through processing is
reduced. However, representative sampling is critical for quantitative analysis (20).
The results are affected by the particle size of the material. The use of Fourier transform Raman spectrometers with a longer wavelength laser of 1064 nm eliminates the
problem of any ﬂuorescent background. With the utilization of ﬁber optics, real-time
crystallization can be monitored (21). Thus, this method is useful for on-line analysisof pharmaceutical processes.
4.7. Solid-State Nuclear Magnetic Resonance Spectroscopy
Solid-state nuclear magnetic resonance (SSNMR) spectroscopy is a more advanced
method for differentiating the polymorphs of a material. The substance is placed ina strong magnetic ﬁeld and subjected to radiofrequency radiation. The individual
nuclei experience different magnetic environments and thus show different changes
in resonant frequency characterized by chemical shift. SSNMR spectra show sharp
resonance at chemical shifts characteristic of the molecular and crystal structure.
The polymorphs are differentiated by their characteristic spectra.
This method is suitable for the study of molecular motions in a wide range oftime scales (102–1010 sec) and thus complements the X-ray diffraction method,which is limited to motions that are relatively fast (1018 sec). It has a few
advantages. It can be used for characterization of solid-state forms that cannot becrystallized and studied by the X-ray diffraction method. It is also useful for
quantifying components of heterogenous mixtures. In contrast to IR and Raman
spectroscopy, the results are less affected by the particle size of the test material.
© 2005 by Taylor & Francis Group, LLC

100

Chan and Heng

5. OTHER PHYSICAL PROPERTIES
It is undoubted that the type of physical characterization tests for a drug or excipient
depends very much on the material concerned as well as the processing involved.
Material testing can be broadly divided into two types, namely physical testing
and functionality testing. Physical testing, which is used to determine properties suchas size, solubility, and crystal form is generally more direct and the procedures are
better established. Functionality testing which evaluates, for example, lubricity, ﬂow,
creep, and tack is less well established but, if carried out, may yield useful information about the raw materials and their potential effects on the processing.
With the introduction of automated helium pycnometer, true densities of raw
materials can be determined with ease and at a high degree of accuracy. The true
density can serve to assure the formulator the identity of the material and sometimes
reveal the state of raw materials, like partial changes of a powder from anhydrous tohydrated form.
Packing studies of the powder can reveal its rheological properties. Thesestudies are carried out by ﬁlling a volumetrically calibrated cylinder with powder
and tapping it. From the weight of powder ﬁlled and the changes in volume of thepowder on tapping, changes in apparent densities can give information about thepowder ﬂowability (22). A small change in apparent density before and after tapping
indicates good ﬂow properties. The Hausner ratio, the ratio of tapped density topoured density has been found to be extremely sensitive to particle shape (23).
The poured density is the undisturbed packing density of a powder in a calibrated
cylinder after ﬁlling, usually done by passing powder through a sieve. The tapped
density is the packing density after tapping a bed of powder until no change inthe packing density is seen. An alternative expression used to predict powder ﬂowability is the compressibility index or Carr index, which is the ratio of the difference between the tapped and poured densities to the tapped density, expressed asa percentage.
Flowability of a powder may be determined directly using a ﬂow cup, which isoften vibrated, or indirectly by the angle of repose. The angle of repose measurement
usually involves forming a conical powder heap and measuring the maximum
inclination of heap. The powders that can ﬂow well give small angles of repose. A
variation of the heap forming measurement is to use a loosely packed powder bed
or transparent cylinder partially ﬁlled with powder and slowly rotating the powder
bed away from the initial horizontal plane of the powder surface. The angle ofinclination when sliding of powder just occurs is used to characterize the powder
ﬂowability. Determination of powder avalanches is a simple and efﬁcient way toevaluate the ﬂow properties of pharmaceutical powders. Powder ﬂow properties
are assessed by comparing their ﬂow indices using a powder ﬂowability analyzer(TSI Incorporated, USA). The ﬂow analyzer consisted of a transparent acrylic drum
ﬁtted on a vertical bayonet-type mount (Fig. 8).
The drum could be programmed to rotate at user-deﬁned rates. A metal meshcollar was ﬁtted onto the inner circumference of the drum to prevent the sliding of
powder particles down the circumferential wall instead of avalanching. Test powders
should be sieved before being poured into the sample drum.
Analysis should be performed at a range of drum speeds in order to determine
the ﬂow index, as calculated by the equation described as follows:© 2005 by Taylor & Francis Group, LLC

Drug Substance and Excipient Characterization

101

Figure 8 Avalanche powder ﬂowability tester.

Flow index ¼

n
1X
Si
n i¼1

ð5:1Þ

where n is the total number of speeds tested and Si is the standard deviation of thetested speed.
Strange attractor diagrams are generated by plotting the time difference
between each avalanche and the next formed throughout the test duration. Theseplots provide a visual comparison of the ﬂow properties of powders. Free-ﬂowing
powders will generate strange attractor diagrams that are dense and closer to theorigin. In addition, their calculated ﬂow indices will be correspondingly small.
Shear studies of powder bed can also be carried out to evaluate the cohesiveness of powders. There are many variations of shear cells for evaluation of powder
cohesiveness.
The change in the packing properties of powders under pressure is used to
study the compactability of powders. This study can be made using compression
punches attached to pressure transducers (24). The force exerted and the displacement can be utilized to calculate useful parameters for assessing the compactabilityof a powder or powder mix.
For polymers, mechanical testing such as creep testing of ﬁlms formed can provide information on the suitability of the polymer or the additives added for theirﬁlm forming function (25). When polymers are used as a binder, adhesive properties
in addition to polymer viscosity may be determined. The adhesive property can beevaluated by the measurement of tack or stickiness. This measurement involves
determining the force required to detach two platens held together by the polymer
solution. Other tests that may be carried out include measurements for surface© 2005 by Taylor & Francis Group, LLC

102

Chan and Heng

activity, glass transition temperature, cloud point, and adhesion strength of dried
polymer.

6. COMMONLY USED EXCIPIENTS IN GRANULATION
Excipients for granulation can be largely divided into two categories, as bulking
agents and as functional additives. It is true that bulking agents or ﬁllers also servea function in that they form the core or structure of a dosage form. Nevertheless,bulking agents generally differ from the functional additives in that they are usuallyinert materials that are relatively inexpensive. Functional additives include binders,disintegrants, lubricants, colorants, and stabilizing agents. Besides the pharmacopoeia, several recently published handbooks can provide a compilation of commonlyused pharmaceutical excipients (26,27).
The choice of excipients depends on a number of factors, namely, the drug
used, the process involved, the formulator, and the cost of excipient. Differences will
be seen in the choice of excipients by innovator companies and generic companies
as they have different cost considerations. Some granulation processes like ﬂuid
bed granulation would require tighter control of drug and excipient speciﬁcations
compared with wet granulation using a paddle mixer. In ﬂuid bed, besides thecontrol of particle size distribution, particle density of excipient should not be too
greatly different from that of the drug. Extrusion–spheronization would generally
require microcrystalline cellulose.
A very common ﬁller is lactose, although other sugars, dicalcium phosphate,starch, pregelatinized starch, and microcrystalline cellulose are also used. The
starches and microcrystalline cellulose are also disintegrants in tablets. For tablets,
other commonly used disintegrants include sodium starch glycolate, croscarmellose,
crospovidone, and low-substituted hydroxypropylcellulose. Lubricants are usually
not added till prior to ﬁlling or tableting of the granules. The most commonly usedlubricant is magnesium stearate. Other lubricants used include calcium stearate,
stearic acid, wax, hydrogenated vegetable oil, talc, and starch. Much work has been
done on lubricants and it is well established that the physical characterization of the
lubricant is very important to ensure consistency in functionality, especially whena change is made in the supplier (28).
Binders used in granulation consist of a wide variety of sugars and polymers—
natural, semisynthetic, and synthetic. Sugars used include sucrose, glucose, and sorbitol. Examples of natural polymers are acacia, alginic acid, sodium alginate, gelatin,and starch. There is an inherent variability in the natural polymers of different
batches and this sometimes gives rise to problems in production. It is essential tocharacterize binders for their viscous properties, at the least, to minimize potential
processing problems. The semisynthetic binders include ethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. By comparison with the natural binders, variability between
batches of the semisynthetic binders from the same supplier can be expected to bemuch less. For each polymer type, a number of viscosity grades are available. The
two types of synthetic binders in use are polyvinylpyrrolidone and polyethylene glycol. Polyvinylpyrrolidone is widely used in both wet massing and ﬂuid bed granulation. The main application of polyethylene glycol as a binder is in melt granulation.
Other excipients employed in pharmaceutical products include colorants,
coating aids, stabilizers, pH modiﬁers, and release rate modiﬁers. They play very
© 2005 by Taylor & Francis Group, LLC

Drug Substance and Excipient Characterization

103

important roles and would require speciﬁc characterization tests. In the making of a
product, the functional excipients to be added must be carefully selected to ensurethat the ﬁnal product is bioavailable and esthetically pleasing. As all raw materials
have to undergo a processing schedule for conversion of the materials to the ﬁnishedproduct, it is likely that the processing can be very unpredictable if standardizing of
raw materials has not been carried out.

7. COMPATIBILITY OF DRUG AND EXCIPIENT
In the formulation of any pharmaceutical product, it is imperative to ensure thatthe ingredients used are compatible with one another. Incompatibilities can occur
between drug and excipient as well as between the excipients themselves. Incompatibilities may be manifested through many modes, such as acid–base interaction andcomplex formation, resulting in lower potency and/or stability and eventually poor
therapeutic efﬁcacy of the product. It is therefore essential to avoid incompatibilities
and this is achieved by carrying out studies to detect potential interactions between
the components used in the formulation.
7.1. Stability Study
This is the traditional method of detecting incompatibilities. Mixtures of the drug
and excipient are prepared and stored under exaggerated conditions of heat, light,
and humidity. A detailed discussion on the ‘‘realistic’’ proportions of drug and excipient to be used in the investigation was reported by Akers (29). The mixtures are
examined for any physical change and aliquot samples are withdrawn for assay of
the intact drug at varying time intervals. Incompatibility is reﬂected by various signs
such as appearance of precipitate and decrease in the concentration of intact drug.
7.2. Thermal Analysis
A relatively simple approach for the investigation of potential interaction between
a drug and an excipient can be carried out using differential scanning calorimetry.
The drug, individual excipients, and binary mixtures of the drug and excipient are
separately scanned at a standard rate over a temperature range that encompasses
all the thermal features of the drug and excipients. Each mixture consists of 50%
drug and excipient in order to maximize the likelihood of an interaction. The thermograms of the mixtures and the appropriate individual components are compared.
Interaction is deduced by changes in the thermal features such as elimination orappearance of a peak in the thermogram of the mixture. This is illustrated in Figure 9.
Changes in shape, onset, maximum temperature, and relative height of the peaks
may also indicate interaction. However, it should be cautioned that these changes
could also arise from physical mixing of the components.
A big advantage of differential scanning calorimetry over the traditional
stability test is the speed of determination. However, like all methods, differential
scanning calorimetry has its own limitations. It is not applicable if the test materials
exhibit properties that make data interpretation difﬁcult, such as eutectic formation,
coincident melting, and dissolution of one component in the melt of the other. It is
not advisable to rely on differential scanning calorimetry alone to determine incompatibility. Chrzanowski et al. (30) reported that differential scanning calorimetry© 2005 by Taylor & Francis Group, LLC

104

Chan and Heng

Figure 9 Thermograms indicating drug–excipient interaction.

indicated no incompatibilities in mixtures of fenretinide–excipient and mefenidil–
excipient, whereas the traditional stability study showed some incompatibilities.
Hence, differential scanning calorimetry should only be used to supplement thestability test by eliminating the incompatible excipients and reducing the numberof test samples.

7.3. Chromatographic Methods
Chromatography was ﬁrst used for the separation of colored leaf pigments. The
operation of chromatography is based on the distribution of a material between astationary phase and a mobile phase. The stationary phase can be a solid or a liquid
supported on a solid while the mobile phase can be a gas or a liquid which ﬂows continuously around the stationary phase. The different components in a mixture can beseparated and identiﬁed as a result of differences in their afﬁnity for the stationary
phase.
In addition to its application in the separation and identiﬁcation of materials,
chromatography is also employed to detect potential interactions between materials.
Both thin-layer chromatography and liquid chromatography are commonly employed in this area of study. In thin-layer chromatography, the stationary phaseconsists of a powder adhered onto a glass, plastic, or metal plate. The powders commonly used are silica, alumina, polyamides, cellulose, and ion-exchange resins. Solutions of the drug, excipient, and drug–excipient mixture are prepared and spotted on
the same baseline at one end of the plate. The plate is then placed upright in a closed
chamber containing the solvent, which constitutes the mobile phase. As the solvent
moves up the plate, it carries with it the materials. Those materials which havea stronger afﬁnity for the stationary phase will move at a slower rate. The material
is identiﬁed by its Rf value, which is deﬁned as the ratio of the distance which thematerial has moved to the distance the solvent front has moved. The position of
the material on the plate is indicated by spraying the plate with certain reagents or© 2005 by Taylor & Francis Group, LLC

Drug Substance and Excipient Characterization

105

Figure 10 Chromatograms illustrating drug–excipient interaction.

exposing the plate to ultraviolet radiation. If there is no interaction between the
drug and excipient, the mixture will produce two spots whose Rf values are identicalwith those of the individual drug and excipient. If there is interaction, the complex
formed will produce a spot whose Rf value is different from those of the individualcomponents.
In liquid chromatography, the distribution of the material between the solid
stationary phase in a column and the liquid mobile phase is determined. The material
is identiﬁed by the time taken for it to elute from the column. Solutions of the drug,
excipient, and drug–excipient mixture are prepared and injected into the column.
The materials will elute from the column at different speeds, depending on their afﬁnity for the column. The concentration of the material that elutes from the column isdetected and plotted against time to give to a chromatogram. If there is interaction
between the drug and excipient, the complex formed will exhibit an elution time different from those of the individual components. This is illustrated in Figure 10,
which shows the chromatograms of the drug, excipient, and drug–excipient mixture
plotted together. Similarly, gas chromatography may be used.

8. CONCLUSION
The greatest difﬁculty for any process technologist is to decide on the type and extent
of material characterization to be undertaken such that it is cost-effective in the longrun. Often, it is the problem from the production run that necessitates further material characterization to be carried out either for the purpose of resolving the problem
or to prevent future occurrences. This chapter serves to identify the more common
material characterization methods that can be carried out and the potentially useful
information that can be inferred from the tests. It is hoped that the discussion of themany methods of material characterization could help in the choice of characterization methods for material testing.
© 2005 by Taylor & Francis Group, LLC

106

Chan and Heng

REFERENCES
1. Heywood H. The evaluation of powders. J Pharm Pharmac 1963 (suppl 15):56T.
2. Wadell H. Volume, shape and roundness of rock particles. J Geol 1932; 40:443.
3. Stanley-Wood NG. Particle characterisation by size, shape and surface for individual
particles. Stanley-Wood NG, ed. Enlargement and Compaction of Particulate Solids.
London: Butterworths, 1983:18.
4. Kaye BH. Multifractal description of ragged ﬁne particle proﬁle. Particle Char 1984;
1:14.
5. Kaye BH. Speciﬁcation on the ruggedness and/or texture of a ﬁne powder proﬁle by its
fractal dimension. Powder Technol 1978; 21:1.
6. Flook AG. The use of dilation logic on the Quantimet to achieve dimension characterisation of textured and structured proﬁles. Powder Technol 1978; 21:295.
7. Meakin P. Simulations of aggregation processes. Avnir D, ed. The Fractal Approach to
Heterogeneous Chemistry. Chichester: Wiley, 1990:131–160.
8. Allen T. Particle Size Measurement. 4th ed. London: Chapman and Hall, 1990.
9. Svarosky L. Characterization of powders. Rhodes MJ, ed. Principles of Powder
Technology. Chichester: John Wiley, 1990:35.
10. Washington C. Particle Size Analysis in Pharmaceutics and Other Industries. U.K: Ellis
Horwood, 1992.
11. British Standard 3406, Part 4, 1963.
12. Timbrell V. A method of measuring and grading microscopic spherical particles. Nature
1952; 170:318.
13. Russ JC. Computer-Assisted Microscopy. New York: Plenum Press, 1990.
14. Sing KSW. Adsorption methods for surface area determinations. Stanley-Wood NG,
Lines RW, eds. Particle Size Analysis. Cambridge, U.K: The Royal Society of Chemistry,
1992:13.
15. Lowell S, Shields JE. Particle Surface Area and Porosity. 2nd ed. London: Chapman andHall, 1983:205.
16. Buckley HE. Crystal Growth. New York: Wiley, 1951:29.
17. Haleblian J, McCrone W. Pharmaceutical applications of polymorphism. J Pharm Sci
1969; 58:911.
18. Li ZG, Harlow RL, Foris CM, Li H, Ma P, Vickery RD, Maurin MB, Toby BH. Polymorph determination for the GP IIb/IIIa antagonist, roxiﬁban, using a combination ofelectron diffraction and synchrotron x-ray powder diffraction techniques. J Pharm Sci
1999; 88(3):297.
19. Bottom R. The role of modulated temperature differential scanning calorimetry in thecharacterization of a drug molecule exhibiting polymorphic and glass forming tendencies.
Int J Pharm 1999; 192:47.
20. Taylor LS, Zograﬁ G. The quantitative analysis of crystallinity using FT-Raman spectroscopy. Pharm Res 1988; 15(5):755.
21. Findlay WP, Bugay DE. Utilization of Fourier transform-Raman spectroscopy for the
study of pharmaceutical crystal forms. J Pharm Biomed Anal 1998; 16:921.
22. Yamashiro M, Yuasa Y, Kawakita K. An experimental study on the relationships
between compressibility, ﬂuidity and cohesion of powder solids at small tapping numbers. Powder Technol 1983; 34:225.
23. Kostelnik MC, Beddow JK. New techniques for tap density. In: Hausner HH, ed. Modern Developments in Powder Metallurgy IV, Processes. Proceedings of the 1970 International Powder Metallurgy Conference. New York: Plenum Press, 1970.
24. Watt PR. Tablet Machine Instrumentation in Pharmaceutics: Principles and Practice.
Chichester: Ellis Horwood, 1988.
25. Okhamafe AO, York P. Interaction phenomena in pharmaceutical ﬁlm coatings andtesting methods. Int J Pharm 1987; 39:1.

© 2005 by Taylor & Francis Group, LLC

Drug Substance and Excipient Characterization

107

26. Handbook of Pharmaceutical Excipients. Washington, DC: American Pharmaceutical
Association, London: Pharmaceutical Society of Great Britain, 1986.
27. Brittain HG, ed. Analytical Proﬁles of Drug Substances and Excipients. San Diego: Academic Press, 1993.
28. Chowhan ZT. Excipients and their functionality in drug product development. Pharm
Tech 1993; 17:72.
29. Akers MJ. Preformulation testing of solid oral dosage form drugs. Can J Pharm 1976;
11:1.
30. Chrzanowski FA, Ulissi LA, Fegely BJ, Newman AC. Preformulation excipient compatibility testing. Application of differential scanning calorimetric method versus a wet
granulation simulating isothermal stress method. Drug Dev Ind Pharm 1986; 12:703.

© 2005 by Taylor & Francis Group, LLC

4Binders and Solvents
Ehab Hamed, Derek Moe, and Raj Khankari
CIMA Labs Inc., Eden Prairie, Minnesota, U.S.A.

John Hontz
Biovail, Chantilly, Virginia, U.S.A.

1. INTRODUCTION
Binders are adhesives that are added to solid dosage formulations. The primary roleof binders is to provide the cohesiveness essential for the bonding of the solid particles
under compaction to form a tablet. In a wet-granulation process, binders promote
size enlargement to produce granules and thus improve ﬂowability of the blend during the manufacturing process. Binders may also improve the hardness of the tablets
by enhancing intragranular as well as intergranular forces. In a direct compression
process, binders often act as ﬁllers and impart compressibility to the powder blend.
The cohesive properties of binders may reduce friability of the tablets and thus aid
in their durability and elegance. Although the purpose of using binders in a tablet formulation is not to inﬂuence its disintegration and dissolution rate, these properties
may be modiﬁed due to the altered wettability of the formulation.

2. TYPES OF BINDERS
Binders are usually natural polymers, synthetic polymers, or sugars. The selection of
the type of binder for a particular system is quite often empirical and dependent on
the previous experience of the formulator, in conjunction with examination of excipient compatibility studies. Selection of the quantity of binder required in a particular system can be determined by optimization studies, using parameters such as
granule friability, tablet friability, hardness, disintegration time, and the drug dissolution rate. Some commonly used binders in wet granulation with their usual concentration range, along with the granulating system are listed in Table 1. Basic
properties of some widely used binders with their method of incorporation will be
discussed in this section (1–4).

109© 2005 by Taylor & Francis Group, LLC

110

Hamed et al.

Table 1 Commonly Used Granulating Systems

BinderNatural polymers
StarchPregelatinized starch
GelatinAcaciaAlginic acid
Sodium alginate
Synthetic polymers
PVP

Methyl cellulose
HPMC

Na-CMC
Ethyl cellulose
SugarsGlucoseSucroseSorbitol

Percentage usedin granulating
systemMethod ofincorporation

Percentage
used informulaSolvent

Wet mixing
Wet mixing
Dry mixing
Wet mixing
Wet mixing
Dry mixing
Wet mixing

2–5
2–5
5–10
1–3
3–5
1–5
1–3

Water
Water
Water
Water
Water
Water
Water

5–25
10–15

Wet mixing

0.5–5

Water orhydroalcoholic solution

5–10

Dry mixing
Wet mixing
Dry mixing
Wet mixing

5–10
1–5
5–10
2–5

Water

2–15

Water orhydroalcoholic solution

5–10

Dry mixing
Wet mixing
Dry mixing
Wet mixing
Dry mixing

5–10
1–5
5–10
1–5
5–10

Water

5–15

Ethanol

2–10

Wet mixing
Wet mixing
Wet mixing

2–25
2–25
2–10

Water
Water
Water

25–50
50–67
2–25

5–10
10–15
3–5

Source: Modiﬁed from Ref. 3.

2.1. Natural Polymers
2.1.1. Starch
Starch is a polymeric carbohydrate obtained from various plant sources, such as
potato, wheat, maize, rice, and tapioca. It is a GRAS-listed material and traditionally
was one of the most widely used tablet binders. It is insoluble in cold water and inalcohol but it gelatinizes in hot water to form a paste. Starch paste can be preparedby dispersing starch in 1–1.5 parts of cold water for initial wetting followed by addition of two to four times as much boiling water with continuous stirring until a translucent paste is obtained. This paste is further diluted by cold water to the desiredconcentration. Alternatively, starch paste can also be prepared by heating the cold
water suspension of starch to boiling in a steam-jacketed kettle with constant stirring.
Freshly prepared starch paste is used at a concentration of 5–25% (w/w) in atablet granulation. Relatively soft and friable granules are produced when starch
paste is used as a binder. Consequently, it yields tablets that disintegrate readily.
During the wet-massing process, high viscosity of the starch paste can sometime
make it difﬁcult to evenly distribute the binder in the powder blend.
© 2005 by Taylor & Francis Group, LLC

Binders and Solvents

111

2.1.2. Pregelatinized StarchPregelatinized starch is a modiﬁed starch used in tablet formulations as a binder,
diluent, and disintegrant. It is obtained by chemically and mechanically processing
the starch to rupture all or part of the starch granules. This process renders starch
ﬂowable, directly compressible, and soluble in warm water without boiling. As abinder in a wet-granulation process, pregelatinized starch can be used either as a solution reconstituted in water or as a dry blending followed by wetting with water. The
latter process requires two to four times more binder to achieve the same binding effect.
Pregelatinized starch is available in fully or partially pregelatinized forms. The
degree of pregelatinization determines its solubility in cold water. Cold-water soluble
fraction for a partially pregelatinized starch is 10–20%. Starch 1500 is partially pregelatinized starch containing 20% maximum cold-water soluble fraction, which makes
it useful for wet granulation. The water-soluble fraction acts as a binder, while theremaining fraction facilitates the tablet disintegration process.
2.1.3. Gelatin
Gelatin is a mixture of puriﬁed protein fractions obtained by partial acid hydrolysis(Type A gelatin) or alkali hydrolysis (Type B gelatin) of animal collagens. It is insoluble in cold water and in alcohol, but is soluble in hot water. In hot water, gelatin forms
a gel on cooling to 35–40 C. At temperatures >40 C, the system exists as a solution.
Therefore, the gelatin solutions must be used when warm to avoid gel formation.
During the preparation of gelatin solution, gelatin must be wetted in cold waterand then heated with gentle agitation to ensure dissolution. The agitation intensity must
be kept low to prevent air entrapment in the viscous solution. Use of gelatin as a binder
is limited in general-purpose tablets because it produces tablets characterized by highhardness and slow disintegration. However, these properties of gelatin along with its
smooth mouth feel can prove to be advantageous in a lozenge formulation.
Gelatin reacts with aldehydes, aldehydic sugars, anionic and cationic polymers,
electrolytes, metal ions, plasticizers, preservatives, and surfactants. In a wet-granulation
process of a formulation containing color, the migration of dyes toward the uppersurface of the static bed during the drying operation is often ampliﬁed by the presenceof gelatin due to its high afﬁnity for dyes. The gelatin solutions are susceptible to microbial contamination upon storage, therefore freshly prepared solutions should be used.
2.1.4. Acacia
Acacia is a natural gum obtained from the acacia trees. It is a complex, loose
aggregate of sugars and hemicelluloses. It is commercially available in a powdered
form, a granular form, or as a spray-dried product. As a tablet binder, it is usedin an aqueous solution or added in dried form prior to moistening with water. Acacia
forms very hard tablets, which disintegrate slowly. Aqueous solutions are susceptible
to bacterial and enzymatic degradation. It is incompatible with amidopyrine, cresol,
phenol, ethanol, ferric salts, and a number of other substances. Acacia, which was
widely used in the past as a tablet binder, is rarely used today, in favor of one of
the many synthetic polymers.
2.1.5. TragacanthTragacanth is a naturally occurring dried gum. It poses similar problems as those ofacacia. Dry addition to the blend followed by addition of water works better thanaddition of the solution, because it is difﬁcult to prepare and use the mucilage.
© 2005 by Taylor & Francis Group, LLC

112

Hamed et al.

2.1.6. Alginic Acid
Alginic acid is a polymannuronic acid extracted from seaweed. It is used as a binderand disintegrating agent at concentrations between 1% and 5%. It slowly hydrolyzes
at room temperature and is insoluble in water. Therefore, it is best incorporated in adry state. It is incompatible with strong oxidizing agents. It forms insoluble alginateswith the alkaline earth metals and group III metals, with the exception of magnesium. These alginates may delay disintegration of the tablets due to their gelling
properties.
2.1.7. Sodium Alginate
Sodium alginate slowly dissolves in water to form a viscous solution. A 3–5% solution typically is used in wet-granulation processes. It has also been used in sustained
release formulations because it delays the dissolution of a drug from tablets. It is
hygroscopic and its aqueous solution is susceptible to microbial contamination.
2.2. Synthetic Polymers
2.2.1. Polyvinylpyrrolidone (Povidone)
Polyvinylpyrrolidone (PVP) is versatile and one of the most commonly used binders.
It is readily soluble in water and freely soluble in alcohol and many other organic
solvents. It is available in a variety of grades of different molecular weights. PVP
is generally used in the form of a solution; however, it can be added to the blendsin the dry form and then granulated in situ. It is frequently used as a binder in effervescent and chewable tablets because the tablets manufactured using PVP as a binder
generally harden with age. Aqueous or hydroalcoholic solutions of PVP are used togranulate insoluble materials and alcoholic solutions are used for granulating soluble
materials. It is used as a binder at concentrations between 0.5% and 5%. Low- to
medium-viscosity grades are preferred since the high-viscosity grades of PVP havebeen known to cause dissolution problems. It is highly hygroscopic and picks up signiﬁcant amounts of moisture at low relative humidities and can deliquesce at highrelative humidities.
2.2.2. Methyl Cellulose
Methyl cellulose (MC) is a long-chain substituted cellulose in which 27–32% of thehydroxyl groups are in the form of methyl ether. It is available in a variety of gradesof different degrees of substitution and average molecular weight. Therefore, it offers
considerable latitude in binding strength. Efﬁciency of MC as a binder improves withincreasing molecular weight. Low- or medium-viscosity grades are preferred whenused as a binder. It may be added as a dry powder or as a solution. Although anaqueous solution of 1–5% can be used to granulate soluble or insoluble excipients,
it is a better binder for soluble excipients such as lactose and mannitol. MC produces
granulations that compress easily. Granulation produced using 5% MC solution isequivalent in hardness to 10% starch paste. It produces robust tablets with moderate
hardness, which does not increase with age.
MC is practically insoluble in hot water, ethanol, chloroform, ether, and saturated salt solutions. In cold water, it swells and disperses slowly to form a clear toopalescent, viscous dispersion. To produce an aqueous solution, the appropriatequantity of MC powder is suspended in 25% of the required amount of water at© 2005 by Taylor & Francis Group, LLC

Binders and Solvents

113

80 C. The remaining amount of water is added cold, or ice water is added to the hotslurry with vigorous stirring in order to cool it down to 20 C. A clear aqueous solution of MC is obtained. MC can also be mixed as a dry powder with another powder
prior to mixing with cold water or may be moistened with an organic solvent such as
95% ethanol prior to the addition of water.
2.2.3. Hydroxypropyl Methyl Cellulose (Hypromellose)
Hydroxypropyl methyl cellulose (HPMC) is a propyleneglycol ether of MC. HPMC
is available in a variety of viscosity grades. Its binding properties are comparable tothose of MC. Concentrations of 2–5% (w/w) may be used as a binder in either wetor dry-granulation processes. HPMC is soluble in cold water and forms a viscous
colloidal solution. To prepare an aqueous solution, HPMC is ﬁrst hydrated in
20–30% of required water at 80–90 C with vigorous stirring. Cold water is added
to produce the required volume. Hydroalcoholic solutions or mixtures of waterand other water-miscible solvents such as glycol can also be used to dissolve HPMC.
HPMC is ﬁrst dispersed in the organic solvent, at a ratio of ﬁve to eight parts ofsolvent to one part of HPMC. Cold water is then added to produce the required
volume. HPMC is incompatible with some oxidizing agents.
2.2.4. Sodium Carboxymethyl Cellulose
Sodium carboxymethyl cellulose (Na-CMC) is a sodium salt of carboxymethyl ethersof cellulose. It is available in a variety of molecular weights which inﬂuence theviscosity of the solution and its swelling properties. It easily disperses in water at
all temperatures to form a clear colloidal solution. Its aqueous solubility varies withits degree of substitution, which is the average number of hydroxyl groups substituted per anhydroglucose unit. A 5–15% solution may be used for the granulationof soluble as well as insoluble powders. The granulations produced using Na-CMC
as a binder are softer, but have good compressibility. It forms tough tablets ofmoderate hardness. Na-CMC is a highly hygroscopic material. It can adsorb a large
quantity (>50%) of water at high relative humidities. Therefore, the tablets using
Na-CMC as a binder have a tendency to harden with age. Na-CMC is incompatible
with strongly acidic solutions and with metal salts of iron, aluminum, zinc, etc.
2.2.5. Ethyl Cellulose
Ethyl cellulose, an ethyl ether of cellulose, is available in a variety of grades, which
differ in their viscosity. Low-viscosity grades are used as binders in concentrations of
2–10% in ethanol. Ethyl cellulose produces softer granules, which compress into
tablets that easily disintegrate. However, the dissolution of the active ingredient fromthese tablets may be slower because ethyl cellulose is insoluble in water. Ethyl cellulose may be used in a dry form or in an ethanolic solution for wet granulation. Ethyl
cellulose is a good nonaqueous binder for water sensitive formulations.
2.2.6. Polyethylene Glycol
Polyethylene glycols (PEGs), by themselves, have limited binding action; however,they can enhance the effectiveness of tablet binders and impart plasticity to granules.
They can also be used in thermoplastic granulations. In this process, a powder blend
containing 10–15% (w/w) of PEG-6000 is heated to 70–75 C to obtain a paste-like© 2005 by Taylor & Francis Group, LLC

114

Hamed et al.

mass, which forms granules if stirred while cooling. This technique is used in lozenge
formulations.
2.2.7. Polymethacrylates (Eudragit)
Polymethacrylates (Eudragit NE 30D and Eudragit RS 30D) can be used as binders
in aqueous or nonaqueous wet-granulation processes. They are supplied as 30% aqueous dispersions. Dilution with water prior to use is recommended. Eudragit RS 30D
is incompatible with magnesium stearate.
2.2.8. Polyvinyl Alcohol
Polyvinyl alcohols (PVAs) are available in a variety of viscosity grades. Viscosity
ranges from 10 to 100 cps lend themselves for tablet granulations. PVAs arewater-soluble polymers. They form softer granulations, which yield tablets that do
not harden with age.
2.3. Sugars
2.3.1. Glucose (Dextrose)
Glucose, when applied as a syrup in concentrations >50% in wet-granulation processes, exhibits good bonding properties. It produces moderately strong granules
and tablets, which are hard and brittle. Glucose is also used as a direct compression
tablet diluent and binder, primarily in chewable tablets. Anhydrous dextrose adsorbs
signiﬁcant amounts of moisture at 25 C and 85% relative humidity to form a monohydrate. The monohydrate also absorbs moisture at 85% relative humidity. Dextrose
is a reducing sugar and in its aldehyde form, can react with amines, amides, aminoacids, etc. Brown coloration may occur in tablets containing dextrose and strong
alkali or amines.
2.3.2. Sucrose
Sucrose is commercially available in several forms such as granular, ﬁne granular,ﬁne, superﬁne, and confectioners sugar. The confectioners sugar is most commonlyused in wet-granulation formulations. Sucrose syrup, containing 50–67% (w/w)
sucrose, is used as a binder in wet-granulation processes. It can also be used as a
dry binder where it is granulated with water or hydroalcoholic solutions. Like glucose, sucrose produces strong, but hard and brittle tablets. The amount of binder
determines the tablet hardness. Softer granules can be obtained by using hydroalcoholic mixtures as granulating solutions. Finely divided sugar is hygroscopic. Tablets
containing large amounts of sucrose may harden with age, which may result inslower disintegration. In systems where quick overwetting occurs, the amount andthe rate of addition of the sucrose syrup must be carefully monitored. Use of sucrosewith starch paste may improve the tablet quality. Sucrose is incompatible with aluminum. It hydrolyses in the presence of acids. Contamination of powdered sucrosewith heavy metals may lead to incompatibility with substances such as ascorbic acid.
2.3.3. Sorbitol
Sorbitol is an optical isomer of mannitol. It is highly hygroscopic at relative humiditiesof 65% and above. Therefore, it used as a humectant in pharmaceutical formulations.
© 2005 by Taylor & Francis Group, LLC

Binders and Solvents

115

Whenever this property of sorbitol as a moisture control agent is desirable, it can beused as a binder. Up to 2–20% of sorbitol can be added as 10–25% aqueous solution
in wet-granulation formulations.

2.4. New Binders
Recently, several new natural and synthetic binders have been investigated for potential applications in pharmaceutical formulations. Nearly all the natural binders
investigated were gums obtained from different plant origins, including Khaya
gum (5), Leucaena leucocephala seed gum (6), Anacardium occidentale gum (7), Gellan gum (8), and a combination of detarium gum and veegum (9). While some ofthese materials have been approved by the U.S. FDA for use as food additives,
the issues of compendial requirements, lack of literature support, and potential
reproducibility problems associated with materials obtained from plant origin canlimit their applicability in the pharmaceutical industry. New synthetic binders thathave been investigated include maltrodextrins (10) and chitosan derivatives (11).

3. FACTORS INFLUENCING BINDER EFFICIENCY
The function of binders in a tablet formulation is to impart strength and to reduce
the friability of granules and tablets. Several factors inﬂuence the effectiveness ofa binder in a formulation. Some of these factors are related to the drug and otherexcipients in the formulation and others are related to the binder and solvent
system used. Storage conditions as well as granulation process parameters can alsosigniﬁcantly affect the binder efﬁciency.

3.1. Properties of the Drug and Other Excipients in the Formulation
3.1.1. Particle Size
The primary particle size of the drug or excipients can affect granule strength, porosity, and consolidation rate during high-shear granulation. Smaller particles withhigher surface areas have more contact points to allow the formation of stronger
granules than larger particles when granulated with enough binder (12,13). However,
because of the greater surface area, the solvent and binder requirements increase as
the primary particle size decreases (14–16). Therefore, to better anticipate the effectof reducing the excipients’ primary particle size on granule properties, the degree ofliquid saturation and binder level must be considered. At the same binder and solvent level, excipients with larger particle sizes consolidate easier and produce lessporous granules as compared to ﬁner particles (17,18).
Another factor that can be related to the excipients’ primary particle size is the
distribution of drug through different size granules. When the drug particles were
smaller than the ﬁller, larger granule size fractions exhibited the highest drug content
and when the drug particles were larger, the highest drug concentration was found in
the smallest granule size fraction (12). The results can be explained in terms of theability of small drug particles to form stronger granules that resist breakdown duringhigh-shear granulation and grow to a further extent than those formed primarily bylarger ﬁller particles.
© 2005 by Taylor & Francis Group, LLC

116

Hamed et al.

3.1.2. Solubility
The solubility of drugs and other excipients in the granulating solvent can signiﬁcantly affect the granules’ properties. Increasing the excipients’ solubilities in the
granulating solvent decreased the solvent requirement and led to the formation of
granules of tighter particle size distribution and reduced friability (19,20). Accordingly, lactose-based granules are formed at a lower degree of water saturation compared to insoluble ﬁllers such as dicalcium phosphate (21,22) and calcium hydrogen
phosphate (23). The ﬁndings can be attributed to the increased plasticity of the moist
lactose agglomerates owing to its solubility in water, which increased the propensity
for particle coalescence and growth during high-shear granulation processes. Holmet al. (24) described lactose granulation as less sensitive to moisture content andkneading intensity than calcium hydrogen phosphate.
Changing the formulation proportions of water-soluble excipients can dramatically alter the granules’ properties. The addition of microcrystalline cellulose to alactose-based formulation increased the solvent requirement and produced larger
granules for both PVP and gelatin-based granulations (25). Increasing the starchcontent in a lactose:starch-based formulation leads to the formation of smaller granules with a wider particle size distribution (26). The results were explained in terms ofwater absorption by starch particles and the formation of weaker granules that could
not grow in size to the same extent as when starch was absent (27).
Drug solubility in the granulating solvent can affect its distribution in different
granule size fractions. Drugs with high solubility in the granulating solvent have ahigher tendency to migrate during drying creating a drug-rich crust. Abrasion during
subsequent milling leads to the formation of highly concentrated ﬁnes relative tolarger granules (13).
3.2. Properties Related to the Binder and Solvent System
3.2.1. Mechanical Properties of the Binder
The mechanical and ﬁlm-forming properties of a binder determine the strength anddeformation behavior of a binder matrix. These properties of the binder matrix primarily determine the effectiveness of the binder. The tensile strengths of the ﬁlms ofacacia, gelatin, methylhydroxyethyl cellulose, PVP, and starch prepared with varying
moisture levels by equilibration at different relative humidities were reported (28).
Figure 1 shows the effect of moisture content on the tensile strength of the binders
mentioned earlier. The results show that acacia and PVP form weak ﬁlms while gelatin ﬁlms possess the highest tensile strength. PVP was also reported to exhibit low
values of Young’s modulus showing that it is the most deformable binder (28). Thishigh deformability of PVP aids in consolidation during compaction. Consequently,
PVP is considered the most preferred wet binder by many (29).
3.2.2. Binder–Substrate Interactions
As mentioned earlier, signiﬁcant determinants of the granule and tablet strength
are wettability of the substrate by the binder solution, binder cohesion, andbinder–substrate adhesion (30). Rowe (31–33), in a series of publications, presented
theoretical approaches to predict the binder–substrate interactions. According toRowe, dense nonfriable granules are expected when the spreading coefﬁcient of binder over substrate is positive while negative spreading coefﬁcient leads to the formation of porous granules (31). For a low-polarity substrate, such as griseofulvin, either© 2005 by Taylor & Francis Group, LLC

Binders and Solvents

117

Figure 1 The effect of moisture content on the tensile strength of binder ﬁlms. &, gelatin;
G, methylhydroxyethylcellulose; , starch; &, acacia; , PVP. The vertical bars show thelimits of error of the means at P ¼ 0.95. (From Ref. 28.)

PVP or starch would be the optimal binder while for high-polarity substrates, such as
theophylline, acacia or HPMC would be the optimal binder (31). PVP and HPMC
were reported to have positive spreading coefﬁcient over lactose, acyclovir, and pentoxyﬁlline with the latter having the highest spreading coefﬁcient and acyclovir having the lowest spreading coefﬁcient (34). When granulated in ﬂuid bed with bothbinders, pentoxyﬁlline produced the least friable granules followed by lactose andthen Acyclovir. The results also showed that PVP is more efﬁcient than HPMC
due to the lower work of cohesion and adhesion of the latter (34). This approachis based solely on the hypothesis that optimum spreading of the binder is the main
criterion for successful formulation. It does not take into account other equallyimportant factors, such as disintegration, dissolution, and ﬂow properties. However,the studies show the potential of using the theoretical approach in binder selection
and formulation optimization.
PVP-based granulation of detergent-cleaned hydrophilic glass beads produced
larger granules with more crushing resistance and lower friability than those ofdimethylsilane surface treated hydrophobic glass beads (35). The results can be
attributed to the better adhesion of PVP to hydrophilic surfaces.
3.2.3. Binder Solution Viscosity and Surface Tension
To better understand the importance of binder solution viscosity and surface tension, the mechanism of granule formation must be considered. When two particles
collide during granulation, they either coalesce or spring back from each other. It
is the balance of the kinetic energy of the colliding particles against the other forces
acting to bring the particles together that decides the outcome of the collision process© 2005 by Taylor & Francis Group, LLC

118

Hamed et al.

(36,37). The forces that help dissipate the collision energy and keep the colliding particles together include the static pendular bridge (surface tension effect), viscous andinterparticle friction forces (17).
Increasing binder solution viscosity increased the granule size and decreased
the amount of binder required to initiate granule growth in both high-shear (37)and ﬂuid-bed (36) granulation processes. However, when the binder solution viscosity is very high, problems with binder spreading and distribution arise. The highestbinder solution viscosity that can be used depends on the excipients and drug properties and the processing parameters, such as the ability of existing pump and/or spraysystems to handle viscous liquids. Experiments in high-shear granulators with initialbinder solution viscosities exceeding 100 mPa.s have been reported (38).
When different molecular weights of PVP and HPMC were dissolved in water,
reductions in surface tension were observed (39). The decrease in surface tension was
higher for HPMC but independent of the concentrations of both binders and inversely dependent on the molecular weight of PVP (39). Decreasing binder solution surface tension decreased the capillary suction pressure and decreased the friction
resistance to consolidation and, therefore, increased the granule consolidation rate,
but also increased the minimal attainable granule porosity, i.e., granules consolidated fast but not as far (18). Decreasing the binder solution surface tension was also
reported to decrease the liquid requirement to attain overwetting (40).
3.2.4. Solvent Properties
Granule properties can be signiﬁcantly affected by changing the granulating solvent.
The effect stems from the change in excipient solubility and wettability, as well as themechanism of granule consolidation. In the pharmaceutical industry, only aqueous,hydroethanolic, and ethanolic solvent systems are widely used. Lactose granulations
prepared using ethanolic PVP solution had higher porosity and friability comparedto those prepared using water as a granulating solvent (41). For hydroethanolic solvent systems, increasing the ethanol content has been shown to increase tablet
strength (41). The results were attributed to the increased fragmentation tendencyof granules when ethanol contents were increased (42). Changing the solvent system
can affect the formulation excipients’ wettability and inﬂuence binder distribution.
For example, PVP distribution in low-shear granulation process improved whenwater was replaced with a hydroalcoholic solution (43).
3.3. Storage Conditions
Storage conditions can severely alter the tablet properties through their effect on thebinder’s physical characteristics. For example, the hardness and disintegration timeof Ranitidine tablets prepared using the PVP wet granulation method decreased
when the tablets were stored under elevated moisture levels (44). PVP can absorb
a signiﬁcant quantity of water when exposed to elevated humidity, which decreases
the polymer glass transition temperature (45,46). PVP is proposed to stay in a glassy
stage at room temperature at a relative humidity 55% and completely convert
to the rubbery state at room temperature at a relative humidity >75% (45). Suchchanges in the physical state of a binder can dramatically change a tablet’s hardness,
friability, disintegration, and drug release. Moreover, the presence of other additives
in the formulation can augment the plasticizing effect of moisture and cause the granuleand tablet properties to change at a lower moisture level than those used in accelerated
stability protocols.
© 2005 by Taylor & Francis Group, LLC

Binders and Solvents

119

HPC was reported not to have a glass transition temperature, but rather melt
at a temperature of 190–195 C (46). When compared to PVP, tablets prepared using
HPC maintained its dissolution proﬁle after storage for 24 weeks under different
moisture/temperature conditions while those prepared using PVP showed a reduction in pyrydazine release when stored at 40 C/75% relative humidity (46).
4. PROCESSING PARAMETERS FOR COMMONLY USED BINDERS
4.1. Polyvinylpyrrolidone
4.1.1. High-Shear Granulation
The granulation process in high-shear equipment is inﬂuenced by a score of variables
including impeller speed, amount of binder and granulating solvent, liquid addition
rate, wet massing time, method of binder incorporation (wet vs. dry), method ofsolution addition (dripping vs. atomization), equipment design, and chopper speed.
These parameters inﬂuence the binder performance through their combined effects
on the binder distribution/dissolution, the degree of saturation, and the extent towhich granules are allowed to grow and densify before they are broken down by
the high-speed chopper.
4.1.1.1. Impeller Speed. Impeller speed is the most signiﬁcant parameter
affecting the binder performance in high-shear granulation. Increasing the impeller
speed in PVP and PVP–PVA copolymer-based formulations increases the granulesize (21,22,47–49) and the bulk and tapped density (21,49), but decreases the percent
ﬁnes (47,49) and the granule porosity (21,49). However, the effect of impeller speed
on binder performance is dependent on the degree of solvent saturation, the binder
amount, the stage at which the impeller speed is varied (liquid addition vs. wet massing), and the properties of the formulation materials. At a low degree of solvent
saturation or with an insufﬁcient amount of binder, the effect of increasing impeller
speed is in favor of breaking up the weak nuclei/agglomerates and hindering any
further granule growth (26,50).
4.1.1.2. PVP Concentration. Figure 2 shows a plot of crushing strength ofdicalcium phosphate granules vs. binder concentration for PVP in comparison toother binders (51).
As the binder concentration increases, the crushing strength of the granules
increases. The plot also shows that starch and gelatin can produce much stronger
granules with lower concentrations compared to acacia, PVP, or PEG 4000 (51).
As expected, the particle size of granules also increases as the binder concentration
increases. Figure 3 shows a plot of mean particle size of lactose granules vs. binderconcentration (25).
The intragranular bonds formed during granule drying that contribute to thetablet strength include cohesion of binder ﬁlm and binder substrate adhesion. Jarosz
and Parrott (52) showed that the radial and axial tensile strengths of dicalcium
phosphate tablets increased with increasing concentrations of PVP in the formulation (Fig. 4).
High molecular weight PVP produces larger calcium hydrogen phosphate granules than hydrolyzed gelatin and low-viscosity HPMC (38). When compared to PVP,
gelatin-based granules start growing at a lower degree of liquid saturation and thedependence of granule size on binder concentration was more prominent (38). Cutt
et al.(53) compared glass ballotini granules prepared using PVP, hydrolyzed gelatin,and HPMC. PVP produced the least friable granules at lower concentrations and© 2005 by Taylor & Francis Group, LLC

120

Hamed et al.

Figure 2 Crushing strength of wet granulated dicalcium phosphate. Binders: , gelatin;& , potato starch mucilage; , acacia; D, povidone; and , PEG 4000. (From Ref. 51.)

HPMC produced the most friable and smallest granules owing to its lower work ofadhesion and cohesion (53). Gelatin produced the strongest granules that needed
more work to compress due to their higher resistance to deformation (53).
4.1.1.3. Liquid Addition Rate and Wet Massing. Liquid addition rate can signiﬁcantly inﬂuence binder distribution and granular uniformity. Lower water addition rate improves PVP–PVA copolymer distribution and reduces the liquid
requirement to obtain an acceptable granulation (26,54). Hydroalcoholic and alcoholic solutions can behave differently due to heat generation and faster evaporationin high-shear mixers. The effect of liquid addition rate is dependent on the solubilityof the formulation excipients in the solvent used. Slower PVP solution addition rateenhances granule growth and decreases porosity of the insoluble dicalcium phosphate granulations (21); lactose-based formulations, on the other hand, are less sensitive to liquid addition rate (22,49). Increasing the wet massing time of PVP-based
formulations increases granules size and density, while decreasing the percentage ofﬁnes and granule porosity (16,21,49,54).
4.1.1.4. Method of Binder Incorporation. PVP can be incorporated in the
granulation either by dry or by wet addition methods. The method of binder incorporation affects the granule’s properties through its effect on binder dissolution and© 2005 by Taylor & Francis Group, LLC

Binders and Solvents

121

Figure 3 Plot of the mean granule size as a function of binder concentration for the granulation of lactose. (From Ref. 25.)

distribution. However, given the good hydration and high solubility in combination
with the use of high impeller and chopper speed, PVP is usually uniformly distributed when incorporated by either method using water, hydroalcoholic, or alcoholic
solvents. Nevertheless, a higher PVP level may be needed with the dry addition
method to obtain similar granulation results.
4.1.2. Fluid-Bed Granulation
4.1.2.1. PVP Concentration and Molecular Weight. Binder solution concentration is one of the most crucial parameters controlling granule properties in ﬂuid-bed
granulations. Increasing PVP concentration increases the granule size, narrows the
granule size distribution, and improves granule ﬂowability and strength (55,56).
The increase in granule size can be related to the increase in binder solution viscosity with a subsequent increase in droplet size together with an increase in theforce binding the particles at the higher binder concentration.
However, granule size enlargement with increasing PVP level reaches a plateau
at a critical PVP concentration (25,34). Increasing the PVP level beyond this criticalconcentration does not lead to further growth of granules but rather widens the size
distribution and decreases the friability of the granules (25).
4.1.3. Roller Compaction
4.1.3.1. PVP Concentration. The effect of binder concentration on theproperties of granules and tablets prepared by roller compaction is dependent onother processing parameters including feed rate, roll pressure, and speed. Increasing
the binder level increases tablet hardness and decreases their friability due to the© 2005 by Taylor & Francis Group, LLC

122

Hamed et al.

Figure 4 The inﬂuence of povidone on the tensile strength of tablets of dibasic calcium phosphate dihydrate compressed at 2268 kg (______) and at 4536 kg (- - - - -). D, axial; , radial.
(From Ref. 52.)

imparted plasticity of the formed granules (57). However, at high binder level,
increasing the roll pressure increases the tablet friability and decreases the tablet’s
hardness due to the formation of less friable granules with higher fragmentation
resistance during compression (25). When the PVP level was reduced to 1%,
the granules properties were dependent on the drug properties (58). Increasing
the roll pressure in this case had no effect on tablet hardness or friability.
However, increasing the roll and feed rate can lead to a slight decrease in tablet
friability (58).
4.1.4. Extrusion/Spheronization
Several processing factors can affect the binder performance during extrusion andspheronization processes including hydration level, extruder speed, shape, hole size,
spheronizer speed, and residence time. While the use of microcrystalline cellulose
alone or in combination with lactose is widely adopted, the addition of binders can
aid in the formation of a plastic mass than can be easily extruded and spheronized.
Increasing the PVP or starch/gelatin level increases the pellet size and decreases theirfriability (59).
© 2005 by Taylor & Francis Group, LLC

Binders and Solvents

123

When microcrystalline cellulose was spray dried with PVP, HPC, HPMC, NaCMC, and pregelatinized starch, the properties of the produced pellets were
improved in terms of yield, sphericity, and surface smoothness (60). PVP and
HPC were described as superior to other binders in terms of water requirements,
process sensitivity, and yield (60).

4.2. Cellulosic Polymers
4.2.1. High-Shear Granulation
4.2.1.1. Polymer Concentration. The effect of cellulosic polymer concentration on granule properties is dependent on their method of addition. In the wet addition method, increasing the concentration of HPC, different viscosity grades of
HPMC and MC in lactose–cornstarch–microcrystalline cellulose systems increases
the percentage of binder-rich oversize granules (61). The effect can be attributed
to the increase in binder solution viscosity and heterogenous binder distribution.
In the dry addition method, the effect of increasing polymer concentration on a
granule’s properties depends on the nature of the polymer and its molecular weight/
viscosity. Increasing the concentration of HPC and low-viscosity HPMC (3 cP)
increases the median granule size (61). Increasing the concentration of mediumand relatively high-viscosity HPMC (6 and 15 cP) and MC is accompanied by aslight decrease in granule median size and increase in the percentage of oversized
granules (61). The different behavior can be related to the extent and rate of binder
dissolution as well as binder adhesiveness at different degrees of hydration.

4.2.2. Fluid-Bed Granulation
4.2.2.1. Polymer Concentration. Similar to a high-shear granulation process,the effect of increasing HPMC and HPC concentrations on granule properties isdependent on their method of addition in ﬂuid-bed granulation. The polymers are
more uniformly distributed when added by the wet addition method and the granulesize and strength increase with increasing the polymer concentrations (62,63). In thedry addition method, HPMC is more concentrated in the larger granules andthe granule size is independent of the concentration of HPMC (62,64). Agitating
the ﬂuid bed, however, showed no difference in HPMC and HPC distributions
between the wet and dry addition methods (65). In general, HPC produced stronger
granules than HPMC when added in the dry state since it maintains its ﬂexibility andadhesiveness at low moisture content, which allows more binding during drying (65).
Increasing the level of MC, on the other hand, is not accompanied by an increase in
granule size or strength when it is included by both dry and wet addition methods(65). MC has the lowest thermal gelation temperature and thus it loses its adhesiveness at the low moisture level applied in ﬂuid-bed granulation.

4.3. Gelatin
Gelatin was one of the most commonly used binders during the 1960s and 1970s.
Recently, the use of gelatin in pharmaceutical formulations has signiﬁcantly reduced.
Many factors contributed to the lower popularity of gelatin including its high© 2005 by Taylor & Francis Group, LLC

124

Hamed et al.

binding ability and the resultant slow tablet disintegration, and perhaps most importantly, the introduction of new semisynthetic binders whose methods of preparation
are easier and exhibited better reproducibility and reliability than gelatin.
In gelatin-based formulations, granule properties are highly sensitive to thelevel of gelatin used (54,66). Gelatin produces stronger granules than CMC, PEG(67,68), MC (69), acacia, and PVP (25) due to the high tensile strength of the gelatinﬁlm compared to other binders. In ﬂuid-bed granulation processes, increasing thegelatin concentration increases the granular size up to a certain critical concentration
beyond which the granule size becomes independent of gelatin concentration (25).
The granulation method can affect the properties of granules and tablets prepared using gelatin through their effect on gelatin distribution within the granules.
Acetaminophen granules and tablets prepared by wet massing, roller compaction,and spray drying of the substrate-binder slurry were compared (70–72). Wet massing
produced a sponge-like binder matrix embedding substrate particles while the roller
compaction produced a distribution of discrete binder particles in the substrateparticles. Spray drying coated the granules with an outer shell of the binder andproduced superior tablets when compared to wet massing and roller compaction(70–72).
4.4. Starch
Despite the reproducibility problems associated with a variety of starch sources andthe method of paste formation, starch paste is still a relatively popular binding agent
in the pharmaceutical industry owing to its superior compatibility with many drugs.
The granule properties are greatly affected by the method of starch paste preparation, in particular the gelatinization temperature. Starches obtained from different
sources start gelatinization at different temperatures (corn starch starts at 75 C
and potato starch starts at 60 C) and yield pastes with different concentration gradient viscosities (73). Increasing the temperature at which starch is gelatinizedincreases the degree of gelatinization with a subsequent increase in tablet hardness(73). Variability in ascorbic acid tablet properties decreases when starch paste wasprepared and pumped under precise temperature control (74).
Starch paste concentration can also affect granule properties. When comparedwith diluted paste (5%, w/w) with good ﬂuidity, a concentrated paste (15%, w/w)
with high viscosity produced lactose granules with a sharper particle size distribution
when using a high-shear mixer (75). Nevertheless, high impeller speed and longer
processing time was needed for deaggregation and a better distribution of theconcentrated starch paste. However, diluted starch paste produced stronger granules, better compressibility, and longer disintegration time (76).
Starch can also be used as a disintegrant owing to its wicking and swelling
properties. Starch paste by itself is not sufﬁcient to introduce effective disintegration
and a disintegrant, starch or other, is usually recommended to enhance the effect of
the starch introduced as a paste. When the quantity of disintegrant starch exceedsthat of paste starch, the disintegration time decreases as the compression force
increases. When paste starch is used in higher quantity than dry, the disintegration
time increases with compression force. The effect can be related to different disintegration mechanisms introduced by disintegrant and starch pastes (77).
When starch is dextrinized by the addition of a-amylase, the resultant paste
produces stronger granules with better ﬂowability that produce tablets with shorter
disintegration time, lower friability, and less variability in weight and hardness.
© 2005 by Taylor & Francis Group, LLC

Binders and Solvents

125

However, excessive dextrinization leads to the formation of paste with lower adhesive and tackiness properties and poor binding capabilities (78). Starch can be also
modiﬁed through pregelatinization or cross-linking. Cross-linking does not improve
the granulation ability of conventional starch. When compared to conventionaland cross-linked starches, pregelatinized starch yields coarser granules with lower
friability (79).

REFERENCES
1. Wade A, Walker PJ, eds. Handbook of Pharmaceutical Excipients. 2nd ed. London: The
Pharmaceutical Press, 1994.
2. Lieberman HA, Lachman L, Schwartz JB, eds. Pharmaceutical Dosage Forms: Tablets.
Vol. 1. 2nd ed. New York: Marcel Dekker, Inc., 1989.
3. Kristensen HG. Binders. Encycl Pharm Technol 1993; 451–465.
4. Mendes RW, Roy SB. Tableting excipients, part II. Pharm Tech 1978; 3:61–74.
5. Odeku OA, Itiola OA. Evaluation of Khaya gum as a binder in a paracetamol tablet
formulation. Pharm Pharmacol Commun 1998; 4:183–188.
6. Deodhar UP, Paradkar AR, Purohit, AP. Preliminary evaluation of leucaena leucocephala seed gum as a tablet binder. Drug Dev Ind Pharm 1998; 24(6):577–582.
7. Chukwunweike Onukwo G, Okoye J. Evaluation of anacardium occidentale gum asa binder in lactose based tablet formulations. Bole Chim Farm 1997; 136:569–574.
8. Antony PJ, Sanghavi NM. A new binder for pharmaceutical dosage forms. Drug Dev
Ind Pharm 1997; 23(4):417–418.
9. Attama AA, Adikwu MU, Esimone CO. Binary combination of detarium gum and veegum as a binder in sodium salicylate tablets. Bole Chim Farm 1999; 138:199–202.
10. Soyeux P, Delacourte A, Delie B, Lefevre P, Boniface B. Inﬂuence of optimization ofoperating parameters with a new binder in wet granulation. I: use in powder form.
Eur J Pharm Biopharm 1998; 46:95–103.
11. Aiedeh KM, Taha MO. Synthesis of chitosan triethylene glycol phthalate and its evaluation as a binder in wet granulation procedures. Die Pharmazie 1999; 54:614–619.
12. Vromans H, Poels-Janssen HGM, Egermann H. Effect of high shear granulation on
granulate homogeneity. Pharm Dev Technol 1999; 4:297–303.
13. Van den Dries K, Vromans H. Relationship between inhomogeneity phenomenon andgranule growth mechanisms in a high-shear mixer. Int J Pharm 2002; 247:167–177.
14. Paris L, Stamm A. Optimal massing liquid volume determination by energy consumption
measurement: study of the inﬂuence of some physical properties of solvent and products
used. Drug Dev Ind Pharm 1985; 11(2,3):361–386.
15. Tapper GI, Lindberg NO. Granulation of some lactose qualities with different particle
size distributions in a domestic type mixer. Acta Pharm Suec 1986; 23:47–56.
16. Schaefer T, Holm P, Kristensen HG. Wet granuation in laboratory scale high shear
mixer. Pharm Ind 1990; 52(9):1147–1153.
17. Iveson SM, Lister JD, Ennis BJ. Fundamental studies of granule consolidation part 2:
effects of binder content and binder viscosity. Powder Technol 1996; 88:15–20.
18. Iveson SM, Lister JD. Fundamental studies of granule consolidation part 2: quantifying
the effects of particles and binder properties. Powder Technol 1998; 99:243–250.
19. Wells JI, Walker CV. The inﬂuence of granulating ﬂuids upon granule and tablet properties: the role of secondary binding. Int J Pharm 1983; 15:97.
20. Dias VH, Pinto JF. Identiﬁcation of the most relevant factors that affect and reﬂect thequality of granules by application of canonical analysis. J Pharm Sci 2002; 91(1):273–281.
21. Schaefer T, Holm P, Kristensen HG. Comparison between granule growth in a horizontal and a vertical high speed mixer. I. Granulation of dicalcium phosphate.. Arch Pharm
Chem Sci Ed 1984; 14:1–16.
© 2005 by Taylor & Francis Group, LLC

126

Hamed et al.

22. Schaefer T, Holm P, Kristensen HG. Comparison between granule growth in a horizontal and a vertical high speed mixer. II. Granulation of lactose. Arch Pharm Chem Sci Ed
1986; 14:17–29.
23. Kristensen HG, Holm P, Jaegerskou A, Schaefer T. Granulation in high speed mixers.
Part 4: effect of liquid saturation on the agglomeration. Pharm Ind 1984; 46(7):763–767.
24. Holm P, Jaegerskou A, Schaefer T, Kristensen HG. Granulation in high speed mixers.
Part 1: effect of process variables during kneading. Pharm Ind 1983; 45(8):806–811.
25. Rohera BD, Zahir A. Granulations in a ﬂuidized-bed: effect of binders and their concentrations on granule growth and modeling the relationship between granules sizeand binder concentration. Drug Dev Ind Pharm 1993; 19(7):773–792.
26. Holm P, Schaefer T, Larsen C. End point detection in a wet granulation process. Pharm
Dev Technol 2001; 6(2):181–192.
27. Holm P. Effect of impeller and chopper design on granulation in a high speed mixer.
Drug Dev Ind Pharm 1987; 13(9–11):1675–1701.
28. Healey JNC, Rubinstein MH, Walter V. The mechanical properties of some binders usedin tableting. J Pharm Pharmac 1974; (suppl 26):41.
29. Shangraw RF, Demarest DA Jr. A survey of current industrial practices in the formulation and manufacture of tablets and capsules. Pharm Tech 1993; 17:32.
30. Readind SJ, Spring MS. The effects of binder ﬁlm characteristics on granule and tablet
properties. J Pharm Pharmac 1984; 36:421–424.
31. Rowe RC. Binder–substrate interactions in granulation: a theoretical approach based on
surface free energy and polarity. Int J Pharm 1989; 52:149–154.
32. Rowe RC. Surface free energy and polarity effects in the granulation of a model system.
Int J Pharm 1989; 53:75–81.
33. Rowe RC. Polar/non-polar interactions in the granulation of organic substrates withpolymer binding agents. Int J Pharm 1989; 56:117–122.
34. Planinsek O, Pisek R, Trojak A, Srcic S. The utilization of surface free-energy parameters
for the selection of a suitable binder in ﬂuidized bed granulation. Int J Pharm 2000;
207:77–88.
35. Cutt T, Fell JT, Rue PJ, Spring MS. Granulation and compaction of a model system. I.
Granule properties. Int J Pharm 1986; 33:81–87.
36. Ennis BJ, Tardos G, Pfeffer R. A microlevel-based characterization of granulation phenomena. Powder Technol 1991; 65:257–272.
37. Hoornaert F, Wauters PAL, Meesters GMH, Pratsinis SE, Scarlett B. Agglomeration
behavior of powders in a lodige mixer granulator. Powder Technol 1998; 96:116–128.
38. Ritala M, Jungersen O, Holm P, Schaefer T, Kristensen HG. A comparison between binder in the wet phase of granulation in a high shear mixer. Drug Dev Ind Pharm 1986;
12(11–13):1685–1700.
39. Parker MD, York P, Row RC. Binder–substrate interaction in wet granulation. 2: theeffect of binder molecular weight. Int J Pharm 1991; 72:243–249.
40. Pepin X, Blanchon S, Couarraze G. Power consumption proﬁles in high-shear granulation. I: liquid distribution in relation to powder and binder properties. J Pharm Sci 2001;
90(3):322–331.
41. Wikberg M, Alderborn G. Compression characteristics of granule materials. VII. The
effect of intragranular binder distribution on the compactibilty of some lactose granulations. Pharm Res 1993; 10(1):88–94.
42. Alderborn G. Granule properties of importance to tableting. Acta Pharm Suec 1988;
25:229–238.
43. Shah NH, Railkar AS, Phuapradit W, Zeng FW, Chen A, Infeld MH, Malick W. Effectof processing techniques in controlling the release rate and mechanical strength of hydroxypropyl methylcellulose based hydrogel matrices. Eur J Pharm Biopharm 1996; 42(3):183–187.

© 2005 by Taylor & Francis Group, LLC

Binders and Solvents

127

44. Uzunarslan K, Akbuga J. The effect of moisture on the physical characteristics of ranitidine hydrochloride tablets prepared by different binders and techniques. Drug Dev Ind
Pharm 1991; 17(8):1067–1081.
45. Kiekens F, Zelko R, Remon JP. Effect of the storage conditions on the tensile strength oftablets in relation to the enthalpy relaxation of the binder. Pharm Res 2000; 17(4):490–493.
46. Fitzpatrick S, McCabe JF, Petts CR, Booth SW. Effect of moisture on polyvinylpyrrolidone in accelerated stability testing. Int J Pharm 2002; 246:143–151.
47. Lindberg NO, Jönsson C. The granulation of lactose and starch in a recording high-speed
mixer, Diosna P25. Drug Dev Ind Pharm 1985; 11(2,3):387–403.
48. Vojnovic D, Chicco D, El Zenary H. Doehlert experimental design applied to optimization and quality control of a granulation process in a high shear mixer. Int J Pharm 1996;
145:203–213.
49. Badawy SIF, Menning MM, Gorko MA, Gilbert DL. Effect of process parameters oncompressibility of granulation manufactured in high-shear mixer. Int J Pharm 2000;
198:51–61.
50. Vojnovic D, Selenati P, Rubessa F, Moneghini M. Wet granulation in a small scale highshear mixer. Drug Dev Ind Pharm 1992; 18(9):961–972.
51. Armstrong NA, March GA. J Pharm Sci 1976; 65:200.
52. Jarosz PJ, Parrott EL. Factors inﬂuencing axial and radial strength of tablets. J PharmSci 1982; 71:607–610.
53. Cutt T, Fell JT, Rue PJ, Spring MS. Granulation and compaction of a model system. III.
Compaction properties of the granules. Int J Pharm 1989; 49:157–161.
54. Lindberg NO, Jonsson C. Granulation of lactose in a recording high-speed mixer, Diosna
P25. Drug Dev Ind Pharm 1983; 9(6):959–970.
55. Aulton M, Banks M. The factors affecting ﬂuidized bed granulation. Manuf Chem Aeros
News December 1978.
56. Wan LSC, Heng PWS, Ling BL. Fluidized bed granulation with PVP K90 and PVP
K120. Drug Dev Ind Pharm 1995; 21(7):857–862.
57. Sheskey PJ, Dasbach TP. Evaluation of various polymers as dry binders in the preparation of an immediate-release tablet formulation by roller compaction. Pharm Tech
1995:98–112.
58. Murray M, Laohavichien A, Habib W, Sakr A. Effect of process variables on rollercompacted ibuprofen tablets. Pharm Ind 1998; 60(3):257–262.
59. Varshosaz J, Kennedy RA, Gipps EM. Effect of binder level and granulating liquid on
phenylbutazone pellets prepared by extrusion–spheronization. Drug Dev Ind Pharm
1997; 23(6):611–618.
60. Law MFL, Deasy PB. Use of hydrophilic polymers with microcrystalline cellulose toimprove extrusion–spheronization. Eur J Pharm Biopharm 1998; 45:57–65.
61. Kokubo H, Nakamura S, Sunada H. Effect of several cellulosic binders on particle size
distribution of granules prepared by a high-speed mixer. Chem Pharm Bull 1993;
41(12):2151–2155.
62. Kokubo H, Nakamura S, Sunada H. Effect of several cellulosic binders on particle
size distribution in ﬂuidized bed granulation. Chem Pharm Bull 1995; 43(8):1402–1406.
63. Xu, G, Sunada H, Zhang R. Indomethacin controlled release matrix tablet prepared by
wet granulation procedure. Chem Pharm Bull 1997; 45(1):214–216.
64. Dasbach T, Sheskey P, Caswell O. Evaluation of the Use of Methocel in Fluid Bed Granulation as a Dry Binder. Dow Product Information Publications, 2002.
65. Kokubo H, Nakamura S, Sunada H. Effect of several cellulosic binders and method of
their addition on the properties and binder distribution of granules prepared in an agitating ﬂuidized bed. Chem Pharm Bull 1998; 46(3):488–493.
66. Nagykaldi VA, Gyarmati L. Untersuchungen zur feuchtgranulation im diosna-mscher V
25. Pharm Ind 1980; 42(5):526–531.
© 2005 by Taylor & Francis Group, LLC

128

Hamed et al.

67. Solvang S, Finholt P. Effect of tablet processing and formulation factors on dissolution
rate of the active ingredient in human gastric juice. J Pharm Sci 1970; 59(1):49–52.
68. El-Gindy NA, Smaha MW, El-Marandy HA. Evaluation of binder activities on the physical properties and compression characteristics of granules prepared by two different
modes. Drug Dev Ind Pharm 1988; 14(7):977–1005.
69. Schaefer T, Worts O. Control of ﬂuidized bed granulation. IV. Effect of binder solution
and atomization on granule size and size distribution. Arch Pharm Chem Sci Ed 1978;
6:14–25.
70. Seager H, Burt I, Ryder J, Rue PJ, Murray S, Beal N, Warrack JK. Int J Pharm Tech
Prod Manuf 1998; 1:36.
71. Seager H, Rue PJ, Burt I, Ryder J, Warrack JK. Int J Pharm Tech Prod Manuf 1981;
2:41.
72. Rue PJ, Seager H, Ryder J, Burt I. Int J Pharm Tech Prod Manuf 1980; 1:2.
73. Makino T, Kitamori N. Importance of gelatinization degree of starch paste binder in
hardness and disintegration of tablets. Chem Pharm Bull 1995; 43(3):514–516.
74. Makino T, Wada N, Kitamori N. Preparation temperature in ﬂuidized-bed granulation
on resultant tablet properties. Chem Pharm Bull 1995; 43(3):473–475.
75. Makino T, Kitamori N. Effect of starch paste concentration on particle size distributionof ﬁne granules produced by agitation granulation. Chem Pharm Bull 1995; 43(7):1231–1233.
76. Hill PM. Effect of compression force and corn starch on tablet disintegration time.
J Pharm Sci 1975; 65(11):1694–1696.
77. Hill PM. Starch paste granulation: binder dilution effects on granulations and tablets.
J Pharm Sci 1976; 65(2):313–314.
78. Bandyopadhyay AK, Chaudhuri B, Bhattacharjee PK. Starch paste granulation I: effectof dextrinized corn starch mucilage as binding agent on granulation and tablet quality.
Aust J Pharm Sci 1980; 9(3):85–89.
79. Visavarungroj N, Herman J, Remon JP. Crosslinked starch as binding agent. I. Conventional wet granulations. Int J Pharm 1990; 59:73–78.

© 2005 by Taylor & Francis Group, LLC

5Spray Drying and Pharmaceutical
Applications
Metin Çelik
Pharmaceutical Technologies International, Inc., Belle Mead, New Jersey, U.S.A.

Susan C. Wendel
Elan NanoSystems, King of Prussia, Pennsylvania, U.S.A.

1. INTRODUCTION
Spray drying is one of the oldest forms of drying and one of the few technologies
available for the conversion of a liquid, slurry, or low-viscosity paste to a dry solid(free-ﬂowing powder) in one unit operation (1). Figure 1 shows a general spray-drying process schematically. The simplicity and ﬂexibility of the spray-drying process
make it ideal for handling a wide variety of pharmaceutical products.
1.1. BackgroundThe ﬁrst detailed description of the drying of products in spray form was mentioned
in a patent of 1872 entitled ‘‘Improvement of Drying and Concentration of Liquid
Substances by Atomizing’’ (2). However, this process found its ﬁrst signiﬁcant applications in the milk and detergent industries in the 1920’s (3). In current times, spraydrying is utilized extensively in many aspects of our daily life from food products,
cosmetics, and pharmaceuticals to chemicals, fabrics, and electronics. Typicalpharmaceutical examples include spray-dried enzymes (such as amylase, protease,lipase, and trypsin), antibiotics (such as sulfathiazole, streptomycin, penicillin, andtetracycline) and many other active pharmaceutical ingredients, vitamins (such as
ascorbic acid and vitamin B12), and excipients for direct compression (such as lactose,mannitol, and microcrystalline cellulose).
1.2. Advantages and Limitations
There are several reasons why the technology of spray drying has found many applications in numerous industries. It is a continuous process. As long as liquid feed cancontinue to be supplied to the drying system the spray-dried product will continue tobe produced. In some instances, this process has been operated for months without
interruption. The physical properties of the resulting product (such as particle size
129
© 2005 by Taylor & Francis Group, LLC

130

Çelik and Wendel

Figure 1 A schematic representation of a general spray-drying process with primary and secondary product separation.

and shape, moisture content, and ﬂow properties) can be controlled through theselection of equipment choices and the manipulation of process variables. The actual
spray-drying process is almost instantaneous as the major portion of the evaporation
takes place in as short a time as milliseconds or a few seconds at most, depending on
the design of the equipment and process conditions. This makes spray drying well
suited for heat-sensitive products. In addition, corrosive and abrasive materials
can be readily accommodated because the contact between the mechanical partsand materials is minimal as compared to other granulation processes. Also, spraydryers have few moving parts. In fact, careful selection of various components canresult in a system having no moving parts in direct contact with the product. Operation
requirements of small and large dryers are the same. This makes spray drying a laborcost-effective process, especially for high-volume products. Last, the spray-drying
process can be fully automated. Commercial-scale spray dryers are controlled by programmable logic controllers or solid-state controllers. These control systems monitor
exhaust air temperature or humidity and provide an input signal that, by way of a
setpoint, modulates the energy supplied to the process (4).
Like all other granulation processes, spray drying also has some limitations.
For example, it is not typically well suited for producing granules with mean particle
size >200 mm as shown in Figure 2. It also has poor thermal efﬁciency at lower inlet
temperatures and the exhaust air stream contains heat, which often requires sophisticated heat exchange equipment for removal.

2. SPRAY DRYING PROCESS STAGESThe spray-drying process is carried out in three fundamental stages as shown
schematically in Figure 3. The ﬁrst stage is atomization of a liquid feed into ﬁne© 2005 by Taylor & Francis Group, LLC

Spray Drying and Pharmaceutical Applications

131

Figure 2 Range of mean particle sizes achievable by control of atomizer operation at low to
medium feed rates.

droplets. In the second stage, spray droplets mix with a heated gas stream and thedried particles are produced by the evaporation of the liquid from the droplets.
The ﬁnal stage involves the separation of the dried powder from the gas stream
and collection of these powders in a chamber. The second stage (i.e., the mixing
and drying step) has also been considered as separate steps (5). The following sections
detail each of these stages, their process parameters, and related equipment details.

2.1. Atomization
Atomization is the process by which a liquid is disintegrated into many ﬁne droplets.
The formation of a spray with high surface/mass ratio is highly critical for optimum
liquid evaporation conditions and, consequently, the desired properties of the resulting product. Although ideally the sizes of all droplets should be the same, in practicalterms formation of droplets with a narrow size distribution would be satisfactory.
2.1.1. Atomizer Types and Designs
Formation of the atomized spray requires application of a force. The commerciallyavailable systems employ one of the following in order to create an atomized spray:
centrifugal energy, pressure energy, kinetic energy or sonic energy, and vibrations.
2.1.1.1. Centrifugal Atomizers. Centrifugal atomizers utilize either a rotating
disk or a wheel to disintegrate the liquid stream into droplets (6). Examples of rotary
atomizers are shown in Figure 4. These devices form a low-pressure system and awide variety of spray characteristics can be obtained for a given product throughcombinations of feed rate, atomizer speed, and atomizer design. The droplet size distribution is fairly narrow for a given method and process conditions but the mean
droplet size can be varied from as small as 15 mm to as large as 250 mm, dependingon the amount of energy transmitted to the liquid. Larger mean sizes require larger
drying chamber diameters. Wheels are well suited for producing sprays in the ﬁne tomedium-coarse size range while disks are used to produce coarse sprays.
Rotary atomizers normally operate in the range of 5000–25,000 rpm with wheel
diameter of 5–50 cm. The mean size of the droplet produced is inversely proportional© 2005 by Taylor & Francis Group, LLC

132

Çelik and Wendel

Figure 3 Schematic of spray-drying process shown in stages: stage I: atomization; stage II:
spray–air contact and evaporation; stage III: product separation. (From Ref. 5.)

to the wheel speed and directly proportional to the feed rate and its viscosity. Solid
content and surface tension are the other factors having minor effects on the droplet
size. For example, an increase in feed rate may slightly increase the particle size, but
the use of a variable-speed drive on the centrifugal atomizer facilitates correction to
the speciﬁed size.
Centrifugal atomizer designs include wheels with vanes or bushings and vaneless disks. Vaned atomizer wheels produce sprays of high homogeneity and are themost commonly used as compared to other designs. In this type of atomizer, liquid
fed onto a wheel moves across the surface until contained by the rotating vane.
© 2005 by Taylor & Francis Group, LLC

Spray Drying and Pharmaceutical Applications

133

Figure 4 Common rotary atomizers. (Courtesy of Niro Pharma Systems.)

The liquid ﬂows outward under the inﬂuence of centrifugal force and spreads overthe vane, wetting the vane surface as a thin ﬁlm. At very low liquid vane loadings,
the thin ﬁlm can split into streams. No liquid slippage occurs on a wheel once liquid
has contacted the vanes. Whether radial or curved, the vanes prevent transverse ﬂow
of liquid over the surface. Abrasive materials are best handled using atomizer wheels
with bushings. Since the feed material is in direct contact with rotating parts,
the bushings feature wear-resistant surfaces and require additional maintenance.
Vaneless (disk) designs are often applied when coarse powders are required at highproduction rates.
Bulk pharmaceutical excipients and ﬁne chemicals, such as antacids, are often
produced using centrifugal atomizers. The particles produced by this technique are
generally free ﬂowing and, unless intentionally produced with very ﬁne atomization,
dust free. The porous structure of the particles provides increased solubility and therelatively low density and friability of these particles result in generally good compaction properties. Also, the batch-to-batch reproducibility and dryer-to-dryer transferability of this technique are excellent. As mentioned earlier, if larger spray-driedparticles are desired, larger production drying chambers must be employed.
2.1.1.2. Kinetic Energy Nozzles. Kinetic energy is applied in the form of twoﬂuid or pneumatic atomization. This is the most commonly used atomization technique within the pharmaceutical industry. Here, atomization is accomplished by theinteraction of the liquid with a second ﬂuid, usually compressed air. High air velocities are generated within the nozzle for effective feed contact, which breaks up the feed
into a spray of ﬁne droplets. Neither the liquid nor the air requires very high pressure,with 200–350 kPa being typical. A typical two-ﬂuid nozzle is shown in Figure 5.
Particle size is controlled by varying the ratio of the compressed airﬂow to thatof the liquid. The main advantage of this type of atomization is that the liquid has arelatively low velocity as it exits the nozzle; therefore, the droplets require a shorter

Figure 5 Schematic presentation of a typical two-ﬂuid nozzle. (Courtesy of Niro Pharma
Systems.)© 2005 by Taylor & Francis Group, LLC

134

Çelik and Wendel

ﬂight path for drying. Because many pharmaceutical applications use relatively small
spray dryers, pneumatic nozzles are often used. Another advantage is the simple
design that lends itself to easy cleaning, sterile operation, and minimal contamination. Pneumatic nozzles can be designed to meet the most stringent requirements
for sterile or aseptic applications. Special consideration must be given to supplying
a sterile source of compressed air for atomization.
Another type of kinetic energy nozzle is the three-ﬂuid nozzle. The spraycharacteristics obtained by two- and three-ﬂuid nozzles are similar when atomizing
low-viscosity feeds at up to intermediate feed rates. Use of the second air stream withthree-ﬂuid nozzles causes a waste of energy, except for high feed rates of low-viscosity feeds.
2.1.1.3. Pressure Nozzles. The second most common form of atomization
for pharmaceutical applications is hydraulic pressure nozzle atomization. Here,the feed liquid is pressurized by a pump and forced through a nozzle oriﬁce as ahigh-speed ﬁlm that readily disintegrates into ﬁne droplets. The feed is made torotate within the nozzle, resulting in a cone-shaped spray pattern emerging fromthe nozzle oriﬁce. Rotary motion within the nozzle can be achieved by use of swirl
inserts or spiral grooved inserts (Fig. 6). The swirl inserts have comparatively large
ﬂow passages and enable such nozzles to handle high solids feed without causing any
wear or clogging.
Because the liquid spray exits the nozzle with a relatively high velocity, a spraydrying chamber at least 2.5 m in diameter and 3.0 m in cylinder height is usuallyrequired to operate with pressure nozzles.
The differential pressure across the oriﬁce determines the mean droplet diameter. The distribution about the mean is similar to, but in most cases is narrower

Figure 6 Schematic presentation of pressure nozzles. (Courtesy of Niro Pharma Systems.)© 2005 by Taylor & Francis Group, LLC

Spray Drying and Pharmaceutical Applications

135

than, two-ﬂuid atomization. In contrast, sprays from pressure nozzles handling highfeed rates are generally wider in distribution and coarser than sprays from vaned
wheels. At low feed rates, spray characteristics from nozzles and wheels are comparable. Mean size of spray is directly proportional to the feed rate and inversely
proportional to the pressure.
Pressure nozzles are generally used to form coarse spray-dried particles (120–
300 mm mean particle size) with good ﬂow properties. Antibiotics are a typical application for such a dryer.
2.1.1.4. Sonic Energy Atomizers. The use of sonic energy and vibrations
for atomization in spray drying has found growing interest in the last two decades.
However, this type of atomizer has not yet found signiﬁcant commercial applications. The advantages of sonic nozzles operating at low pressure and having wide
ﬂow channels suggest that they may be suitable for abrasive and corrosive materials,
but it is most likely that sonic nozzles will continue to be developed as atomizers for
special applications, such as very ﬁne sprays of mean size 20 mm, where the nature of
the spray angle and cone minimizes droplet coalescence (7).
2.1.2. Atomizer Selection
The function of any atomizer is to produce as homogenous a spray as possible. The
nature of the feed, the characteristics of the spray, and the desired properties of theresulting dried product play very important roles in the selection of the atomizer
type. With proper design and operation, nozzles and rotary atomizers can produce
sprays having similar droplet size distribution. In all atomizer types, the size of droplets can be altered by either increasing or decreasing the atomization energy (e.g.,increased atomization energy results in smaller droplet size). For a given amountof energy, the viscosity and surface tension values of the feed inﬂuence the size ofthe droplet (e.g., higher values result in larger spray droplets).
In general, rotary atomizers are utilized to produce a ﬁne to medium-coarse
product with a mean size of 20–150 mm though larger spray-dried particles can also
be obtained if a very large drying chamber is used. Nozzle atomizers are used to produce spray-dried product with a coarse mean particle size of 150–300 mm (8).
For a given spray-drying application, the selection between rotary and nozzle
atomizers involves the following considerations (9):
1. The feed capacity range of the atomizer for which complete atomization is
attained
2. Atomization efﬁciency
3. The droplet-size distribution at identical feed rates
4. Spray homogeneity
5. Operational ﬂexibility
6. The suitability of dryer chamber design for atomizer operation
7. Feed properties
8. The atomizer experience available for the product in question.

2.2. Spray–Air Contact and Evaporation
Once the liquid is atomized, it must be brought into intimate contact with the heatedgas for evaporation to take place equally from the surface of all droplets. This contact step takes place within a vessel called the drying chamber. The heated gas is© 2005 by Taylor & Francis Group, LLC

136

Çelik and Wendel

introduced into the chamber by an air dispenser, which ensures that the gas ﬂows
equally to all parts of the chamber.
2.2.1. Spray–Air Contact
The way in which spray contacts the drying air is a critical factor in spray-drying
operations. Spray–air contact is determined by the position of the atomizer in relation
to the air inlet.
Inlet air is introduced to the drying chamber via an air disperser, which uses perforated plates, or vaned channels through which the gas is equalized in all directions.
It is critical that the air entering the disperser is well mixed and has no temperature
gradient across the duct leading into it; otherwise, the drying will not be even within
the chamber. The air disperser is normally built into the roof of the drying chamber
and the atomization device is placed in or adjacent to the air disperser. Thus, instantand complete mixing of the heated drying gas with the atomized clouds of droplets
can be achieved.
Spray droplet movement is classiﬁed according to the dryer chamber layout
and can be designated as cocurrent, countercurrent, or mixed ﬂow although these
designations are not complete representations of the actual conditions.
1. Cocurrent ﬂow is the conﬁguration in which the spray and drying air passthrough the dryer in the same direction. This arrangement is widely used
and is ideal for heat-sensitive products. Spray evaporation is rapid, the drying air cools accordingly, and overall evaporation times are short. The particles are not subject to heat degradation. In fact, low-temperature
conditions are achieved throughout the entire chamber in spite of very
hot air entering the chamber.
2. Countercurrent ﬂow is the conﬁguration in which the spray and the air
enter at the opposite ends of the dryer. This arrangement has excellent heatutilization. Countercurrent ﬂow is used with nozzle atomization and is well
suited for meeting the ﬁnal spray-dried properties of non-heat-sensitive
materials.
3. Mixed ﬂow is the conﬁguration in which both cocurrent and countercurrent ﬂows are incorporated. The advantage of this type of arrangement
is that coarse free-ﬂowing products can be produced in relatively small drying chambers. In mixed ﬂow systems the powder is subjected to higher particle temperature. A mixed ﬂow system can be integrated with a ﬂuid-bed
drying chamber when lower particle temperatures are necessary.
The spray–air contact design can be selected according to the required particle
size and the temperature to which the dried particle can be subjected. For example, if
a low product temperature must be maintained at all times, a cocurrent rotary atomizer is selected for producing ﬁne particles while a countercurrent pressure atomizer is preferred for obtaining coarser particles. If coarse particles with predetermined
porosity and bulk density properties are desired, a countercurrent pressure nozzle
atomizer is well suited as high product temperature can be maintained for obtaining
the desired porosity and bulk density of the resulting product. For obtaining coarse
spray-dried particles of heat-sensitive materials, a mixed ﬂow nozzle system can beselected. Integration with a ﬂuid bed is recommended for agglomerated or granulated powders.
© 2005 by Taylor & Francis Group, LLC

Spray Drying and Pharmaceutical Applications

137

2.2.2. Drying
The largest and most obvious part of a spray-drying system is the drying chamber.
This vessel can be tall and slender or have a large diameter with a short cylinder
height. Selecting these dimensions is based on two process criteria that must be
met. First, the vessel must be of adequate volume to provide enough contact time
between the atomized cloud and the heated gas. This volume is calculated by determining the mass of air required for evaporation and multiplying by the gas residencetime, which testing or experience dictates.
The second criterion is that all droplets must be sufﬁciently dried before they
contact a surface. This is where the vessel shape comes into play. Centrifugal atomizers require larger diameters and shorter cylinder heights. In contrast, nozzle atomizer systems must have narrower and taller drying chambers. Most spray dryer
manufacturers can estimate, for a given powder’s mean particle size, the dimensions
that are needed to prevent wet deposits on the drying chamber walls.
2.2.3. Drying Gas
In pharmaceutical applications of spray drying, the feedstock can be prepared bysuspending or dissolving the product to be spray dried in water. However, the utilization of a wide variety of organic solvents in feedstock preparations is also common.
Alcohols, such as ethanol, methanol, and isopropanol are preferred organic solventsin spray drying of pharmaceuticals although other organic solvents such as ketones
are also used in other industries; often the synthesis process upstream from the drying step determines the solvent selection. The drying characteristics of the solvents
are also important. For example, a solvent with a low boiling point may be the only
choice for heat-sensitive materials.
Although evaporating organic solvents by a spray drying process is very efﬁcient due to the resulting shorter residence time, as compared to the evaporationof water, the risk of explosion makes the use of these solvents very hazardous. Therefore, an inert gas, usually nitrogen instead of air, must be used as drying gas for theevaporation of the solvents. Use of inert gas requires the use of a closed-cycle system
for spray drying in order to recover the solvent and to limit the gas usage. However,for small drying tests and laboratory work, the nitrogen can be used without recirculation, using a carbon bed on the exhaust gas to collect the solvent.
2.3. Dried Powder Separation
Powder separation from the drying air follows the drying stage. In almost every case,spray-drying chambers have cone bottoms to facilitate the collection of the dried
powder.
Two systems are utilized to collect the dried product. In the ﬁrst type of system,
when coarse powders are to be collected, they are usually discharged directly fromthe bottom of the cone through a suitable airlock, such as a rotary valve. The gas
stream, now cool and containing all of the evaporated moisture, is drawn fromthe center of the cone above the cone bottom and discharged through a side outlet.
In effect, the chamber bottom acts as a cyclone separator. Because of the relatively
low efﬁciency of collection, some ﬁnes are always carried with the gas stream. These
must be separated in a high-efﬁciency cyclone followed by a wet scrubber or in afabric ﬁlter (bag collector). Fines collected in the dry state (bag collector) are often
added to the larger powder stream or recycled. When very ﬁne powders are being© 2005 by Taylor & Francis Group, LLC

138

Çelik and Wendel

produced, the side outlet is often eliminated and the dried product together with theexhaust gas is transported from the chamber through a gooseneck at the bottom of
the cone. The higher loading of entrained powder affects cyclone design but has little
or no effect on the bag collector size.
In the second type of system, total recovery of dried products takes place in theseparation equipment. This type of system does not need a product-conveying system; therefore, the separation efﬁciency of the equipment becomes very critical.
Separation of dried product from the air inﬂuences powder properties by virtue ofthe mechanical handling involved during the separation stage. Excessive mechanicalhandling can produce powders with a high percentage of ﬁnes.

3. PROCESS LAYOUTS
The most widely used spray-drying process layout is the open-cycle layout in which
the air is drawn from the atmosphere, passed through the drying chamber, andexhausted back to the atmosphere. This layout is used for aqueous feedstock andemploys air as the drying gas. There are numerous variations of open-cycle layout
systems, two of which are common in pharmaceutical applications (Fig. 7) (10).
The most common and cost-effective layout utilizes a high-efﬁciency cyclone andscrubber (Fig. 7A). In this layout, the loss of very ﬁne particles to the atmospherecannot be prevented. If the desired particle size of the spray-dried product is too
small to be recovered by cyclone and scrubber systems then the use of a layout
employing a bag ﬁlter is recommended (Fig. 7B).
Closed-cycle layouts are mainly used for nonaqueous (i.e., organic solvents)
feedstock and generally require the use of inert gas as the drying medium. They
are also employed when ﬂammable, explosive, or toxic products are used in the spraydrying process or atmospheric pollution is not permitted. Figure 8 illustrates theﬂow diagram for a closed-cycle layout schematically (11). These systems requirea good control of the scrubbing–condensing stage at precise temperatures.

Figure 7 Typical layout of the open-cycle spray dryer system: (A) cyclone/scrubber and(B) bag ﬁlter. a, air; f, feed; p, spray-dried product. 1, spray dryer chamber; 2, cyclone;
3, wet scrubber; 4, bag ﬁlter/collector. (Adapted from Ref. 10.)© 2005 by Taylor & Francis Group, LLC

Spray Drying and Pharmaceutical Applications

139

Figure 8 Typical layout of the closed-cycle spray dryer system: c, coolant (diluent); f, feed; l,solvent recovery; p, spray-dried product. 1, dried powder; 2, cyclone; 3, liquid-phase indirect
heater; 4, heat exchanger; 5, scrubber–condenser. (Adapted from Ref. 11.)

In addition to open-cycle and closed-cycle systems, there are semiclosed-cycle
layouts which are not strict in terms of type of drying medium and are operated
under slight vacuum conditions.

4. THEORY OF SPRAY DRYING FUNDAMENTALS
4.1. Droplet Formation
4.1.1. Rotary Atomizer
During rotary atomization, bulk liquid feed is accelerated to a high centrifugal velocity. During this acceleration, the liquid feed forms a thin ﬁlm over the rotating surface. For smooth disk atomizers, the ﬁlm or liquid feed disintegrates into droplets at
the edge of the wheel by one of the three mechanisms: (a) direct droplet formation,(b) ligament formation, or (c) sheet formation as shown in Figure 9, respectively. The
type of droplet formation mechanism that occurs during processing is a function of
the surface tension and viscosity of the feed as well as the wheel speed and feed rate(12). Direct droplet formation occurs at low wheel speeds when surface tension andviscosity dominate the atomization mechanism. The other variables that could
potentially affect direct droplet formation are inertia and air friction. However,
due to liquid slippage on the surface of the wheel, inertia is limited and the low
release velocities minimize air friction effects so that the effect of these variables
is minimized at low wheel speeds. As wheel speeds and feed rates increase, theamount of feed in each vane increases giving rise to ligaments instead of dropletson the periphery of the wheel. These ligaments disintegrate into droplets with larger
droplets forming from feeds with higher viscosity and higher surface tension.
While the ﬁrst two atomization mechanisms are partially controlled by the physicalproperties of the feed, sheet formation is a result of inertial forces becoming predominant over these properties. At high wheel speeds and feed rates, the ligaments join
to form a liquid sheet that extends beyond the edge of the wheel. The liquid sheet© 2005 by Taylor & Francis Group, LLC

140

Çelik and Wendel

Figure 9 Smooth disk atomizer droplet formation mechanisms: (A) direct droplet formation,(B) ligament formation, and (C) sheet formation. (From Ref. 12.)disintegrates into a broad droplet distribution as it extends from this edge. In orderto produce a narrow droplet distribution from this mechanism, high wheel speeds are
combined with low wheel loading, which is often achieved with a decreased feed rate.
In contrast, a vaned wheel directs the ﬂow of the liquid feed across the surface
of an inner liquid distributor in which liquid slippage over the surface of the distributor occurs until there is contact with the vane or channel. The feed then ﬂows outward due to centrifugal force and forms a thin ﬁlm across the surface of the vane. As
the liquid ﬁlm leaves the edge of the vane, droplet formation occurs as a result of theradial and tangential velocities experienced. Atomizer wheel characteristics thatinﬂuence droplet size include speed of rotation, wheel diameter, and wheel design,e.g., the number and geometry of the vanes.
4.1.2. Two-Fluid Nozzle
Using the two-ﬂuid nozzle, also referred to as a pneumatic nozzle, atomization isachieved by impacting the liquid feed with high-velocity air, which results in highfrictional forces that cause the feed to disintegrate into droplets. In order to achieve
optimal frictional conditions, this high relative velocity between liquid and air can beaccomplished by either expanding the air to sonic velocities or destabilizing the thinliquid ﬁlm by rotating it within the nozzle prior to spray–air contact.
There are several two-ﬂuid nozzle designs available to produce the conditions
necessary for liquid–air contact. A common design is one in which the liquid andair come into contact outside the nozzle. This nozzle is often referred to as an external mixing nozzle and its main advantage is the greater control available over the© 2005 by Taylor & Francis Group, LLC

Spray Drying and Pharmaceutical Applications

141

atomization through the independent control of both the liquid and the air streams.
Other two-ﬂuid nozzle designs include: (a) an internal mixing design with the air andliquid contacting within the nozzle head, (b) a combined internal–external mixing
design created by using two airﬂows in the nozzle head (also called three-ﬂuid),and (c) a pneumatic cup design with liquid–air contact occurring at the rim ofa rotating nozzle head.
In general, two-ﬂuid nozzles are capable of producing small droplet sizes overa wide range of feed rates. These droplets are then carried away from the nozzle by
the momentum of the spray and the expanding atomizing air. The most importantvariable involved in the control of droplet size is the mass ratio of airﬂow to feed
rate, which is also known as the air-to-feed ratio. An increase in this ratio causes
a decrease in droplet size. This ratio generally ranges from 0.1 to 10. At ratios
approaching 0.1, atomization is difﬁcult even for low-viscosity feeds while a ratioof 10 approaches the limit above which atomization occurs using excess energy without an appreciable decrease in particle size (13).
Sprays formed by two-ﬂuid nozzles are symmetrical with respect to the nozzle
axis and have a cone-shaped pattern. The angle of this cone is called the spray angle
and, for two-ﬂuid nozzles, it is narrow and cannot be varied greatly by adjusting the
air-to-feed ratio. The maximum spray angle available is 70–80 , which can beobtained by employing the maximum feed rate and airﬂow in a high-throughput
nozzle. In general, an increase in air pressure will increase the spray angle if the feed
rate is maintained at a constant level as long as the maximum angle has not beenobtained. Spray angles are maintained if an increase in airﬂow is accompanied byan increase in feed rate resulting in a similar air-to-feed ratio.

4.2. Droplet Drying Mechanisms
Evaporation of water from a spray is often characterized using a curve that describes
the change in drying rate as a function of time. This drying rate curve or evaporation
history is a function of temperature, humidity, and the transport properties of thedroplet formulation as well as the air surrounding the droplet. However, many characteristics of droplet evaporation can be characterized using a general drying rate
curve (Fig. 10).
The general drying rate curve has three main phases: an initial drying phase,a phase in which the rate of drying is mainly constant, and a ﬁnal phase during which
the rate of drying decreases (falling rate phase) (15). During the second phase, theremoval of moisture from the droplet is at a near-constant rate representing the highest rate achieved during the evaporation history. This constant evaporation rate
results in a near-constant droplet surface temperature with the wet bulb temperature
representing the droplet temperature. During this phase, the majority of the droplet
moisture is removed. The droplet surface is maintained at saturation by moisturemigration from within the droplet to the surface. In contrast, during the falling ratephase, the rate of moisture migration is rate limiting to the drying rate causing
a decrease in the overall rate of drying. The surface moisture content is no longer
maintained and the droplet temperature rises.
This general drying rate curve is directly applicable to the spray-drying process.
The initial drying phase begins during the spray–air contact phase immediately upon
contact of the droplet with the drying air. During this initial phase, as the drying rateincreases toward equilibrium, a slight increase in droplet surface temperature occurs.
© 2005 by Taylor & Francis Group, LLC

142

Çelik and Wendel

Figure 10 General drying rate curve. (From Ref. 14.)The drying rate continues to increase until equilibrium across the droplet–air interface is established and the drying rate becomes constant. In the later phase, the solid
layer of the spray-dried particle becomes rate limiting to mass transfer and the drying
rate decreases. The evaporation rate continues to decrease until the droplet reaches
equilibrium moisture content with the surrounding air stream unless the product isremoved from the spray dryer before equilibrium moisture content is reached.
In addition, all evaporation histories, regardless of material type or spray dryer
conﬁguration, have two main points in common: the majority of the evaporationis completed in an extremely short time interval, usually <1.5 sec, and the temperature of the drying air decreases rapidly during evaporation.
While the general evaporation history is representative of the processes occurring during spray drying, the actual rate of moisture migration is affected by several
factors including the temperature of the surrounding air. If the inlet temperature isso high that the evaporation rate is higher than the moisture migration rate needed
to maintain surface wetness, the constant rate drying phase is very short. This isbecause a dried layer forms instantaneously at the droplet surface that acts as a barrier to additional moisture transfer and retains moisture within the droplet causing
the surface temperature to be much higher. In contrast, lower inlet temperatures
actually yield a lower initial drying rate with a surface temperature equal to wet bulb
temperature for a longer period of time.
It is important to note that the drying curve is only representative. In reality,
there are no deﬁned points during an evaporation history. Some phases may noteven occur or will be very short depending on the process conditions. One exampleof this is a spray-drying process for a heat-sensitive material where the inlet temperature is low. In this case, the initial phase may extend until a critical point where
moisture migration becomes rate limiting, effectively eliminating the constant rate
drying period. In reality, the actual evaporation rate is dependent on several factors
including the droplet shape, composition, physical structure, and solids concentration. The actual drying time is a sum of the constant rate period and the falling rate
period until the desired moisture content is achieved.
© 2005 by Taylor & Francis Group, LLC

Spray Drying and Pharmaceutical Applications

143

4.3. Effect of Formulation on Droplet-Drying Mechanisms
Droplet composition also plays a signiﬁcant role in droplet evaporation history.
Typically, sprays are differentiated into three main types: pure liquids, feeds containing undissolved solids, and feeds containing dissolved solids (16).
4.3.1. Pure Liquid Sprays
For sprays composed of pure liquids, the droplet evaporates away completely. While
this type of spray is not useful for pharmaceutical formulations, its behavior is representative of very dilute feed materials. The evaporation of pure liquids is dependent
on the dryer conﬁguration. For low-velocity sprays in a low-velocity air stream(countercurrent dryer) or for low-velocity sprays in a high-velocity air stream (cocurrent dryer), the evaporation of the pure liquid spray causes the air temperature andthe evaporation rate to decrease. Pure liquid sprays having a wide droplet distribution evaporate more quickly than narrow distributions having the same mean droplet size due to the smaller droplets in the wide distribution. In addition, the size
distribution of the droplet changes during evaporation. If the initial spray is a homogenous or very narrow distribution, the mean droplet diameter decreases during evaporation. In contrast, if the initial spray is nonhomogenous or a wide distribution,then the mean droplet diameter initially increases prior to decreasing. In general, a
distribution is the best representation of a spray since the mean of this distribution
may not adequately describe all characteristics of the distribution. For dryer conﬁgurations of high relative velocities such as coarse atomization in cocurrent or fountain-type dryers, the droplets travel farther before a given fraction is evaporated.
The relative velocity between droplet and drying air affects evaporation rates moresigniﬁcantly at higher velocities and higher drying temperatures.
4.3.2. Feeds Containing Insoluble Solids
For droplets containing insoluble solids, the droplet temperature is equal to the wet
bulb temperature of the pure liquid droplet during the constant rate phase since insoluble solids have negligible vapor pressure lowering effects. The total drying is thesum of the two drying periods. The drying time for the ﬁrst period is short comparedto the falling rate period. The falling rate period depends on the nature of the solid
phase and can be estimated given the speciﬁc gravity of the feed slurry, the density ofthe dried product, and the thermal conductivity of the gaseous ﬁlm around the droplet, where gaseous ﬁlm temperature is the average between the exhaust temperatureand droplet surface temperature. The droplet surface temperature is equal to theadiabatic saturation temperature of the suspension spray.
4.3.3. Feeds Containing Dissolved Solids
Droplets containing dissolved solids have lower evaporation rates than pure liquid
droplets of equal size. The dissolved solids decrease the vapor pressure of the liquid,
thus reducing the driving forces for mass transfer. Drying results in the formation ofa solid crust at the droplet surface, which does not occur from pure liquid droplets.
Vapor pressure lowering causes droplet temperature to increase over wet bulb temperature as in the previous two examples. Formation of dried solid during evaporation
has a signiﬁcant effect on the subsequent evaporation history. During evaporation,
spray–air contact and constant rate period occur but may be shorter. The main effectof dissolved solids is seen when the ﬁrst period of drying ends and droplet moisture© 2005 by Taylor & Francis Group, LLC

144

Çelik and Wendel

content falls to critical value representing the formation of the solid phase at the surface. During the falling rate period, the migration of moisture decreases due to resistance to mass transfer caused by solid phase increasing. Last, the heat transfer isgreater than the mass transfer and the droplet temperature increases. Vaporizationof the moisture within the droplet during this phase may occur if the transfer is sufﬁciently high.
The relationship between mass transfer and heat transfer for droplets containing dissolved solids can lead to the formation of many different particle morphologies depending on process conditions and material characteristics. Charlesworth andMarshall have deﬁned these morphologies as falling into two groups dependent on
the temperature of the drying air relative to the boiling point of the droplet solution
during the major part of the evaporation period (Fig. 11) (17).
If the air temperature exceeds the boiling point of the droplet solution, then avapor will be formed. As the solid crust forms around each droplet, vapor pressure
within the droplet is formed and the resultant effect of this pressure is dependent on
the nature of the crust. A porous crust will release the vapor, but a nonporous crust
may rupture resulting in fractured particles or ﬁnes from disintegrated particles.
Alternately, the droplet temperature may not reach boiling point levels due tococurrent airﬂow or because the residence time of droplets in the hottest regions of
the dryer is often very short. In this case, moisture migration occurs through diffusion and capillary mechanisms.
In both cases, the porosity of the solid crust is often evident in the characteristics of the falling rate period of the drying curve. If the ﬁlm is highly nonporous, therate will fall sharply and the evaporation time will be prolonged. However, if a highly

Figure 11 Potential spray-dried particle morphologies in relation to process conditions andmaterial characteristics. (From Ref. 17.)© 2005 by Taylor & Francis Group, LLC

Spray Drying and Pharmaceutical Applications

145

porous ﬁlm exists, then vapor is easily removed from the droplet–air interface andthe drying rate is similar to that found during the ﬁrst period of drying.
These drying mechanisms result in a range of particle shapes including solid,
hollow, shriveled, and disintegrated, examples of which are shown in Figure 12.
However, it is important to note that particle morphology is also dependent on several material characteristics including solubility, temperature of crystallization, melting point, and thermal conductivity since they will also impact the rate of crust
formation, the porosity of the crust, and the subsequent drying rate.
It is also possible to inﬂuence particle density and size distribution through themodiﬁcation of process parameter settings such as atomizer settings, temperaturelevels, and feed rates (18). For example, an increased feed rate while maintaining
a constant inlet temperature results in particles that have higher moisture content
and a resultant increased bulk density. By increasing the temperature of the feedstock, the ability of the feed to be atomized is often improved due to the reduction
in ligament formation causing an increase in the bulk density of the dried particles.
Also, an increase in the concentration of the feed solids often increases the bulk density of the dried particle, as does the use of a rotary atomizer, since many wheel
designs reduce air entrapment. Alternatively, bulk density may be decreased throughfeed aeration or an increase in inlet temperature. Also, cocurrent spray-air contact isoften effective for reduction in bulk density because the wettest droplets encounterthe hottest air facilitating rapid evaporation and air entrapment. It is important tonote that the outlined process modiﬁcations are generally applicable, but that exceptions to each can be found based on material characteristics.
In a similar manner, it is often possible to inﬂuence spray-dried particle
size distribution by changing process parameter settings. As mentioned earlier, thesize of the droplets formed during atomization is affected by process parameterssuch as atomization type, atomizer settings, feed solids concentration, feed physicalFigure 12 Various particle forms of skim milk powder. (Courtesy of Niro Pharma Systems.)© 2005 by Taylor & Francis Group, LLC

146

Çelik and Wendel

properties, and drying temperatures. The size of the resultant particles following evaporation is a function of the initial droplet size as well as the material characteristics
such as solid state and ﬁlm formation mechanisms.

5. SPRAY DRYING APPLICATIONS
5.1. Feasibility Assessments
Before any spray-drying application work begins, it may be advantageous to conduct
the following simple, qualitative tests at the laboratory bench using very little material to determine the feasibility of the application (19). A rheological proﬁle of thesolution or suspension should be evaluated or, alternatively, a small sample can betested to see if droplets from a stirring rod can be readily formed. In the latter test,
if the liquid strings from the surface or forms peaks, then high viscosity is indicatedand the product may not be a candidate for spray drying without formulation
changes. The behavior of non-Newtonian ﬂuids (pseudoplastic, thixotropic, dilatant,etc.) has been found to inﬂuence atomization and the resultant droplet size (20).
However, while it is expected that Newtonian and non-Newtonian ﬂuids atomize differently, this difference was not found to be as important as the more signiﬁcanteffect of the wheel speed on droplet size. It is also important to note that highly
viscous materials cannot be atomized by pressure nozzles.
Once the effect of viscosity has been evaluated, it may be advisable to dry a few
drops of product on a glass slide using a heated air gun. During this bench drying
test, the air temperature is recorded and the material is observed for the presenceof stickiness, color changes, or other physical changes. If the dried powder is foundto be suitable at the air temperature applied, it can be placed on a variable temperature hot bench to determine the temperature at which the powder becomes tacky.
For spray drying to be successful, this temperature must be higher than the outlet
temperature of the dryer.
If the initial feasibility evaluation is successful, it is reasonable to commit additional materials for a spray-drying trial. A laboratory dryer at least 500 mm in diameter is recommended for such tests. Bench-scale spray dryers are available but arelimited in their ability to provide adequate atomization or sufﬁcient process air ﬂow
for the successful production of dried particles. The laboratory unit, however, combined with very ﬁne atomization (two-ﬂuid or rotary) will often produce acceptableproduct for further testing. A series of tests can be performed at different inlet–outlet
temperature combinations using small quantities of material and these samples canbe tested for chemical stability to evaluate thermal effects from process air contact.
The relationship between outlet temperature and ﬁnal product moisture can also beestablished for this scale. While samples produced in a laboratory dryer are suitablefor evaluating the effect of spray drying on the product, they are not suitable for use indownstream processing because the ﬁne particle distribution produced as a result of
the small drying chamber dimensions may not be representative of the ﬁnal spraydried product.
Production of coarser particles requires a larger, pilot-scale dryer, which in turnrequires larger feed volumes. This pilot-scale work is often conducted at a spraysdrying development center since many companies have laboratory dryers but few
have the sizes and variety of process types needed to fully develop a spray-dried product from pilot scale through 1/10th of the commercial scale and into ﬁnal production. These facilities are usually found at spray-drying manufacturers or custom© 2005 by Taylor & Francis Group, LLC

Spray Drying and Pharmaceutical Applications

147

processing companies. In addition to having the equipment, manufacturers andcustom processors often have the expertise to more quickly optimize productcharacteristics.
5.2. Spray Drying to Produce a Specific Type of Particle
Because of its inherent costs, spray drying is not always considered as a processing
option for many conventional formulations. However, when a specialized particle
type is required by the active ingredient or dosage form, spray drying can becomea feasible alternative to more conventional manufacturing processes. Such particle
types include microcapsules, controlled release particles, nanoparticles, and liposomes. The application of spray drying to pharmaceuticals has been extensively
discussed in review articles (21,22).
5.2.1. Granulation
Spray drying is a unique process in several ways as compared to other granulation
methods. The feedstock is a homogenous liquid, which results in the uniform distribution of all components of the spray-dried product in the same ratio in each individual particle and eliminates the concerns of uniformly granulating dry components
with a liquid. While granule characteristics may exhibit batch-to-batch variation,
which in turn may inﬂuence the compaction behavior of the formulation or the
postcompaction properties of the tablet, granules produced using spray drying are
extremely consistent in terms of particle size, bulk density, and compaction behavior.
These features make spray drying a suitable process for the production of directly
compressible excipients such as lactose, microcrystalline cellulose, and mannitol.
Spray-dried lactose is by far the most commonly encountered spray-dried excipient(21).
Many granulation methods utilize mechanical energy to transform very ﬁneparticles into granules. Although shear forces are employed in nozzle and centrifugal
atomizers to create sprays, this form of energy will not destroy microencapsulatedmaterial as can happen in high-shear granulation. In spray drying, some trial anderror is encountered in establishing the nozzle combinations and liquid pressures
to obtain equivalent particle size distribution during scale-up; however, the resultant
powder will have similar physical properties such as bulk density and compaction.
Also, it is important to note that, within the spray dryer, the product is never in contact with moving parts, which facilitates the proper cleaning process greatly.
If the granulation size is a critical criterion for a given formulation, then theselection of the granulation process may be determined based on the desired particle
size and feasible operating temperatures. Figure 13 compares the general particle size
limitations of numerous granulation techniques.
As seen in this ﬁgure, the spray-drying process results in smaller-size particles
as compared to some other granulation methods such as ﬂuid-bed granulation or
high-shear (high-intensity) granulation. One option for producing larger agglomerates using spray-drying technology is to employ ﬂuidized spray drying, which combines the features of the spray-drying process with ﬂuid-bed granulation. The resultof this process is particles similar to those obtained from a ﬂuid-bed granulation
operation, and yet the process is a continuous type in contrast to the batch operationof a ﬂuid-bed granulator. In a ﬂuidized spray-drying system, the bottom cone of aconventional spray dryer has been modiﬁed to include an integral ﬂuid bed© 2005 by Taylor & Francis Group, LLC

148

Çelik and Wendel

Figure 13 Particle size range of the methods utilized in particle growth. (From Ref. 21.)

(Fig. 14). When this process is implemented, atomization and spray–air contact
occur as they do in a conventional spray dryer. However, when the partially driedparticles reach the lower portion of the dryer, instead of undergoing product separation, the particles are ﬂuidized by the second stream of drying gas. Controlled temperature and humidity of this ﬂuid bed gas stream ensure that the particles retain
enough moisture to be suitable for agglomeration. At the end of the process, each
granule is an agglomerate of spray-dried droplets. Droplets that dry completely
before agglomerating and granules that experience attrition during ﬂuid-bed drying
create ﬁnes, which are entrained in the gas stream and carried upward to the drying
gas exhaust. As a result, these ﬁnes pass through the atomized spray, providing an
additional opportunity for agglomeration. Fines that are carried through the exhaust

Figure 14 Schematic of ﬂuidized spray drying system (FSDTM). (Courtesy of Niro Pharma
Systems.)© 2005 by Taylor & Francis Group, LLC

Spray Drying and Pharmaceutical Applications

149

Figure 15 Schematic of an integrated ﬂuid-bed dryer (IFDTM). (Courtesy of Niro Pharma
Systems.)

are collected in cyclones or a bag collector and can be pneumatically recycled into
the dryer.
A variation of this system is the integrated ﬂuid-bed dryer (Fig. 15). This system includes integrated ﬁlter bags, which are suspended from the chamber roof. This
roof is perforated and serves a dual purpose as a gas disperser. The chamber above
the roof contains clean gas that supplies the inlet process drying air and also has an
exhaust point for clean gas, since any remaining ﬁnes are entrapped in the ﬁlters.
Products produced using ﬂuidized spray drying have a broader particle size distribution and lower bulk density than the particles produced by conventional spraydryers with a typical mean size particle size range of 150–400 mm. This process is notmeant to replace conventional spray drying processes but instead is a feasible alternative for spray drying applications that require larger mean particle sizes.
5.2.2. Modiﬁcation of Solid-State Properties
Characterization and modiﬁcation of solid-state properties of drug substances areprofoundly important in developing pharmaceutical products with the desired drug
release properties. The importance of the process understanding and improvement of
the dissolution rate for poorly water-soluble drugs has been known for decades (24).
Particle size reduction methods (such as grinding, micronization, and ball milling),
precipitation, melt quenching, freeze drying, and spray drying have been used
extensively for improving the solubility and dissolution rate of poorly water-soluble
materials (25–30). These processes generally impart a polymorphic change in the
drug substance by transforming a low-energy crystalline form to a higher-energy
crystalline form or amorphous form.
Spray drying has many advantages over the other methods in achieving such
improvements. First, the spray-dried particles are generally free-ﬂowing and spherical; thus, no additional processing (such as dry granulation) is needed before compaction of these particles. The hollow structure of the spray-dried particles
increases the solubility and subsequent dissolution rate of the drugs by several folds.
For example, the dissolution rate of poorly water-soluble salicylic acid was found tobe almost instantaneous and 60 times faster when spray dried as compared to that of
the original powder (25).
© 2005 by Taylor & Francis Group, LLC

150

Çelik and Wendel

In addition, the energy of the amorphous state depends, to some extent, on themethod of preparation (26). The rapid nature of the spray-drying process (i.e., theshort residence time of the droplets during drying) improves the stability of otherwise unstable amorphous forms.
Last, the spray-drying process is suitable for integration of stability agents(such as PVP and PEG) into spray-dried particles. Spray drying of the poorly soluble
drug with 50% PVP resulted in enhanced dissolution when compared to a physicalmixture of micronized drug with PVP (27). A physically stable amorphous formof ibuprofen, which has a low melting point, was obtained when spray dried in
the presence of 50–75% PVP (28). Recently, in a study on the effect of spray drying
varying lactose/PEG compositions, it was found that the most amorphous particles
were obtained when PEG was present at 10% (w/w) concentration. Conversion tomore crystalline materials occurred over time and the crystallization of lactose
appeared to be retarded at low PEG concentrations (29). In other work, theincreased amount and molecular weight of PVP was found to have the potential
to increase the physical stability of amorphous lactose (30).
5.2.3. Microencapsulation
The preparation of microcapsules involves the coating of particles or liquid dropletswith a biodegradable polymer. Applications for microspheres in the pharmaceuticalindustry include controlled release, particle coating, ﬂavor stabilization, taste masking,and physical or chemical stabilization. Microencapsulation can be achieved through anumber of processes, but, in general, an active pharmaceutical ingredient (API) is
trapped within a reservoir or matrix. This process often begins with the preparationof a three-phase, immiscible system containing a liquid vehicle, a core particle, anda coating material or polymer. Several manufacturing techniques can be employed
to deposit the polymer around the particle and cause this coating to become rigid.
These methods include spray drying, Wurster ﬂuid-bed coating, pan coating, coacervation, and emulsion evaporation. In the spray-drying process, the encapsulation process is achieved in one step in which desolvation and thermal cross-linking occur
concurrently and the particle is coated. A review of the main factors involved in theapplication of spray drying for achieving microencapsulation references many works
which detail pharmaceutical applications, especially drug delivery systems (31).
Microencapsulation is a process that is often used for the purpose of providing
controlled release of a protein or drug. Several authors have studied microencapsulation formulations manufactured from a spray-drying process as a means to achieve
controlled release. In one case, the effect of polymer hydrophilicity on API release
was evaluated and the most hydrophilic polymer was found to gel faster and retard
drug release the most (32). The size and cohesiveness of the resultant spray-driedparticles were found to be a function of the polymer and also affected drug releasewith the smaller, more cohesive particles tending to agglomerate and delay drug
release. In another case, release of a model drug was controlled using a spray-dried,
water-activated, pH-controlled microsphere (33). Water inﬂux into the microcapsulecaused buffer to dissolve and adjusted the inner pH causing the fraction of unionizeddrug to increase resulting in the increased release of the drug.
One speciﬁc polymer type that has been employed in the spray drying of microspheres to modify release is acrylic resin. A commercial blend of neutral methacrylicacid esters was used for the preparation of spray-dried controlled release microcapsules containing model drugs (34). Dissolution results of tablets compressed from the© 2005 by Taylor & Francis Group, LLC

Spray Drying and Pharmaceutical Applications

151

microspheres showed successful controlled release with advantages over a matrix
system. In a similar study, sustained release and enteric tablets were prepared bydirectly compressing spray-dried microspheres produced using different types ofacrylic resins (35). Complete enteric properties were observed for tablets made from
pH-dependent, anionic acrylic polymers, while a sustained release proﬁle wasobserved for tablets made from microspheres containing pH-dependent, cationicacrylic polymers.
Two common biodegradable polymers used in microencapsulation are polylactide (PLA) and polylactide-co-glycolide (PLGA). The efﬁcacy of spray drying as amethod for PLA and PLGA microsphere preparation was investigated using a model
lipophilic drug (36). The spray-drying process was tailored to each polymer and themicrospheres obtained were evaluated for shape, size, drug content, and polymer
inﬂuence on these characteristics. Polymer type, polymer molecular weight, andpolymer concentration were shown to be the greatest contributing factors to thesecharacteristics. In-vitro dissolution testing revealed different release proﬁles depending on polymer type and microsphere morphology.
5.2.4. Inhalation Dosage Forms
In order for inhalation dosage forms to be clinically effective, the drug should
deposit in the lower airways. In general, the site of drug deposition in the lungs
depends on the particle size and size distribution of the drug particles or droplets,
the inhaler device and formulation, the patient’s breathing patterns, and airway geometry (37). Generally, the aerosol particles or droplets must be <5 mm aerodynamic
diameter to be deposited into the lower respiratory tract.
A formulation of mucoadhesive microspheres for nasal administration was
examined through the preparation of microspheres containing active and one oftwo polymer types using a spray-drying procedure (38). The mean diameter of thespray-dried particles was 3–5 mm and surface morphology was dependent on polymer
type. Microspheres containing active and either polymer were more mucoadhesive
than any of the starting materials alone and the dissolution rate decreased withincreasing polymer content.
The ability to control the particle size and density of particles for inhalation
was investigated using lactose solutions atomized with a two-ﬂuid nozzle and driedin a laboratory scale dryer. It was found that droplet size during atomization wasaffected by nozzle oriﬁce diameter and atomization airﬂow but not by feed concentration. However, dried particle size was inﬂuenced by feed concentration and it wassuggested that the shell thickness of the hollow particles increased with increasing
feed concentration (39).
An alternative method of atomization for the formation of respirable particles
is the airblast atomizer. This type of two-ﬂuid nozzle introduces a liquid feedpumped at a slow rate into a high-velocity gas stream via single or multiple jets. Thisatomizer type was utilized at laboratory scale to evaluate the effect of grounded vs.
electrostatically charged tower conﬁgurations on the median particle size of thespray-dried product (40). This study found signiﬁcant differences between the two
conﬁgurations with the latter producing small particles but compromising collection
efﬁciency.
© 2005 by Taylor & Francis Group, LLC

152

Çelik and Wendel

5.2.5. Nanoparticles
Attempts have been made to manufacture particles on the nanometer scale forapplications such as controlled release and intravenous delivery systems. A comparison evaluating the processability and solid dosage performance of spray-dried
nanoparticles and microparticles was conducted (41). In this study, nanoparticle suspensions were prepared by wet comminution in the presence of stabilizers, converted
into dried particles using a spray-drying process and subsequently compressed.
Compacts prepared from microparticles and nanoparticles were found to differ intheir internal structure and micromechanical deformations.
In another study, solid, lipid nanoparticles were produced using high-pressure
homogenization and loaded with drug using hot or cold methods for lipophilic orhydrophilic drugs, respectively (42). Surfactant addition was investigated and stability and entrapment efﬁciency were evaluated. Long-term sterile storage of these dispersions was difﬁcult and spray drying was investigated as a potential, feasible
technique.
The feasibility of developing nanoparticles for aerosol delivery has also been
investigated (43). The spray-dried nanoparticles produced using one carrier typewere found to be hollow while others had a continuous matrix. Particle size was measured before spray drying and after the spray-dried powder was re-dissolved. Bothcarrier types resulted in an increase in particle size after spray drying, although bothwere found to remain in the nanometer range after drying and were suitable for efﬁcient lung delivery.
5.2.6. Liposomes
Another particle type capable of being produced by spray drying is liposomes. Traditional preparation of liposomes begins with the preparation of a solution containing
the lipids to be used in a volatile organic solvent mixture. Following ﬁltration of thesolution, the solvent mixture is removed under conditions which ensure that phaseseparation does not occur. The dry lipid mixture is then hydrated by an aqueous
mixture containing the drug to be entrapped. Last, this mixture is dried. Spray drying is one method available for accomplishing one or both of these drying steps. For
example, lipid vesicles were produced using a spray-drying process instead of the ﬁrst
step of the traditional process (44). Vesicles containing phosphatidyl choline(soybean lecithin) were produced by extruding the phospholipid through a 0.2 mm
polycarbonate membrane followed by spray drying with 10% lactose. The particle
size, vesicle size distribution, and stability of the multilamellar vesicles were measured. The mean particle diameter after spray drying with a rotary atomizer was
7 mm and the dry particles could be reconstituted in water to liposomes without
any major change to the vesicle size distribution. In addition, the chemical stabilityof the liposomes was not signiﬁcantly affected by the spray-drying process. In subsequent work, the same authors utilized spray drying for the hydration step of the
traditional process (45).
5.2.7. Peptides and Proteins
Recent advances in biotechnology have made it possible to use macromolecules suchas peptides and proteins as therapeutic agents. Spray drying has been used for decades for processing antibiotics, vaccines, and, for the last few decades, macromolecular drugs.
© 2005 by Taylor & Francis Group, LLC

Spray Drying and Pharmaceutical Applications

153

The effect of spray drying process parameter settings on the activity of peptides
and proteins is often difﬁcult to study. Consequently, enzymes are frequently used asmodel protein drugs due to the ease with which their activity can be determined.
Investigations of the application of spray drying for the production of some enzymes
and proteins and the effects that processing parameters have on enzyme activity havebeen discussed in a review article (21).
Many proteins and peptides are susceptible to degradation upon spray drying
due to relatively high temperatures. In a recent study, the effects of inlet and outlet
temperatures on some spray-dried peptides and proteins were reported (46). In
another study, enzyme activity was found to be susceptible to spray-drying temperature and only half of its activity remained after spray drying without additives at outlet temperatures <50 C (47). In this study, it was found that the activity of aformulation consisting of enzyme and mannitol was maintained at outlet temperatures <50 C and compromised at temperatures >50 C. Replacing mannitol with trehalose stabilized the spray-dried enzyme and its activity was maintained at 100% at
an outlet temperature of 100 C.
5.2.8. Dry Elixirs and Emulsions
A dry elixir is a novel dosage form developed by spray-drying actives and excipients
dissolved or suspended in ethanol/water mixtures. One example is a dry elixir inwhich the feed solution contained actives, dextrin, and sodium lauryl sulfate in a
mixture of ethanol/water (48). The spray-dried product was spherical in shape witha smooth surface and a mean diameter of 13 mm. A comparison with the active in
powder form revealed a major decrease in dissolution time from >60 to 2 min.
A similar dosage form to the dry elixir is the dry emulsion. In this case, theemulsiﬁed drug or oily drug solution with additives is spray dried to produce dry
emulsion particles. A dry emulsion of a water-insoluble nutrient was studied andrelease from the spray-dried particle was found to be dependent on the type andamount of oily carrier and surfactant used (49). Differences in release among the different formulations were attributed to the differences in the physical state of the drug
and surfactant in the dried particle.
5.2.9. Effervescent Products
Spray-dried particles have also been incorporated into effervescent products. In one
study, spray drying was used to protect a degradation-sensitive active by coating ﬁneparticles of the drug with a sugar alcohol solution (50). In vivo results of tablets
made using the spray-dried particles combined with coated citric acid and sodium
bicarbonate revealed that the active was rapidly absorbed from the tablet.
5.2.10. Other Process Variations
Two variations of the spray-drying process have been developed in response to product requirements. The ﬁrst variation is spray congealing. In this process, solids suchas wax or monoglycerides are melted. Other ingredients such as drugs, ﬂavors, or fragrances are dissolved or suspended in the molten material. This molten feed issprayed using the same basic spray-drying equipment except that no heat source isrequired. Depending on the freezing point of the feed, ambient or chilled air may
be used during the drying process. This process has been described in more detailand a comparison between particles produced by both the spray drying and the© 2005 by Taylor & Francis Group, LLC

154

Çelik and Wendel

spray congealing techniques has also been drawn (51). One study compared microcapsules produced using both methods and found that the solvent used, the lipid
type, and the chain length were variables that inﬂuenced the surface properties ofboth particle types (52,53).
A second variation of the spray drying process is spray freeze drying. In thisprocess, the feed is sprayed into freezing air causing the droplets to freeze. The frozen
droplets are subsequently sublimed under vacuum conditions producing a dry product. One study investigated this method further by eliminating the use of vacuum
conditions for sublimation (54). In this study, the feasibility of spraying pharmaceutical solutions at atmospheric pressure was investigated using very low air temperatures and desiccated air for the removal of the water from the frozen particles. The
process resulted in ﬁne, free-ﬂowing powder with a high surface area, good wetting,and good solubility characteristics.
Another type of atomization employed for pharmaceuticals is supercritical
ﬂuid nebulization. The process uses carbon dioxide as an aerosolization aid, which
permits drying at lower temperatures than is usually needed in conventional spraydrying (55). Within the atomization system, supercritical carbon dioxide is intimately
mixed with aqueous solutions containing API, often proteins or peptides. The outcome is the formation of microbubbles, which are rapidly dried in <5 sec, resulting
in dried particles predominately <3 mm in diameter (56,57). This method is generally
applied for the production of materials for pulmonary use or to achieve increased
bioavailability (58).

6. CONCLUSION
Spray drying has found many applications in numerous industries. The scale-up of
the spray drying process is less troublesome as the operation requirements of small
and large dryers are the same when compared to other conventional granulation
processes such as high-shear granulation method.
Spray drying, being a continuous process, is well suited for the production of
bulk drug substances and excipients. Using this process, the physical properties of
the resulting product (such as particle size and shape, moisture content, and ﬂow
properties) can be controlled through the selection of equipment choices and manipulation of process variables; thus, the ﬁnal spray-dried particulate matter may notneed further processing (wet or dry granulation) before compaction. In addition,
the spray-drying process matches the directives outlined in the Process Analytical
Technology Initiative which is currently being guided and championed by the
FDA (59).
Spray-drying processes offer several advantages when solid-state properties ofdrug substances need to be modiﬁed. Using this process, solubility and dissolution
rates of properties of poorly soluble materials can be increased several fold andthe stability of the amorphous form of the materials can be improved signiﬁcantly.
Because of its initial inherent costs, spray drying is not always considered as aprocessing option for many conventional formulations, especially for small batch
size operations. However, when a specialized particle type is required by the active
ingredient or dosage form, spray drying can become a feasible alternative to moreconventional manufacturing processes. Such particle types include microcapsules,
controlled release particles, nanoparticles, and liposomes.
© 2005 by Taylor & Francis Group, LLC

Spray Drying and Pharmaceutical Applications

155

ACKNOWLEDGMENTS
We gratefully acknowledge the contributions of Niro Pharma Systems, speciﬁcally
Bob Turock and Jim Schell, for providing the content for several of the ﬁgures andFred Shaw, whose chapter on spray drying in the ﬁrst edition of this book provided
guidance and content. We also acknowledge the signiﬁcant contribution of Keith
Masters whose handbook was referenced extensively as a leading text in the ﬁeld.

REFERENCES
1. Traub DA. Spray Dryers, Part 1, Process Heating, August 2001. hhttp://www.processheating.com/CDA/ArticleInformation/Drying_Files_Item/0,3274,61137,00.htmli.
2. Percy SR. Improvement in drying and concentrating of liquid substances by atomizing.
US Patent 125,406, April 9, 1872.
3. Masters K. Introduction. Spray Drying Handbook. 5th ed. Essex, U.K: Longman Scientiﬁc Technical, 1991:1–20.
4. Traub DA. Spray Dryers, Part 2, Process Heating, September 2001. hhttp://www.processheating.com/CDA/ArticleInformation/Drying_Files_Item/0, 3274, 63175, 00.htmli.
5. Masters K. Spray drying fundamentals: process stages and layouts. Spray Drying Handbook. 5th ed.. Essex, U.K: Longman Scientiﬁc Technical, 1991:24.
6. Masters K. Spray drying fundamentals: process stages and layouts. Spray Drying Handbook. 5th ed. Essex, U.K: Longman Scientiﬁc Technical, 1991:26.
7. Masters K. The process stages of spray drying. Spray Drying Handbook. 5th ed. Essex,
U.K: Longman Scientiﬁc Technical, 1991:268.
8. Masters K. Spray drying fundamentals: process stages and layouts. Spray Drying Handbook. 5th ed.. Essex, U.K: Longman Scientiﬁc Technical, 1991:31.
9. Masters K. The process stages of spray drying. Spray Drying Handbook. 5th ed. Essex,
U.K: Longman Scientiﬁc Technical, 1991:271.
10. Masters K. Spray drying fundamentals: process stages and layouts. Spray Drying Handbook. 5th ed. Essex, U.K: Longman Scientiﬁc Technical, 1991:43.
11. Masters K. Spray drying fundamentals: process stages and layouts. Spray Drying Handbook. 5th ed. Essex, U.K: Longman Scientiﬁc Technical, 1991:47.
12. Masters K. The process stages of spray drying. Spray Drying Handbook. 5th ed. Essex,
U.K: Longman Scientiﬁc Technical, 1991:199.
13. Masters K. The process stages of spray drying. Spray Drying Handbook. 5th ed. Essex,
U.K: Longman Scientiﬁc Technical, 1991:255.
14. Traub DA. The Drying Curve, Part 2, Process Heating, October 2002. hhttp://www.process-heating.com/CDA/ArticleInformation/Drying_Files_Item/0, 3274, 84744, 00.
htmli.
15. Masters K. Drying of droplets/sprays. Spray Drying Handbook. 5th ed. Essex, U.K:
Longman Scientiﬁc Technical, 1991:309.
16. Masters K. Drying of droplets/sprays. Spray Drying Handbook. 5th ed. Essex, U.K:
Longman Scientiﬁc Technical, 1991:326.
17. Charlesworth DH, Marshall WR. Evaporation for drops containing dissolved solids.
AIChE J 1960; 6(1):9–23.
18. Masters K. Drying of droplets/sprays. Spray Drying Handbook. 5th ed. Essex, U.K:
Longman Scientiﬁc Technical, 1991:345.
19. Shaw F. Spray drying as a granulation technique. Parikh DM, ed. Handbook of Pharmaceutical Granulation Technology. New York: Marcel Dekker, 1997:93–96.
20. Filkova I, Weberschinke J. Apparent viscosity of non-Newtonian droplet on the outlet ofwheel atomizers. Mujumdar AS, ed. Drying ’82. New York: McGraw Hill, 1982:
165–170.
© 2005 by Taylor & Francis Group, LLC

156

Çelik and Wendel

21. Broadhead SK, Rouan E, Rhoads CT. The spray drying of pharmaceuticals. Drug Dev
Ind Pharm 1992; 18(11,12):1169–1206.
22. Wendel SC, Çelik M. An overview of spray-drying applications. Pharm Technol 1997;
21(10):124–156.
23. Kadam KL. Granulation Technology for Bioproducts. Boca Raton, FL: CRC Press,
1990.
24. Fincher JH. Particle size of drugs and its relationship to absorption and activity. J PharmSci 1968; 57(11):1825–1835.
25. Kawashima Y, Satio M, Takenaka H. Improvement of solubility and dissolution rate ofpoorly water-soluble salicylic acid by a spray-drying technique. J Pharm Pharmacol 1975;
27:1–5.
26. Pikal MJ, Lukes AL, Land JE, Gaines K. Quantitative crystallinity determination forbeta-lactam antibiotics by solution calorimetry: correlations with stability. J Pharm Sci
1978; 67:767–773.
27. Junginger K, Wedler M. Acta Pharm Technol 1984; 30(1):68.
28. Corrigan OI, Holohan EM, Reilly MR. Physicochemical properties of indomethacin andrelated compounds co-spray dried with polyvinyl-pyrrolidone. Drug Dev Ind Pharm
1985; 11(2,3):677–695.
29. Corrigan DO, Healy AM, Corrigan OI. The effect of spray drying solutions of polyethylene glycol (PEG) and lactose/PEG on their physicochemical properties. Int J Pharm
2002; 235(1,2):193–205.
30. Berggren J, Alderborn G. Effect of polymer content and molecular weight on themorphology and heat- and moisture-induced transformations of spray-dried composite particles of amorphous lactose and poly(vinylpyrrolidone). Pharm Res 2003; 20:1039–1046.
31. Re MI. Microencapsulation by spray drying. Drying Technol 1998; 16(6):1195–1236.
32. Wan LS, Heng PW, Chia CG. Spray drying as a process for microencapsulation and theeffect of different coating polymers. Drug Dev Ind Pharm 1992; 18(9):997–1011.
33. Sutinen R, Laasanen V, Paronen P, Urtti A. pH-controlled silicone microspheres for controlled drug delivery. J Controlled Release 1995; 33:163–171.
34. Palmieri GF, Wehrle P, Stamm A. Evaluation of spray-drying as a method to prepare
microparticles for controlled drug release. Drug Dev Ind Pharm 1994; 20(18):2859–2879.
35. Takeuchi H, Handa T, Kawashima Y. Controlled release theophylline with acrylic polymers prepared by spray drying technique. Drug Dev Ind Pharm 1989; 15(12):1999–2016.
36. Pavanetto F, Genta I, Giunchedi P, Conti B. Evaluation of spray drying as a method forpolylactide and polylactide-co-glycolide microsphere preparation. J Microencap 1993;
10(4):487–497.
37. Gonda I. Targeting by deposition. Hickey AJ, ed. Pharmaceutical Inhalation Aerosol
Technology. New York: Marcel Dekker, Inc., 1992:61–82.
38. Vidgren P, Vidgren M, Aronen P, Vainio P, Nuutinen J. Nasal distribution of radioactive
drug administered using two dosage forms. Eur J Drug Metab Pharmacokinet 1991;
3:426–432.
39. Elversson J, Millqvist-Fureby A, Alderborn G, Elofsson U. Droplet and particle size
relationship and shell thickness of inhalable lactose particles during spray drying.
J Pharm Sci 2003; 92:900–910.
40. Dunbar CA, Concessio NM, Hickey AJ. Evaluation of atomizer performance in production of respirable spray-dried particles. Pharm Dev Technol 1998; 3(4):433–441.
41. Lee J. Drug nano-and microparticles processed into solid dosage forms: physical properties. J Pharm Sci 2003; 92(10):2057–2068.
42. Muller-Mehnert RH, Lucks JS, Schwarz C, Ruhl D, et al. Solid lipid nanoparticles (sln)alternative colloidal carrier system for controlled drug delivery. Eur J Pharm Biopharm
1995; 41(1):62–69.
43. Sham JO, Zhang Y, Finlay WH, Roa WH, Libenberg R. Formulation and characterization of spray-dried powders containing nanoparticles for aerosol delivery to the lung. Int
J Pharm 2004; 269:457–467.
© 2005 by Taylor & Francis Group, LLC

Spray Drying and Pharmaceutical Applications

157

44. Goldbach P, Brochart H, Stamm A. Spray-drying of liposomes for a pulmonary administration. Part 1. Chemical stability of phospholipids. Drug Dev Ind Pharm 1993;
19(19):2611–2622.
45. Goldbach P, Brochart H, Stamm A. Spray-drying of liposomes for a pulmonary administration. Part 2. Retention of encapsulated materials. Drug Dev Ind Pharm 1993;
19(19):2623–2636.
46. Costantino HR, Andya JD, Nguyen PA, Dasovich N, Sweeney TD, Shire SJ, Hsu CC,
Maa YF. Effect of mannitol crystallization on the stability and aerosol performance ofa spray-dried pharmaceutical protein, recombinant humanized anti-ige monoclonal antibody. J Pharm Sci 1998; 87:1406–1411.
47. Broadhead J, Ruan SK, Rhodes CT. The effect of process and formulation properties on
the properties of spray dried b-galactosidase. J Pharm Pharmacol 1994; 46:458–467.
48. Kim CK, Soon YS. Development of digoxin dry elixir as a novel dosage form usinga spray-drying technique. J Microencap 1995; 12(5):547–566.
49. Takeuchi H, Sasaki H, Niwa T, Hino T, Ozawa H, et al. Design of redispersible dry
emulsion as an advanced dosage form of oily drug (vitamin E nicotinate) by spray-drying
technique. Drug Dev Ind Pharm 1992; 18(9):919–937.
50. Timmington H. Improved aspirin. Chemist Druggist 1973; 199:482–483.
51. Killen MJ. Process of spray drying and spray congealing. Pharm Eng 1993; 13(Jul–Aug),
56:58–62.
52. Eldem T, Speiser P, Altorfer H. Polymorphic behavior of sprayed lipid micropellets andits evaluation by differential scanning calorimetry and scanning electron microscopy.
Pharm Res 1991; 8(Feb):178–184.
53. Eldem T, Speiser P, Hincal A. Optimization of spray-dried and -congealed lipid micropellets and characterization of the surface morphology by scanning electronmicroscopy.
Pharm Res 1991; 8(1):47–54.
54. Mumenthaler M, Leuenberger H. Atmospheric spray-freeze drying: suitable alternativein freeze dry technology. Int J Pharm 1991; 72(27):97–110.
55. Sievers RE, Huang ETS, Villa JA, Kawamoto JK, Evans MM, BrauerPure PR. Lowtemperature manufacturing of ﬁne pharmaceutical powders with supercritical ﬂuid aerosolization in a bubble dryer. Appl Chem 2001; 73(8):1299–1303.
56. Sievers RE, Karst U. Methods for ﬁne particle formation. U.S. Patent 5,639,441, June
1997.
57. Sievers RE, Karst U. Methods and apparatus for ﬁne particle formation. U.S. Patent
6,095,134, August 2000.
58. Sievers RE, Karst U, Milewski PD, Sellers SP, Miles BA, Schaefer JD, Stoldt CR, Xu
CY. Formation of aqueous small droplet aerosols assisted by supercritical carbon dioxide. Aerosol Sci Tech 1999; 30:3–15.
59. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CVM),
Ofﬁce of Regulatory Affairs (ORA). Guidance for Industry: PAT—A Framework
for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance,
September 2004.

© 2005 by Taylor & Francis Group, LLC6Roller Compaction Technology
Ronald W. Miller
Bristol-Myers Squibb Company, New Brunswick, New Jersey, U.S.A.

1. INTRODUCTION
This chapter is different from the original; new works, ﬁndings, and best practices
from various investigators since 1997 have been added. The interested reader will
have to wait for a comprehensive book (in preparation now) to link numerous journal
articles, chapters, and investigative works for technology completeness.

2. POWDER GRANULATION AND COMPACTION
Powder granulation is a process of powder size enlargement that incorporates small
particles into larger ones. The deﬁnition of granulation comprises a range of different
size enlargement methods that can be classiﬁed as either dry or wet. In wet methods, a
suitable liquid is used to agglomerate the small powder particles into a mass. The wet
mass is subsequently dried and sized for further downstream processing needs. Wet
granulation methods have been the most widely used powder granulation technology
in the production of pharmaceutical products, particularly in modern pharmaceuticalmanufacturing.
The chief reasons to granulate powders for the manufacture of pharmaceutical
dosage forms are described by Kristensen and Schaefer (1): To improve powder ﬂow properties for dosage ﬁlling and compression
processes
 To eliminate wet granulation induced degradants and to improve productstability
 To prevent active product ingredient from segregating
 To reduce bulk volume, thereby minimizing storage and enhancing transport
 To reduce potential environmental and safety hazards.
Kristensen and Schaefer provide ample literature references in their chapter inthe Encyclopedia of Pharmaceutical Technology about granulation size enlargement
methods (1): Capes (2,3), Pietsch (4,5), Sherrington and Oliver (6), Kapur (7). Others
referenced about wet granulation technologies are Kristensen and Schaefer (8),Lindberg (9), Fonner et al. (10), Anderson et al. (11), and Ghebre-Sellassie (12).
159© 2005 by Taylor & Francis Group, LLC

160

Miller

3. BACKGROUND
Granulation methods are used in the pharmaceutical industry to enlarge and densify
small powder particles into larger ones typically to improve powder ﬂow so that thematerial can be processed effectively and efﬁciently further into solid dosage forms.
There are two methods of granulation, wet and dry. Wet granulation methods arewidely described in the literature: Encyclopedia of Pharmaceutical Technology (Granulations) is solely devoted to this technology (1). Dry granulation operations do notuse moisture or heat to process powders into densiﬁed granules. The pharmaceuticalindustry employs two methods of dry granulation: slugging and roller compaction.
Little has been written about pharmaceutical dry granulation technology. Its
contemporary use in the industry is 50–60 years, beginning in the late 1940s. However, its popularity has risen in the last 15 years in parallel with the increased
research on new efﬁcacious active pharmaceutical ingredients (API) in the pharmaceutical industry. A number of these new API cannot be processed so easily using
wet granulation and drying processing steps, because of their chemical fragility
and sensitivity. Therefore, this pushes the need for the use of dry granulation processing techniques to advance new API in the 21st century.
Brieﬂy, in dry pharmaceutical granulation processing, the powder particles areaggregated under high pressure, typically a pressure of 30–70 bar. Particulate mattercan be aggregated when compressed at high pressure because of bonding forces developed by the direct contact between the solid surfaces. The high pressure serves toimprove the contact area between the surfaces and thus the overall bonding strength.
Sometimes a binding agent is needed to provide additional bonding strength.
In the pharmaceutical industry, dry granulation processing in the 1950s–1970s
favored a process called slugging. This process design consisted of feeding powder
into a large compression machine, such as a Stokes D3 type compression machine,where the powder was compressed into large tablets or slugs, typically in theorder of 1 in. diameter with a tablet gauge of about 0.25 in. The tablet slugs were
subsequently milled by a separate sizing machine to an appropriate particle size
distribution, and further processed into pharmaceutical capsules, powder for oralsuspensions, sachets, or tablet dosage forms. The slugging process is still used today
by only a few manufacturing ﬁrms that have old pharmaceutical formulation processes. Today, modern pharmaceutical formulation processes introduced into theAmericas, Western Europe, Australia, and parts of Asia do not use this kind ofdry granulation equipment in newly developed formulations. The slugging process
is a relic of the past in modern pharmaceutical technology; roller compaction is
the key technology to future dry granulation processing.
Some characteristics are described brieﬂy about the slugging process to complete the technology information for the reader. The slugging process is externallyinﬂuenced by raw material feed properties such as powder cohesiveness, density, ﬂow
characteristics, and powder particle size distribution. The slugging machine’s design
characteristics such as machine type, feed hopper, feed frame, die diameter, toolingfeatures, compression speed, and slugging pressure also inﬂuence the slugging process and the ﬁnal product properties. In general, the key processing operational
aspect of slugging is to maintain a uniform powder ﬁll weight into the dies during
the dynamics of the slugging process. This assures the best chance to manufacture
uniform powder slugs and, ultimately, uniform densiﬁed granules. The compression–slugging setup is a key essential to maximizing the slugging throughput andminimizing the hopper feed-frame and die powder ﬂow problems associated with© 2005 by Taylor & Francis Group, LLC

Roller Compaction Technology

161

Table 1 Disadvantages of Slugging
Single batch processing
Frequent maintenance changeover
Poor process control
Poor economies of scale
Low manufacturing throughput per hour

Excessive air and sound pollution
Increased use of storage containers
Increased needs of manufacturing space
Increase of logistics
More energy and time required to produce
1 kg of slugs than 1 kg of roller compact

Source: From Ref. 13.

the process. Slugging compression is normally performed at 4–6 tons hydraulic pressure, at a rate of 10–30 turret revolutions per minute. The speciﬁc machine tonnage,
turret speed, and roll dwell time required for the process are dependent on the
powder blend’s physical properties, the tooling conﬁguration, machine parts, andultimately the slug speciﬁcations. Typical slugging machine output ranges from 30
to 50 kg/hr and the machines are not instrumented with modern devices to control
their performance. There are many disadvantages with the slugging technology in thepharmaceutical industry (Table 1).

4. BENEFITS OF ROLLER COMPACTION
This chapter brieﬂy identiﬁes key aspects of roller compaction technology. Unlike
the slugging process technology, roller compaction technology is well suited for
dry granulation agglomeration in the era of modern development of active pharmaceutical ingredients in pharmaceutical plants.
The increasing scale of manufacturing pharmaceutical products worldwide, theneed for high processing rates, together with increased levels of good manufacturing
practices, necessitate controlled dry granulation processes with as few processing
steps as possible. This has been accomplished by instrumenting roller compactors
to automate and control the mechanical process. Roller compaction technology
plays a very important role in providing competitive cost control, safety, and quality
products in the pharmaceutical industry. Key roller compaction beneﬁts are identiﬁed in Table 2.
Table 2 Advantages of Roller Compaction
Simpliﬁes processing
Facilitates powder ﬂow
Uses minimal energy to operate
Requires less man-hours to operate
Improves drug dosage weight control
Reproduces consistent particle density
Produces good tablet and capsuledisintegration
Eliminates aqueous and solvent granulating
Source: From Ref. 13.
© 2005 by Taylor & Francis Group, LLC

Uses less raw materials
Eliminates water-induced degradants
Improves process cycle time
Prevents particle segregation
Facilitates continuous manufacturing
Improves content uniformity
Does not require explosion proof room/
equipment
Produces a dry product that is processscaleable

162

Miller

5. COMPACTION THEORY
The bonding forces in a dry aggregate are important to granulation properties suchas granule integrity, ﬂowability, friability, density, compressibility, and size fordownstream manufacturing process steps (1). Rumpf and coworkers described thebonding mechanisms occurring during dry granulation as a mixture of van der
Waals forces, mechanical interlocking, and a recombination of bonds establishedbetween freshly created surfaces, and solid bridges, created because of partial melting
and solidiﬁcation during compression (14). A general theory describes particle bonding related to roller compaction in the Handbook of Pharmaceutical Granulation
Technology (13). The process of dry granulation relies on interparticulate bond formation. Granule bond formation is characterized in different stages, which usuallyoccur in the following order:
1.
2.
3.
4.

Particle rearrangement
Particle deformation
Particle fragmentation
Particle bonding.

Particle rearrangement occurs initially as powder particles begin ﬁlling void
spaces. Air begins to leave the powder blend’s interstitial spaces, and particles begin
to move closer together. This action increases the powder blend’s density. Particle
shape and size are key factors in the rearrangement process. Spherical particles willtend to move less than particles of other shapes because of their close initial packing
to one another. Particle deformation occurs as compression forces are increased.
This deformation increases the points of contact between particles where bonding
occurs and is described as plastic deformation (13).
Particle fragmentation follows as the next bonding stage. This occurs atincreased compression force levels. At this stage, particle fracturing creates multiple
new surface sites, additional contact points, and potential bonding sites. Particle
bonding occurs when plastic deformation and fragmentation occur. It is generally
accepted that bonding takes place at the molecular level, and that this is due tothe effect of van der Waals forces (13).
When powder granules undergo an applied force or stress, a stress force isreleased from the granules. The granules attempt to return to their original shapeor form; this is described as elastic deformation. A deformation that does not totally
recover after the stress is released is a plastic deformation. Elastic and plastic deformations can occur simultaneously, but one effect usually predominates.
Parrott identiﬁed three theories of compression bonding: mechanical, intermolecular, and liquid-surface ﬁlm. Mechanical bonding purports that individual particles undergo elastic, plastic, and brittle deformation. Bonding of this nature occurs
because particle surfaces intertwine, forming mechanical bonds. Intermolecular theory
identiﬁes that there are some unsatisﬁed surface ions that have a potential need tobond to one another. Under pressure, intermolecular forces become pushed together
close enough so that van der Waals forces can act to consolidate particles. The liquidsurface ﬁlm theory identiﬁes that bonding occurs because of the existence of a thinliquid ﬁlm. The thin liquid ﬁlm is generated from pressure induced by the energyof compression. This mechanism acts as a bonding agent promoting mechanicalstrength and an enlarged particle (15). Very little information is written about this last
theory.
© 2005 by Taylor & Francis Group, LLC

Roller Compaction Technology

163

Dehont et al. provided a simpliﬁed approach to roller compaction theory (16).
They described that powder granules move through stages in the feed area. The
material is drawn into the gap by rubbing against the roll surfaces. The densiﬁcationthat occurs in this area is particle rearrangement. At this stage, the speed of thepowder is slower than the peripheral speed of the rollers. Figure 1 represents compactor rolls in the horizontal plain; powder is pushed vertically downward into
the compaction area.
Note in Figure 1, a ¼ nip angle, b ¼ material in volume space. The material islocated in the compaction area between a and the horizontal axis (Fig. 1). At thisstage, the material undergoes additional compaction forces. The particles undergo
plastic deformation and are bonded. Dehont’s team noted that nip angle varies
according to the material characteristics of particle size and density and the angle
is about 12 (16). They deﬁned the neutral angle, g, which corresponds to the point
where the pressure applied by the rollers is the greatest on the material. They alsodeﬁned elastic deformation, d, and that occurs after the compact begins leaving
the compression roll area. Compacted ﬂakes may increase in size due to material
elastic deformation and actually may have a larger thickness than the roll gap, e (16).
Dehont et al. developed Eq. 5.1 for the linear variation of ﬂake thickness at a
speciﬁc roll diameter (16):e1 ¼ Dðd0 =d1  d0 Þð1  cos aÞð5:1Þ

where e1 is ﬂake thickness, D is roll diameter, d0 is material density at angle a, and d1
is ﬂake density. Dehont et al. assumed that the material in the compaction
area remains horizontal and moves at the peripheral speed of the rollers. They
also considered that the angle a is independent of the roller diameter size and notedthat the ﬂake thickness e1 depends on the roller speed, the roller surface, and thecompaction pressure. All these parameters inﬂuence the density of the ﬂake d1.
Dehont et al. concluded that if the same ﬂake thickness were obtained with different
roller diameters, the ﬂake density would be greater with larger-diameter rollers (16).
This is due to the greater nip angle formed with the larger rolls allowing more material to be compacted.
R. W. Heckel considered the compaction of powders analogous to that of aﬁrst-order chemical reaction. The pores were the reactant and the densiﬁcation of
the material the product. The proportionality between the change of the density withthe pressure and the pore fraction was the process kinetics (17). Heckel explained

Figure 1 Front view of compactor rolls in horizontal plane. (From Ref. 16.)
© 2005 by Taylor & Francis Group, LLC

164

Millermathematical constants that described the compaction behavior of a given powderand developed a mathematical relationship, Eq. 5.2 (17):lnð1=1  DÞ ¼ KP þ lnð1=1  D0 Þ

ð5:2Þ

where D is the relative powder density, D0 is the relative loose powder density at zeropressure, P is the pressure applied, 1  D is the pore fraction, and K is the proportionality constant.
The expression of density–pressure relationship permitted the determination ofdensity values in the range of the pressures investigated. Heckel described mathematically that the curved region when plotting ln(1/1  D) vs. P is associated with powder densiﬁcation (17). This occurred by a mechanism of individual particle movementin the absence of interparticle bonding. Heckel concluded that the densiﬁcation represented by the linear region of the plot, ln (1/1  D) vs. P, occurred by plastic
deformation of the compact after an appreciable amount of interparticle bonding
had taken place. For quantitative reasons, Heckel, redeﬁned the mathematicalexpression denoting a constant, A ¼ ln(1/1  D0), which is quantitatively valid
except at low pressures. He postulated that the constant A, which is somewhat larger
than ln(1/1  D0), represents the degree of packing achieved at low pressures asa result of rearrangement processes before appreciable amounts of interparticle
bonding take place (17). Heckel postulated that K, the slope of the linear region,
is a measure of compact densiﬁcation by plastic deformation.
Heckel concluded that density–pressure data indicate that the rate of thechange of density with pressure, any pressure, is proportional to the pore fractionin the compact at that pressure. Additionally, density–pressure curves may bedescribed by two parameters. He theorized that one was related to low-pressure densiﬁcation by interparticle motion. The second measured the ability of the compact todensify by plastic deformation after appreciable interparticle bonding.
J. R. Johanson identiﬁed, through very comprehensive mathematical models
and relationships, material properties, press dimensions, and operating conditions
for roll compactors. For more information, the interested person should read theentire reference (18). In part, he explained that roller compaction involves a continuous shear deformation of the granules into a solid mass.
To satisfy the theory’s assumption, it was postulated that the material be isotropic, frictional, cohesive, and compressible. Figure 2 depicts material in a press
that undergoes shear deformation into a solid mass (18). In Figure 2, Po ¼ horizontal pressure between rolls, y ¼ angular position of roll bite, a ¼ nip angle, 2d ¼ rolldiameter D, h ¼ height above the roll centerline at which feed pressure Po is applied,Pm ¼ horizontal pressure at y ¼ 0, and S ¼ roll gap.
Johanson pointed out that no roller compactor theories at that time determined the angle of the nip and the bulk density at y ¼ a, except by actually rolling
the granular solid in a roll press. He also provided a method to calculate the nipangle and the pressure distribution between the rolls. His calculations determined
the pressure distribution above and in the nip area (18).
He provided the technical rationale to calculate the nip pressures in the nip
region. He showed that material trapped in a volume Va between arc-length segments 4L, must be compressed to volume Vy between the same arc-length segments.
The relationship requires that the bulk densities ga, gy in volumes Va, Vy be related
by Eq. 5.3 (Fig. 3) (18):© 2005 by Taylor & Francis Group, LLC

Roller Compaction Technology

165

Figure 2 Front view of compactor rolls in horizontal plane, depicting powder regions at
different compaction forces. (From Ref. 18.)

ga =gy ¼ Vy Va

ð5:3Þ

In Figure 3, P0 ¼ horizontal pressure between rolls, y ¼ angular position of roll
bite, a ¼ nip angle, 2d ¼ roll diameter D, h ¼ height above the roll center line at
which feed pressure P0 is applied, Pm ¼ horizontal pressure at y ¼ 0, S ¼ roll gap,
DL ¼ arc-length segments, Va ¼ material trapped in volume space described by
arc-lengths, Vy ¼ compressed volume space described by arc-lengths, ga and gy ¼
respective powder bulk densities in volume spaces Va and Vy, and K ¼ a material
property constant for a given moisture content, temperature and time of compaction. Johanson stated that the pressure sy at any y < a can be determined as a

Figure 3 Front view of compactor rolls, depicting nip angle. (From Ref. 18.)
© 2005 by Taylor & Francis Group, LLC

166

Millerfunction of the pressure sa, at y ¼ a, by the pressure–density relationship. It wasunderstood that, for increasing pressures, log density was a linear function of log
pressure (19).
Johanson found that the nip angle does not depend on the magnitude of theroll force or the roll diameter. He demonstrated that the nip angle was affected very
little by the geometry of the press or the cut grooves on the roll surface. It was mostly
inﬂuenced by the nature of the materials that were compressed. The very compressible materials, with small K-values, had very large nip angles. On the other hand,incompressible materials, with large K-values, had very small nip angles. Ultimately,
Johanson’s results showed that material properties determine the maximum pressurethat a roller press applies to material.
Parrott evaluated compacting of several pharmaceutical powders into compact
sheets that were sized by an oscillating granulator into granules. He studied ﬂake
thickness, bulk and tap densities, angle of repose, and ﬂow rate after sizing. His work
demonstrated that one could improve most granule densities but not necessarily
improve granule ﬂow properties (20). Nearly all particulate matter can be aggregatedwhen compressed at high pressure. In some cases, pressure alone cannot achieve sufﬁcient bonding strength; therefore, a binding agent is required to be added to thepowder blend (1). Polymeric binders added to mixtures at certain percentages form
highly viscous bridges between particle-to-particle powders. When the polymericmixtures are compressed, they increase the overall compact strength and enhance
particle-to-particle bonding and can improve powder ﬂowability.
Pietsch described a compaction capacity throughput equation for a roller compactor using ﬂat rolls. The equipment capacity equation is theoretical in nature; it
assumes that all compact is 100% usable for downstream processing needs. Compact
capacity throughput, Cc, can be determined by Eq. 5.4 (4):
Cc ¼ pDlhA n60g

ð5:4Þ

where Cc is the roller compactor throughput (kg/hr), D is the roller diameter (cm),l is the roller length, working width (cm), hA is the gap width between the rollers, sheet
thickness (cm), n is the number of revolutions per minute (1/min), and g is the apparent
sheet density (kg/cm3).

6. DESIGN FEATURES OF ROLLER COMPACTORS
Certainly, a key enhancement that highlights today’s pharmaceutical industry stateof-the-art roller compactors is programmable logic controllers (PLCs). They areused to control and monitor mechanical parts that regulate screw feed rate, roll
speed, pressure and gap, vacuum deaeration, and mill speed. This section will not
discuss PLC designs.
Brieﬂy, a key machine innovation, vacuum deaeration, was a new importantfeature design added by some roller compactor vendors in the early mid-1990s.
The design feature has been shown to help premodify raw material density prior
to compacting and increase throughput (21). Other equipment features such as multiple horizontal or angled feed screws have assisted in manufacturing a uniform raw
material feed across the rolls (21,22). Newly designed roll machine blocks, featuring
cantilever roll systems, offer more efﬁcient ways to clean, handle, and facilitate
product and equipment changeovers. New storage hoppers and various screw feeder
designs have improved delivery of poor ﬂow powder to the rolls.
© 2005 by Taylor & Francis Group, LLC

Roller Compaction Technology

167

Figure 4 Twin horizontal feed screw system with vacuum deaeration system. (Courtesy of
Alexanderwek Inc., USA.)A history of hopper and feed screw designs showed that each design evolved tofacilitate and improve powder ﬂow to the compactor feed screw conveyance system.
Feed hopper designs shown in Roller Compaction Technology for the PharmaceuticalIndustry depict designs used in older compactor models (23). Dehont et al. described
the powder compaction feeding systems that were in use up to 1989 (24).
Speciﬁc hopper designs were used when material had good rheological characteristics. Materials that had good but unique ﬂows, and needed to be evenly distributed across the roll-surface, such as granular salts, used hoppers that had guiding
ﬂaps. When the powder material had poor rheological characteristics, a vertical ﬂap
distribution box was ﬁtted under the hopper. It primarily was used when compacting
ores. Force feeder designs are more commonly used in the pharmaceutical industry.
They are employed with various conﬁgured designs and shapes to supply poorly
ﬂowing powder to the nip roll region (23). Pietsch described modern feed screw system designs; depicting a vertical force-feeding screw with a slightly tapered end, an
inclined feed screw, a vertical, tapered, and blade-angled feed screw, and a horizontal(single or dual) straight feeder screw(s). These designs are described and pictured(25). Innovatively designed feed screw systems are used commercially in roller compactors worldwide. An example is shown in Figure 4.
Sizing devices are now trimly ﬁtted to the compactor body and controlled byvariable speed drives. Most compacters no longer require a separate milling machine
in tandem to size compacts as required by slugging technology. Roller compactors
have clean-in-place systems that offer environmental and safety features. These systems minimize human exposure to chemicals. See Roller Compaction Technology for
the Pharmaceutical Industry for additional information (23).

7. ROLL CONFIGURATION
Compactor design features have evolved over the years. By the mid-1970s, research
revealed a number of roll design improvements that increased compacting efﬁciency.
Three key conditions were identiﬁed, at that time, which optimized the roll compact
throughput and minimized leakage of noncompacted powder (26): Adequate powder supply must enter the gripping zone, Powder must be conveyed fully into the narrowest part of the roller gap,
 Compaction pressure must be distributed as uniformly as possible acrossthe whole roller-gripped powder mass.
© 2005 by Taylor & Francis Group, LLC

168

MillerEquipment engineers and researchers worked on improving feeding equipment
systems and roll designs to satisfy and maximize the above conditions. Some of the
key advances are identiﬁed in Ref. 21 and are re-emphasized in this chapter.
Because of powder feed variability at the nip and in the roll gap regions, powder leakage is produced during the compaction process. This situation produces
excessive ﬁnes and possible undesirable processed material. Usually, this problem
is caused by uneven powder ﬂow and compact formed when the powder is fed
toward the middle of the roll width. Granules produced under these conditions
are typically not optimal for further pharmaceutical processing.
Trials performed by Funakoshi et al. using rectangular aperture chutes, ﬁtted
at the end of a feed screw, aided in preventing uneven powder ﬂow across the rollwidth. Funakoshi’s team demonstrated the positive effects of having a concavoconvex roller pair ﬁtted with inner ring walls. This feature counteracted side seal
effects (fractured or incomplete compacted edges). They also designed and tested
other rolls (concavo-convex with rim), which allowed the powder to distribute more
uniformly across the roll width. This design reportedly minimized powder leakage
during compaction (26). Funakoshi’s team also showed that when the roll rim innerangle is zero the powder is not adequately and uniformly delivered to the grippingand compacting zones. This occurred because the stationary side seals acted as resistors to the powder ﬂow (26). Their work demonstrated that the formed compact andthe compaction pressure (using standard rolls) produced an uneven compact acrossthe roller ends because of side seal friction. When they employed the newly designed
concavo-convex rimmed rolls, it protected the compact from the adverse side seal
fracturing effect. Funakoshi et al. also determined a proper selection of rimmed rollers, which delivered adequate powder to the compaction zone and also conveyed
powder fully across the roller gap region. They concluded that the height and slopeof the inner walls’ rims optimally inﬂuenced the side seal effect. A 65 inner wall
slope produced 2.5–3.0% ﬁnes’ leakage during the compaction of lactose. Whenthe rolls had no inner wall rims, the ﬁnes’ leakage was 15%. In summary, the team
optimized the compact and pressure distribution along the rolls by using the concavo-convex rimmed shaped rolls and found the best roll design was still dependent
on raw material properties (26).
Parrott further substantiated the usefulness of the rimmed concavo-convex
roller pair to increase the density of several pharmaceutical powders. His work
resulted in optimizing a process with an uncompacted leakage rate of 5%. The optimization depended on the physical properties of the powder and the machine operating conditions such as the roller gap, feed screw speed, and roll speed (27). Some of
their key design feature ﬁndings are summarized:
 Installing a concavo-convex roll surface rather than a ﬂat roller pair
 Installing rectangular feed chute and ﬂaps
 Designing cylindrical, conical/cylindrical, or tapered variable speed auger
feed screws
 Optimizing the roll rim angle to 65 Installing digital and analog variable feed screw controllers
 Developing horizontal and variable screw feed systems.
Jerome et al. in the 1980s studied the effects of compactor adjustments on powder blend properties. His team’s research showed that pressure applied by the movableroller is not a predominant factor. They found that the most important variable wasthe compactor feed screw in relation to the roll speed. More will be said about this© 2005 by Taylor & Francis Group, LLC

Roller Compaction Technology

169

point later in the chapter. Jerome correlated improved tablet compression hardness tothe feed screw speed in relation to the speed of the rolls (28). Roll conﬁgurations arewell documented (23). Most compactors now have one ﬂoating roll and one ﬁxed rolleach on separate bearing blocks and this is illustrated in Figure 5. Currently, one pharmaceutical manufacturer of roller compactor equipment has a ﬁxed roll-pair system.
This roll design system relies on powder gravity feed and a specially designed compression feed screw to continuously deliver powder to the ﬁxed roll pair (23).
Pietsch described two pairs of rollers with different diameters D1 and D2, withidentical roll gaps hA. He theorized that if the peripheral speed of both pairs of rollers is the same, roller compaction takes place more gradually in the case of the larger
roll pair. At the same time, the larger-diameter roll pair pulls a larger powder volume
into the nip region, resulting in a higher-density compacted product. The largerdiameter roll pair also minimizes air entrainment more efﬁciently than the smallerdiameter roll pair when both are operating at the same peripheral speed (25). Pietschnoted that the peripheral roll speed and particulate powder speed are not equivalent
in the entire compaction zone. Throughput does not increase proportionally withroll speed.
There are two effects that hinder throughput: starved conditions in the feedzone and too much squeezed air from the particle mass that ﬂows upward andagainst the powder ﬂow, reducing the supply of material to the nip area (25).
What is the optimum roll speed for a compaction process? What factors does theformulating scientist or process engineer need to consider to maximize compact quality and compaction throughput? Johanson (29) attempted to answer these questions
by predicting roll-limiting speeds for briqueting presses. He developed mathematicalexpressions considering even the gas and liquid effects as they can theoretically be

Figure 5 Fixed and ﬂoating roll pair. (From Ref. 13.)© 2005 by Taylor & Francis Group, LLC

170

Millersqueezed from a solid mass. Solid properties, press dimensions, and operating conditions were evaluated to predict optimum roll speeds. The results necessary for a quality
briquette are most critical for low-density ﬁne particles. Johanson’s work showed therelation between feed pressure and roll speed to essentially be proportional to thematerial’s permeability (porosity). For example, when the initial powder was compacted, sized, and recompacted, the bulk powder permeability increased; however,when the powder was compressed, the compression force decreased, and compactor
feed pressure force requirement decreased signiﬁcantly. Johanson (29) also demonstrated that if the compactor feed pressure is kept constant and the press speed isincreased, the maximum pressure applied to the briquette decreases as the roll speed
increases. As a result, the briquette density and strength decrease likewise. For
additional information, the interested reader should peruse the reference list.
Sheskey and Hendren in 1999 studied the effect of roll surface conﬁguration on
the drug release and physical properties of a hydroxylpropylmethyl cellulose(HPMC) matrix controlled-release dosage form (30). Smooth and axial-grooved
roll surface designs were studied using a Vector Model TF-Mini roller compactor(Vector Corporation, Marion, IA). Their hypothesis was that the greater the depthof the concavity on the roll surface, the pressure exerted on the powder being compacted would not be as evenly displaced as with a smooth roll surface. Therefore, aswith tablet tooling design, the top of the crown area of the compacted ribbon would
theoretically be softer than the rest of the ribbon. However, the results of a particle
size distribution test performed on milled ribbons generated using both smooth andaxial-grooved roll pairs showed similarity between tested samples. In addition,
results showed little difference in tablet crushing strength values between samples
manufactured using either type (smooth, axial-grooved) of roll surface design. Drugrelease proﬁles of tablets prepared from roller compacted granulations using bothroll surface conﬁgurations were also similar. It was noted that the authors did notmeasure product throughput rates to address the possibility of improved efﬁciency
when using an axial-grooved roll pair vs. a smooth roll pair.

8. FEED SCREW DESIGN
The consistency and evenness of the powder feed into a roll pair determines toa large extent, how complete a compact is made and ultimately the success of a compaction process. Most roller compacting systems suffer the disadvantage of leakage,i.e., 20–30% powder particles (depending on the formulation) are not compacted.
This primarily occurs because of uneven powder feed and powder slippage between
individual loose particles and the roll surfaces. Under these conditions, it is usuallynecessary to recycle the uncompacted powder or ﬁnes. Recycling a compaction process is a signiﬁcant drawback because of additional capital expenditure, labor costs,
and increased throughput time.
The chief objective of roller compaction is to consistently make an agglomerateof sufﬁcient strength that meets the required density, granulometry, and powder ﬂow
speciﬁcations. The key operational goal in compacting is to maintain a pressure
range on the feedstock, independent of the ﬂuctuating powder granulometry and
ﬂow into the rolls, to maintain a consistent compact. The compaction process ismanaged by controlling the input material, the quantity per unit of time, the roll
speed, and the roll gap. Allowing the roll gap to ﬂoat unchecked could inﬂuence
the production rate and the compact quality. Therefore, it is important to control© 2005 by Taylor & Francis Group, LLC

Roller Compaction Technology

171

the compaction process by setting a constant powder feed rate during the compaction operation.
Design innovations on the powder feed input side of the roller compactor arecomplex. The complexity is double-edged: powder materials, which ﬂow and move
well, are more easily handled on the feed side of the compactor. These types of materials generally do not necessarily need signiﬁcant densiﬁcation to marginally improvetheir ﬂow handling characteristics on a large scale. On the other hand, poor ﬂowing
and low-density powders require special equipment and considerations to feed acompactor. Additionally, it is necessary to maintain a constant powder ﬂow andquantity of material to the rolls during the compaction process. Therefore, the delivery feed system plays a very important role in delivering poor ﬂowing low-density
bulk powder materials to the roll compactor.
Johanson, in 1995, described an arch-breaking hopper design that effectively
delivered poor ﬂowing powder from the hopper to a horizontal feed screw. The
unique hopper design eliminated the ‘‘rat-holing’’ effect of poor ﬂowing powders
during hopper voiding and is described in Figure 6 (31).
Miller noted that the total compaction power requirement is the sum of thepower required for the feed screw(s) and the roll drive (13). Feed screws not only
convey the powder material from the compactor storage hopper but they also help
deaerate the powder in the process. The deaeration of the powder acts as a minicompactor by precompacting the material just prior to roll compaction. Optimum compaction pressures and feed screw designs vary widely for different powder material
properties. Changes in bulk powder density and feed screw speeds will affect the rollgap, the compaction pressure, the throughput, and the quality of the compact (13).
Weggel indicated that feed screw torque varies directly with the precompaction
pressure (32). He suggested that by maintaining a constant feed screw pressure, thecompactor operator can control the compact quality. Variations in precompaction
pressure and in the compacting pressures are directly related to feed screw amperages
and the roll drive motor. The compaction pressures are dependent on a continuous
ﬂow of powder into the feed screw area. If the powder feed ﬂow is intermittent or

Figure 6 Arch-breaking hopper design. (From Ref. 31.)
© 2005 by Taylor & Francis Group, LLC

172

MillerFigure 7 Roller compaction: compacts. (Courtesy of R.W. Miller.)interrupted, this will affect the feed screw amperage readings and eventually the roll
drive readings. Weggel noted that forcefeeding the material deaerated the feedstockand reduced the roll pressure loads. He found that it was more efﬁcient to achieve
maximum densiﬁcation during several stages of the roller compaction process (32).
Miller noted, in 1996, that the design of vertical cylindrical feed screws appears
to feed powder uniformly to the circumference of the feed screw (13). However, he
concluded that the powder feeding to the rolls did not coincide with the general rectangular shape of the compactor throat. The observed drawback was that the powder did not get delivered evenly across the rolls; the middle of the rolls received more
powder than the rolls’ edge. This potentially created a poor quality compact;
a strong middle compact that is weak at the ends because of frayed edges. Frayedcompact edges give rise to uncompacted material and excess ﬁnes (13). An exampleof the phenomena was depicted when using a light yellow-green color feedstock,which after roller compaction using a twin feed screw system produced a homogenous colored compact. The same feedstock passed through a compactor designed witha single vertical feed screw, exhibited a sinusoidal colored compact (Fig. 7). Miller indicated that a multiple horizontal feed screw design system provided a more uniform
powder distribution across the rolls in area and in volume than a single vertical feedscrew system. This applied to either vertical or horizontal single feed screw systems(13).
9. FUTURE TRENDS IN GRANULATION TECHNOLOGY
A number of these attributes, best technology practices, and features were rated fortheir industrial and pharmaceutical importance and reported by Miller and Sheskey
in 2001 (33). Survey ﬁndings evaluated future industry usage of roller compaction
technology in technical operations and in research and development (Fig. 8).
Worldwide pharmaceutical manufacturing technical operations predict signiﬁcantly increased roller compaction usage in the future. Research and development
scientists indicated worldwide that they are currently involved with roller compac© 2005 by Taylor & Francis Group, LLC

Roller Compaction Technology

173

Figure 8 (A) Roller compaction current usage in company technical operations. (FromRef. 33.) (B) Roller compaction current usage in R&D projects. (From Ref. 33.)

tion technology to develop new formulations. Some key reasons why this is the caseis that most API discovered now are very sensitive to water and heat and have low
bulk densities. The authors concluded that these combined factors push roller
compaction technology to the forefront as the preferred processing technology for
new pharmaceutical chemicals for solid-dose formulations in the pharmaceuticalindustry (33). It also appears that pharmaceutical companies are chieﬂy content tohave the right technology in place to deliver the granulation form needed in theeasiest, quickest, and most efﬁcacious manner.
A signiﬁcant survey response indicated the importance of both design and service features to advance roller compaction technology (33). There seems to be anassorted blend of needs that are due in part to vendor past performances, such asreliability, technical support programs, and service history. There is also a component of innovation, new technology advances, such as cantilevered rolls and operator
touch screens with parametric feedback [Table 3, courtesy of the American Pharmaceutical Review (33)].

10. NEW FINDINGS
P. Guigon and O. Simon, Compiegne Universite de Technologie, Compiegne Cedex,
France, recently presented experimental results using a laboratory KomarekÕ
B100QC press (Fig. 9). They demonstrated that when using a single feed screw (without vacuum deaeration system), to feed a roll press, the stress exerted on the compact
was neither homogenous on the roll width nor constant with time.
The heterogeneity was characterized by measuring light transmission througha sodium chloride compact. The team showed that the powder packing that took
place in the last ﬂight of the feed screw caused heterogenous feeding pressure. The
heterogenous feeding pressure caused the heterogenous compact properties (34).
The team developed a mathematical model to link feed screw geometry to the stress
distribution in the compact. The author notes that this ﬁnding is contrary to© 2005 by Taylor & Francis Group, LLC

174

MillerTable 3 Preferences for Compactor Design and Service Features
Compactor design andservice features
Machine performance and reliability
Vendor spare parts availability
Variety of model sizes
Vendor IQ and OQ program
Vendor service history
Cantilevered vs. double-bearing rolls
Vendor delivery time
Ease of cleaning
Variety of roll patterns
Vendor training support
Touch screens with parameter feedback
Other

Number of responses

Average rating

56
55
61
51
48
49
54
54
51
54
60
11

4.5
4.2
4.1
3.9
3.9
3.8
3.8
3.7
3.7
3.5
3.2
3.2

Note: 5 ¼ high, 1 ¼ low preferences.
Source: From Ref. 33.

the Johanson model noted earlier in this chapter and quite revealing. The laboratory
press was specially instrumented with two ﬂush mounted piezoelectric transducers
ﬁtted on the smooth upper roll (130 mm diameter by 50 mm width). The transducers
measured stress (0–200 MPa) exerted on the roll surface at 15 mm from both sides of
the roll. The position of the piezoelectric transducers was deﬁned once per revolution; the roll speed, screw feeder speed, and hydraulic pressure were also measured
and recorded (Fig. 10).
The team measured the compact density by the distribution of light transmitted
through the sodium chloride compact. Guigon indicated that the milled sodium
chloride crystals were oriented by the applied stress and therefore the incident light
was not diffused similarly in all directions (34). The stress applied on the compact isFigure 9 Side and front view of Komarek B100QC press used to determine geometry feedsystem and stress distribution and applied on compact. (From Ref. 34.)
© 2005 by Taylor & Francis Group, LLC

Roller Compaction Technology

175

Figure 10 (A) Applied stress on the compact during one rotation period of feed screw. (B)Corresponding gray level on the numerical image of light transmitted through the compact.
Sodium chloride d50 ¼ 74 mm, Vr ¼ 10 rpm, Vs ¼ 25.3 rpm. (From Ref. 34.)

neither homogenous on the roll width nor constant with time. Guigon points outthat the stress maximum for the same sensor varies from one rotation to the next
and comparing the left and right sensors, one has a low signal while the other hasa high signal during each turn. He noted that the maximum stress measured for eachroll revolution was a cycle of the time equal to the time period of the feed screw(Fig. 11).
Figure 12 shows a good representation of the heterogeneity of the appliedstress, illustrating that the maximum stresses are not applied to the center of the roll
but more toward the roll edges. The scientists showed that the applied stress on thecompact in the roller gap is due to the feed pressure distribution from the feed screw.
The nature of the feed pressure was due to the pushing of the powder in the last
spiral of the feed screw. The team took many stress proﬁle readings to measure
the heterogeneity of the applied stress, as it was not constant or homogenous along
the roller width (Fig. 12).
Graphically, the light transmitted through the salt compact and the maximum
measured stresses (from the two locations on the roll) enabled the stress measurement throughout the compact in the gap. The compact zones that had endured lessstress transmitted less light and therefore appeared darker (34).
Guigon sketched the feeding zone just prior to roll compaction (Fig. 13). He
indicated that the feed screw exit pressure was a function of the geometry and surface© 2005 by Taylor & Francis Group, LLC

176

MillerFigure 11 Stress proﬁles recorded simultaneously on the (A) left and (B) right transducer vs.
number of roller rotations during consecutive turns. (Screw speed, Vs; roller speed, Vr; sodium
chloride (Vr ¼ 8.4 rpm, Vs ¼ 22.3 rpm). (From Ref. 34.)

properties of the feed screw and of the compressibility of the powder. Summarizing
his ﬁndings, the pressure at a location (y, z planes, perpendicular to the x-direction of
motion) of the feeding plane will vary due to the motion of the last ﬂight of thescrew. When the wall of the screw ﬂight is far from the feeding plane (top part of
Fig. 13), the powder between the ﬂight and the feeding plane is not compacted
and the localized pressure at the feeding plane is low. When the ﬂight at this location
moves forward, the powder ﬁrst compacts without moving signiﬁcantly, increasing
progressively its density and local pressure at the feeding plane.
The team proved the observation with two dynamic motion picture experiments. The ﬁrst study showed the motion of particles at the check plate wall andconﬁrmed by video analysis that the particles do not move continuously in the feedzone (34). Guigon noted that the powder particles are almost stationary. Then, thepowder moves forward before stopping again. The velocity ﬂuctuations havethe same period as the screw. The second experiment consisted of using sodium
chloride and pushing the material to the rolls by means of a piston-feeding device.
The compact is shown in Figure 14 with light passing through it. Most notably,
the densest part of the compact is through the center, where most of the light istransmitted.
The work by Guigon and Simon provided new meaning to the importance ofthe feed screw pushing powder into the rolls and the feed screw design’s inﬂuence
on compact formation. The author of this chapter raises some questions on how amultiple feed screw system under vacuum deaeration environment would affect compact formation. No information has been published on investigating these aspects.
© 2005 by Taylor & Francis Group, LLC

Roller Compaction Technology

177

Figure 12 Distribution of stresses applied to a compact during the dynamic state of roller
compaction. (From Ref. 34.)

Figure 13 Sketch of the feeding zone. (From Ref. 34.)
© 2005 by Taylor & Francis Group, LLC

178

MillerFigure 14 Distribution of stresses applied to a compact, by piston pushed material into rolls,
not feed-screw pushed. (From Ref. 34.)

11. DEAERATION THEORY
A key factor limiting compaction throughput and quality is air entrapment in powder materials. During compression, air-occupying voids between particles are compressed and squeezed. The gas pushes through the powder causing powder
ﬂuidization and a nonuniform level of powder at the roll gap. It is best describedin Figure 15. This situation limits compact throughput and creates a nonuniform
compact density. Air entrapment creates excess ﬁnes prior to sizing because of ‘‘spidering’’ compact edges.
The spidering condition occurs when gases rush across the inside of a compact
to thinly and weakly formed ﬂaked edges. The ﬂake edges break apart perpendicular
to the compaction direction. The compact edge breakage appears ‘‘saw tooth’’ inFigure 15 Pattern of gas escape from nip region. (From Ref. 36.)
© 2005 by Taylor & Francis Group, LLC

Roller Compaction Technology

179

structure and varies in length depending on the nature of the powder binding properties, the amount of air entrainment, and the roll dwell time.
Johanson predicted theoretical compactor operating conditions to handle air
entrapment effects in materials. In general, he concluded that the critical compacting
pressure level is dependent on a number of factors: roll diameter and speed, powder
permeability, compressibility, and compact strength. Johanson indicated, when
applying these principles in commercial application, that a compactor operator
would have to operate the press at slightly less than maximum pressures to allow
for material inconsistencies and variable in-feed ﬂow rates (35).
Johanson and Pietsch described the forces at work in a roll press when powders
are compacted (25,35,36). Johanson illustrated the three typical work phases during
compaction Figure 16. The ﬁrst region is the initial solids contact pressure with thefeed screw. Pressure at this point is nil, P0. Later, as the solids begin to get pushed
and gripped by the rolls, pressure continues to build. Ultimately, the solids are
moved into the narrowest point of the nip angle where the maximum pressure occurs
at pmax. The second region describes the solid’s density increase through compaction
and densiﬁcation occurs rapidly, in less than a second. Some materials have properties that after discharge from the compactor undergo elastic deformation, which can
reduce the compact’s density, expressed by the dotted curve. The third region offorce at work is air pressure. Models such as the one described take into account that
it is dependent on the porosity of the particulate solids compacted. If the porosity of
the compacted material remains high enough during the compaction process, airpressure can escape and vent during and after compaction. On the other hand, if
the material has low porosity, air pressure builds up to high levels because it cannot
escape easily. This can be seen in several ways, one of which is through expansion of
the compact bursting. Bursting can be associated with a popping sound when operating the compactor. The second way occurs when the compacted sheet breaks intoslivers or ‘‘spidering’’ at the compact edges.
Both Johanson and Pietsch reported that expanding gas in a compact is detrimental to the compaction process: by reducing the compaction throughput andincreasing the amount of ﬁne particles. Johanson illustrates the effects of roll speed
and powder porosity on air pressure in a compacted sheet (43). He shows a relativelarge roll speed operating range when compacting a permeable (porous) powder. Air
entrainment does not limit roller speed for coarse granular powders. On the otherFigure 16 Compaction work phases. (From Ref. 43.)
© 2005 by Taylor & Francis Group, LLC

180

Millerhand, when compacting very ﬁne powders, the operating roll speed range is signiﬁcantly reduced because of air entrainment.
Miller indicated that the evenness of the powder feed into the rolls determines,
to a large extent, the success of compaction. Roller compactor systems suffer fromtwo disadvantages: as the powder feed bulk density approaches 0.3 g/cm3 or less,the compaction throughput efﬁciency decreases. Secondly and concurrently, theuncompacted powder leakage generally increases around the rolls (21). Miller, in
1994, described a new machine design improvement that used vacuum deaeration
to remove air entrainment from the powder just prior to the nip angle during roller
compaction. The multiple beneﬁts of such action are signiﬁcant when compacting
low-density raw materials (21):









More uniform powder feed to the rollers
Less voltage and amperage variability for the roll pairMore uniform and strong compact
Less powder leakage
Greater yieldLess powder adhering to the compact prior to sizing
Higher compact throughput
Less airborne particles.

The newly designed equipment involved a compactor ﬁtted with two horizontal
feed screws, which featured vacuum deaeration. Speciﬁcally, the roller compactor
was equipped with a conical storage hopper containing a variable speed agitator.
Bulk powder was fed directly from the top of the hopper to the top of twin horizontal auger feed screws, which directly transported the powder to the nip roll area (13).
Top and side views of the design features are shown in Figure 17 .
A novel stainless steel encasing that leads to the compactor rolls encloses thevariable-speed auger screws. Just before the nip area, a pair of sintered stainless steel
segments are assembled within the horizontal auger feed system, which can operate
under partial vacuum. A small, self-contained vacuum pump draws negative pressure through a dry ﬁlter and a stainless steel line connected to the sintered assembly
plates. The partial vacuum is adjustable from 0.1 to 0.8 bars. The compaction rolls

Figure 17 Compactor side view of auger feed screw system and sintered plate segment.
(From Ref. 13.)© 2005 by Taylor & Francis Group, LLC

Roller Compaction Technology

181

operate at different speeds and are supported on heavy-duty bearings in such a waythat the lower roll is ﬁxed and the upper roll is slightly movable in the vertical plane.
The deaerated material passes through the roll pair, which is under inﬁnitely variable
hydraulic pressure. The deaeration, auger feed screws’ design and speed, roll speed,
and hydraulic roll pressures are the main factors in producing a compact withspeciﬁed properties.
In several experiments, Miller studied the effects of using horizontal twin auger feedscrews under partial vacuum (Alexanderwerk Inc. Horsham, PA, USA, model 50/75
compactor). The feed powder was vacuum deaerated just before roller compaction.
The experimental design showed that the compactor’s deaeration feed system signiﬁcantly increased compaction output and minimized powder leakage when compacting
very low-density blends (<0.35 g/cm3); remarkable results were observed (22).
To evaluate the effectiveness of the compactor’s deaeration system, a test was
designed to process a low-density active drug blend with and without the activateddeaeration system. The test showed how much material was compacted with thedeaeration system engaged and how much material was compacted when it was
not engaged. The test also determined how much material was not compacted (powder roll leakage) in each case. Details of the experimental plan are found in Ref. 38.
Results of this experiment showed that under the inﬂuence of vacuum deaeration,
the compactor produced throughputs of 100 kg/hr and the resultant noncompacted
material leakage rate was <2%. The vacuum deaeration was so effective that there
was no need to recirculate the noncompacted powder back to the rolls to meet processing speciﬁcations. Under a second set of compacting conditions, vacuum deaeration was not activated and the process typically produced 70–80 kg/hr of densiﬁed
compact. The powder leakage rate increased to 20–30%. During this set of conditions, the powder ﬂow to the roll pair was uneven and the ribbon compact was
not uniform. Processing this formulation for a long period of time under these conditions would have required recirculation equipment to return the uncompacted
powder to the rolls for further processing (21,37,38). Table 4 for compactor parameters (trials 1 and 2).
In several other trials, Miller also studied the effects of using two different compactor’s vacuum deaeration systems (Table 5). The tests, similar to the ones previously described, were carried out using differently designed compactors. The
objective of these trials was to increase the active bulk density of the feedstock from
0.22 to 0.61 g/cm3 (13). Miller reported that the compactor, machine 1, containing
the horizontal twin screws and the vacuum deaeration design as described in Figure.
17, produced granules with 0.63–0.64 g/cm3 density at 80 kg/hr yield. When thevacuum deaeration was not activated the desired granule density speciﬁcation could
not be achieved. Table 6 (trials 1 and 2) for operating parameters and results.
A second compactor, machine design 2 (Fig. 18), did not densify the active
drug granules during the ﬁrst compaction run when employing vacuum deaeration.
After a second compaction pass with vacuum deaeration, trial 2, the powder density
was increased slightly to 0.58 g/cm3. It appeared that the level of vacuum being
applied to the active drug substance, in machine 2, was insufﬁcient, ineffective, or
not optimally positioned, even at its maximum vacuum deaeration level (13). Table
7 (trials 1–3) for machine 2 operating parameters and results.
Miller’s experiments evaluated the effects of powder density; screw feed speed,roll speed, roll pressure, vacuum deaeration pressure, compaction rate, and the compaction leakage rate. Test results demonstrated that the ﬁrst compactor’s deaerationand feed system designs signiﬁcantly increased compaction output. The new equip© 2005 by Taylor & Francis Group, LLC

182

MillerTable 4 Compactor Operating Conditions and Yields for Poor
Following Low-Density Active Drug Blend, Formulation 1, Vacuum
Deaeration and Non Vacuum Deaeration Trials
Formulation 1
Conditions
Powder density (g/cm3)
Screw feed (rpm)Roll speed (rpm)
Vacuum (bar)Roll pressure (bar)Compact rate (kg/hr)
Compact leakage rate (kg/hr)

Trial 1

Trial 2

0.25–0.35
52
8
(0.78–0.78)
60–65
100
2

0.25–0.35
52
8
0
60–65
70–80
15–20

Source: From Ref. 13.

ment design and process provided high compact yields and virtually eliminated powder leakage, obviating the need for expensive powder recirculation equipment. The
ﬁrst compactor’s vacuum deaeration design (Fig. 17) proved to be superior to thatof the second machine (Fig. 18) when compacting an active bulk drug with a densityof approximately 0.2 g/cm3. In summary, a new critical condition, vacuum deaeration, had been identiﬁed in optimizing roller compacting effectiveness and efﬁciency(13). Miller concluded that four key processing conditions must exist to optimize
roller compaction throughput and minimize powder leakage around the rolls (13): Adequate powder supply must enter the gripping zone.
 Powder must be fully conveyed into the narrowest part of the roller gap.
 Compaction pressure must be distributed as uniformly as possible over thewhole of the roller-gripped powder mass.
 Sufﬁcient vacuum deaeration must be effectively distributed prior to the niproll region, particularly for low bulk density powder feed stock.
12. ROLLER COMPACTION AND NEAR-INFRARED SPECTROSCOPYWork by this author in the mid-1990s investigated roller compaction and near-infrared spectroscopy (NIRS) technology, by examining three different active ingredient
Table 5 Compactor Operating Conditions and Yields for Poor
Flowing Low-Density Active Drug Blend, Formulation 2, Vacuum
Deaeration and Non-vacuum Deaeration Trials
Formulation 2
Conditions
Powder density (g/cm3)
Screw feed (rpm)Roll speed (rpm)
Vacuum (bar)Roll pressure (bar)Compact rate (kg/hr)
Compact leakage rate (kg/hr)
Source: From Ref. 13.
© 2005 by Taylor & Francis Group, LLC

Trial 1

Trial 2

0.25–0.35
52
8
(0.78–0.78)
60–65
150
1.3

0.25–0.35
52
8
0
60–65
100–11020–30

Roller Compaction Technology

183

Table 6 Operating Parameters and Results of Compactor Machine
Design 1 When Compacting Poor Flowing Low-Density Active Drug
Substance Blends
Conditions

Trial 1

Trial 2

Initial density (g/cm3)
Powder density (g/cm3)
Screw feed (rpm)Roll speed (rpm)
Vacuum (bar)Roll pressure (bar)Compact rate (kg/hr)

0.22
0.63–64
52
8
0.65
50
80

0.22
0.45
52
8
0
50
42

Source: From Ref. 13.

blends subjected to different compaction conditions and mapped speciﬁc in-processroller compaction processing steps and relationships. Miller illustrated the use of
NIRS to map, in the static mode, roller compaction unit operations. This was theﬁrst published work about using any spectroscopy to map roller compaction processing steps (39).
Blends were compacted using an Alexanderwerk roller compactor, model
WP50/75N (Alexanderwerk Inc., Horsham, PA) ﬁtted with vacuum deaeration.
All compacts were sized through a continuous series double rotary granulator ﬁtted
with 3.15 and 1.25 mm mesh screens, respectively. Blends were ﬁnally mixed for
2 min and compressed into tablets using a Kilian E 150 press (Kilian & Co Inc.,
Horsham, PA), which was equipped with standard concave 11 mm diameter tooling.
NIR spectral analysis was conducted using a Rapid Content Analyzer, model
6500 NIR spectrophotometer (Foss NIRSystems, Silver Spring, MD). NIRS
libraries were developed for each active drug concentration and the speciﬁc

Figure 18 Compactor front view of vertical feed screw system with vacuum deaeration.
(From Ref. 13.)© 2005 by Taylor & Francis Group, LLC

184

MillerTable 7 Operating Parameters and Results of Compactor Machine Design 2 When
Compacting a Poor Flowing Low–Density Active Drug
Conditions

Trial 1

Trial 2

Trial 3

Initial density (g/cm3)
Powder density (g/cm3)
Screw feed (horizontal) (rpm)Screw feed (vertical) (rpm)Roll speed (rpm)
Vacuum (bar)Roll pressure (bar)Compact rate (kg/hr)

0.22
0.45
30
260
6
0.34
50
40

0.45
0.58
30
260
6
0.34
50
48

0.22
0.46
30
260
6
0
50
36

Source: From Ref. 13.

compactor’s process critical control point’s (PCCP’s) operating conditions, details of
the experimental plan are referenced (39).
The NIRS absorbance shows (optical density) differences between 10 and
20 bar roll pressure compacts and also differences between compacts manufactured
with and without vacuum deaeration (Fig. 19). The associated NIR ibuprofen/
starch compact spectra also show an absorbance (optical density) hierarchy. The
higher the roll pressure with vacuum deaeration the greater the NIR optical density(10 bar, no vacuum <10 bar, vacuum <20 bar, no vacuum <20 bar, vacuum).
Figure 20 further illustrates the NIRS ibuprofen/starch 50/50-compaction evaluation. Figure 20 compares the two levels of roll pressure with and without vacuum
deaeration to a third parameter, compaction roll power consumption (CRPC).
CRPC is a power force measured from the roll drive that is continuously monitored
throughout the compaction operating process. An ibuprofen/starch compact trend
analysis shows that the greater the roll pressure with vacuum deaeration the greater
the CRPC (10 bar, no vacuum <10 bar, vacuum <20 bar, no vacuum <20 bar,vacuum). The analysis demonstrates that employing vacuum deaeration increased
the CRPC at both low and high roll pressure levels. As the vacuum deaeration
increased, the width and gauge of the ibuprofen/starch powder compacts also
increased. Additional characterizations for aspirin/starch and acetaminophen/starch compacts were completed, Ref. 39.

Figure 19 NIR absorbance processing 50/50 Ibuprofen/Starch compacts. (From Ref. 39.)
© 2005 by Taylor & Francis Group, LLC

Roller Compaction Technology

185

Figure 20 50/50 Ibuprofen/Starch compacts CRPC compactor and NIR corresponding
values. (From Ref. 39.)

Figure 21 depicts granule NIRS sensitivity to vacuum deaeration and roll pressure sized compacts. In general, granules produced from sized compacts manufactured without vacuum deaeration and at lower roll pressure levels exhibited higher
optical density. NIR spectra of 90/10 ibuprofen-processing effects are shown in Figure 22: ﬁnal blend, compact 20 bar roll pressure (vacuum deaeration) and granules
made from the same corresponding conditions. The results demonstrated that successive ibuprofen/starch processing steps, compacting, and sizing produced uniquely
different NIR absorbance amplitudes.
13. ROLLER COMPACTION AND PAT
A new FDA guideline initiative (2003–2004), Process Analytical Technologies (PAT)
encourages manufacturers to use real time in-line, on-line, or at-line nondestructive
sensory technologies to monitor process critical control points. The PAT frameworkaddresses every aspect from incoming raw materials to optimization to continuous
improvement. It starts with processability of the incoming raw materials; their attributes would be used to adjust the process parameters. The incoming material attributes could be used to predict or adjust optimal processing parameters. The link
between PAT and the new 21st Century Good Manufacturing Practices initiative,
from the FDA’s perspective, is ‘‘quality depends on knowledge and PAT brings

Figure 21 90/10 Aspirin/Starch granules NIR absorbance with compactor settings. (FromRef. 39.)© 2005 by Taylor & Francis Group, LLC

186

MillerFigure 22 NIR absorbance 90/10 Ibuprofen/Starch processing effects. (From Ref. 39.)

more knowledge and understanding of processes. This is the point where science andrisk-based decisions can be made in terms of manufacturing per Dr. A. Hussain’’(40).
In 2002–2003 Gupta, Morris, and Peck from Purdue University Industrial
Physical Pharmacy School began a series of noninvasive real-time investigations.
Evaluating roller compaction by NIR in the dynamic mode, the team monitored
the variation of compacted ribbon strength that could adversely affect particle sizeand distribution of granules obtained after milling a compact (41). Their thinking
was that both the ribbon strength and the particle-size distribution can be determined off-line but it is time consuming. The ability to use NIR spectra to quantify
the compact strength, the particle size, and to estimate postmilling particle-size
distribution could be done in real time. The most obvious NIR spectral change that
occurs in compacts or tablets prepared under increasing pressure is an upward shift
in the NIR spectral baseline (39). Kirsch and Drennen used the slope of the best-ﬁtline through spectra to quantify this upward shift and found a linear correlation
between this slope and the tablet hardness determined by the diametral compression
test (42). Gupta et al. applied this treatment to correlate the slope of the best-ﬁt line
through the NIR spectra with the strength of compacts was determined using thethree-point beam bending technique (41). Additionally, slope values were correlated

Figure 23 MCC compacts: effect of roll speed. (From Ref. 41.)
© 2005 by Taylor & Francis Group, LLC

Roller Compaction Technology

187

Figure 24 Relationship between slope of NIR spectrum and compact strength. (FromRef. 41.)to the particle-size distribution of granules produced from milled compacts. Realtime on-line techniques were used to monitor the roller compaction unit operation
for microcrystalline cellulose and 10% active blend. The spectra collected on the
different compact segments prepared from the same material under the same roller
compactor settings showed little variation, suggesting good reproducibility in thedata collection by the NIR sensor. A signiﬁcant shift in the NIR spectra wasobserved for compacts prepared at different roll speeds.
At constant feed screw speeds, the spectra shifted toward lower absorbancevalues with increasing roll speed (Fig. 23). This shift was observed with compacts
prepared from both the placebo and the 10% tolmetin blends. The shift in the
NIR spectra may be quantiﬁed, using the slope of the spectral baseline or using
the slope of the best-ﬁt line, by regression analysis through the spectrum (41). Useof the slope of the best-ﬁt line was advantageous over the slope of the baseline since
the best-ﬁt line uses information from the entire spectrum. The normalized force
values for the compacts showed strong linear correlation with the slopes of the spectral best-ﬁt lines (Fig. 24). It was observed that the particle-size distribution of themilled compacts exhibits a steady decrease in the d90, d50, and d10 values with increasing roller-compactor roll speed at constant rate (Fig. 25).

Figure 25 Relationship of milled 100% compacts at various roll speeds. (From Ref. 41.)
© 2005 by Taylor & Francis Group, LLC

188

MillerFigure 26 Milled tolmetin 10% compacts. (From Ref. 41.)

The values for the particle-size distribution for the milled 10% tolmetin compacts correlated well with the slopes of the spectral best-ﬁt line (Fig. 26). This clearlyshows the potential of the technique in predicting the particle-size distribution ofmilled compacts under a given set of milling conditions. Multivariate analysis of
the spectral data using PLS regression analysis conﬁrmed the ability of the slopeof the spectral best ﬁt to estimate the compact strength and the postmilling particle-size distribution. For greater detail in this expanding new technology area theinterested reader should examine the references.

ACKNOWLEDGMENTS
The author gratefully acknowledges and thanks Carol G. Miller for her contributions and assistance in editing and data manuscript control. The author thanks
and appreciates Dr. Pierre Guigon, Professor and Director of Chemistry at the University of Technology of Compiegne, France, for his collaborative contributions to
the text. The author thanks and appreciates Mr. Abhay Gupta, Ph. D. former graduate student at the Industrial Physical Pharmacy School of Purdue University, West
Lafayette, IN, USA. The author acknowledges and thanks Mr. Leonard Minervini,
Alexanderwerk, Inc., Hatboro, PA, USA, for electronic ﬁles of photographs andpictures.

REFERENCES
1. Kristensen HG, Schaefer T. Granulations. Swarbrick J, Boyland J, eds. Encyclopedia of
Pharmaceutical Technology. Vol. 7. New York: Marcel Dekker, 1993:121–126.
2. Capes CE. Particle size enlargement. Williams J, Allen T, eds. Handbook of Powder
Technology. Vol. 1. Amsterdam: Elsevier, 1980.
3. Capes CE. Particle size enlargement. Grayson M, Eckroth D, eds. Kirk-Othmer Encyclopedia of Chemical Technology. Vol. 21. 3rd ed. New York: Wiley, 1978:77–105.
4. Pietsch WB. Size enlargement by agglomeration. In: Fayed M, Otten L, eds. Handbook of
Powder Science and Technology. New York: van Nostrand Reinhold Co, 1984:Chap. 7.
5. Pietsch WB. In: Roth D, ed. Agglomeration Techniques for the Manufacturing of
Granular Materials with Speciﬁc Product Characteristics. The Institute for Briquettingand Agglomeration Proceedings. Vol. 25. Erie, PA: Gannon University, 1997:49–164.
6. Sherrington PJ, Oliver R. In: Granulation. London: Heyden & Son, 1981.
© 2005 by Taylor & Francis Group, LLC

Roller Compaction Technology

189

7. Kapur PC. Adv Chem Eng 1978; 10:55.
8. Kristensen HG, Schafter T. Drug Dev Ind Pharm 1987; 13:803.
9. Lindberg N. Industrial wet granulation. Acta Pharm Suec 1988; 25(special issue):
185–280.
10. Fonner DE, Anderson NR, Banker GS. Granulation and tablet characteristics. In:
Lieberman HA, Lachman L, eds. Pharmaceutical Dosage Forms. Tablets. Vol. 2. New
York: Marcel Dekker, Inc., 1982:Chap. 5.
11. Anderson NR, Banker GS, Peck GE. Principles of improved tablet production systemdesign. In: Lieberman HA, Lachman L, eds. Pharmaceutical Dosage Forms. Tablets.
Vol. 3. New York: Marcel Dekker, Inc., 1982:Chap.1.
12. Ghebre-Sellassie I. Pharmaceutical Pelletization Technology. New York: Marcel Dekker
Inc, 1989.
13. Miller RW. Roller Compaction Technology. Parikh DM, ed. Handbook of Pharmaceutical Granulation Technology. Vol. 81. New York: Marcel Dekker Inc, 1997:99–150.
14. Pietsch WB. Roll Pressing. London: Heyden, 1976.
15. Parrot EL. Pharmaceutical Dosage Forms. Vol. 2. New York: Marcel Dekker Inc,
1990:203–204.
16. Dehont FR, Hervieu PM, Jerome E, Delacourte A, Guyot JC. Briquetting and granulation by compaction: a new granulator-compactor. Wells J, Rubinstein M, eds.
Pharmaceutical Technology, Tableting Technology. Vol. 2. London: Ellis Horwood,
1993:1–11.
17. Heckel RW. Density-pressure relationships in powder compaction. Trans Metall Soc
AIME 1961; 221:671–675.
18. Johanson JR. Rolling Theory for Granular Solids. Trans Am Soc Mech Eng 1965:
842–848.
19. Jenike AW, Shield RT. Plastic ﬂow of Coulomb solids beyond original failure. J Appl
Mech 1959; 26:599–602.
20. Parrott EL. Densiﬁcation of powders by concavo-convex roller compactor. J Pharm Sci
1981; 70(30):288–291.
21. Miller RW. Advances in pharmaceutical roller compactor feed system designs. Pharm.
Technol 1994:154–162.
22. Shileout G, Lammens RL, Kleinebudde P. Dry granulation with a roller compactor Part
1: the function units and operational modes. Pharm Technol Eur 2000:24–35.
23. Miller RW. Roller Compaction Technology for the Pharmaceutical Industry. Encyclopedia of Pharmaceutical Technology. New York: Marcel Dekker, Inc., 2003 (on-line).
24. Dehont FR, Hervieu PM. Briquetting and granulation by compaction new granulator
compactor for the industry. Drug Dev Ind Pharm 1989; 15(14–16):2245–2263.
25. Pietsch W. Size enlargement by agglomeration. Fayed M, Otten L, eds. Handbook of
Powder Science, and Technology. 2nd ed. New York: Chapman and Hall, 1997:
347–364.
26. Funakoshi Y, Asogawa T, Satake E. Use of a novel roller compactor with a concavoconvex roller pair to obtain uniform compacting pressure. Drug Dev Ind Pharm 1977;
3(6):555–573.
27. Parrott EL. Densiﬁcation of powders by concavo-convex roller compactor. J Pharm Sci
1981; 70(3):288–289.
28. Jerome E. Measurement of resulting forces on a roller compactor. Drug Dev Ind Pharm
1991; 17(12):1571–1591.
29. Johanson JR. Predicting limiting roll speed for briquetting presses. Proceedings of the
13th Institute for Briquetting and Agglomeration. Vol. 13. 1975:89–99.
30. Sheskey PJ, Hendren J. The effects of roll compaction equipment variables, granulation
technique, and HPMC polymer level on a controlled-release matrix model drug formulation. Pharm Technol 1999; 23(3):90–106.
31. Johanson JR. Roll press feed systems. Proceedings of the 24th Institute for Briquettingand Agglomeration, October. Vol. 24. 1995:149–163.
© 2005 by Taylor & Francis Group, LLC

190

Miller

32. Weggel RW. The basics of force-feed roll briquetting. Manuf Eng 1982:107–109.
33. Miller RW, Sheskey PJ. Survey of current industrial practices and preferences of roller
compaction technology and excipients year 2000. Am Pharm Rev Spring 2001;
4(1):24–35.
34. Guigon P, Simon O. Correlation between the geometry of feeding system and the stress
distribution applied on the compact. In: Roth D, ed. Proceedings of the 27th Institute for
Briquetting and Agglomeration, Providence, RI, Nov 2001. Vol. 27. Erie, PA: Gannon
University, 2001:31–41.
35. Johanson JR, Cox BD. Fluid entrainment effects in roll press compaction. Proceedings ofthe 20th Institute for Briquetting and Agglomeration. Vol. 20. 1987:251–263.
36. Dec RT. Problems with processing of ﬁne powders in roll press. Proceedings of the 24th
Institute for Briquetting and Agglomeration. 1995; 24:199–210.
37. Miller RW. Using vacuum–deaeration feed system to minimize powder leakage duringroll compaction. Powder Bulk Eng 1997; 11(2):71–75.
38. Miller RW. Vacuum deaeration advances in pharmaceutical roller compaction technology. Proceedings of the 24th Institute for Briquetting and Agglomeration 1995;
Vol. 24:165–173.
39. Miller RW. Roller compaction optimization—NIR in-process mapping. J Pharm Technol
1999; yearbook supplement:30–39.
40. Miller RW. Process analytical technologies PAT part 2. Am Pharm 2003; 6(1):52–61.
41. Gupta A, Peck GE, Morris KR. Near infrared monitoring of roller compaction. In:
Roth, ed. Proceedings of the Institute of Briquetting and Agglomeration. Vol. 28. Erie,
PA: Gannon University, 2003:20–34.
42. Kirsch JD, Drennen JK. Nondestructive tablet hardness testing by near-infrared spectroscopy: a new and robust spectral best-ﬁt algorithm. J Pharm Biomed Anal 1999; 19(3–4):
351–362.
43. Johanson JR. Reducing Air Entrainment Problems in Your Roll Press. Powder and Bulk
Engineering 1989; 3(2):43–46.

© 2005 by Taylor & Francis Group, LLC

7High-Shear Granulation
Rajeev Gokhale*
Incyte Corporation, Wilmington, Delaware, U.S.A.

Yichun Sun and Atul J. Shukla
College of Pharmacy, University of Tennessee, Memphis, Tennessee, U.S.A.

1. INTRODUCTION
Granulation is the process of agglomeration of a powder mixture, which results in theenlargement of the particles. This is often necessary for manufacturing of solid dosage
forms such as tablets. The materials, which are compressed into tablets, must possess adequate ﬂowability, density, and compressibility. This is because the requisite amount of
powder mixture required to compress each tablet is ﬁlled into the die cavity by volume
and not by weight. This requirement of adequate ﬂowability, density, and compressibility
is particularly important during a high-speed tablet production where the dwell time isoften short. For example, active pharmaceutical ingredients such as ibuprofen and acetaminophen, which have inadequate ﬂow and compression properties, and a relative highdose, are often granulated prior to compression into tablets. Thus, the overall purpose of
granulation is to improve the ﬂowability and compressibility of the powder mixture.
Besides improving the ﬂowability and compressibility, the granulation process can alsoDensify the powder mixture and reduce dust
Narrow the particle size distribution of the powder mixture
Ensure uniform distribution of the drug in the powder mixture
Improve the dissolution characteristics of the ﬁnished tablets.

The three commonly used granulation methods include wet granulation, dry
granulation, and hot-melt granulation. These methods are categorized based on
the type of binder and the process employed during granulation. The equipment thatis used during the granulation processes is classiﬁed into the following three major
categories, based on the shearing strength it generates on the powder bed:
1. Low-shear granulators—twin shell (Peterson Kelly, PK) with an agitatorbar, dough mixer or planetary mixer, ribbon blenders, and ﬂuid bed
granulator without the rotogranulator*

Present Address: Merck Research Laboratories, West Point, Pennsylvania, U.S.A.
191© 2005 by Taylor & Francis Group, LLC

192

Gokhale et al.

2. Medium-shear granulators—ﬂuid bed granulators with a rotogranulator
attachment
3. High-shear granulators.
The granulation techniques can affect the physical properties of the resulting
granules, which then subsequently affect the tableting process, the quality, and theperformance of the ﬁnished tablets, as illustrated in the following examples.
An extended release of matrix tablet formulation for metoprolol tartrate (100 mg)
was prepared with three different granulation processes: direct compression, ﬂuid-bed,or high-shear granulation (1). Different grades of hydroxypropylmethylcellulose(HPMC) (Methocel K4M, K15M, K100M, and K100LV) were used as ﬁllers andbinders. Direct compression formulations exhibited poor ﬂow, picking and sticking
problems during tableting. High-shear granulation produced hard granules, which were
difﬁcult to mill. However, they yielded good tablets. Granules produced by the ﬂuid-bed
granulation process appeared to have satisfactory ﬂow and tableting performance.
A hydrophilic matrix tablet formulation containing 60–70% drug, and lowor medium-viscosity grades of HPMC for extended oral delivery of zileuton, wasprepared using the wet-granulation techniques (2). The granules were prepared withplanetary (low shear) and high-shear granulators. In vitro drug release was evaluatedusing USP apparatus 1. Slower drug release was achieved from the granules preparedwith the high-shear granulation process, because of the slower water penetration into
the denser and less porous granules.
A high-shear mixer was utilized for the evaluation of pregelatinized,
cross-linked, waxy corn starches as binding agents in the wet-granulation process (3).
Lactose granules prepared in a high-shear mixer showed a larger average size than
granules prepared in a low-shear mixer (planetary mixer), using the same amount ofbinding solution. The granules produced with high-shear mixer had lower friability
than those prepared with the planetary mixer.
High-shear granulation has been one of the most commonly used methods
to produce granules since the early 1980s (4). Hence, this chapter discusses in detail,the equipment, process variables, formulation requirements, granulation end-point
determination, and scale-up considerations of the high-shear granulation process.
2. HIGH-SHEAR GRANULATORS
Most of the high-shear granulators consist of a mixing bowl, a three-bladed impeller,
and an auxiliary chopper. The shape of the mixing bowl could be cylindrical or conical. The mixing bowl can be jacketed for heating or cooling the contents in the bowl,
by circulating hot or cool liquid or steam through the jacket. An impeller is
employed to mix the dry powder and spread the granulating ﬂuid. The impeller ofthe high-shear mixer granulator normally rotates at a speed ranging from 100 to
500 rpm. The function of the chopper is to break down the wet mass to produce
granules. The rotation speed of the chopper ranges from 1000 to 3000 rpm. The
high-shear granulator could be termed as either vertical or horizontal, based on
the orientation and the position of the impeller. The vertical high shear granulator
could be either a top-driven or a bottom-driven unit. Figure 1 shows the schematic
view of a top-driven vertical high-shear granulator, ULTIMAGRALTM/ULTIMAPROTM. Figure 2(a–c) shows photographs of choppers and impellers of top-driven
vertical high-shear granulators: ULTIMATM, GMXTM, and GMATM. Figure 3(a–d)
shows photographs of top-driven, vertical, high-shear granulators: UltimaGral 150,
© 2005 by Taylor & Francis Group, LLC

High-Shear Granulation

193

Figure 1 Schematic view of top-driven vertical high shear granulator. (ULTIMAGRALTM/ULTIMAPROTM courtesy of Niro Pharma Systems.)

Figure 2 (A) Photograph of an ULTIMATM top-driven impeller and chopper. (Courtesyof Niro Pharma Systems.) (B) Photograph of a GMXTM top-driven impeller and chopper(Courtesy of Vector Corporation.) (C) Photograph of GMATM top-driven impeller andchopper (Courtesy of L. B. Bohle.)© 2005 by Taylor & Francis Group, LLC

194

Gokhale et al.

Figure 3 (A) Photograph of a top-driven vertical high shear granulator (UltimaGral 150).
(Courtesy of Niro Pharma Systems.) (B) Photograph of a top-driven vertical high shear granulator. (GMX 10 courtesy of Vector Corporation.) (C) Photograph of a top-driven verticalhigh shear granulator. (GMA 1200 courtesy of L. B. Bohle.) (D) Photograph of a top-driven
vertical high shear granulator. (Courtesy of Glatt Air Techniques.)

GMX 10, GMA 1200, and Glatt. Figure 4 shows the schematic view of abottom-driven vertical high-shear granulator, with a horizontal chopper shaft(PMA through-the-wall design). Figure 5(A) and 5(B) shows photographs of top
views of bottom-driven impellers with horizontal choppers (Diosna and Glatt). Figure6(A–C) shows the photographs of bottom-driven vertical high-shear granulators:
Pharma MatrixTM PMA600 Podium, Diosna P 150, and Glatt. Figure 7 shows theschematic view of a horizontal high-shear granulator (Loedige). Figure 8 shows aphotograph of a plow-shaped mixing blade and a chopper inside a horizontal© 2005 by Taylor & Francis Group, LLC

High-Shear Granulation

195

Figure 4 Schematic view of a bottom-driven vertical high shear granulator with horizontal
chopper shaft. (PMA through-the-wall courtesy of Niro Pharma Systems.)

high-shear mixer granulator (Loedige). Figure 9 shows a photograph of a horizontal
high-shear mixer granulator (FKM-1200–Loedige).
The size of the high-shear granulators varies considerably from the smalllaboratory-scale models to large production-scale models, depending on the type ofthe model and end use. High-shear granulators are often equipped with granulation
end-point control devices, which are used to detect the end point of the granulation
process. Some of the recently introduced features in high-shear mixer granulators areclean in place (CIP) or wash in place (WIP), and one-pot processing. High-shear
granulators with CIP or WIP features can be cleaned easily, without removing thebowl, the impeller, and the chopper. The advantage of the one-pot processing systemis that the wet granules can be dried in the same bowl without additional equipment
for drying. Some of the suppliers of the commercially available high-shear granulators are listed in Table 1.
3. HIGH-SHEAR GRANULATION PROCESS
3.1. Wet Granulation
The composition of a powder mixture for granulation generally consists of an active
pharmaceutical ingredient (API), a ﬁller, a disintegrant (usually not included in controlled release tablets), and a binder.
A high-shear wet-granulation process includes the following steps:
1. Loading all the ingredients into the mixing bowl, which can be accomplished by either of the following methods: gravity feeding with manualor pneumatic valve, and vacuum feeding.
2. Mixing of dry ingredients such as API, ﬁller, and disintegrant, at highimpeller and chopper speeds for a short period of time (2–5 min).
3. Addition of a liquid binder (either binder solution or solvent) into the powder mixture, while both the impeller and the chopper are running at a low
speed.
© 2005 by Taylor & Francis Group, LLC

196

Gokhale et al.

Figure 5 (A) The top view of a bottom-driven impeller with a horizontal chopper. (Courtesyof Diosna.) (B) The top view of a bottom-driven impeller with a horizontal chopper inside aconical shaped mixing bowl. (Courtesy of Glatt Air Techniques.)

4. Wet massing with both the impeller and the chopper running at a highspeed.
5. Removal of the resulting wet granules from the granulator bowl, and drying them using an appropriate drying technique such as ﬂuid-bed or tray
drying.
6. Sieving the dried granules.
The high-shear wet-granulation process offers several advantages over theother granulation processes. These include: Short processing time Use of less binder solution
 Granulation of highly cohesive materials containing hydrophilic polymers,
which is not achievable with low-shear granulation processes
 Greater densiﬁcation and production of less friable granules
 Production of reproducible granules with a uniform particle size distribution© 2005 by Taylor & Francis Group, LLC

High-Shear Granulation

197

Figure 6 (A) Photograph of a bottom driven Pharma MatrixTM PMA600 Podium/
Through-The-Wall. (Courtesy of Niro Pharma Systems.) (B) Photograph of a bottom driven
Mixer–Granulator. (P 150 courtesy of Diosna Dierks & Soehne GmbH.) (C) Photograph of abottom driven high shear granulator. (Courtesy of Glatt Air Techniques.) Reduction of process dust, thus minimizing exposure to workers
 Obtaining predictable granulation end-point determination.
Despite the above advantages, the process is not immune to challenges such as: Production of less compressible granules, compared to low-shear granulation processes Narrow range of operating conditions
A commonly employed high-shear granulation process requires multiple unit
operations, such as drying and sieving after wet granulation. The preferred drying
method is ﬂuid-bed drying, because of the distinct advantages over tray drying.
However, a primary problem inherent in the two-step process of high-shear mixer
granulation and ﬂuid-bed drying is the possibility of exposure of the workers and© 2005 by Taylor & Francis Group, LLC

198

Gokhale et al.

Figure 7 Schematic view of a horizontal high shear mixer granulator. (Courtesy of Loedige.)the environment to potentially toxic materials during the transfer of the wet granules
from the high-shear granulator to the ﬂuid bed. In order to remedy the contamination
problem, the processing suites need to be operated under a negative pressure using
powerful air ﬁltration systems. Moreover, dehumidifying and heating of a large volume
of air is also necessary during the ﬂuid-bed drying process. Regulating the airﬂow andﬁltering the exhaust air during the drying process could also be challenging.
However, the above problems can be remedied by a one-pot approach in which
the high-shear wet-granulation and drying processes are combined into a single step.
This approach saves time, since cleaning and validating a single bowl is inherently
easier than tackling two or three units. For example, a Mi-Mi-Pro high-shear granulator, combined with microwave, was employed to study the effect of process variables on the properties of the granules obtained, for the mixture of alpha-lactose
monohydrate and microcrystalline cellulose (MCC) (5). The one-pot high-shear
granulators are commercially available from several manufacturers. Options such

Figure 8 Photograph of a plough-shaped mixing blade and a chopper inside a horizontal
high shear mixer granulator. (Courtesy of Loedige.)© 2005 by Taylor & Francis Group, LLC

High-Shear Granulation

199

Figure 9 Photograph of a horizontal high shear mixer granulator. (FKM-1200 courtesy of
Loedige).

as oscillating the bowl during drying, vacuum drying, gas-assisted vacuum drying,and microwave drying are also available. Figure 10 shows the schematic view of asingle-pot processor ULTIMAPROTM, based on the ULTIMAGRALTM with avacuum drying system. Figure 11 shows the photo of UltimaPro 600 single-pot processor at a swinging position (Niro Inc., Pharma Systems Division).
Another approach is to modify the wet-granulation process. This process iscalled moisture-activated dry-granulation process. The moisture-activated drygranulation process consists of two steps, wet agglomeration of the powder mixture
followed by moisture absorption stages. A small amount of water (1–4%) is added
ﬁrst to agglomerate the mixture of the API, a binder, and excipients. Moistureabsorbing material such as MCC and potato starch is then added to absorb any
excessive moisture. After mixing with a lubricant, the resulting mixture can thenbe compressed directly into tablets. Hence, this process offers the advantages of
wet granulation, but eliminates the need for a drying step.
The applicability of a 25 L high-shear mixer for moisture-activated dry granulation of phenobarbital was investigated by Christensen et al. (6). MCC, potato starch,or a mixture of 50% of each was used as moisture absorbing material. The results ofthe study showed that the physical properties of the tablets were primarily affected by
the water content, the moisture absorbing material, and the compression force.
3.2. Hot-Melt Granulation
Hot-melt granulation in a high-shear granulator is a versatile approach. Hot-melt
granulation utilizes a binder, which is a solid or semisolid at room temperatureand melts at a temperature below the melting point of API. Generally, the melting
point of such binders is between 30 C and 100 C. The binder, when heated nearits melting point, liquiﬁes or becomes tacky. This tacky and liquiﬁed form of binder
agglomerates the powder mixture, which upon cooling forms a solid granulated
mass. The energy to melt the binder may be derived from heat dissipated from thecirculating hot liquid, such as steam, water, or oil through jacketed bowl, or heatgenerated by the friction of high-shear mixing. A solvent such as water or an organic© 2005 by Taylor & Francis Group, LLC

200

Gokhale et al.

compound is not necessary to initiate particle binding in this method. The resultant
granules are compressed into tablets.
A series of studies have been carried out by Schaefer and his colleagues toinvestigate the effects of formulation and process variables on the hot-melt granulation process, and the properties of the obtained granules (7–13).
In spite of numerous granulation options available to a formulator, high-shear
wet granulation remains the method of choice.
4. MECHANISM OF HIGH SHEAR WET GRANULATION
The high-shear wet-granulation process can be divided into ﬁve stages as shown
below, namely, mixing, adding binder solution, wetting and nucleation, consolidation and growth, and granule attrition and breakage.

The binder solution or the granulating liquid is distributed through the powder
bed by mechanical agitation created by the impellers. At this stage, the powder mixture becomes wetted and initiates agglomeration via nucleation. Nucleation of particles occurs by the formation of liquid bridges between primary particles, which
adhere together to form agglomerates. At this stage, the concentration of liquid
phase in the powder mixture is relatively low, but high enough to establish liquid
bridges. The addition and distribution of binder solution can have a major impact
on the particle size distribution and quality of the granules. Poor liquid distribution
produces granules with a wide particle size distribution. These granules could include
large, overwetted particles, as well as small dry particles.
Granule growth is dominated by one of the two mechanisms: coalescenceor layering (14). Coalescence is agglomeration which occurs by collision and consolidation of deformable nuclei/granules, provided the agglomerates could withstandthe shear forces applied by the impellers. Layering occurs when ﬁne particles stickto larger particles or granules coated with binder. Free liquid on the surface of
agglomerates, which renders the necessary bonding strength and plasticity to theagglomerate, is required for coalescence or layering. The free liquid on the surfaceof the agglomerates can be from the addition of more binder solution or from© 2005 by Taylor & Francis Group, LLC

High-Shear Granulation

201

Table 1 List of High-Shear Granulator Suppliers
Supplier

Granulator

Contact information

DIOSNA Dierks &Soehne GmbH

Diosna P
high-shear
granulators

Glatt Air Techniques

VG high-shear
granulators

Key International,
Inc.

KG-5
high-shear
granulators

L.B. Bohle Inc.

GMA, VMA, and
BMG high-shear
granulators

Littleford Lodige

KFM and MGT
high-shear
granulators

Niro Inc. Pharma
Systems Division

ULTIMAGRALTM,ULTIMAPROTM,
and PMA highshear granulators

Vector Corporation

GMX
high-shear
granulators

270 Route 46 Rockaway, NJ 07866,
Tel: (973) 586–3708,
Fax: (973) 586–3731,
e-mail: marc_kaufman@servo-lift.com
20 Spear Rd,
Ramsey, NJ 07446,
Tel: (201) 825–8700,
Fax: (201) 825–0389,
e-mail: info@glattair.com
480 Route 9,
Englishtown, NJ 07726,
Tel: (732) 536–9700,
Fax: (732) 972–2630,
e-mail: info@keyinternational.com
L.B. Bohle, LLC,
700 Veterans Circle,
Suite 100,
Warminster, PA 18974,
Tel: (215) 957–1240,
Fax: (215) 957–1237,
e-mail: info@lbbohle.com
Lodige Process Technology, Inc.,
203 Forrester Creek Way,
Greenville, SC 29607,
Tel: (864) 254–9194,
www.loedige.de9165 Rumsey Road,
Columbia, MD 21045,
Tel: (410) 997–7010,
Fax: (410) 997–5021,
e-mail: info@niroinc.com
Vector Corporation,
675 44th St.
Marion, IA 52302–3800,
Tel: (319) 377–8263,
Fax: (319) 377–5574,
www.vectorcorporation.com

Zanchetta(A division of
Romaco)ROTO
high-shear
granulators

Romaco USA,
242 West Parkway,
Pompton Plains, NJ 07444,
Tel: (973) 616–0440,
Fax: (973) 616–9985,
e-mail: usa@romaco.com

the expulsion of liquid inside the agglomerates due to the consolidation of theagglomerates.
Granule attrition and breakage reduce the granule size. Granule breakage
is determined by the dynamic granule strength and the shear forces within the© 2005 by Taylor & Francis Group, LLC

202

Gokhale et al.

Figure 10 Schematic view of a single-pot processor ULTIMAPROTM based on the ULTIMAGRALTM with a vacuum drying system. (Courtesy of Niro Pharma Systems.)

granulator. If the impact forces are larger than the granule strength, continuous
breakage and immediate coalescence of the granules takes place (15). However, when
the granule strength exceeds the impact forces, granules will not break. In that case,granule growth is more static, i.e., the exchange of primary particles between the

Figure 11 Photograph of an UltimaPro 600 single pot processor (granulator is in a swinging
position with an operator). (Courtesy of Niro Pharma Systems.)© 2005 by Taylor & Francis Group, LLC

High-Shear Granulation

203

granules is minimal. Thus, there is a balance between agglomerate growth and degradation of the granules.
The liquid level in the powder bed in a high-shear granulator plays a key role in
the growth of granules. Granule growth and consolidation (densiﬁcation) occur atthe same time in the high-shear granulation process. Since deposition of free liquidon the surface of agglomerates is required for coalescence or layering to occur, maintenance of the free liquid on the surface of the agglomerates is critical for the growthof granules in a high-shear wet-granulation process (16). The agglomeration of ﬁne
particles is controlled mainly by the liquid saturation of the moist agglomerates,
which is the percentage of intragranular voids ﬁlled with the liquid. Increasing theamount of granulating liquid reduces the yield stress necessary to deform theagglomerates in collision, thus allowing growth by coalescence with other granules.
This deformation also makes it possible to consolidate the granules, which further
increases the liquid saturation level and squeezes additional ﬂuid to the granule surface for continued growth.
The moist agglomerates can exist in the following three states, based on theamount of the liquid they contain: the pendular state, the funicular state, and thecapillary state. The three states can be distinguished by the relative liquid saturationof the pores S, which is the ratio of pore volume occupied by the liquid to the total
volume of the pores available in the agglomerate.
Agglomerates are in the pendular state when the liquid saturation of the pores
S < 25%; in the funicular state when S is between 25% and 80%; and in the capillarystate when S > 80%. The liquid saturation S is determined by the amount of binder
solution and the intragranular porosity, which can be calculated based on thefollowing equation (17):S¼Hð1  eÞ
r
e

ð4:1Þ

where H is the ratio of the mass of liquid binder to the mass of solid particles, e is theintragranular porosity, and r is the particle density.
Therefore, the formulation, process, and granulator factors that affect thedegree of liquid saturation would play a critical role in deﬁning the robustness ofthe granulation process and the properties of the granules obtained. The effects ofthe starting material properties, the type of granulator, and its operation on the
granule growth can be evaluated by assessing the changes in the intragranularporosity, which occur during the process, since intragranular porosity affects thedegree of liquid saturation as indicated by Eq. (4.1). The properties of the
granules, such as particle size distribution, porosity, and content uniformity would
affect the properties and performance of the dosage forms prepared from these
granules.
4.1. Liquid Requirement
The optimal amount of liquid binder used for high-shear granulation is within a narrow range. If the optimal amount of binder solution is not used, there could beneither growth nor lump formation during the wet-granulation process. In theory,
the amount of liquid used during the wet-granulation process should be equal toor just exceed the liquid content corresponding to 100% liquid saturation. However,some grades of lactose and dicalcium phosphate (DCP) could be granulated by coalescence at liquid saturation far below 100% (18). It would be desirable to predict the© 2005 by Taylor & Francis Group, LLC

204

Gokhale et al.

required amount of liquid binder based on the formulation composition. However,this is a challenging task, since the liquid binder required for high-shear granulation
depends on a number of formulation and process factors, such as physicochemical
properties of the starting materials (API and excipients), type of the binder used,
impeller speed, wet-massing time, etc.

5. FACTORS AFFECTING THE GRANULATION PROCESSAND GRANULE PROPERTIES
Performance and physical properties of the compressed tablets are driven by properties of the granules. Yajima et al. (19) examined the relationship between particle size
distribution and physical properties of the obtained granules (e.g., angle of repose,
angle of spatula, loose bulk density, tapped bulk density, compressibility) and theresulting tablets (hardness and weight variation of tablets). The particle size distribution of the granules used for tablet compression was expressed as a function of median particle size, and standard deviation with a logarithmic normal distribution.
Physical properties of granules and the compressed tablets were signiﬁcantly affectedby this factor. Tablet hardness increased as the median particle size decreased, when
the standard deviation was <1.0.
In another example, Wikberg et al. (20) produced 11 granulations of a common
ﬁller (lactose) and three granulations of a high-dose drug (dipentum) by wet
granulation with polyvinylpyrrolidone (PVP) as binder, in a high-shear mixer granulator. The agglomeration process was varied to produce granules with varying
granule porosity. The granule fragmentation during compression was evaluated bymeasurements of air permeability of the tablets. The results showed that the degreeof granule fragmentation during compression was related to the granule porosity
before compaction. A granulation with a higher porosity had a higher fragmentation
propensity during compression. The tablet strength correlated well with the degree offragmentation, i.e., a granulation with a higher degree of fragmentation yielded
tablets of a higher hardness. Variations in compactibility can be explained by variations in granule porosity for the same formulation that was wet granulated under
different process conditions. Therefore, the formulation variables and granulation
process should be controlled to produce granules with the desired properties. Since
granule formation in high-shear wet granulation is dependent on the degree of liquidsaturation, the factors that inﬂuence the degree of liquid saturation should be optimized to obtain an optimal granulation formulation. The factors that affect thedegree of liquid saturation (which depends on the amount of liquid added as wellas on the densiﬁcation of the granules) are formulation, process, and apparatus variables. Hence, the granulation process and the properties of the granules are affectedby the aforementioned variables.
5.1. Formulation Variables
Besides the API, excipients such as a ﬁller or ﬁllers, a disintegrant (not applicable tocontrolled release), and a binder are also included in the powder mixture of a tablet
formulation. The ﬁllers used in tablet formulations can be classiﬁed into two categories, based on their water solubility: soluble ﬁllers such as lactose, sucrose, mannitol, etc., and insoluble ﬁllers such as MCC, starch, calcium carbonate, calcium
phosphate, etc. The binders used in the wet granulation process are water-soluble© 2005 by Taylor & Francis Group, LLC

High-Shear Granulation

205

polymers such as gelatin, PVP, HPMC and sugars such as glucose, sucrose, and sorbitol. Some of the commonly used disintegrants are sodium starch glycolate, crosslinked PVP, and cross-linked sodium carboxymethylcellulose. These excipients areavailable in various grades from vendors. Hence, the physical properties such as particle size distribution, particle shape, surface morphology, surface area, and solubility of API and excipients in the binder solution could vary considerably. The rate
and the ﬁnal degree of densiﬁcation are controlled by the physical properties suchas particle size distribution, particle shape, surface morphology, surface area, solubility in the binder solution, etc., of the starting materials. Therefore, the physicalcharacteristics of drug and drug loading, the types and amount of excipients, andthe type and amount of binder used could affect the rate and the ﬁnal degree of
densiﬁcation of the resulting granules. Moreover, these aspects of the powder mixture can also affect the amount of liquid required for granulation and the degreeof liquid saturation in the agglomerates, during the wet-granulation process, which
in turn affect the physical properties of the obtained granules.
5.2. Effects of Starting Materials
The physical properties of the granules are inﬂuenced by the physical properties ofthe starting materials. For example, the shape, size, and size distribution of the particles of the starting materials can affect the packing pattern of a powder mixture,and ultimately the ﬁnal degree of densiﬁcation and the strength of the resulting granules. The extent of granule densiﬁcation affects the degree of liquid saturation of thepowder mixture, and the amount of liquid binder required for granulation. The total
surface area of the starting materials, related to the particle size and porosity of thestarting materials, will affect the amount of liquid binder required for granulation.
The liquid adsorption of the starting material could also affect the amount of liquidbinder required for wet granulation. Therefore, the amount of binder solution required for granulation depends on the formulation composition, and the physicalcharacteristics of the starting materials. In a study by Schaefer et al. (21), whenthe mean particle size of lactose was decreased, the amount of liquid required for
granulation was increased to obtain a similar particle size of granules in high-shear
granulation.
The inﬂuence of the primary particle size of DCP on granule growth in aLödige M5GR high-shear mixer granulator was investigated by Schaefer et al.
(22). Two batches of DCP, one with a narrower particle distribution and smaller
geometric mean diameter, and the other with a wider particle size distribution anda larger geometric mean diameter were used. The batch with the narrower particle
size distribution and smaller geometric mean diameter was more easily densiﬁed thanthe one with the wider particle size distribution and a larger geometric mean diameter, because it was overwetted at lower moisture content. The granules with wider
particle size distribution were produced from the DCP with a wider particle size distribution and larger geometric mean diameter.
The strength of wet agglomerates can be dominantly affected by the degree ofliquid saturation and the primary particle size of the starting materials. Consequently, the growth mechanism and drug content uniformity of the resulting granules can be affected.
The inﬂuence of the primary particle size of lactose on the breakage of erythrosine granules was investigated by van den Dries et al. (4). The results showed thata decrease in particle size of the starting material, lactose, led to a decrease in© 2005 by Taylor & Francis Group, LLC

206

Gokhale et al.

breakage of granules. When granule breakage was absent, the granules remained
intact and the preferential layering of the smallest particles yielded inhomogenous
granules.
The effect of particle size of the lactose on the homogeneity of low-dose steroid
hormone distribution in granules produced in high-speed mixers was studied by
Vromans et al. (23). When a micronized low-dose steroid hormone was granulatedwith unmicronized lactose at 250 rpm, inhomogeneity of active was observed. The
coarse particle size fractions of the granules were found to be superpotent, up to
150% of the mean drug content, whereas the ﬁne size fraction showed a corresponding subpotency of 50%. However, when the particle size of lactose was reduced,
a better drug distribution was seen. This was attributed to an increase in the tensile
strength of the nuclei due to the smaller particle size of lactose.
The effect of particle size of lactose on the homogeneity of estradiol granules
prepared in a 10 L high-shear mixer was studied by van den Dries et al. (15). Threedifferent particle sizes of lactose were granulated with 0.1% micronized estradiol(5 mm) using an aqueous solution of hydroxypropyl cellulose (HPC) as a binder.
Granules prepared with the largest lactose particles (141 mm) yielded a homogenous
granulate. However, after a prolonged processing time, demixing was observed.
Contrary to the largest particles, granulation with the smaller lactose particles (23and 50 mm) led to demixing in the ﬁrst minute, although to a lesser extent. It was
concluded that granulation with the largest particles resulted in breakage of the granules, thereby preventing demixing. However, once the granules were strong enough(smaller particle size and prolonged process time) to survive the shear forces, demixing was observed. The extent of demixing depended on the particle size difference.
The size distribution of granules prepared from three different tablet excipients, lactose, glucose, and mannitol, in a high-shear granulator, were studied by bothsieve analysis and laser light diffractometry (24). Both the shapes and the size distribution of the granules produced from the three excipients differed.
The crystallinity of the starting materials affected the granulation process andthe properties of the granules. The effect of crystallinity of MCC on wet granulation,in binary mixtures of MCC and corn starch (CS), was investigated by Suzuki et al.
(25). The crystallinity of MCC was modiﬁed, producing amorphous material by
milling in a jet mill (J-MCC) and a vibrational rod mill (R-MCC). Crystallinity of
J-MCC was nearly equal to that of intact MCC (I-MCC), but that of R-MCC
was remarkably low due to the mechano-chemical effect. The growth rate of granules
with R-MCC was greater than that with I-MCC and J-MCC. The formulations containing I-MCC and J-MCC produced granules with a core (MCC and CS) aroundwhich CS was layered. R-MCC provided granules in which CS and abraded MCC
were homogenously mixed. In addition, R-MCC remarkably decreased the difference in drug content among the size fractions of granules compared with I-MCC.
The decrease in crystallinity of MCC increased the abrasion of the material by the
impeller. This resulted in a greater growth rate of granulation.
The physical properties of the API also affect the wet granulation process andthe properties of the resulting granules. For example, when the particle shape of the
API was changed from spherical to plate like due to a change in the crystallization
solvent, the compressibility of the resulting granules dramatically decreased (26).
The effect of the particle size of DPC 963 (API) on the characteristics of granules prepared by high-shear wet granulation was evaluated by Badawy et al. (27).
Particle agglomeration was affected by the particle size of the drug substance.
Granule geometric mean diameter and fraction with particle size greater than© 2005 by Taylor & Francis Group, LLC

High-Shear Granulation

207

250 mm was inversely proportional to the particle size of the drug substance. The
granules prepared with the smaller particle size had higher porosity, thus suggesting
lower tendency for granule densiﬁcation than those manufactured with the larger
particle size. The compressibility of the granules was increased with decreasing particle size of the drug substance. The effect of particle size on granulation growth is
the result of increased densiﬁcation propensity from increased drug particle size.
In another study, a high-shear mixer granulator was used for pelletizing a drug.
High-dose pseudoephedrine-HCl pellets were produced with MCC in a high-shear
mixer granulator (28). The drug loading and drug particle size inﬂuenced the bulk
and true densities of the resulting pellets.
5.3. Effects of Type and Amount of Binder Solution Used
A binder is normally required for the wet-granulation process. The binder can be
added into the powder mixture as a dry powder followed by the addition of water,or an appropriate solvent to activate binding. Alternatively, the binder can also be
added into the powder mixture as a binder solution. Because of the higher densiﬁcation of the wet agglomerates, the high-shear granulation process normally only needs
two-thirds to three-quarters of the liquid required during the low-shear granulation
process (18). The bonding characteristics of the binders used for wet granulation
could vary due to the differences in their physicochemical properties. Therefore,
the type of binder used for granulation can inﬂuence the granulation process, theamount of binder required for granulation, and the physical properties of theobtained granules.
For example, the effect of binder solutions on the size of DCP granules wasinvestigated by Ritala et al. (29). Five different binders, PVP (Kollidone 90), polyvinylpyrrolidone–polyvinylactate copolymer (PVP–PVA copolymer), hydrolyzed
gelatin and HPMC (Methocel E5 and Methocel E15) were studied. The granules prepared with PVP and hydrolyzed gelatin possessed a larger mean particle size andlower intragranular porosity when the same volume of binder solutions was used.
The other three binder solutions behaved similarly. This could be due to the higher
densiﬁcation of DCP granule caused by PVP and hydrolyzed gelatin. Thus, the granules had higher liquid saturation with lower volumes of the binder solutions. It wasapparent that increasing the concentration of the binder solution in the powder
mixture increased the mean granule size.
In another study, Ritala et al. (30) investigated the differences between ﬁve
binders during wet granulation using a high-shear granulator. The binders used
for the study were PVP K90, PVP K25, PVP–PVA copolymer, Methocel E5, andMethocel E15. The results demonstrated that the binder solutions with high surface
tension, such as PVP solutions, produced denser granules with larger mean particle
size than those with low surface tension, such as PVP–PVA copolymer, Methocel E5,
and Methocel E15. The difference of granule growth by different binders in highshear wet granulation could be due to the variation of surface tension of the binder
solutions.
The amount of binder and granulating liquid used during granulation affect
the granulation process and the physical characteristics of the prepared granules.
In general, the granules are ﬁner when the amount of granulating liquid used for
granulation is decreased. For example, the size of the granules prepared from threetablet excipients, lactose, glucose, and mannitol, increased when the amount of
granulation liquid was increased (24). Similar results were observed for granulating© 2005 by Taylor & Francis Group, LLC

208

Gokhale et al.

mixtures of mannitol and MCC (31). When the mixtures were granulated in a highshear mixer using HPC as the binder, the mean particle size of the granules increased
with increasing amounts of water and concentration of the binder.
Generally, an increase in binder concentration could result in the production oflarger granules. However, this is not always the case with starch paste since it could
behave differently from the other binders. For example, a high-shear mixer was utilized for evaluation of pregelatinized and pregelatinized, cross-linked, waxy corn
starches as binding agents in the wet-granulation process (3). Increasing the concentration of the binders decreased the average granule size; however, no difference infriability of the granules was observed. The use of pregelatinized or pregelatinized,
cross-linked starches as a paste provided larger and less friable granules than when
the binder was added in the dry form.
The effect of starch paste concentrations on the particle size distribution of ﬁne
granules, produced by high-speed mixer, was investigated by Makino (32). When alow concentration (5%) of starch paste was used, the growth of granules occurred
mainly during the massing time, since a relatively large amount of free water wasavailable from the paste. Only the mean particle size of the granules became larger
without changing the particle size distribution of the granules during granulation.
However, when a high concentration (15%) of starch paste was used, rapid deaggregation of granules occurred due to the applied shear force, following the formationof large granules, immediately after the addition of the starch paste. Deaggregationof these large agglomerates became predominant during the wet-massing stage, andhence, the size distribution of the granules became narrower. Longer massing time
was also required when a high concentration (15%) of starch paste was used, since
only a small amount of water exuded from the more concentrated starch paste during the agitation.
Besides the effect on the particle size of the granules, the amount of binder
solution used in the wet-granulation process can also affect the content uniformityof the granules. The effects of the amount of binder solution on the content uniformity of the oily drug D-alpha-tocopheryl acetate (VE) in granules obtained by highshear wet granulation was investigated by Kato et al. (33). When the amount ofbinder solution was below the amount of water required to reach the plastic limit(minimum amount of water required for the powder mixture to form a large agglomerate when kneaded), the content of VE was <50% in the fractionated ﬁne granules,
but was >200% in the fractionated large granules. Large variations were seen in thecontents of VE even if the granulation time was extended up to 30 min. When theamount of binder solution was at or above the amount of water required to reachthe plastic limit, less variation was observed in the content of VE throughout the
granules, and the content of VE was fairly uniform.
In another study, the effect of the amount of water as the granulating liquidand HPC as a binder on the pharmaceutical properties of granules of two model
drugs, ascorbic acid and ethenzamide, was investigated by Miyamoto et al. (34).
The dependence of drug content uniformity of these two model drugs on the granulesize was also investigated in this study. For a water-soluble drug, ascorbic acid, anappreciable dependence of drug content on granule size was not observed in model
formulations. However, for a poorly water-soluble drug, ethenzamide, more drug
was found in small-size granules (<75 mm). The drug content of ethenzamide insmall-size granules decreased with increasing amounts of HPC and granulation
liquid. These observations suggested that drug content uniformity is inﬂuenced© 2005 by Taylor & Francis Group, LLC

High-Shear Granulation209

not only by drug solubility in the binder solution, but also by the amounts of granulation liquid and the type of the binder used.
Granule friability is also inﬂuenced by the binder concentration and the amountof granulating liquid added to the formulation during granulation. For a new API
granulated with lactose and Avicel PH 101 using low-viscosity HPMC (Pharmcoat603), increasing the binder concentration and the amount of water tended to produce
higher wet-mass consistencies. Granule friability decreased with an increase in thebinder level. An inverse relationship was observed between granule friability and theamount of water added to the formulation, especially at lower drug concentrations (35).
The binder can inﬂuence not only the physical properties of the granules, butalso the performance of the ﬁnished tablets. For example, within a certain range ofbinder concentrations and granulating liquid, increasing the amount of binder or
granulating liquid actually decreases the compressibility of the granules (26). In
another study, the effect of different types of binders such as PVP K30, HPMC
(Cellulose HP-M 603), maltodextrin (Lycatab DSH), pregelatinized starch (Lycatab
PGS), and low substituted hydroxypropyl cellulose (L-HPC) (type LH 11) on thehardness of placebo and paracetamol tablets using high-shear granulation technique
was compared by Becker et al. (36). The placebo granules comprised only lactose andMCC (Avicel PH 102). The binders were added at 2%, 6%, and 10% in the dry form
and water was used as the granulating liquid. The median particle size increased withincreasing binder concentrations from 2% to 6% except when L-HPC was used as thebinder. The median particle size of the granules decreased with increasing binderconcentrations from 2% to 6% when L-HPC was used as the binder. The granulestrength, and the hardness (crushing strength and friability) of the resulting tablets
increased with increasing binder concentrations. In the preparation of model tablets
containing paracetamol, PVP K30 (6%) and Cellulose HP-M 603 (6%) turned out tobe the binders of choice with respect to crushing strength of the ﬁnished tablets.
Lycatab PGS, Lycatab DSH, and L-HPCC-LH 11 could not be used to produce
paracetamol tablets that met the requirements.
The amount of granulating water can also affect the physical properties andcompressibility of MCC, which is one of the most commonly used ﬁllers. The
mechanism of forming hard granules with MCC, using a high-shear mixer granulator, was investigated by Suzuki et al. (37). The hardness of the MCC granules
increased with granulation time and the amount of water added. The speciﬁc surface
area decreased during the granulation process. Crystallite size of cellulose decreased
with granulation time and with increasing amounts of water added. MCC granules
were strengthened with longer granulation time and greater amounts of water, thus
resulting in a more intricate network due to the strong shear force of the impeller.
The effect of granulating water level on the physical–mechanical properties of
MCC and siliciﬁed microcrystalline cellulose (SMCC) was investigated by Habib
et al. (38). Granules containing either MCC or SMCC were prepared at different
water levels using a high-shear mixer. The resulting granules were tray dried. The
water level ranged from 0% to 100%. Increasing the water level affected the granuleparticle size, increased the granular density and ﬂow properties of the granules, anddecreased the porosity and compactibility. The compactibilities of both materials
were similar and acceptable at each granulating water level up to 40%. However,both the materials showed poor compactibility at higher water levels. The effect ofamount of water used for granulation did not have a statistically signiﬁcant difference on the compressibility of MCC and SMCC. SMCC did not offer practicaladvantages over MCC, other than better ﬂow in the powder form, which could be© 2005 by Taylor & Francis Group, LLC

210

Gokhale et al.

attributed to slightly larger particle size and the presence of silicon dioxide in its
structure.

5.4. Effect of Process Variables
Process variables play a critical role in the granulation process since they inﬂuence
how the binder liquid is distributed in the powder bed and the degree of densiﬁcation
for the powder mixture. The degree of powder densiﬁcation affects the level of liquidsaturation of the moist agglomerates. Therefore, process variables could inﬂuence
properties such as particle size distribution and the drug content uniformity of theobtained granules. Speciﬁcally, the process variables affecting the granulation process and the physical properties of the obtained granules are:







Load of the granulator bowl
Impeller speed
Granulating solution addition method
Granulating solution addition rate
Chopper speed
Wet-massing time.

The following examples illustrate how varying the aforementioned process
variables inﬂuences the properties of the granules obtained using a high-shear wetgranulation process.
Processing variables such as impeller speed, granulating solution addition rate,
total amount of water added in the granulation step, wet-massing time, etc., were
evaluated using a Plackett–Burman experimental design in a study by Badawy
et al. (39). The results showed that granule compressibility of the lactose-based formulation is extremely sensitive to the processing conditions. The granule particle size
was increased by increasing the amount of water added, high impeller speed, andshort wet-massing time. The wet-massing time and impeller speed also had a signiﬁcant impact on granulation compressibility. Increasing the impeller speed and wetmassing time decreased granule porosity and fragmentation propensity, which led
to the decreased hardness of the ﬁnished tablets.
The shear effects of the impeller on the properties of granules prepared fromsurface treated sericite were investigated by Oulahna et al. (40). Surface treatedsericite was granulated with an alcoholic solution of polyethylene glycol 20,000 using
a high-shear granulator at three different impeller speeds (100, 500, and 1000 rpm).
The properties of the granules produced under different impeller speeds were examined in terms of porosity, friability, and binder content. The results indicated thatheterogenous granules (in terms of binder concentration) with ﬁner particles and awider particle size distribution were obtained at a low impeller speed (100 rpm).
However, at higher impeller speeds, homogenous granules with less ﬁne particles
and a narrower size distribution were observed. Moreover, the porosity of the granules decreased with increasing impeller speeds. Therefore, mechanical energy
brought to the powder bed by the impeller is as important as the physicochemical
characteristics of the powder–binder pair in affecting the granule properties.
The effect of granulation processing parameters, ﬁll ratios, impeller speed,
chopper speed, and wet-massing time on granule size distribution of placebo formulations was studied by Bock et al. (41). High ﬁll ratios in the bowl resulted in an
increased proportion of ﬁnes in the obtained granules. Increasing the impeller speed© 2005 by Taylor & Francis Group, LLC

High-Shear Granulation211

and the massing time increased the granule size. The speed of the chopper did notaffect granule size distribution for the formulations tested.
The mode of addition of the liquid binder can affect the characteristics of the
granules (42). When water, used as a binder liquid, was added to the powder mixture
by atomization, granules with a slightly narrower particle size distribution wereobtained.
The effects of massing time on the properties of the granules of hydrophilicpolymer-based controlled-release formulations were studied by Timmins et al.
(43). The formulations consisted of 30% sodium alginate, 10% HPMC, and 50%
diltiazem hydrochloride or verapamil hydrochloride. The increase in massing time
resulted in an increase in the mean granule size of the formulations. This could betrue for all the matrix controlled release formulations, which contain a high concentration of the hydrophilic polymers.
The effect of reducing drug loading and mixing time on the content uniformityof a low-dose drug was investigated by Kornchankul et al. (44). Buspirone hydrochloride was used as a model drug and was mixed with other ingredients in two different concentrations (0.5% and 5%, w/w) in a T. K. Fielder high-shear mixer at ahigh impeller speed (522 rpm) and a high chopper speed (3600 rpm) for up to
32 min. Samples were withdrawn from nine locations in the mixer at speciﬁc time
points using a side-sampling thief probe. The optimum time to mix the 0.5% w/w
formulation was 8 min, while it was only 1 min for the 5% w/w formulation.
MCC was granulated with water in a high-shear mixer (37). The hardness of
the MCC granules increased with granulation time and the amount of water added.
The speciﬁc surface area was reduced during the process. These ﬁndings suggested
that the long-chain structures in MCC were disrupted, resulting in smaller units withshorter chain lengths due to the strong shear force of the impeller. These smaller
units then formed a network within the granules. Thus, MCC granules were strengthened with longer granulation time and greater amounts of water, resulting in amore intricate network. The change in MCC chain length and physical structure
can be experimentally detected using the small-angle x-ray scattering and wide-angle
powder x-ray diffraction methods.
MCC granules were prepared by wet granulation with water in a high-shear
mixer granulator (45). Samples of wet granules were taken at different time points
after addition of water to examine the physical characteristics of the granules usingnear-IR spectrometry, thermogravimetry, and isothermal water vapor adsorption.
The results indicated that the degree of interaction between MCC and water increased with granulation time due to the change of physical structure of MCC during
the granulation process.
5.5. Effect of Granulator Design
A variety of high-shear granulators with varying processing designs are commercially available. The orientation of the mixing chamber in the granulators is either
vertical or horizontal. The vertical granulators could be bottom or top driven.
Besides the conﬁguration difference, a signiﬁcant difference exists among the mixers
in terms of the shapes of the mixing bowl and impeller blades. For example, the vertical top-driven mixer granulators utilize a curved blade design, thus allowing thetips of the mixing blade to reach the side wall of the mixing bowl, which is also
curved in a shape similar to the blade. On the other hand, the vertical bottom-driven
high-shear granulators (such as Diosna) have a conical mixing bowl with a ﬂat blade© 2005 by Taylor & Francis Group, LLC

212

Gokhale et al.

design. The blade is parallel to the lid and the bottom of the bowl, and only a small
portion of the impeller blade directly sweeps off the side wall of the conical mixing
bowl. During mixing and granulation, the conical mixing bowl pushes the powder
toward the center of the bowl for efﬁcient mixing. The differences in impeller blades
and mixing bowl designs of the different commercially available high-shear granulators are expected to result in different ﬂow patterns and powder ﬂow dynamics in thebowl.
During the wet-granulation process, the impellers impact the powder mixture
and keep the mixture moving. During this process, binder solution is distributed
and the powder mixture is compacted and densiﬁed. Relative swept volume, thevolume swept out per second by impellor and chopper divided by the volume of
the mixer, is the indicator of the work input on the powder material inside the bowlof the granulator. Changes in the granulator design could affect the relative swept
volume of the granulation process, which in turn could change the degree of densiﬁcation of the wet agglomerates. As a result, the optimal amount of granulating
liquid and the physical properties of the resulting granules may be altered. Therefore,
the design of high-shear granulators must be taken into consideration during the wet
granulation process.
Schaefer et al. found that there was a difference between the horizontal (Lödige
M5GR) and vertical (Fielder PMAT 25 VG) granulators in terms of granule growthfor DCP (22). The degree of liquid saturation required was higher for the vertical(Fielder PMAT 25 VG) granulator in order to obtain the same granule size. Agglomeration of DCP began at lower degrees of liquid saturation in the horizontal (Lödige
M5GR) granulator. This could be because the rolling motion of granules in the horizontal (Lödige M5GR) granulator facilitated agglomeration, whereas stronger
mechanical forces in the vertical (Fielder PMAT 25 VG) granulator promoted thebreakage of granules. A similar trend was observed for lactose granulation (46) as
well.
The effects of impeller and chopper design upon granule growth of DCP ina laboratory high-speed mixer (Fielder PMAT 25) were investigated by Holm (47).
Three different changeable impeller blades with the same surface area were constructed. The angles of inclination were kept at 30 , 40 , and 50 . The granules withlow porosity were obtained at high impeller speed for the inclination angles at 40
and 50 . The effects of the impeller design with respect to the blade inclinationand impeller rotation speed can be explained in terms of the volume of powder mixture swept out by the impeller. The relative swept volumes for the impellers at threedifferent inclination angles were 2.2, 2.82, and 3.36 at 400 rpm. A high-swept volume
causes high densiﬁcation of the agglomerates and narrow granule size distributions.
Chopper size and rotation speed had no effect on the granule size distribution
because the primary function of the chopper is to disturb the uniform ﬂow patternof the mass.

6. GRANULATION END-POINT DETERMINATION
The granule properties for a given formulation are a function of the process parameters such as the impeller speed, amount of granulating ﬂuid, and granulation time
(wet-massing time). Therefore, the time to end the granulation process during a highshear granulation process becomes critical. The properties of the granules produced
determine, in part, the ultimate quality and performance of the ﬁnished dosage© 2005 by Taylor & Francis Group, LLC

High-Shear Granulation

213

forms. Thus, the determination of the granulation end point becomes necessary. The
ultimate goal of end-point determination in a granulation process is to obtain an
indication of formation of granules with the desired physical properties, such as
acceptable mean particle size range and porosity. The measurements of changes during the granulation process are employed for end-point determination. The advantages of using an appropriate method to determine the granulation end point arelisted below:
 Process optimization––

Evaluate raw material
Determine optimal end point Batch reproducibility––

Use end point to achieve batch to batch consistency
Document adherence to batch protocol

 Process trouble shooting––

Detect mechanical problems
Identify mixing irregularities

Several different approaches have been explored for granulation end-point
determination. These approaches can be classiﬁed into two major categories: indirect
measurements and direct measurements. In the indirect measurements, the electricaland mechanical parameters of the granulator motor are monitored since the changesof these parameters are related to the changes in the consistency of the powder mixture in the wet granulation process. Faure’s study (48) has conﬁrmed that there is a
close relationship between the wet-mass consistency/viscosity of samples prepared ina mixer granulator and physical properties of the dry granules produced from thewet mass. The physical properties of the dry granules include granule size distribution, bulk density, friability, and ﬂow characteristics. Variations in the formulationand process affect the relationships between the wet-mass consistency and drygranule properties, and the net power consumption of the mixer granulator.
In the direct measurements, the physicochemical properties of the powder mixture are monitored during the wet-granulation process. These properties could bemass conductivity and granule size.

6.1. Indirect Measurements
In the indirect measurement, both electrical and mechanical characteristics of the
motor are monitored to control the granulation end point. The electrical characteristics of the motor are motor current and power consumption. The mechanical characteristics of the motor are torque and tachometry.
The power consumption of a granulator motor is related to the resistance ofthe mass mixture to the granulator blades, which varies with the consistency ofthe powder mixture. Power consumption used as granulation end point control
has been related to the level of liquid saturation of the moist agglomerates (49), densiﬁcation of wet mass (30,50,51), and granule growth (52). Leuenberger proposedthat the liquid amount required for granulation corresponds to the plateau in the
power consumption record proﬁle (53).
© 2005 by Taylor & Francis Group, LLC

214

Gokhale et al.

Figure 12 A typical power consumption proﬁle obtained from a commercially available highshear granulator. (From Ref. 53.)

High-shear granulators capable of monitoring the granulation end point using
power consumption are commercially available. Figure 12 shows a typical power
consumption proﬁle obtained from a commercially available high-shear granulator
with an end-point determination (53). It is evident that the proﬁle consists of ﬁve
phases during the wet granulation process. In Phase I, the powder mixture is moistened by adding the granulation liquid. Since the formation of liquid bridges is notobserved between primary particles, power consumption does not increase during
this granulation phase. In Phase II, the liquid bridges begin to form among the primary particles, thus resulting in granule formation. The power consumption increases
dramatically in this phase. In Phase III, as more granulation liquid is added, theinterparticular voids are ﬁlled by the granulation liquid and coarser granules areformed. The power consumption remains relatively constant in this phase. In Phase
IV, liquid saturation of the powder bed is reached, and more coarse granules areformed. The power consumption increases in this phase. In Phase V, as more granulation liquid is added, a suspension is formed. The power consumption starts
declining in this phase. It has been noticed that only the granules formed during
Phase III are usable for further dosage form development. Thus, the power consumption proﬁle can be used to monitor the granulation process and to determine
the granulation end point.
The drawback of monitoring power consumption is that the signal is affectedby a number of factors, such as product (formulation), equipment, or process variables. For example, the densiﬁcation properties of the starting materials, type andamount of binder used, addition rate of binder solution, impeller speed, etc., inﬂuence the power consumption proﬁle. Wear and tear of the granulator could also
affect the power consumption signal. Thus, the power consumption proﬁle for a
granulation process is formulation and process speciﬁc.
The end-point control of granulation by power consumption measurement in a
25 L high-shear mixer was investigated by Holm et al. (42). The effect of impeller
design, impeller speed, liquid addition rate, type of binder, and mixing ratios between lactose and starch on the correlation between power consumption and granule© 2005 by Taylor & Francis Group, LLC

High-Shear Granulation

215

growth was investigated in the liquid addition phase of the process using a fractional
factorial experimental design. A linear correlation between power consumption andmean granule size was observed. The correlation was dependent on the impeller
design, the impeller speed, and the type of binder. However, a granulation end-point
control, based on power consumption was not found to be sensitive to variations in
the lactose:starch ratio. An end-point control based on the peak detection method
was not generally applicable, because a peak in the differentiated power consumption signal could not be identiﬁed in all the experiments.
Monitoring of power consumption was also explored for automating the wetgranulation process (54). A vertical high-shear mixer (300 L Collette Gral) was
instrumented with a control unit, which controls the continuous addition of granulating liquid in relation to the consistency of the powder mass by power consumption
measurement. The instrumentation comprised an important approach for automatedprocess control, and on-line documentation of critical process parameters withrespect to validation. Similarly, a signal analysis system with memory-programmableautomatic process control for determining power consumption in a high-shear mixer
was introduced by Laicher et al. (55). The signal analysis system made it possible toperform gliding mean value calculations of the measuring signal and to evaluate thesignal ﬂuctuations. The granulation end point was determined by curve analysis.
Using this system, granules with a reproducible particle size distribution were obtained from active ingredient paracetamol or ibuprofen/excipient mixtures, which
either showed a tendency to form lumps, in the case of overwetting (paracetamol),or required a short granulation time due to low melting point (ibuprofen).
Since power consumption is related to both current and voltage of the motor, it
would be logical to use motor current for granulation end-point control. However,
the motors used in high-shear granulators are induction motors, which use alternating current that lags behind the voltage. Therefore, it is inappropriate to determine
granulation end point by monitoring motor current or the simple combined productof current and voltage (51). The power consumption of induction motors can be
expressed by the following equation:
pﬃﬃﬃPower ¼ 3 IV cos yð6:1Þ
where I is the current, V is the voltage, and y is the phase difference between current
and voltage.
An alternative to power consumption is torque measurement. A high-shear
mixer was instrumented with a new capacitive sensor, a watt meter, and a straingauge torque sensor (50). Placebo formulations containing DCP, MCC 101, MCC
102, and lactose were granulated in the high-shear granulator. A similar map (proﬁleof torque measurement or power consumption) of the granulation process was
obtained for power consumption and torque measurement.
In another study (51), a high-shear vertical mixer/granulator was instrumented
to monitor power consumption, direct torque (signal from impeller shaft), and reactive torque (signal from the motor). Of the three methods used, direct torque generated the most descriptive proﬁle for the granulation process. Granules produced forthe test formulations, based on the end points determined using direct torque measurement, resulted in tablets with acceptable hardness. Measurement of direct torquecould also detail the granulation process of an overwetted formulation.
Torque proﬁles of granulation of MCC or lactose in a high-shear granulator
with various operating conditions were studied by Kornchankul et al. (56). The© 2005 by Taylor & Francis Group, LLC

216

Gokhale et al.

torque measurement for each batch of granules obtained was correlated with the corresponding tablet characteristics. The scatter plots of tablet hardness indicated thatthe hardness of tablets prepared with MCC granules was >7 Kp, as long as the end
torque was <100 lb in., granulation rate was < 0.4 lb in./sec, and granulation extent
was <13,000 lb in. sec.
The relevance of end-point determination based on torque measurement incontrolling performance characteristics of compressed tablets such as hardness, friability, disintegration time, and dissolution time was determined by Achanta et al.
(57). The measurement of torque was used to determine the end point of the granulation process in a high-shear granulator. With increasing end-point levels, tablets
compressed with the corresponding granules were found to be harder.
6.2. Direct Measurements
During the high-shear wet-granulation process, the binder liquid is dispersed in the
powder mixture. At this point, the wetted powder becomes agglomerated and densiﬁed. Thus, the physical properties (particle size, density, consistency) of the powder
mixture change with time during the granulation process. This change in the properties of the powder mixture can be used as an indication of the end point of the granulation process.
6.3. Consistency Measurement Using a Probe
One approach to determine the granulation end point is based on monitoring thechange of the consistency or strength of the wet mass during the granulation process.
This approach was ﬁrst developed by the Boots Company for Diosna high-shear
mixers (18). The Disona-Boots probe is designed to detect changes in the momentumof granules, in a constant velocity region of the mass, with the use of strain gauges
mounted on the probe. To avoid bias due to random events (e.g., production of large
lumps due to inhomogenous solution distribution), signal pulse heights, samplingtimes, and pulse density are all considered to attain the ﬁnal signal. The signal is normalized over a calibrated range of forces from 0% to 100%. The criterion for endpoint indication is that the signal obtained during the granulation process must be
greater than the preset value. When properly developed and calibrated for a given
high-shear granulator, the probe can be successfully used to determine a repeatablegranulation end point, i.e., granules with a similar particle size and density are
obtained. However, the signal obtained from the probe is granulator and formulation dependent.
6.4. Acoustic Emission
Acoustic emission monitoring detects and analyzes the sound produced by a process
or system. During the wet-granulation process, particle size, ﬂow properties of thepowder mixture, and degree of powder densiﬁcation change with time because of
the addition of binder and formation of agglomerates. The change of physical properties of the powder mixture could affect the acoustic emission signal. Thus, thistechnique can be used to map the granulation process and determine its end point.
The technique is noninvasive, sensitive, and relatively inexpensive.
The acoustic emissions during the wet granulation of a model formulation containing lactose and MCC were monitored using acoustic emission sensors (58). The© 2005 by Taylor & Francis Group, LLC

High-Shear Granulation

217

sensors were attached to the outside of the high-shear mixer bowl. Undergranulated
to overgranulated granules were prepared by varying the quantity of the binder solution. Average signal level increased with increasing amount of the added binder solution and wet-massing time. A strong correlation between the acoustic emissions andthe physical properties of the granules at the end of the granulation process wasdemonstrated. This technique was capable of monitoring changes in physical properties such as particle size, ﬂow properties, and compression properties of powdermaterial during granulation.

6.5. Image Analysis
In the direct measurement techniques, one of the successful methods is monitoring
the granulation processing based on the particle size of the granules.
A novel system to continuously monitor granule growth in a high-shear
granulation has been developed by Watano et al. (59). The system consists of animage processing system and a particle image probe comprising a CCD camera,
lighting unit, and air purge system. High-shear granulation was conducted using
pharmaceutical powders, and granule size and product’s yield of various size ranges
were continuously measured by the developed system. Sieve analysis of the granules
sampled out during the granulation was simultaneously conducted, and the data
were compared with that of the on-line image processing system. A close relationshipwas found between both the data, thus proving that the system could monitor the
granule growth accurately and continuously throughout.
Such an image processing system was further developed to automatically control the wet-granulation process by Watano et al. (60). Besides the image probe, afuzzy control system using a linguistic algorithm employing ‘‘if-then’’ rules with aprocess lag element was developed to control granule growth accurately. The system
consisted of an image processing and a fuzzy control system. An image probe continuously monitored granule images through the sidewall of the vessel. The images
were digitized by the image processing system, and granule median diameter andshape factor were calculated automatically. The difference between the desired andmeasured granule diameters was used as an input for fuzzy reasoning. The result of
fuzzy reasoning was used to control the output power of the liquid feed pump. The
system could control granule growth with high accuracy, regardless of changes in theoperating conditions.

7. FORMULATION DEVELOPMENT (OPTIMIZATION)
The pharmaceutical properties of the granules, which can signiﬁcantly affect the performance and properties of the ﬁnished dosage forms are controlled by multiple
interrelated variables such as formulation, process, and granulator parameters. In
most cases, the nature and characteristics of the excipients and API used in the formulation are ﬁxed. Thus, only the amount of granulating liquid and granulation process variables need to be optimized. ‘‘Design of experiment (DOE)’’ is often used to
optimize the granulation process. In experimental designs, a number of cause factors
which comprise volume of binder solution, impeller speed, massing time, etc., andresponse variables (dependent variables), which comprise mean particle size, tablet
hardness, time for 50% of drug released, etc., are selected. The relationship between© 2005 by Taylor & Francis Group, LLC

218

Gokhale et al.

cause variables and response variables is established mathematically. The optimal
response variables can then be obtained by selecting the optimal cause variables.
A Box-Behnken design was used to optimize the composition and process factors for formulations containing mannitol and MCC, which were granulated in ahigh-shear mixer and compressed into tablets (31). Simultaneous optimization of
crushing strength, disintegration time, and ejection force of the tablets was carriedout to ﬁnd optimal regions in the design space for these tablet properties. The composition of the tablet mixture and the process of tablet manufacturing were optimized using such statistical techniques.
A central composite experimental design was used to optimize a granulation
process in a high-shear mixer for a hydrophilic matrix tablet formulation (61).
The parameters tested were the amount of water in the hydroalcoholic granulation
liquid, the amount of granulation liquid, and the massing time. The results indicatedthat the amount of granulation liquid was the most important parameter, followedby the amount of water in the granulation liquid. The inﬂuence of the massing time
was negligible. A formulation with granule friability below 20% was obtained under
optimal processing conditions.
The wet-granulation process by a high-speed mixer granulator for two model
drugs, ascorbic acid and ethenzamide, was optimized through experimental design(spherical central composite experimental design) and simultaneous optimization
methodology (34). The amount of water (granulation liquid) and HPC (binder) were
simultaneously optimized with regard to the four pharmaceutical properties, including yield, drug content uniformity, geometrical mean diameter of granules, anduniformity of granule size. A simultaneous optimal point incorporating four pharmaceutical properties was obtained using the generalized distance function. The
experimental values of the four response variables obtained in newly prepared granules were found to correspond well with the predicted values of granules containing
both ascorbic acid and ethenzamide.
Various experimental designs have been explored by Vojnovic et al. to optimize
wet-granulation process variables. Some of these examples are described below.
Wet granulation of lactose and corn starch in a 10 L high-shear mixer was optimized using a response surface design (62). The effect of the process factors, impeller
speed, amount of water added, and granulation time on the properties of the granules were investigated. Moisture level had a major effect on geometric mean diameterand ﬂow rate of the granules. The impeller speed markedly inﬂuenced the geometricmean diameter, geometric standard deviation, compactibility index, and percentage
of granules smaller than 1250 mm. The granulation time affected the compactibility
index of the granules. Theoretical optimum conditions were obtained for the following ﬁve response variables: geometric mean diameter, geometric standard deviation,
ﬂow rate of the granules, percentage of granules smaller than 1250 mm, and compactibility index. These results were comparable to the experimental results.
A central composite response surface design was employed to optimize a wetgranulation process for lactose and corn starch in a 10 L high-shear mixer (63). The
effect of the optimal combination of three independent variables (moisture level,
impeller speed, and granulation time) on four properties (geometric mean diameter,
percentage of particles smaller than 1250 mm, geometric standard deviation, and ﬂowrate) of the granules was investigated by the simultaneous optimization method. The
optimum zone determined in 10 L high-shear mixer was analyzed for scale-up. The
same product was manufactured at a 50 L scale and optimum theoretical results were
© 2005 by Taylor & Francis Group, LLC

High-Shear Granulation

219

obtained for the four response variables. These results were in agreement with theexperimental data.
Optimization of wet granulation of a placebo formulation in a 10 L high-shear
mixer was carried out using an experimental design, which combined the Scheffe
simplex-centroid design and Doehlert experimental matrix (64). Lactose, corn starch,and MCC were used as excipients. Mixing ratios of these excipients were selected asformulation factors. The impeller speed and granulation time were chosen as independent variables. A two-phase experimental strategy was employed. The optimalcomposition of the three excipients was determined in the ﬁrst phase and the optimal
process conditions to obtain a geometric mean diameter >150 mm was determined in
the second phase.
The optimization of wet granulation in a 10 L high-shear mixer was investigated using a nonclassical mixture experimental design, which combines mixture
experimental design with the ponderation function (65). HPMC, lactose, corn starch,and MCC were used as excipients, while PVP was used as a binder. The introductionof such a modiﬁcation in the experimental design allowed selection of an experimental matrix, which could provide enough information with a relatively low number ofexperiments and at a minimal cost.

8. PROCESS SCALE-UP
The formulation and process for a new API are normally optimized using small-scaleequipment, owing to a limited amount of API. The granulators used during thedevelopment stage are laboratory scale models. The formulation is generally ﬁxed
during the clinical trial studies. However, the production batches are manufactured
with large-scale equipment. For a solid dosage form prepared using the wet-granulation process in a high-shear granulator, product scale-up could be challenging. Thisis because of signiﬁcant differences between laboratory and production models ofhigh-shear granulators in terms of the design, shape, size, and geometry of the impellers. Even though the composition of the formulation is similar, the physical properties of the obtained granules could be dramatically different because of thedifferences between laboratory scale and production scale granulators. These differences in the physical properties of the granules could signiﬁcantly affect the properties and performance of the ﬁnal tablets.
The ultimate goal of product scale-up is to maintain similar processing conditions for the production batches as those used at the laboratory scale so that theproperties of the granules produced after scale-up would not change signiﬁcantly.
Therefore, it is imperative to identify and monitor key process parameters during
the product development stage, so that the tablets produced from the large-scale
granulation batch perform similarly to those produced from the small-scale batch.
The liquid saturation level of the agglomerates during a high-shear wetgranulation process plays an essential role in terms of granule growth, as discussed
previously. It is desirable to maintain a constant level of liquid saturation during thescale-up. From Eq. 4.1, liquid saturation level is controlled by both moisture
content and intragranular porosity. The moisture content is determined by theamount of applied granulation liquid. The intragranular porosity is affected by
the impaction caused by the impeller and wet-massing time. Due to the different geometric shapes and sizes of the granulator and impeller, and ﬁll ratio in the mixing
bowl, maintaining constant liquid saturation level could be problematic.
© 2005 by Taylor & Francis Group, LLC

220

Gokhale et al.

8.1. Linear Scale-up
As described earlier, the process and formulation factors that affect the granulation
process and physical properties of the obtained granules are: rate of addition of thebinder solution, impeller speed, wet-massing time, and the amount of binder or granulating liquid used. Ideally, the amount of binder and granulation liquid will bescaled up by linearly increasing the amount of water with the batch size. If the timeof binder solution addition is kept constant by increasing the rate of binder addition
during scale-up, then the variables that need to be controlled narrow down to impeller speed and wet-massing time. Different approaches have been proposed to control
impeller speed. These approaches include maintaining a constant impeller tip speed,
maintaining a constant relative swept volume, or maintaining a constant Froudenumber (dimensionless number) during the scale-up process. The wet-massing time
can be determined by the granulation end-point determination such as power consumption. However, due to the difference in the size and shape of the mixing bowl
and impeller between laboratory and production scale granulators, linear scale-up
may not work.
A constant relative swept volume and a constant impeller tip speed during the
granulation of lactose in three Gral high-shear mixers (Gral 10, 75, and 300 L), did
not result in a comparable process for different sizes of granulators (66). Thus, even
within the same type of high-shear granulators, compensatory changes in the volume
of binder ﬂuid, impeller speed, and wet-massing time to produce equivalent granules
during scale-up may be required.
The ease of scale up could be formulation dependent, and some formulations
are not affected by the batch size. If the formulation is easy to densify, then the speedof the impeller may not affect the properties of the obtained granules. In one study(67), alpha-lactose monohydrate was granulated using a PVP K 30 (2.5% on dry
material) binder solution. The wet granulation process was optimized in a Gral
10 L granulator using a two-factor (water content and impeller tip speed), three-level
experimental design. The granulation process was then scaled down from a ColletteGral 10 L (8 L batch size) to a serial minigranulator (Pro-C-epT Mi-Pro) with different bowl volumes of 5 L, and 1900, 900, and 250 mL. In all mixer volumes, the impeller tip speed range used did not inﬂuence the granule or tablet properties. In all bowl
volumes, the inﬂuence of water concentration on actual yield, particle size distribution, and granule friability was similar.
In another study, the formulation containing 5% API, 47.35 % of MCC, and47.35% of pregel starch was granulated using different sizes of high-shear granulator
ranging from 2 to 25 L (68). A 23 factorial design was used to investigate the effects
of scale-up variables including amount of binder solution, wet-massing time, andimpeller tip speed on the physical properties of the obtained granules. It was shownthat the characteristics of the granulations made under different conditions werehighly reproducible. The excipient system of MCC and pregel starch produced arobust formulation that was resistant to changes during the scaling-up process inthe high-shear mixers.
Unfortunately, most formulations are not scalable. For example, a less homogenous liquid distribution, a wider granule size distribution, and a higher intragranular porosity of the obtained granules were found for the scale-up batches when
DCP was granulated using different sizes of high-shear granulator. This could be
due to the decreased swept volume in the larger granulator during scale-up (18).
© 2005 by Taylor & Francis Group, LLC

High-Shear Granulation

221

In another study, a model formulation was developed in a small-scale highshear granulator (Diosna P 1-6) (41). It was easy to scale up to the P 10 granulator
without changing the formulation or the granulation conditions. However, further
scale-up to Diosna P 25 and P 100 granulators, which are large-scale machines,
resulted in granules which were smaller than those prepared in the laboratory scaleequipment.
To achieve linear scale-up for formulations that are sensitive to the changes
during the scale up, the parameters used during the laboratory scale granulation
process have to be similar to those used during the production scale process. Twoprocesses may be considered similar if there is a geometrical, kinematic, and dynamic
similarity (69). Two systems are considered to be geometrically similar if they havethe same ratio of linear dimensions. Two geometrically similar systems are kinematically similar if they have the same ratio of velocities between corresponding points.
Two kinematically similar systems are dynamically similar when they have the sameratio of forces between corresponding points. For any two dynamically similar systems, all the dimensionless numbers necessary to describe the process are the same(70). Dimensionless number of the process is scale independent, and thus can be
employed for scale-up of granulation.
Dimensional analytical procedure was ﬁrst introduced by Lord Rayleigh in
1915 (71). It is a process whereby the variables pertinent to a physical problem aresystematically organized into dimensionless groups/numbers. Assuming the absenceof chemical reaction and heat transfer, the following inﬂuencing and independent
variables are pertinent to the wet-granulation process (72):
DP: net impeller power consumption (motor power consumption minus thedry blending baseline level)
R: impeller radius
N: impeller speed
h: height of granule bed in the bowl
r: granule bulk or speciﬁc density
Z: granule dynamic viscosity
The only three fundamental quantities are mass (M), length (L), and time (T).
Buckingham theorem (p-theorem) (73) states that when there are i physicalvariables and dimensional constants and j fundamental qualities (such as mass,
length, and time), the number of dimensionless groups/numbers in a complete set
is equal i  j.
Therefore, according to the Buckingham theorem, there are four dimensionless
numbers for a high-shear granulator.
Newton (power) number (Np) relates the drag force acting on a unit area of theimpeller to the inertial stress:
Np ¼

DP
rN 3 R5

ð8:1Þ

Reynolds number (Re) relates the inertial force to the viscous force:
Re ¼

rNR2
Z

ð8:2Þ

Froude number (Fr) is the ratio of the centrifugal acceleration to the gravitation constant (g). It can be used as a criterion for dynamic similarity of granulators:© 2005 by Taylor & Francis Group, LLC

222

Gokhale et al.

Fr ¼

RN 2
g

ð8:3Þ

Geometric number (ratio of characteristic lengths) h/R is related to ﬁll level inthe bowl.
An ideal scenario is that the granulation processes in laboratory scale and production scale granulators are geometrically, kinematically, and dynamically similar.
However, the shape and size of granulators currently available vary from manufacturer to manufacturer. Therefore, it is difﬁcult for the granulation processes to begeometrically, kinematically, and dynamically similar. For example, Collette Gral10, 75, and 300 are not geometrically similar (66).
One practical approach during scale-up is to keep the processes dynamicallysimilar, which is deﬁned by the same dimensionless numbers for the two different
sizes of granulators. Therefore, dimensionless numbers such as Froude number
can be used for scale-up.
Froude number was suggested as a criterion for dynamic similarity and ascale-up parameter during wet granulation (66). Lactose granules prepared in Gral
high-shear mixers of three different capacities (Gral 10, 75, and 300 L) werecompared. The granulation process regarding temperature increase and particle size
distribution could be scaled up by keeping the Froude number constant. It therefore
seems appropriate to characterize and compare different mixers by the range of the
Froude numbers. A matching range of the Froude numbers would indicate thepossibility of scaling up the batch even for the mixers such as Collette Gral 10,75, and 300 that are not geometrically similar. Hence, systematic consideration isneeded to select laboratory and high-production scale granulators to develop a solid
dosage form, which requires high-shear granulation in the manufacturing process.
The Froude numbers of each granulator can be calculated based on Eq. 8.3. If
the Froude numbers for the laboratory scale granulator cannot be matched, linear
scale-up is unlikely.
Dimensionless power relationship between power number and the product of
Froude number, Reynolds number, and ﬁll ratio could be another approach forscale-up (74). A model formulation granulated in different conditions (batch size,
blade speed) with different sizes of high-shear granulators, but presenting similar
wet-mass characteristics (bulk density and consistency) led to dry granules of similar
properties such as granule size distribution, density, friability, and ﬂow. The wet
masses were characterized by the bulk density and consistency, as measured by mixer
torque rheometry. The power consumption of the granulator was monitored with apower meter. The power number, Reynolds number, Froude number, and bowl ﬁllratio were calculated for each running condition. The relationship between the
power number and the product of Reynolds number, Froude number, and bowl ﬁllratio can be established by plotting the decimal logarithms of power number vs. thedecimal logarithms of the product of Reynolds number, Froude number, and bowl
ﬁll ratio. The results showed that under certain conditions, a common scale-up master curve could be drawn from the data gathered for each bowl, and such a curve
could be used for the determination of power consumption of a mixer granulator
at a deﬁned granulation end point for scale-up.
Dimensionless numbers such as Froude number can also be used to design andselect high-shear granulators of different scales. It is therefore necessary to characterize and compare high-shear granulators of different types and sizes by the range of© 2005 by Taylor & Francis Group, LLC

High-Shear Granulation

223

the Froude numbers. A matching range of the Froude numbers would indicate thepossibility of a scale-up, even for the mixers that are not geometrically similar(66). Froude number of a granulator is determined by both impeller speed and thediameter of the impeller as shown in Eq. 8.3. When the diameter of the impeller isﬁxed, the Froude number of a granulator can still be varied by adjusting the impeller
speed. Therefore, it would be desirable for the production scale granulator to beequipped with variable speeds. Hence, the range of Froude numbers for each sizeof granulator needs to be considered in the design of the high-shear granulators.
A systematic approach should be followed to select laboratory scale and production
scale granulators.
The matching Froude numbers for different size granulators provide the possibility of linear scale-up. However, some precautions are still needed for the geometric dissimilarity of mixing bowl vessels, and the shape of the impellers in the
granulators of different types and scales.
During scale-up, after selecting the granulator with matching Froude number
and similarly shaped impeller blades, the granulation end point can be determined byany one of the techniques described earlier. A new approach for scale-up based on
the use of power consumption, as the granulation end-point determination, is shown
below.
Integration of the impeller power (watts) vs. time (seconds) proﬁle for highshear granulator was also explored for scale-up of high-shear granulation (75).
The energy parameter impeller work during the wet-granulation process of a model
MCC formulation in 5 or 10 L was recorded and normalized, based on the weight ofthe dry powder mixture. The relationship between work of granulation and cohesion
indexes (slopes of the tablet breaking strength vs. compression force proﬁles), or
granulation size distributions was evaluated. Independent of granulator make ormodel, the impeller work measured during granulation correlated quantitatively withchanges in the granulation bulk and tapped densities, average particle size of the ﬁnished powders, and cohesion index. Granulation end points were accurately predicted for 25, 65, and 150 L high-shear granulators on the basis of development
work on 5.0 and 10 L equipment using impeller work values normalized for theweight of dry powders in the granulator (W sec/g).
8.2. Nonlinear Scale-up
If linear scale-up cannot be achieved, the amount of binder solution, the impeller
speed, and the wet-massing time should be optimized. For example, Kristensen
attempted to compensate the less efﬁcient mixing from large-scale granulation byincreasing the relative amount (ratio between granulation liquid and starting materials) of granulation liquid used (76). Rekhi et al. recommended maintaining a constant tip speed, scaling up the granulation liquid linearly, and adjusting the
granulation time based on the ratio of impeller speeds between the granulators usedin both the scales (77).
8.3. Utilization of Optimization Techniques
Since scale-up of high-shear granulation is still a ‘‘trial and error’’ process due to thecomplexity of the granulation process and lacks standards for granulators of different types and sizes, the DOE approach can be useful during production. The process
variables for the large-scale production can be optimized by using the DOE© 2005 by Taylor & Francis Group, LLC

224

Gokhale et al.

technique with relatively less number of trials. Alternatively, the granulation process
can be optimized in such a way that the process is scale independent.
A spherical central composite experimental design was used to design experiments (78). Granules were prepared in the two batches (2 and 5 kg batches) using ahigh-speed mixer granulator. Except for the rotation speed of the impeller, theoperation conditions such as chopper speed, mixing time, and granulation time were
kept constant during the granulation processes. The concentration of ethanol in the
aqueous binder solution and the total volume of binder solution used were selected
as independent variables. The yield of granules, geometric mean particle size, andgeometric standard deviation were employed as dependent variables. A computerized optimizing technique based on a response surface methodology was developed.
A universal optimal formulation unaffected by manufacturing scale could beobtained by minimizing the integrated optimization function. The optimized characteristics measured at the production scale coincided well with those obtained atlaboratory scale, suggesting that this approach could be useful in minimizing thescale-up problems.

9. CONCLUSION
High-shear granulation is one of the most important unit operations in the production of tablets. Various innovative approaches have been explored to simplify andcontrol the granulation process, and improve the quality of the produced granules.
Some of these novel approaches include using a one-pot granulation system, moisture-activated dry granulation and hot-melt granulation techniques, and different
granulation end-point techniques. However, both the process and formulation parameters for each formulation still need to be individually optimized due to the complexity of the number of variables involved during the granulation process and theuniqueness of the formulation. Moreover, the relationship between the propertiesof the ﬁnished tablets and unit operations for tableting, such as wet granulation, drying, milling, and tablet compression, is inconclusive. Therefore, a systematic evaluation of all formulation and process variables involved in the manufacturing of tablets
is required for the optimization of production of tablets. Future advancement in theequipment and granulation techniques could further improve the granulation process, thus resulting in better quality of the granules.

REFERENCES
1. Nellore RV, Rekhi GS, Hussain AS, Tillman LG, Augsburger LL. Development of
metoprolol tartrate extended-release matrix tablet formulations for regulatory policy
consideration. J Control Release 1998; 50:247–56.
2. Qiu Y, Hui HW, Cheskin H. Formulation development of sustained-release hydrophilic
matrix tablets of zileuton. Pharm Dev Technol 1997; 2:197–204.
3. Visavarungroj N, Remon JP. Crosslinked starch as a binding agent. II. Granulation ina high shear mixer. Int J Pharm 1990; 65:43–48.
4. van den Dries K, de Vegt OM, Girard V, Vromans H. Granule breakage phenomena ina high shear mixer; inﬂuence of process and formulation variables and consequences on
granule homogeneity. Powder Technol 2003; 133:228–236.
© 2005 by Taylor & Francis Group, LLC

High-Shear Granulation

225

5. Kiekens F, Cordoba-Diaz M, Remon JP. Inﬂuence of chopper and mixer speeds andmicrowave power level during the high-shear granulation process on the ﬁnal granulecharacteristics. Drug Dev Ind Pharm 1999; 25:1289–1293.
6. Christensen LH, Johansen HE, Schaefer T. Moisture-activated dry granulation in a highshear mixer. Drug Dev Ind Pharm 1994; 20:2195–2213.
7. Schaefer T, Holm P, Kristensen HG. Melt granulation in a laboratory scale high shear
mixer. Drug Dev Ind Pharm 1990; 16:1249–1277.
8. Schaefer T, Holm P, Kristensen HG. Melt pelletization in a high shear mixer. II. Powerconsumption and granule growth. Acta Pharm Nordica 1992; 4:141–148.
9. Schaefer T, Holm P, Kristensen HG. Melt pelletization in a high shear mixer. I. Effects ofprocess variables and binder. Acta Pharm Nordica 1992; 4:133–140.
10. Schaeferand T, Mathiesen C. Melt pelletization in a high shear mixer. IX. Effects of binder particle size. Int J Pharm 1996; 139:139–148.
11. Schaeferand T, Mathiesen C. Melt pelletization in a high shear mixer. VIII. Effects ofbinder viscosity. Int J Pharm 1996; 139:125–138.
12. Schaefer T, Taagegaard B, Thomsen LJ, Kristensen HG. Melt pelletization in a highshear mixer. V. Effects of apparatus variables. Eur J Pharm Sci 1993; 1:133–141.
13. Schaefer T, Taagegaard B, Thomsen LJ, Kristensen HG. Melt pelletization in a highshear mixer. IV. Effects of process variables in a laboratory scale mixer. Eur J PharmSci 1993; 1:125–131.
14. Plank R, Diehl B, Grinstead H, Zega J. Quantifying liquid coverage and powder ﬂux inhigh-shear granulators. Powder Technol 2003; 134:223–234.
15. van den Dries K, Vromans H. Relationship between inhomogeneity phenomena andgranule growth mechanisms in a high-shear mixer. Int J Pharm 2002; 247:167–177.
16. Kristensen HG. Agglomeration of powders. Acta Pharm Suecica 1988; 25:187–204.
17. Kristensen HG, Holm P, Jaegerskou A, Schaefer T. Granulation in high speed mixers.
Part 4: effect of liquid saturation on the agglomeration. Pharm Ind 1984; 46:763–767.
18. Kristensenand HG, Schaefer T. Granulation. A review on pharmaceutical wet-granulation. Drug Dev Ind Pharm 1987; 13:803–872.
19. Yajima T, Itai S, Hayashi H, Takayama K, Nagi T. Optimization of size distribution of
granules for tablet compression. Chem Pharm Bull (Tokyo) 1996; 44:1056–1060.
20. Wikbergand M, Alderborn G. Compression characteristics of granulated materials. IV.
The effect of granule porosity on the fragmentation propensity and the compactibilityof some granulations. Int J Pharm 1991; 69:239–253.
21. Schaefer T, Holm P, Kristensen HG. Wet granulation in a laboratory scale high-shear
mixer. Pharm Ind 1990; 52:1147–1153.
22. Schaefer T, Holm P, Kristensen HG. Comparison between granule growth in a horizontal and a vertical high speed mixer. I. Granulation of dicalcium phosphate. Arch Pharm
Chem, Scientiﬁc Edition 1986; 14:1–16.
23. Vromans H, Poels-Janssen HG, Egermann H. Effects of high-shear granulation on granulate homogeneity. Pharm Dev Technol 1999; 4:297–303.
24. Juppo AM, Yliruusi J, Kervinen L, Strom P. Determination of size distribution of
lactose, glucose, and mannitol granules by sieve analysis and laser diffractometry. Int
J Pharm 1992; 88:141–149.
25. Suzuki T, Watanabe K, Kikkawa S, Nakagami H. Effect of crystallinity of microcrystalline cellulose on granulation in high-shear mixer. Chem Pharm Bull (Tokyo) 1994;
42:2315–2319.
26. Chowhan ZT. Aspects of granulation scale-up in high shear mixers. Pharm Technol 1998;
12:26–44.
27. Badawy SIF, Lee TJ, Menning MM. Effect of drug substance particle size on the characteristics of granulation manufactured in a high-shear mixer. AAPS Pharm Sci Tech 2000:1.
28. Vertommen J, Michoel A, Rombaut P, Kinget R. Production of pseudoephedrine hydrochloride pellets in a high-shear mixer granulator. Eur J Pharm Biopharm 1994; 40:32–35.

© 2005 by Taylor & Francis Group, LLC

226

Gokhale et al.

29. Ritala M, Jungersen O, Holm P, Schaefer T, Kristensen HG. A comparison between binders in the wet phase of granulation in a high shear mixer. Drug Dev Ind Pharm 1986;
12:1685–1700.
30. Ritala M, Holm P, Schaefer T, Kristensen HG. Inﬂuence of liquid bonding strength on
power consumption during granulation in a high shear mixer. Drug Dev Ind Pharm 1988;
14:1041–1060.
31. Westerhuis JA, de Haan P, Zwinkels J, Jansen WT, Coenegracht PJM, Lerk CF. Optimization of the composition and production of mannitol/microcrystalline cellulose
tablets. Int J Pharm 1996; 143:151–162.
32. Makinoand T, Kitamori N. Effect of starch paste concentration on particle size distribution of ﬁne granules produced by agitation granulation. Chem Pharm Bull (Tokyo) 1995;
43:1231–1233.
33. Kato Y, Moroshima K, Hashizume M, Ando H, Furukawa M. Further observation ofcontent uniformity of d-alpha-tocopheryl acetate as an oily drug in granules obtainedby wet granulation with a high-shear mixer. Drug Dev Ind Pharm 2001; 27:781–787.
34. Miyamoto Y, Ryu A, Sugawara S, Miyajima M, Ogawa S, Matsui M, Takayama K,
Nagai T. Simultaneous optimization of wet granulation process involving factor of drug
content dependency on granule size. Drug Dev Ind Pharm 1998; 24:1055–1065.
35. Hariharanand M, Mehdizadeh E. The use of mixer torque rheometry to study the effectof formulation variables on the properties of wet granulations. Drug Dev Ind Pharm
2002; 28:253–263.
36. Becker D, Rigassi T, Bauer-Brandl A. Effectiveness of binders in wet granulation: a comparison using model formulations of different tabletability. Drug Dev Ind Pharm 1997;
23:791–808.
37. Suzuki T, Kikuchi H, Yamamura S, Terada K, Yamamoto K. The change in characteristics of microcrystalline cellulose during wet granulation using a high-shear mixer.
J Pharm Pharmacol 2001; 53:609–616.
38. Habib YS, Abramowitz R, Jerzewski RL, Jain NB, Agharkar SN. Is siliciﬁed wet-granulated microcrystalline cellulose better than original wet-granulated microcrystalline
cellulose? Pharm Dev Technol 1999; 4:431–437.
39. Badawy SI, Menning MM, Gorko MA, Gilbert DL. Effect of process parameters oncompressibility of granulation manufactured in a high-shear mixer. Int J Pharm 2000;
198:51–61.
40. Oulahna D, Cordier F, Galet L, Dodds JA. Wet granulation: the effect of shear on granule properties. Powder Technol 2003; 130:238–246.
41. Bockand TK, Kraas U. Experience with the Diosna mini-granulator and assessment ofprocess scalability. Eur J Pharm Biopharm 2001; 52:297–303.
42. Holm P, Schaefer T, Larsen C. End point detection in a wet granulation process. Pharm
Dev Technol 2001; 6:181–192.
43. Timmins P, Delargy AM, Minchom CM, Howard JR. Inﬂuence of some process variables on product properties for a hydrophilic matrix controlled-release tablet. Eur
J Pharm Biopharm 1992; 38:113–118.
44. Kornchankul W, Hamed E, Parikh NH, Sakr A. Effect of drug proportion and mixing
time on the content uniformity of a low-dose drug in a high shear mixer. Pharmazie
2002; 57:49–53.
45. Suzuki T, Kikuchi H, Yonemochi E, Terada K, Yamamoto K. Interaction of microcrystalline cellulose and water in granules prepared by a high-shear mixer. Chem Pharm Bull
(Tokyo) 2001; 49:373–378.
46. Schaefer T, Holm P, Kristensen HG. Comparison between granule growth in a horizontal and a vertical high speed mixer. II. Granulation of lactose. Arch Pharm Chem, Scientiﬁc Edition 1986; 14:17–29.
47. Holm P. Effect of impeller and chopper design on granulation in a high speed mixer.
Drug Dev Ind Pharm 1987; 13:1675–1701.

© 2005 by Taylor & Francis Group, LLC

High-Shear Granulation

227

48. Faure A, Grimsey IM, Rowe RC, York P, Cliff MJ. Process control in a high shear
mixer-granulator using wet mass consistency: the effect of formulation variables. J PharmSci 1999; 88:191–195.
49. Holm P, Schaefer T, Kristensen HG. Granulation in high-speed mixers. Part VI. Effects
of process conditions on power consumption and granule growth. Powder Technol 1985;
43:225–233.
50. Corvari V, Fry WC, Seibert WL, Augsburger L. Instrumentation of a high-shear mixer:
evaluation and comparison of a new capacitive sensor, a watt meter, and a strain-gage
torque sensor for wet granulation monitoring. Pharm Res 1992; 9:1525–1533.
51. Kopcha M, Roland E, Bubb G, Vadino WA. Monitoring the granulation process ina high shear mixer/granulator: an evaluation of three approaches to instrumentation.
Drug Dev Ind Pharm 1992; 18:1945–1968.
52. Holm P, Schaefer T, Kristensen HG. Granulation in high-speed mixers. Part V. Powerconsumption and temperature changes during granulation. Powder Technol 1985;
43:213–223.
53. Leuenberger H. Granulation, new techniques. Pharm Acta Helv 1982; 57:72–82.
54. Werani J. Production experience with end point control. Acta Pharm Suecica 1988;
25:247–266.
55. Laicher A, Proﬁtlich T, Schwitzer K, Ahlert D. A modiﬁed signal analysis system forend-point control during granulation. Eur J Pharm Sci 1997; 5:7–14.
56. Kornchankul W, Parikh NH, Sakr A. Correlation between wet granulation kinetic parameters and tablet characteristics. Drugs Made Germany 2001; 44:78–87.
57. Achanta AS, Adusumilli PS, James KW. Endpoint determination and its relevance tophysicochemical characteristics of solid dosage forms. Drug Dev Ind Pharm 1997; 23:
539–546.
58. Whitaker M, Baker GR, Westrup J, Goulding PA, Rudd DR, Belchamber RM, Collins
MP. Application of acoustic emission to the monitoring and end point determination ofa high shear granulation process. Int J Pharm 2000; 205:79–92.
59. Watano S, Numa E, Miyanami K, Osako Y. On-line monitoring of granule growth inhigh shear granulation by an image processing system. Chem Pharm Bull (Tokyo) 2000;
48:1154–1159.
60. Watano S, Numa T, Miyanami K, Osako Y. A fuzzy control system of high shear granulation using image processing. Powder Technol 2001; 115:124–130.
61. Bouckaert S, Massart DL, Massart B, Remon JP. Optimization of a granulation procedure for a hydrophilic matrix tablet using experimental design. Drug Dev Ind Pharm
1996; 22:321–327.
62. Vojnovic D, Selenati P, Rubessa F, Moneghini M, Zanchetta A. Wet granulation in asmall scale high shear mixer. Drug Dev Ind Pharm 1992; 18:961–972.
63. Vojnovic D, Moneghini M, Rubessa F, Zanchetta A. Simultaneous optimization of several response variables in a granulation process. Drug Dev Ind Pharm 1993; 19:1479–
1496.
64. Vojnovic D, Moneghini M, Rubessa F. Optimization of granulates in a high shear mixer
by mixture design. Drug Dev Ind Pharm 1994; 20:1035–1047.
65. Vojnovic D, Moneghini M, Chicco D. Nonclassical experimental design applied in the
optimization of a placebo granulate formulation in high-shear mixer. Drug Dev Ind
Pharm 1996; 22:997–1004.
66. Horsthuis GJB, van Laarhoven JAH, van Rooij RCBM, Vromans H. Studies on upscaling parameters of the Gral high-shear granulation process. Int J Pharm 1993; 92:143–150.
67. Ameye D, Keleb E, Vervaet C, Remon Jean P, Adams E, Massart Desire L. Scaling-up ofa lactose wet granulation process in Mi-Pro high shear mixers. Eur J Pharm Sci 2002;
17:247–251.
68. Iskandarani B, Shiromani PK, Clair JH. Scale-up feasibility in high-shear mixers: determination through statistical procedures. Drug Dev Ind Pharm 2001; 27:651–657.

© 2005 by Taylor & Francis Group, LLC

228

Gokhale et al.

69. Leuenberger H. Scale-up of granulation processes with reference to process monitoring.
Acta Pharm Technol 1983; 29:274–280.
70. Zlokarnik M. Problems in the application of dimensional analysis and scale-up of mixing
operations. Chem Eng Sci 1998; 53:3023–3030.
71. Lord R. The principle of similitude. Nature 1915; 95:66–68.
72. Faure A, Grimsey IM, Rowe RC, York P, Cliff MJ. A methodology for the optimizationof wet granulation in a model planetary mixer. Pharm Dev Technol 1998; 3:413–422.
73. Buckingham E. On physically similar systems; Illustrations of the use of dimensional
equations. Phys Rev NY 1914; 4:345–376.
74. Faure A, Grimsey IM, Rowe RC, York P, Cliff MJ. Applicability of a scale-up methodology for wet granulation processes in Collette Gral high shear mixer-granulators. Eur
J Pharm Sci 1999; 8:85–93.
75. Siroisand PJ, Craig GD. Scale-up of a high-shear granulation process using a normalized
impeller work parameter. Pharm Dev Technol 2000; 5:365–374.
76. Kristensen HG. Particle agglomeration in high shear mixers. Powder Technol 1996;
88:197–202.
77. Rekhi GS, Caricofe RB, Parikh DM, Augsburger LL. A new approach to scale-up ofhigh shear granulation process. Pharm Technol 1996; 20:58–67.
78. Ogawa S, Kamijima T, Miyamoto Y, Miyajima M, Sato H, Takayama K, Nagai T. A
new attempt to solve the scale-up problem for granulation using response surface methodology. J Pharm Sci 1994; 83:439–443.

© 2005 by Taylor & Francis Group, LLC

8
Low-Shear Granulation
Tom Chirkot
Patterson-Kelley Co., East Stroudsburg, Pennsylvania, U.S.A.

Cecil Propst
SPI Pharma, Norton Shores, Michigan, U.S.A.

1. INTRODUCTION
Shearing of the powder bed occurs in many granulators. The low-shear granulators
included in this chapter are granulators that, for reasons of agitator speed, sweep
volume, or bed pressures, generate less shear than granulators discussed in otherchapters such as extruders or the high-shear mechanical granulators. Also considered to be low shear, but covered in other chapters, are ﬂuid bed granulators.

1.1. Comparison of Granulators
Comparing ﬁnal granule characteristics in ﬂuid bed, low-shear, and high-shear applications is problematic because it is often difﬁcult for the same formulation to be successfully processed in each piece of equipment. However, some broad conclusions
may be drawn. Two of the characteristics most frequently reported are bulk densityand particle size; therefore, a comparison will be shown for these characteristics.
These granulators may accomplish the same unit operation but the ﬁnal product outcome may be quite different. The differences are a result of varied process requirements in each granulator. The process of wet granulation involves several steps
including blending, liquid binder addition, and wet massing or distribution of theliquid. After charging the powder to the mixer, a blending step is required to achievea homogenous blend. The time required to achieve the blend depends on the amountof movement characteristic of the unit and the size of the unit. Also, the degree ofhomogeneity differs from one type of mixer class to the next. In some classes ofmixers, one can easily overblend and segregate components of the mix.
The binder solution addition step follows the blending step. The selection of
the type of binder and quantity depends on the type of mixer selected for the wet
granulation. Nouh (1) studied a sulfadiazine formulation using several different binders. He worked in both a ﬂuid bed unit and a conventional wet massing–screening
method. When using 5% gelatin as a binder, he noted a 0.968 mm average granulesize in wet massing and 0.574 mm in the ﬂuid bed. For acacia as binder at the 5%229© 2005 by Taylor & Francis Group, LLC

230

Chirkot and Propst

level, the values were 0.90 mm for wet massing and 0.605 mm for the ﬂuid bed. Fora polyvinylpyrrolidone (PVP) binder at the 5% level, the wet massing produced
0.962 mm granule size vs. 0.247 mm for the ﬂuid bed. Surprisingly, the difference
between the methods did not transfer to bulk density results. Both the acacia andthe PVP formulations had similar bulk densities in both methods. The gelatin did
show a difference, yielding 0.476 g/mL for the wet massing and 0.294 g/mL for
the ﬂuid bed. Gore et al. (2) made a comparison among a ﬂuid bed granulator, aplanetary mixer, and a high-shear granulator. They found that the granule yield
between 20 and 100 mesh was 97.7% in the ﬂuid bed, 53.3% in the planetary mixer,
and 71.8% in the high-shear granulator. The respective bulk densities were 0.39, 0.66,
and 0.71 g/mL. For comparison, in a low-shear tumble granulator, Scarpone et al.
(3) found 84% yield between 20 and 100 mesh in a 0.05 m3 (2 ft3) vessel and
50.7% yield in a 2.83 m3 (100 ft3) vessel. Density measurements averaged 0.486 g/
mL for the two trials of a cardiovascular drug formulation in the smaller vessel.
Sheskey and Williams (4) studied a niacinamide formulation in both low- andhigh-shear granulators and concluded that the resulting apparent densities were
nearly identical in both cases. In general, the bulk density values produced in
low-shear tumbling granulators are intermediate in value between those of a ﬂuid
bed and of a high-shear granulator.
Similar conclusions may be drawn about granule morphology as lower-shear
granulators produce ﬂufﬁer, more porous granules than do high-shear granulators.
A ﬁnal note related to morphology: If the low-shear tumbling granulator has a rotating shell, some rounding of granules may be expected as the material ﬂows throughthe angle of repose.

1.2. Binder Issues
Because of improved liquid distribution early in the granulation process, some highshear granulators require 60–80% of the liquid needed in a low-shear mixer. Liquid
requirement for an antacid granulation made in a high-shear horizontal mixer was
4.5% of the total batch, whereas 7% liquid was required for a low-shear planetary
mixer. Some of the low-shear granulators such as the sigma mixer densify granules.
The liquid requirement for the sigma mixer is slightly reduced at 6% for the sameantacid. Some studies indicate that dissolving a solid binder and adding it to thedry mix vs. adding the solid binder to the dry mix and then wetting increases driedgranule hardness (5).
The ﬁnal stage of the wet granulation process is the liquid distribution or thewet massing. This step can be compared with a kneading step during which the voids
between granules are compressed and the granules are thereby densiﬁed. The ﬁnal
density of the granules, therefore, is dependent on the amount of shearing available
in the unit. Because the shear is introduced in the mixing process by mechanicalmeans by moving impellers or blades, these low-shear mixers cannot compress thevoids between the granules solely by mechanical means and thus require more binder
solution to form granules of some integrity.
The combination of less mechanical shear and lower bed pressure allows fora thicker binder deposit, especially when the binder is poured into the granulation
unit instead of sprayed. This thicker ﬁlm often dries to a more effectively spreadable
ﬁlm during the compression of these granules to form tablets. This increased plasticity is especially true at the lower compression forces (Fig. 1). The tablets also have
© 2005 by Taylor & Francis Group, LLC

Low-Shear Granulation

231

Figure 1 Hardness vs. compression forces.

a much lower friability (Fig. 2). The improved friability can be over a much broader
range of compression forces.

2. MECHANICAL AGITATOR GRANULATORSThe machine classes to be considered under mechanical agitator granulators are;(1) ribbon or paddle blender; (2) planetary mixers; (3) orbiting screw mixers; and(4) sigma blade mixers.

Figure 2 Friability vs. compression forces.
© 2005 by Taylor & Francis Group, LLC

232

Chirkot and Propst

2.1. Ribbon or Paddle Blenders
The ribbon blender-type mixer (Fig. 3) is very popular as a dry mixer. However, if
small amounts of liquid are added or if a dry paste is formulated for the machine,
the ribbon blender can serve as a very reliable granulator (5). Most ribbon blenders
are not made to withstand the shaft torque required for manufacturing granules.
One should ensure that the granulator shaft is strong enough before granulating
in a ribbon blender designed to dry mix.
Zoglio et al. (5) studied several kneading times in a chopper ribbon blender anddiscovered an optimum range of kneading times for providing the best granulemechanical properties. A kneading time that is too long densiﬁes the granules. This
increases moisture exposure and particle size and reduces porosity. The tendency ofthe material to stick to the side wall is pronounced in the ribbon blender.
Paddles instead of ribbons decrease sticking problems and the torque required.
Paddle blenders as batch granulators can handle wetter paste. These paddle blenders
are occasionally used as continuous granulators and have both lower torque andmore applications than a continuous ribbon blender. The movement of the paste
helps remove material from the paddles. Formulation of a nontacky paste is aided
by using a substance such as microcrystalline cellulose that helps absorb the excess
moisture from the mix, yet is plastic and nonsticky.
Two very popular ribbon or paddle blenders used as granulators are the topogranulator and the turbulizer.
The topogranulator (Fig. 4) is a batch-style ribbon blender with the ability toeither compress or mechanically ﬂuidize the granulation. Compression while slightly
wet increases the overall inﬂuence of the liquid on the particle size of the granulation.
At the other extreme, ﬂuidization reduces density if used during the granule growthphase or speeds drying. The topogranulator is also a vacuum dryer.
The topogranulator is used extensively to make effervescent products by liquid
addition under vacuum or by the Murry fusion method (6). Murry’s method uses
liberated moisture from the acid in the mix (i.e., hydrous citric acid) to start the
acid–base reaction, which generates more water. Thus, granulating of the sodium
bicarbonate–citric acid mixture can be accomplished. The water produced must be
removed quickly to reproducibly stop the reaction. The topogranultor, because of
its ability to compress the particles into the binding moisture, makes a larger, denser

Figure 3 Ribbon blender.
© 2005 by Taylor & Francis Group, LLC

Low-Shear Granulation

233

Figure 4 Topogranulator.

granulation with lower moisture content. Also, mechanical ﬂuidization and vacuum
drying removes the water from the reaction more quickly, making the process more
reproducible.
Granulation in vacuum removes entrapped air from the particle surface.
Liquid addition into the vacuum provides immediate wetting and also begins thedrying process. This granulation in vacuum allows the manufacturing of a calcium
carbonate-based effervescence with rapid reactivity (7).
The turbulizer is a continuous paddle granulator. By using continuous powder
feeders and liquid metering pumps, the unit produces large quantities of product perhour in a very small space. The unit provides adjustable mixing, shear, and impact
action based on the revolutions per minute (rpm) of the shaft and the angle of the
impact blade. The paddle adjustments also vary the retention time. This machine
has a very low silhouette. Paddles are easily accessible for cleaning and inspection
either through a clam shell- or drop door shell-opening side wall. The unit is jacketed
for material temperature control.
Another continuous paddle granulator made by Teledyne Readco has beenstudied by Ghali et al. (8). The unit is adjustable to produce either low- or highshearing action. The amount of energy induced by the rotating shaft can be selectedby using various types of pins. A rounded granule results from the action of the pin
tip speed and some rolling of the granulation against the ﬁxed vessel wall.

2.2. Planetary Mixers
The planetary motion of these granulators is created by rotating the agitator off anassembly in a direction opposite that of the rotation of the agitator assembly as it
moves around the bowl. The planetary mixers (Fig. 5) are represented by many commercial names including Hobart, Kitchen Aide, Pony, and AMF Glen granulators.
All of these mixers have the same basic makeup, which includes: (a) planetary
motion, (b) removable bowl, and (c) top-drive agitators.
These mixers tend to be better at mixing dry powders in a horizontal plane thanthe vertical. Lack of vertical mixing may require the materials to be dumped andreturned to the bowl to obtain an acceptable dry mix. Reduced vertical mixing© 2005 by Taylor & Francis Group, LLC

234

Chirkot and Propst

Figure 5 Planetary mixer.

is much less a problem in the wet-mix phase, because the materials adhere to theagitator and move in groups without vertical stratiﬁcation.
Remon and Schwartz, working with microcrystalline cellulose and lactose mixtures in a planetary mixer, saw decreased friability of the granule with increasing
massing time (9). This increased massing time improves binder distribution andmechanical strength. Ghanta et al. demonstrated the mechanism of granule growth
in a Hobart mixer (10).
2.3. Orbiting Screw Granulators
The orbiting screw granulator (Fig. 6) is also used mainly for dry mixing. However,the unit has been ﬁtted with the nozzle through the center agitator to add liquids to
dry powders (11). Also, a jacket can provide both heating and cooling. A sinteredmetal plate can allow entry of compressed air through the skin of the mixer or
can exhaust moisture to obtain drying. All of these added features, along with a

Figure 6 Orbiting screw mixer.
© 2005 by Taylor & Francis Group, LLC

Low-Shear Granulation

235

chopper in the side wall, allow this blender to be an effective granulator for powders,slurries, suspensions, and paste. The unit is a very gentle granulator mixer.
2.4. Sigma Blade Mixers
The sigma blade mixer (Fig. 7) is a compressive granulator. Generally, it develops
material into a paste- or dough-type consistency. Often the sigma blade mixer is preceded by a dry mixer. The unit generates liquid distribution with pressure during
granulating. This creates a uniform granulation with binder matrix and good binder
distribution.

3. ROTATING SHAPE GRANULATORS
These vessel shapes are usually some derivation of a cylinder, with a double cone andV-shape (Fig. 8) being common examples. Unlike their ﬂuid bed and high-shear
counterparts, the machine shells rotate around an axis parallel to the ground. The
rotation speed is moderate, and generally falls into a range of 72.2–106.7 m/min(250–350 ft/min) peripheral speed. The rpm value changes as vessel size grows.
A laboratory model may rotate at 25–30 rpm, whereas a larger production model
may rotate at 4–8 rpm. The peripheral speed remains constant in order to maintaina scale-up relationship among vessel sizes.

Figure 7 Sigma blade mixer.
© 2005 by Taylor & Francis Group, LLC

236

Chirkot and Propst

Figure 8 Schematic of the twin-shell blender that allows blending and granulating in a single
vessel. (Courtesy of Patterson-Kelley Co., Division of Harsco Corp., East Stroudsburg, PA.)A second rotating device is located on the same axis of rotation as the shell.
This bar or arm may be supported at both ends or may be cantilevered, with support
only on a single end. The bar is used to impart substantially more energy into thesystem than that delivered by the rotating shell. The bar is driven by an additional,
larger motor that runs independently of the shell motor. The manufacturer’s descriptive names for these bars, such as agitator or intensiﬁer bars, conﬁrm their use.
Unlike the gentle rolling action induced by the shell movement, the bar movement
has a high-speed nature. This should not be confused with high shear because thebar movement produces mainly a convective motion within the material. Indeed,
these machines were originally designed as mixers, with elements of diffusive andconvective mixing. Only later in their evolution did they become granulator-dryers.
The increased peripheral speed of the bar is substantial. As a general rule, they
operate at 10 times the speed of the shell or about 914.4 mpm (3000 fpm). The bars
may also serve as liquid addition devices. The vessels may be jacketed for heating
and cooling if there is a necessity for these options during granulation. They arevacuum capable, which makes them ideal candidates as a single-pot processor for
mixing, granulating, and drying in the same vessel. Ultimate vessel size for these
granulators is constrained by the weight of the agitator bar. The bars have many
parts and must be disassembled often for cleaning. Large bars become increasingly
unwieldy and difﬁcult to remove from the interior of the vessel.
Ample opportunity exists for ﬁne-tuning a granulation process in these machines.
Apparatus variables that can be adjusted are shell speed, bar speed, bar size, and bar
design. Process changes can be made in mix time, liquid addition time, bed temperature, internal vessel pressure, and spray droplet size.
Overwhelmingly, these granulator types are used in batch operations. However, a few manufacturers offer continuous granulating systems that emulate the
combination of forced and rolling agglomeration found in the batch machines.
Besides the issue of validating a continuous process, throughput requirement isusually the inﬂuencing criterion when considering a change from batch to continuous operation.
© 2005 by Taylor & Francis Group, LLC

Low-Shear Granulation

237

Much of the granulation done in the pharmaceutical industry is by wet massing
and, more recently, by ﬂuidized bed (12). Consequently, the literature is rich witharticles describing the many variables studied in these machines. On the other hand,
the rotating shape granulators originated as mixing devices and a paucity of research
articles exist on their usage as granulators. This makes them a fruitful area for future
research.
3.1. Bar Speed and Energy Input
The combination of agitator bar speed and its accompanying energy input wields
a wide inﬂuence on the physical properties of the granulated material. Watano
et al. (13), using a ﬂuidized bed granulator with an agitator blade, varied the rotation
speed of the agitator and observed the effect it had on product density. They wereable to derive a predictive equation that yielded the density value when the agitator
speed was known. The same group measured shape index—the mean ratio of theshort/long diameters—and concluded that as granulation times increased, the shapetended more toward sphericity. The rotating shape granulators vary energy input tothe powder bed by changing the agitator speed or extending the running time of thebar after liquid addition has stopped. A common term for the extended bar period is
postmix time.
A study of a low-shear granulator, with a formulation consisting of lactose,
PVP, and water, that varied the peripheral speed of the bar showed no statisticallysigniﬁcant change in granule density despite the substantial change in bar tip speed
from 636 to 846 to 1056 mpm (14). The tip speed was statistically inﬂuential on theamount of granules found in the yield fraction. The lowest speed produced the best
yield indicating that the higher speeds can degrade the formed granules during
a postmix phase and thereby cause a reduction in yield. The ultimate lower limit
on tip speed is the point where adequate distribution of the binder solution iscompromised.
3.2. Disk Size and Bar Design
Addition of binder liquid with spray heads is available with rotating shape granulators. The double-cone shape is often used with a dry intensiﬁer bar and spray head
combination for granulating. A wide range of bar designs exists for the more typicalsituation of adding liquid through the bar. Blade or knife design is one variable toconsider. The blades extend perpendicularly from the disk circumference and thenbend 90 in a shape often called a ‘‘dog-eared’’ design (Fig. 9).
The blade shape is critical for the liquid addition method. As the blades rotate,
they carve out a toroidal void volume in the ﬂowing powder bed. The liquid exiting
the disk coats the interior of the torus. Proper vessel loading ensures that no liquid
impinges on the wall of the vessel.
The action of the blades is quite vigorous and may cause a problem with very
friable materials. A modiﬁcation to the bar that removes the blades and recesses allnuts and bolts can be used to granulate these fragile materials. Further ﬁne-tuning of
the spray pattern can be accomplished with changes in the positioning of liquid evacuation spacing on the disk circumference. A straight pattern creates droplet ﬂow
orthogonal to the axis of rotation, which allows only a small area of the interior
torus to be coated. An angled pattern creates a substantially wider spray effect, withmore efﬁcient droplet distribution.
© 2005 by Taylor & Francis Group, LLC

238

Chirkot and Propst

Figure 9 Intensiﬁer bar for the twin-shell blender/granulator showing a ‘‘dog-eared’’ design.
(Courtesy of Patterson-Kelley Co., Division of Harsco Corp., East Stroudsburg, PA.)Disk diameter is critical. A large-diameter disk imparts more energy as torqueis a function of diameter. The larger diameter offers more circumference for liquid tobe evacuated and carves out additional void volume in the material. The sweep
volume of the disks is considered a major factor in properly scaling up a granulator(15).

3.3. Liquid Addition Rate
Particle motion is so complex when granulating that it becomes difﬁcult to determine
the optimum rate of liquid addition. Stamm and Paris (16) studied rates of 5, 10, and20 mL/min in a ﬁxed shell, helicoidal mixer with vertical bar, and determined thatthe best results occurred at the slowest rate.
Cliff (17), working in a high-shear granulator, found that a long binder addition time was needed to prevent overdensiﬁcation. Lipps and Sakr (18), using a topspray, ﬂuidized bed granulator, related geometric mean granule size, speciﬁc surface
area, and granule ﬂow properties to the binder ﬂow rate.
In rotating shape granulators, the main energy-imparting function and theliquid distribution function are encompassed within the agitator bar, yielding
a highly efﬁcient system. Liquid is literally ripped into droplets by the peripheral
speed of the bar. Tumbling action ensures that fresh material replaces the wet material during each shell revolution (19). A wide range of liquid addition rates is permissible. The lowest rate is undeﬁned and may involve a slow dropwise addition to thebar. The highest rate is limited to the point when the liquid rate reduces the droplet
making efﬁciency of the bar and results in liquid being forced out in a sheet-likepattern to the powder bed.
When one extends the liquid addition period, the bar continues to abrade thegranules. Favorably, any particles that have been fractured can be rewetted and thefracture surface can easily bind to another particle. This mechanism tends to holddown the oversized fraction without the expected increase in the undersized fraction.
Extremely rapid liquid addition overwhelms the blending capability of the system. Many particles simply do not have enough time to become associated with the
droplets, whereas others become overwet due to the concentrated onrush of liquid.
An additional consequence of high liquid addition rate is that liquid may have difﬁculty releasing from the bar. A back pressure situation develops that may impedeliquid ﬂow in the feed tube and ultimately cause it to reverse its ﬂow. High enoughback pressure can induce a spring-loaded bar to jump from its moorings and damage© 2005 by Taylor & Francis Group, LLC

Low-Shear Granulation239

the interior of the machine. Because the rotating shape granulators are often heatjacketed, the potential exists for them to provide a partially or fully coated, hard
granule.
Use of the dissolved solids binder addition method through an agitator bar
could be problematic. Any undissolved solids may clog the liquid evacuation spacing
on the disk. Also, binder solutions with a viscosity much beyond 300–500 cP may not
atomize readily when released from the disk.
3.4. Droplet Size
Droplet size is a very important variable in ﬂuidized bed granulation. Droplet size is
unimportant in high-shear granulators because the energy exists to readily distributeand redistribute the liquid. Liquid addition in the rotating shape granulators is
unique, for the droplets are released from the ﬂuidizing device or agitator bar. An
analogous situation in a high-shear application would mean that liquid was being
added through the impeller or chopper.
The liquid in a rotating shape granulator is fed through a tube and exits in theinterior of the bar through a distribution slot. A pump can be used for metering theﬂow, or gravity ﬂow may be sufﬁcient, if desired. The speed of rotation of the bar
actually induces an area of lower pressure within the bar to draw in the liquid.
The liquid exits the agitator bar through openings on the circumference of the rotating disk. Openings can be adjusted by placement of spacers that vary in thickness.
A droplet diameter cannot exceed this thickness value, although smaller droplets
may be present. Typical spacer openings are 0.025 cm (0.010 in.) with common adjustment to 0.0125 cm (0.005 in.) and 0.05 cm (0.020 in.), depending on the viscosity of theliquid.
Many granulation methods deliver the liquid at some pressure through a sprayhead. With liquid addition through the bar, only enough pressure is needed to overcome line loss. Undue pressure is actually counterproductive. The atomization isinﬂuenced by pressure and the liquid exiting the disks under high pressure tends
to be sheet-like rather than easily distributed droplets.
Droplet size in a ﬂuid bed has been measured by capturing droplets on a slide
covered with viscous oil. The size has been determined to be in the 20–100 mm
range (20). Less delicate techniques in the rotating shape granulators have shown
droplet sizes of about 250 mm. Agland and Iverson provide an experimental study
showing the relation of liquid droplet size to granule characteristics such as sizeand penetration of liquid (21).
3.5. Vessel Loading
A negative factor for rotating tumble granulators with high-speed internal bars is thetight constraint for ﬁll level. The ﬁll level is usually about 50–65% of the total
volume, and the powder level must have some contact with the bar. Overloading
the vessel impedes the mixing action.
Underloading causes material to ﬂow beneath the bar during vessel rotation,
resulting in liquid spraying on the interior wall. This spray-through can be a factor
in material sticking during a drying step.
Even careful loading of the machine with the dry powder may not be sufﬁcient
to preclude spraying through to the walls. If substantial densiﬁcation occurs during
early liquid addition, the load may drop enough during the ﬁnal stages of liquid© 2005 by Taylor & Francis Group, LLC

240

Chirkot and Propst

addition for liquid to ﬁnd its way to the shell wall. The effective working volume ﬁlllevel can be increased if the tip-to-tip blade diameter is extended.
3.6. Low Shear Single Pot Processing
The rotating shape granulators offer ﬁne potential for single-pot processing (Fig. 10).
Their original design as mixers ensures even minor ingredients are well-distributed in
the dry mix phase prior to granulation.
After granulation, the heated shell and vacuum capability are used for gentle
tumble drying and collection of condensed vapors. The bar can then be used to provide a measure of dry sizing, followed by lubricant addition, and tumble blending.
3.7. Continuous Granulation
Although batch granulation is commonly used, there are some examples of lowshear continuous granulation. A true adaptation of the batch, rotating shape
granulators is the Patterson-Kelley Zig Zag mixer (Figs. 11 and 12). This vessel consists of a high-speed mixing chamber connected to a series of three V-shaped tumble
blenders. The principles of liquid addition and disk speeds covered earlier are equallyapplicable to the Zig Zag.
The typical hold-up volume is half of the total volume of the vessel. The holdup volume can be adjusted somewhat by raising or lowering the discharge end a few
degrees from the horizontal. Residence times are in the 3–5 min range for granulation applications. Two types of granulation mechanisms occur in this machine.
When the material is in the high-speed mixing chamber, the liquid droplets contact
the powder in a manner similar to that of batch units. As the wet material travels
into the tumbling section, rolling agglomeration occurs. The tumbling section splits
its load in half on each revolution, allowing half the material to proceed forward
while the other half recycles to the rear. This action tends to smooth out any inconsistencies.
Scale-up to larger Zig-Zag units is based on constant residence times. Therefore, even in the very largest models, a residence time of 3–5 min can be expected.
The largest models are capable of producing 30,000 kg/hr.

4. SCALE-UP
Often, the most difﬁcult part of implementing a granulation process is the scale-up
step. The many variables involved and the poorly understood relations among thevariables often places scale-up in the realm of trial and error. Hancock et al. (22),using a ﬁxed bowl mixer with meshing blades, linked a torque arm to a dynamometer
to monitor the process. The amplitude of oscillation (torque range) and the mean
torque increase from baseline were the items recorded. Torque showed a relation
for the force required to shear the wet mass and provided an output for determining
the wet mass strength. Integrating the torque-time curve yields the total energy into
the system for a particular time period. Hancock’s group deﬁned the term, cumulative energy of mixing, and postulated its use as a means of scaling up.
Vojnovic et al. (23) determined that peripheral speed of the impeller in a vertical high-shear mixer was an important factor and adjusted this speed as a function© 2005 by Taylor & Francis Group, LLC

Low-Shear Granulation
Figure 10 Schematic diagram of Patterson-Kelley Solids Processor. (Courtesy of Patterson-Kelley Co., Division of Harsco Corp., East Stroudsburg, PA.)241

© 2005 by Taylor & Francis Group, LLC

242

Chirkot and Propst

Figure 11 Schematic of a Zig-Zag, which is an example of a continuous granulating machine.
(Courtesy of Patterson-Kelley Co., Division of Harsco Corp., East Stroudsburg, PA.)of the diameter of the larger mixer. They found this to be an adequate scale-up
method despite a geometric dissimilarity in the two mixers studied.
Further work on the rheologic character of the wet mass and the effect onscale-up was performed by York in a high-shear mixer–granulator (24). It was theorized that the power number–Reynolds number relationship used in the scale-up of
ﬂuid mixing impeller systems could be applicable to the granulation mechanism inhigh-shear mixer. To analyze the relationship, appropriate machine informationneeded to be measured, as did the density and viscosity of the wet mass. Mixer
torque rheometry was used to determine wet mass viscosity, and yielded a pseudoReynolds number with the units of torque. It is interesting to note that some unit
operations textbooks show similar logic in developing scale-up equations for dry
powder mixing (25).

Figure 12 Zig-Zag mixer–agglomerator. (Courtesy of Patterson-Kelley Co., Division of
Harsco Corp., East Stroudsburg, PA.)
© 2005 by Taylor & Francis Group, LLC

Low-Shear Granulation

243

Scaling up the process in a low-shear granulator is a daunting task. Scale-up
equations are usually proprietary to the mixer manufacturers and little is written
about them in the literature. The equations have a sound basis in science but areameliorated by constants and factors that take into consideration empirical feedback
and intuition concerning the machine function.
Most commonly, an energy/volume ratio is established in the smaller vessel.
This ratio is emulated in the larger vessel, with appropriate consideration for theadded mass and the larger motor, to yield an estimated scale-up time.
Scarpone et al. (3) studied a change in granulation technology from a highshear mixing bowl to a V-shaped granulator. Developmental work was done in a
0.056 m3 (2 ft3) vessel and the ultimate production in a 2.83 m3 (100 ft3) vessel.
Scale-up based on the manufacturer’s recommendation was not exact and required
some ﬁne-tuning before the process was established in the larger vessel.
This study provides a detailed look at some of the hazards encountered in scaling up. The initial trial in the 2.83 m3 (100 ft3) production vessel failed to provide anadequate granulation. The main reason for the failure was that the scale-up trial
lacked the active ingredient and contained only excipient. This highlights thenecessity of maintaining as much constancy as possible, both with formulationand process variables. Additional tests with the active ingredient were much closer
to the results gained in the smaller vessel. By the third trial, a successful scale-up
had been achieved. Further studies were conducted to evaluate the inﬂuence ofchanges in the physical characteristics of the active ingredient. For example, densitychanges had an inﬂuence on the binder liquid needed. The researchers were able touse their knowledge from the scale-up to achieve another scale-up on a different
product.
M. Uliveri, M. Eli, and R. Bianchini (unpublished data) also attempted a scaleup in a V-shaped granulator. The laboratory vessel was a 0.056 m3 (2 ft3) model andthe scale-up vessel was a 0.283 m3 (10 ft3). They found it was necessary to increase thebatch size 1.2 times over the direct 10:2 ratio, that the total liquid was 82% of directscale-up, and the granules were slightly larger in the scale-up vessel.
Another scale-up attempt in a V-shaped granulator involved a 2 and 57 L vessel(15). The author used a cumulative torque to mass ratio as a means of relating theprocess in both vessels. A separate, individual method is also provided for scaling-up
the liquid addition time.
Suitably, an article by Ennis et al. (26) highlights the fact that understanding
granulation scale-up is a needed growth area for further research.

5. END-POINT DETERMINATION AND CONTROLThe rapidity by which granulation proceeds makes end-point determination a difﬁcult problem. Growth behavior is nonlinear, preventing easy solutions to the differential equations describing the process (27). Watano et al. (13) used an infrared
moisture sensor to continuously monitor moisture through a PID feedback loop.
The current was used to control the liquid addition pump until a suitable size wasachieved. Leuenberger et al. (28) plotted the power consumption curve in a planetary
mixer and observed ﬁve distinct phases that were dependent on the amount of liquid
added. Zoglio et al. (5), working in a ribbon blender, postulated a potential
end-point determination using speciﬁc pore area. Ghanta et al. (10) installed a slip
ring torque sensor between the Hobart mixer agitator and motor and observed ﬁve© 2005 by Taylor & Francis Group, LLC

244

Chirkot and Propst

phases in the torque proﬁle. This process was repeatable and could be considered for
granulation end point in this type of mixer. Another method uses effusivity to determine the amount of moisture in the granule for end-point determination (29).

6. CONCLUSIONS
Low-shear granulators offer a middle ground solution for many of the problems formulators may encounter. Much denser granules may be produced in these vessels,
compared with a ﬂuid bed device, yet the energy expended is not as great as thatfound in a high-shear machine. Many of the low-shear granulators are extremely
adaptable devices capable of mixing the formulation constituents before granulating,and some even dry the materials after granulation is complete. Ample opportunity isavailable in these granulators for adjustments: energy input may be altered with variable speed drives; droplet size may be changed through judicious selection of sprayheads; and various agitating bar designs may be selected. As with many other granulators, scale-up and end-point detection remain poorly deﬁned. A trial and error
procedure is often the only method to determine end point and scale-up.

REFERENCES
1. Nouh ATI. The effect of variations in concentration and type of binder on the physicalcharacteristics of sulfadiazine tablets and granulations prepared by wet and ﬂuidized-bed
granulation method. Pharm Ind 1986; 48(6):670.
2. Gore AY, McFarland DW, Batuyios NH. Fluid-bed granulation: factors affecting theprocess in a laboratory development and production scale-up. Pharm Technol
1985:114–122.
3. Scarpone AJ, Dalvi UG, Delorimier AE. Preparing tablet granulations in a 100 cu ft
solids processor. Pharm Technol 1986; 10:44.
4. Sheskey PJ, Williams DM. Comparison of low-shear and high-shear wet granulation
techniques and the inﬂuence of percent water addition in the preparation of a controlled-release matrix tablet containing HPMC and a high-dose, highly water-soluble
drug. Pharm Technol 1996:80–90.
5. Zoglio MA, Huber HE, Koehne G, Chan PL, Carstensen JT. Physical aspects of wet
granulation II: factors involved in prolonged and excessive mixing. J Pharm Sci 1976;
65:1205.
6. Murry R. J Pharm Sci 1968; 57:1776–1779.
7. Gergely et al. Effervescent system for effervescent tablets and effervescent granules. US
Patent 5888544, March 30,1999.
8. Ghali S, Contractor AM, Mankad AD, O’Connor RE, Schwartz JB, Auslander DE,
Grim WM. A high-speed mixer for continuous wet granulation. Pharm Technol 1990;
14:60.
9. Remon JP, Schwartz JB. Effect of raw materials and processing on the quality of granules prepared from microcrystalline cellulose-lactose mixtures. Drug Dev Ind Pharm
1987; 13:1.
10. Ghanta SR, Srinivas R, Rhodes CT. Use of mixer torque measurements as an aid to optimizing wet granulation process. Drug Dev Ind Pharm 1984; 10:305–311.
11. Day JH & Co. News bulletin: monitoring particle density, moisture content, particle size,and process weight. Cincinnati, OH, 1983.
12. Schaefer T. Equipment for wet granulation. Acta Pharm Suecica 1988; 25:205.
© 2005 by Taylor & Francis Group, LLC

Low-Shear Granulation

245

13. Watano S, Terashita K, Miyanami K. Determination of end-point with a complex granulation applying infrared moisture sensor. Chem Pharm Bull 1991; 329:1013.
14. Chirkot TS. Characterization of a pharmaceutical wet granulation process in a V-typegranulator. Pharm Eng 1999; 19(4).
15. Chirkot TS. Scale-up and endpoint issues of pharmaceutical wet granulation in a V-type
low shear granulator. Drug Dev Ind Pharm 2002; 28:871.
16. Stamm A, Paris L. Inﬂuence of technological factors on the optimal granulation liquid
requirement measured by powder consumption. Drug Dev Ind 1985; 11:333.
17. Cliff MJ. Granulation end point and automated process control of mixer-granulators:
part I. Pharm Technol 1990; 14:112.
18. Lipps D, Sakr AM. Characterization of wet granulation process parameters using
response surface methodology. 1. Top-spray ﬂuidozed bed. J Pharm Sci 1994; 83:937.
19. Fischer JJ. Liquid-solids blending. Chem Eng 1962; 3(Feb 5).
20. Lindberg NO, Jonsson C. The granulation of lactose and starch in a recording high-speed
mixer, Diosna P25. Drug Dev Ind Pharm 1985; 1:387.
21. Agland S, Iverson S. The impact of liquid droplets on powder bed surfaces. CHEMECA’99, Newcastle, Australia, Sep 26–29, 1999:25.
22. Hancock C, York P, Rowe RC, Parker MD. Characterization of wet masses using
a mixer torque rheometer: 1. Effect of instrument geometry. Int J Pharm 1991; 76:239.
23. Vojnovic D, Moneghini M, Rubessa F, Zanchetta A. Simultaneous optimization of several response variables in a granulation process. Drug Dev Ind Pharm 1993; 19:1479.
24. York P. Granulation using mechanical agitation. Proceedings of IFPRI Annual Meeting,
Urbana, IL, 1995.
25. McCabe WL, Smith JC, Harriot P. Unit Operations of Chemical Engineering. 4th ed.
New York: McGraw-Hill, 1985:846.
26. Ennis BJ, Green J, Davies R. The legacy of neglect in the US. Chem Eng Prog 1994:32.
27. Oliver R, Ford LJ. The role of agglomeration in chemical and process technology. Proceedings of the Institute for Briquetting and Agglomeration, Orlando, FL, 1987:1–32.
28. Leuenberger H, Bier HP, Sucker HB. The theory of the granulating liquid requirement in
the conventional granulation process. Pharm Technol 1986; 11:76.
29. Mathis Instruments. Technical Literature. Fredericton, NB, Canada: Mathis Instruments, 2003.

© 2005 by Taylor & Francis Group, LLC

9Batch Fluid Bed Granulation
Dilip M. Parikh
Synthon Pharmaceuticals Inc., Research Triangle Park, North Carolina, U.S.A.

Martin Mogavero
Niro Pharma Systems, Columbia, Maryland, U.S.A.

1. INTRODUCTION
Fluidization is the unit operation by which ﬁne solids are transformed into a ﬂuidlike state through contact with a gas. At certain gas velocities, the ﬂuid will support
the particles, giving them freedom of mobility without entrainment. Such a ﬂuidized
bed resembles a vigorously boiling ﬂuid, with solid particles undergoing extremely
turbulent motion, which increases with gas velocity. Fluidized bed granulation is aprocess by which granules are produced in a single piece of equipment by spraying
a binder solution on to a ﬂuidized powder bed. This process is sometimes classiﬁed as
the one-pot system. The ﬂuid bed granulation process has received considerable attention within the pharmaceutical industry; however, other process industries, such as
food, agro-chemical, dyestuffs, and other chemical industries, have adopted the ﬂuid
bed granulation process to address particle agglomeration, dust containment, andmaterial handling. The ﬂuidization technique, as it is known today, began in 1942,with the work of the Standard Oil Company (now known as Exxon, in the UnitedStates) and M.W. Kellogg Company, in an effort to produce the ﬁrst catalytic cracking
plant on a commercial scale (1).
Fluid bed processing of pharmaceuticals was ﬁrst reported by Wurster, when
he used the air suspension technique to coat tablets (2,3). In 1960, he reported on
granulating and drying of a pharmaceutical granulation, suitable for the preparationof compressed tablets, using the air suspension technique. In 1964, Scott et al. (4)and Rankell et al. (5) reported on the theory and design considerations of the process, using a fundamental engineering approach and employing mass and thermalenergy balances. They expanded this application to the 30 kg-capacity pilot plantmodel designed for both batch and continuous operation. Process variables, suchas airﬂow rate, process air temperature, and liquid ﬂow rate were studied. Contini
and Atasoy (6) later reported the processing details and advantages of the ﬂuid
bed process in one continuous step.
Wolf (7) discussed the essential construction features of the various ﬂuid bed
components, and Liske and Mobus (8) compared the ﬂuidized bed and traditional247© 2005 by Taylor & Francis Group, LLC

248

Parikh and Mogavero

granulation process. The overall results indicated that the material processed by theﬂuid bed granulator was ﬁner, more free-ﬂowing, and had homogenous granules,
which, after compression, produced stronger and faster disintegration of tablets
than the materials processed by conventional wet granulation. Reviews by Sherrington and Oliver (9), Pietch (10), and a series published on the topic of ‘‘Fluidizationin the Pharmaceutical Industry’’ (11–17) provide an in-depth background on thefundamental aspects of the ﬂuidized bed and other granulation technologies. The
ﬂuidized bed was used only for drying the pharmaceutical granulation efﬁciently
in early days, but now it is employed routinely for drying, agglomeration, pelletization, and production of modiﬁed-release dosage forms using air suspension coating. Because of this, these units are normally classiﬁed as multiprocessor ﬂuid bed
units.
The size enlargement of primary particles has been carried out in the pharmaceutical industry in a variety of ways. One of the most common unit operations usedin the pharmaceutical industry is ﬂuid bed processing. The batch size increase using
ﬂuid bed granulation requires a good understanding of the equipment functionality,
theoretical aspect of ﬂuidization, excipient interactions, and most of all identifying
the critical variables that affect the process of agglomeration.
This chapter will provide the essential understanding of the ﬂuidization theory,
system description that make up the ﬂuid bed processor, and will discuss the criticalvariables associated with the equipment, the product, and the process.

2. FLUIDIZATION THEORY
A ﬂuidized bed is a bed of solid particles with a stream of air or gas passing upward
through the particles at a rate great enough to set them in motion; this velocity,
according to Külling and Simon (18), is higher than the incipient ﬂuidizing velocity,
but lower than the entrainment velocity. When the rate of ﬂow of gas increases, thepressure drop across the bed also increases until, at a certain rate of ﬂow, the frictional drag on the particles equals the effective weight of the bed. These conditions,and the velocity of gas corresponding to it, are termed incipient ﬂuidization and incipient velocity, respectively. The relationship between the air velocity and the pressure
drop is as shown in Figure 1 (19).
At low gas velocities the bed of particles is practically a packed bed, and thepressure drop is proportional to the superﬁcial velocity. As the gas velocity is increased,a point is reached at which the bed behavior changes from ﬁxed particles to suspended
particles. The superﬁcial velocity required to ﬁrst suspend the bed particles is known as
minimum ﬂuidization velocity (umf). The minimum ﬂuidization velocity sets the lower
limit of possible operating velocities, and the approximate pressure drop can be used
to approximate pumping energy requirements. For the agglomeration process in theﬂuid bed processor, the air velocity required is normally ﬁve to six times the minimum
ﬂuidization velocity.
At the incipient point of ﬂuidization, the pressure drop of the bed will be very
close to the weight of the particles divided by the cross-sectional area of the bed(W/A). For the normal gas ﬂuidized bed, the density of the gas is much less thanthe density of the solids and the balance of forces can be shown as
DPmf ¼ W =A

where W ¼ ð1  emf Þrp ðg=gcÞ

© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

249

Figure 1 Relation between the air velocity and pressure drop. (From Ref. 19.)

where DP ¼ pressure drop, emf ¼ minimum ﬂuidization void fraction, A ¼ crosssectional area, W ¼ weight of the particles, rp ¼ density of particles, g/gc ¼ ratio ofgravitational acceleration and gravitational conversion factor.
The fundamental phenomenon of ﬂuidization was recently studied by researchers (20) using a small-scale ﬂuid bed unit. The purpose of the study was to compare
experimental and computational minimum ﬂuidizing velocities (umf) of pharmaceutical materials using miniaturized ﬂuid bed device. Using various materials, researchers found that the experimental method was more capable of describing the ﬂuidizing
behavior of pharmaceutical materials than the computational approach. Computational models of ﬂuidization are based on the behavior of various model particles.
Computational models do not take into account particle size and shape distributions, cohesion and adhesion of pharmaceutical materials.
As the velocity of the gas is increased further, the bed continues to expand andits height increases with only a slight increase in the pressure drop. As the velocity of
the gas is further increased, the bed continues to expand and its height increases,
whereas the concentration of particles per unit volume of the bed decreases. At a certain velocity of the ﬂuidizing medium, known as entrainment velocity, particles arecarried over by the gas. This phenomenon is called entrainment. When the volumetric concentration of solid particles is uniform throughout the bed all the time,
the ﬂuidization is termed as particular. When concentration of solids is not uniform
throughout the bed, and if the concentration keeps ﬂuctuating with time, the ﬂuidization is called aggregative ﬂuidization.
A slugging bed is a ﬂuid bed in which the gas bubbles occupy the entire crosssection of the product container and divide the bed into layers.
A boiling bed is a ﬂuid bed, in which the gas bubbles are approximately of thesame size as the solid particles.
A channeling bed is a ﬂuid bed, in which the gas forms channels in the bed
through which most of the air passes.
A spouting bed is a ﬂuid bed in which the gas forms a single opening throughwhich some particles ﬂow and fall on the outside.
© 2005 by Taylor & Francis Group, LLC

250

Parikh and Mogavero

Figure 2 Various types of ﬂuid beds. (From Ref. 21.)

Figure 2 shows various types of ﬂuid beds (21).
The mechanisms by which air affects ﬂuidization have been discussed by various researchers (13,22–26). When the ﬂuidizing velocity is greater than the incipient
velocity, bubbles of air rise through the bed causing mixing of particles. Mixing does
not generally occur when the bed is ﬂuidized at very low or zero excess gas velocities,
because insufﬁcient bubbles are formed to cause bulk displacement of particles. It is
the gas passing through the bed in the form of bubbles that determines the degree of
mixing. The extent of mixing appears to vary with the particle size. Mixing of particles having a mean particle size of less than approximately 150 mm decreases as theirmean size approaches zero. Different types of beds, described above, are formed
depending on the movement of bubbles through the bed. The pattern of movementof the gas phase in and out of bubbles depends on several factors, including minimum ﬂuidization velocity and particle size. These movements affect heat transfer
between air bubbles and particles. The air distributor at the bottom of the container
has a controlling inﬂuence on the uniform distribution of gas, minimization of deadareas, and maximization of particle movement. The most common reason for mixing
problems, such as segregation in the ﬂuid bed, is the particle density differences. The
main characteristic of the ﬂuid bed is the relative velocity imparted to the particles,
U0, which is a strong function of the size of the particles and the gas velocity in thebed, and was shown to be given by (27)U0  aY 0 ¼ 18Ub a=Db d2© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

251

where a is the average particle size, Ub is the bubble velocity, Db is the bubble diameter, and d is the dimensionless bubble spacing. The ﬁrst expression on the righthand side of equation applies to ﬂuidized beds with no rotating parts, where shear
is induced by the motion of bubbles only.
The extent of segregation can be controlled in part by maintaining high ﬂuidizing velocities and high bowl height–bowl diameter ratio. There are standard air velocities for various processes that can be used as guidelines. The standard velocities are
based on the cross-sectional area at the bottom of the product container.
This is calculated by using the following formula for calculating the air velocity.
Velocity ðm=secÞ ¼ Airflow ðm3 =hrÞ=Area ðm2 Þ  3600
where airﬂow in cubic meters per hour (CMH) ¼ airﬂow (CFM)  1.696.
Standard air velocities are based on the application. Low air velocities such as
0.8–1.4 m/sec are required for drying. The velocities are higher during the earlystages of drying because of the wet mass present in the bowl, but will be reduced
when the product loses its moisture. The objective is to have good particle movement, but to keep the material out of ﬁlters. Particle movement and quick drying
are important during the agglomeration process. Airﬂow velocities are normally
1.0–2.0 m/sec.
An indication of good ﬂuidization is a free downward ﬂow of the granulation
at the sight glass of the drying container. However, improper ﬂuidization can also be
detected by monitoring the outlet air temperature. Every product has a unique constant rate of drying in which the bed temperature remains relatively constant for asigniﬁcant length of time. Therefore, if the outlet temperature rises more rapidly than
anticipated, it will indicate an improper ﬂuidization and the process may have to be
stopped, and manual or mechanical intervention may be required to assist theﬂuidization.

3. SYSTEM DESCRIPTION
A ﬂuid bed processor is a system of unit operations involving conditioning of process
air, a system to direct it through the material to be processed, and have the same air(usually laden with moisture) exit the unit void of the product. Figure 3 shows a typical ﬂuid bed processor with all the components. These components and their utility
in granulation will be reviewed.
An exhaust blower or fan is situated at the downstream end of the ﬂuid bed
processor to draw the air through the entire unit. This arrangement provides negative pressure in the ﬂuid bed, which is necessary to facilitate material loading, maintain safe operation, prevent material escape, and carry out the process under good
manufacturing practice guidelines, all of which will be discussed later in the chapter.
3.1. Air Handling Unit
A typical air preparation system includes sections for preﬁltering air, air heating, airdehumidiﬁcation, rehumidiﬁcation, and ﬁnal high-efﬁciency particulate air (HEPA)
ﬁltering. Generally, outside air is used as the ﬂuidizing medium in a ﬂuid bed processor. For the air to be used for pharmaceutical products, it must be free from dust andcontaminants. This is achieved by placing coarse dust ﬁlters (30–85%) in the air
handling unit (AHU). Figure 4 shows a typical AHU.
© 2005 by Taylor & Francis Group, LLC

252

Figure 3 Fluid bed processor installation with all components.

Figure 4 Typical air handling unit.
© 2005 by Taylor & Francis Group, LLC

Parikh and Mogavero

Batch Fluid Bed Granulation

253

Through years of experience and dealing with various types of materials andvarious climatic conditions, it is known that incoming air must be controlled very
closely. As an example, it has been found that the humidity of the incoming air
can greatly affect the quality of spray granulation, drying, or coating. Therefore,
air preparation systems are now designed to better control the conditions of theincoming air. After the installation of the ﬁlters, distinct heating or cooling sections
are installed in the air handler, depending on the geographical location of the plant.
In an extremely cold climate, where cooling coils (needed in summer months formaintaining uniform dew point) can freeze in winter, a preheating section is placed
ahead of the cooling coils. A typical range for the air after pretreatment that one
should aim at achieving is 15–30 C dry bulb and 3–5 C wet bulb. If the unit islocated in a tropical or humid climate, the humidity removal section is employedﬁrst. The dehumidiﬁcation of the air is extremely important where the outside air
moisture varies over a wide range. In summer, when the outside humidity is high,dehumidiﬁcation of the process air is required to maintain a speciﬁc dew point of
the incoming process air. Rehumidiﬁcation may be necessary during the wintermonths in some regions. A steam injector is used for rehumidifying the dry air. Generally, lower the process air dew point, higher the afﬁnity to entrain moisture andshorter the process time. When granulating extremely ﬁne powders, inlet air dew
point of 15 C is beneﬁcial to reduce static charges and facilitate uniform ﬂuidization.
In many processes, when preheating is required, a bypass loop can be used for preconditioning the air. This loop allows the required process temperature and humidity
to be attained within the system ducts before the product is subjected to ﬂuidization.
After the conditioned air leaves the humidiﬁcation/dehumidiﬁcation section of theAHU, it is ﬁnally heated to the desired process air temperature and then passed
through an HEPA ﬁlter of about 99.90–99.99% capacity. As the process air is treatedand ﬁltered, it is transported by the inlet duct. The air is thus brought into theprocess vessel in the lower plenum.
3.2. Product Container and Air Distributor
With the air at the desired humidity and temperature, it is ready to be passed throughthe bed of solids. Figure 5 shows a typical product container with the air distributor.
The air must be introduced evenly at the bottom of the product container,
through an inlet air plenum. Proper airﬂow in the inlet air plenum is critical to ensurethat equal airﬂow velocities occur at every point on the air distributor plate. If the air is
not properly distributed before it reaches the bottom of the container, uneven ﬂuidization can occur. To facilitate the even ﬂow of powder in the product container, conditioned air is brought in the plenum at various locations by certain manufacturers.
To properly ﬂuidize and mix the material in the container, correct choice of thecontainer and air distributor must be made. The container volume should be chosen,such that the container is ﬁlled to at least 35–40% of its total volume and not morethan 90% of its total volume. Correct choice of the air distributor is important. These
distributors are made of stainless steel and are available with a 2–30% open area.
Typically, the distributor should be chosen such that the pressure drop across the
product bed and air distributor is 200–300 mm of water column. A ﬁne screen of
60–325 mesh normally covers the air distributor and retains the product in thecontainer. This type of sandwiched construction has been used for the last 30 years
in the ﬂuid bed processors. The classic air distributor with the ﬁne product retaining
screen is shown in Figure 5.
© 2005 by Taylor & Francis Group, LLC

254

Parikh and Mogavero

Figure 5 Product container with air distributor.

Keeping the screen and air distributors clean has been challenging. Partially toaddress the cleaning problems and partially to provide an efﬁcient processing, a overlap
gill plate, shown in Figure 6(A) and (B), was introduced in 1990 (28). These new overlap
gill air distributors eliminate the need for a ﬁne screen and perform dual functions as
efﬁcient air distributors and product retainers. Other advantages claimed by the manufacturer are validatable clean in place (CIP), controlled ﬂuidization, and directional
ﬂow of air to discharge the processed product from the container. Because there is no
ﬁne screen, these types of air distributors sometimes sift very ﬁne particles throughthe plate, thus losing part of the batch in the plenum. This sifting of ﬁne powder throughthese types of air distributors is of concern when a container containing product is
moved around on the production ﬂoor, losing some product due to movement of thecontainer. Before selecting these types of single-plate distributors, product particle size
and a sifting test should be performed. But these types of air distributors offer advantages when the airﬂow can be directed to discharge the granulated product from thecontainer in a contained manner. (Please see the material handling options section.)
3.3. Spray Nozzle
A spray is a zone of liquid drops in a gas, and spraying is the act of breaking up aliquid into a multitude of these droplets. The general purpose of spraying is toincrease the surface area of a given mass of liquid, in order to disperse it over the
product area. The primary concern is with the increase of surface area per unit massachieved by spraying. The nozzle is an oriﬁce through which liquid is forced,
normally by compressed air. This is done by one of three general methods: (a) liquid
may be sucked up by a pressure drop created over the nozzle cap, after which
compressed air atomizes the liquid stream by disintegrating it with air jets (b) thecompressed air operates a piston arrangement that pushes the liquid through theoriﬁce and then lets surface tension create droplets or (c) two pressure streams ofliquid impinge upon each other, and so form a highly dispersed, uniform spray.
© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

255

Figure 6 (A) Schematic of the overlap gill plate—gill arrangements. (B) Container with theoverlap gill distributor. (Courtesy of Niro Pharma Systems.)

The type of spray system is usually characterized by one of four nozzle designs(29). Figure 7 shows four types of nozzles.
1. Pressure nozzle: The ﬂuid under pressure is broken up by its inherent instability and its impact on the atmosphere, on another jet, or on a ﬁxed plate.
2. Rotating nozzle (rotary atomizer): Fluid is fed at a low pressure to the center of a rapidly rotating disk, and the centrifugal force breaks up the ﬂuid.
These types of nozzles are used mainly in a spray drying application.
3. Airless spray nozzle: The ﬂuid is separated into two streams that arebrought back together at the nozzle oriﬁce, where upon impingement, they
form drops.
4. Gas atomizing nozzle (two-ﬂuid nozzle): The two-ﬂuid (binary) nozzle
where the binder solution (one ﬂuid) is atomized by compressed air (secondﬂuid) is the most commonly used nozzle for ﬂuid bed granulation (Fig. 8A–
C). These nozzles are available as single-port or multiport designs. Generally, the single-port nozzles are adequate up to the 100 kg batch, but forlarger-size batches multiport nozzles, such as either three-port (Fig. 9) or
six-port (Fig. 10) nozzles are required. When these nozzles are air atomized,
the spray undergoes three distinct phases. In the ﬁrst, the compressed air© 2005 by Taylor & Francis Group, LLC

256

Parikh and Mogavero

Figure 7 Types of nozzle. (From Ref. 29.)(gas) expands, essentially adiabatically, from the high pressure at the nozzle
to that at the ﬂuid bed chamber. The gas undergoes a Joule–Thomson
effect, and its temperature falls. In the second, the liquid forms into discrete
drops. During this atomization, the liquid’s speciﬁc surface area usually
increases 1000 times. In the third, the drops travel after being formed, until
they become completely dry or impinge on the product particles. During

Figure 8 (A) Schematic nozzle showing different parts. (B) Schematic of two-ﬂuid nozzle.
(C) Typical single-port nozzle. (Courtesy of Niro Pharma Systems.)© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

257

Figure 9 Three-port nozzle. (Courtesy of the Vector Corporation.)

this phase, the solvent evaporates and the diameter of the drops decreases.
The energy required to form a drop is the product of the surface tension andthe new surface area. About 0.1 cal/g energy is needed to subdivide 1 g ofwater into 1 mm droplets. The air pressure required to atomize the binder
liquid is set by means of a pressure regulator. The spray pattern and spray
angle are adjusted by adjusting the air cap.
Optimum atomization is achieved by ﬁne adjustment of the air cap and atomization air pressure measured at the nozzle. The binder solution is delivered to thenozzle port through a spray lance and tubing. The peristaltic or positive displacement pump is commonly used to pump the binder solution. The pneumatically controlled nozzle needle prevents the binder liquid from dripping when the liquid ﬂow is
stopped. Nozzle port openings of between 0.8 and 2.8 mm in diameter are most common and are interchangeable.
The two-ﬂuid nozzle in its simpliﬁed model is based on energy transmission asshown below:
Energy þ Liquid ! Two fluid nozzle ! Droplets þ Heat
The ratio of energy dissipation by heat and by the droplet-making process is
difﬁcult to measure. Masters (30) suggested that < 0.5% of applied energy is utilized
in liquid breakup. Virtually, the whole amount is imparted to the liquid and air as
kinetic energy.

Figure 10 Six-port nozzle. (Courtesy of the Glatt Group.)© 2005 by Taylor & Francis Group, LLC

258

Parikh and Mogavero

Figure 11 Conventional bag ﬁlters. (Courtesy of the Glatt Group.)

3.4. Disengagement Area and Process Filters
Once the air leaves the product bed, ﬁne particles need to be separated from the air
stream. Two zones are used in the ﬂuid bed to separate the particles from the air
stream—the disengagement area and the exhaust ﬁlter. In the disengagement area,larger particles lose momentum and fall back into the bed. The velocity of theprocess air is the highest at the center of the processor and approaches zero at
the sidewalls. A process-air ﬁlter system removes the particles from the exhaust
air. The process air is ﬁltered by using bags or cartridges. The bag ﬁlters are widelyused and are available with single-bag or with double-bag conﬁguration, where one
bag is mechanically shaking the particles while the other bag remains functional,
thus facilitating uninterrupted ﬂuidization. This alternate shaking of dual bags
allows the process to be consistent from batch to batch. These ﬁlter bags can be constructed out of nylon, polyester, polypropylene, and polytetraﬂuroethylene (PTFE)
lined materials (Figs. 11–13). To dissipate the potential static charges from theproduct particles, conductive fabrics are also available and are recommended.

Figure 12 Conventional bag ﬁlters with hanging arrangements. (Courtesy of the Vector
Corporation.)© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

259

Cartridge ﬁlters lined with PTFE were introduced to the industry in the 1980s (31).
The standard ﬁltration system normally contains a multiple-cartridge ﬁlter systemwith an alternating blowback pulse arrangement allowing continuous product ﬂuidization. A cleanable polyester 2 mm material is utilized for processing water-solubleand -insoluble materials, which has an electrical conductivity for static-free operation. Recently, cartridges made of stainless steel suitable for CIP have been introduced (32). Various suppliers of the process equipment have ﬁlter arrangements.
The vertical ﬁlter cartridge claimed to provide better cleaning, however, requires
mechanical means to bring the ﬁlters down to replace them. Cartridge ﬁlters locatedat an angle do provide better access to take them out from and place them in theunit. They are equally effective. Figure 14(A) and (B) shows the different cartridge-ﬁlter arrangements in the ﬂuid bed processor. The stainless steel cartridge ﬁlters (Fig. 15) are an expensive alternative to the cloth ﬁlter bags, but provide thepossibility of cleaning, using the automated CIP system. For a potent compoundprocessing these cartridge ﬁlters with a CIP capability is normally recommended.
During the granulation or drying process, cloth ﬁlters are mechanically shaken
to dislodge any product adhered, while cartridge ﬁlters use low-pressure compressed
air blowback system to do the same. Figure 14(A) and (B) shows various PTFE lined
cartridge ﬁlters used in the ﬂuid bed processors.

3.5. Exhaust Blower or FanOnce the air leaves the exhaust ﬁlters, it travels to the fan. The fan is on the outlet
side of the system, which keeps the system at a lower pressure than the surrounding
atmosphere. The airﬂow is controlled by a valve or damper installed just ahead orafter the fan. Manufacturers of the ﬂuid bed normally make the selection of the fan,Figure 13 Production size unit with ﬁlter bags. (Courtesy of the L.B. Bohle Group.)© 2005 by Taylor & Francis Group, LLC

260

Parikh and Mogavero

Figure 14 (A) Cartridge ﬁlter during processing mode. (B) Cartridge ﬁlters during cleaningmode. (Courtesy of the Vector Corporation.)based on the layout and the complexity of the system. Fan size is determined by calculating the pressure drop (DP), created by all the components that make up the ﬂuid
bed processor, including the product at the highest design airﬂow volume.

3.6. Control System
A ﬂuid bed granulation process can be controlled by pneumatic analog control
devices, or state of the art, programmable logic controllers (PLCs) or computers.
The electronic based control system offers not only reproducible batches according
to the recipe but also a complete record and printout of all the process conditions.
Process control technology has changed very rapidly and it will continue to change
as advances in computer technology take place and as the cost of control systems
fall. The CFR Part 11 requirements (33) mandated by the US FDA has created anumber of approaches to ensure that these control systems are complying with the© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

261

Figure 15 Stainless steel ﬁlters. (Courtesy of the Glatt Group.)

current regulation. The concept of process analytical technology (PAT) is covered inanother chapter of this book, as it pertains to the process control, and is discussed
further in this chapter, as it pertains to ﬂuid bed processing in particular.
3.7. Solution Delivery System
The liquid delivery systems operate at a low pressure. A peristaltic pump capable ofdelivering ﬂuid at a controlled rate is desirable. The liquid is transported from thesolution vessel through the tubing, and atomized using a two-ﬂuid (binary) nozzle
in the ﬂuid bed processor.
3.8. Laboratory Units
During feasibility of process development, the supply of active ingredient is scarce.
A smaller unit with all the functionalities of a larger unit is desirable. The processparameters developed at this stage may not be fully scalable; however, one can process 20–100 g of material. Figures 16–18 show various smaller-size units that can beused for process feasibility and preliminary development work.
4. PARTICLE AGGLOMERATION AND GRANULE GROWTH
Agglomeration can be deﬁned as the size enlargement process, in which the starting
material is ﬁne particles and the ﬁnal product is an aggregate in which primary particles can still be identiﬁed. The granules are held together with bonds formed by thebinder used to agglomerate. Various mechanisms of granule formation have been
described in the literature (34–36). The chapter on the theory of granulation in thisbook discusses the theory of granule growth. To summarize, the researchers havesuggested three mechanisms for granule formation. These are
1. Bridges due to immobile liquids form adhesional and cohesional bridging
bonds. Thin adsorption layers are immobile and can contribute to thebonding of ﬁne particles under certain circumstances.
2. Mobile liquids where interfacial and capillary forces are present.
3. Solid bridges formed due to crystallization of dissolved substances duringdrying.
© 2005 by Taylor & Francis Group, LLC

262

Parikh and Mogavero

Figure 16 Tabletop unit. (Courtesy of Pro-cept.)

The type of bonds formed approaches through four transition states, describedby Newitt and Conway-Jones (34) as (1) pendular, (2) funicular, (3) capillary, and (4)droplet, which normally happens during spray drying.
Tardos et al. (37) investigated comprehensive model of granulation. Theydeveloped a pendular bridge apparatus that can be used to test the bridge-forming
characteristics of the binder, and to determine binder penetration and spreading
rates and the critical time of binder strengthening. Iveson (38) reported a mathema-

Figure 17 Tabletop ﬂuid bed processor. (Courtesy of the Glatt Group.)© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

263

Figure 18 Lab unit. (Courtesy of Heinen, Germany.)tical model for granule coalescence during granulation. He found that current models
had one of two limitations; either they only consider whether a bond formed on impact
is strong enough to survive subsequent impacts or they fail to consider the possibilityof bond rupture after formation at all. He developed a new model that takes into
account both the effects of bond strengthening with time and the distribution of
impact forces. He suggested that his model be combined with existing models thatpredict whether or not two granules stick initially on impact, to be able to predictthe probability of permanent coalescence.
Most of the ﬂuid bed granulated products require much less wetting than thehigh-shear granulation or spray dryer processed product. In the ﬂuid bed granulation process, the particles are suspended in the hot air stream and the atomized liquid
is sprayed on it. The degree of bonding between these primary particles to form an
agglomerated granule depends on the binder used, the physicochemical characteristics of the primary particles being agglomerated, and the process parameters.
Schaefer et al. (39) and Smith and Nienow (40) have reported a description of
the growth mechanisms in the ﬂuid bed, where the bed particles are wetted by liquid
droplets in the spray zone. Atomized liquid from the nozzle tends to spread over theparticle surface, as long as there is an adequate wettability of the particle by the ﬂuid(41) Wet particles, on impact, form a liquid bridge and solidify as the agglomerate
circulates throughout the remainder of the bed. Solid bridges then hold particles
together. The strength of the binder determines whether these particles stay as
agglomerates. These binding forces should be larger than the breakup forces andin turn depend on the size of the solid bridge. The breakup forces arise from the
movement of the randomized particles colliding with each other and are related tothe excess gas velocity and particle size.
If the binding forces are in excess of the breakup forces, either in the wet state orin the dry state, uncontrolled growth will proceed to an overwetted bed or productionof excessive ﬁnes, respectively. If a more reasonable balance of forces is present, con© 2005 by Taylor & Francis Group, LLC

264

Parikh and Mogavero

Figure 19 Mechanism of granulation in ﬂuid bed.

trolled agglomeration will occur, the growth of which can be controlled. Maroglou
and Nienow presented a granule growth mechanism in the ﬂuid bed by the use ofmodel materials and scanning electron microscope (42). Figure 19 shows the various
paths a liquid droplet can take and their consequences on the particle growth.
The mechanism of formation of a granule and subsequent growth primarily
progresses through three stages:
1. Nucleation
2. Transition
3. Ball growth
Figure 20 shows the growth of the granule relative to the liquid added. In the
beginning of the spraying stage, primary particles form nuclei and are held together
by liquid bridges in a pendular state. The size of these nuclei depends on the droplet
size of the binder solution. As the liquid addition continues, more and more nuclei© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

265

Figure 20 States of liquid saturation. Liquid bridging state of agglomerates undergoing(A) binding liquid addition and (B) densiﬁcation.

agglomerate and continue the transition from the pendular state to the capillarystate.
The uniqueness of the ﬂuid bed agglomeration process is in, how the liquid
addition and drying (evaporation) steps are concurrently carried out. When the granulation liquid is sprayed into a ﬂuidized bed, the primary particles are wetted andform together with the binder relatively loose and very porous agglomerates. Densiﬁcation of these agglomerates is brought about solely by the capillary forces present
in the liquid bridges. It is therefore important that the quantity of liquid sprayed into
the bed should be relatively large compared with that used in high-shear granulation.
Drying a wet product in a ﬂuid bed is a separate topic, but during the granulation process it becomes an integral part of the process; hence, understanding ﬂuid
bed drying is important before we review the agglomeration process.

5. FLUID BED DRYING
Drying is usually understood to be the removal of moisture or solvent. Drying
involves heat transfer and mass transfer. Heat is transferred to the product to evaporate liquid, and mass is transferred as vapor in the surrounding gas; hence, thesetwo phenomena are interdependent. The drying rate is determined by the factors
affecting the heat and mass transfer. The transfer of heat in the ﬂuid bed takes placeby convection. Convection is the transfer of heat from one point to another within aﬂuid (gas, solid, liquid), by the mixing of one portion of the ﬂuid with another.
The removal of moisture from a product granulated in the ﬂuid bed granulator orin other equipment essentially removes the added water or solvent. This free moisture
content is the amount of moisture that can be removed from the material by drying at
a speciﬁed temperature and humidity. The amount of moisture that remains
associated with the material under the drying conditions speciﬁed is called theequilibrium moisture content (EMC).
© 2005 by Taylor & Francis Group, LLC

266

Parikh and Mogavero

The evaporation rate of liquid ﬁlm surrounding the granule being dried isrelated to the rate of heat transfer by the equation:dw
A¼ h dTdt
H
where dw/dt is the mass transfer rate (drying rate), h is the heat transfer coefﬁcient,
A is the surface area, H is the latent heat of evaporation, and dT is the temperature
difference between the air and the material surface.
Because ﬂuid bed processing involves drying of a product in suspended hot air,the heat transfer is extremely rapid. In a properly ﬂuidized processor, the producttemperature and the exhaust air temperatures should reach equilibrium. Improper
air distribution and hence poor heat transfer in a ﬂuidized bed causes numerous problems such as caking, channeling, or sticking. The capacity of the air (gas) stream toabsorb and carry away moisture determines the drying rate and establishes theduration of the drying cycle. Controlling this capacity is the key to controlling thedrying process. The two elements essential for this control are inlet air temperature
and airﬂow. The higher the temperature of the drying air, the greater its vapor
holding capacity. Since the temperature of the wet granules in a hot gas depends
on the rate of evaporation, the key to analyzing the drying process is psychrometry(44–46).
Psychrometry is deﬁned as the study of the relationships between the material
and energy balances of water vapor–air mixture. Psychometric charts (Fig. 21) simplify the crucial calculations of how much heat must be added and how much moisture can be added to the air. The process of drying involves both heat and masstransfer. For drying to occur, there must be a concentration gradient, which must
exist between the moist granule and the surrounding environment. As in heat transfer, the maximum rate of mass transfer that occurs during drying is proportional to
the surface area, the turbulence of the drying air, the driving force between the solid
and the air, and the drying rate. Because the heat of vaporization must be supplied toevaporate the moisture, the driving force for mass transfer is the same driving force
required for heat transfer, which is the temperature difference between the air andthe solid.
Schäfer and Worts (47) have shown that the higher the temperature difference
between the incoming air and the product, the faster the drying rate. Therefore, product temperature should be monitored closely to control the ﬂuidized bed drying
process.
During ﬂuid bed drying, the product passes through three distinct temperaturephases (Fig. 22). At the beginning of the drying process, the material heats up fromthe ambient temperature to approximately the wet-bulb temperature of the air in thedryer. This temperature is maintained until the granule moisture content is reduced
to the critical level. At this point, the material holds no free surface water, and thetemperature starts to rise further.
The drying capacity of the air depends on the relative humidity (RH) of theincoming air. At 100% RH, the air is holding the maximum amount of water possible
at a given temperature, but if the temperature of the air is raised, the RH drops, andthe air can hold more moisture. If air is saturated with water vapor at a given temperature, a drop in the temperature will force the air mass to relinquish some of its
moisture through condensation. The temperature at which moisture condenses is thedew point temperature. Thus, the drying capacity of the air varies signiﬁcantly during processing. By dehumidifying the air to a preset dew point, incoming air can be© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

267

Figure 21 Psychrometry chart.

maintained at a constant drying capacity (dew point) and hence provide reproducible
process times.
Julia Gao et al. (48) studied the importance of inlet air velocity to dry the
product granulated in a high-shear granulator and dried in a ﬂuid bed dryer. The
manufacturing process involved granulating the dry components containing 63%
water-insoluble, low-density drug in a high-shear granulator, milling the wet mass,and drying in a ﬂuid bed dryer. The granules were dried at an inlet air temperatureof 60 C. Two different air velocities were examined for their effect on drying uniformity of the product. The authors observed that the excessive velocity, indicated by

Figure 22 Product temperature changes during drying. (From Ref. 21.).
© 2005 by Taylor & Francis Group, LLC

268

Parikh and Mogavero

the rapid rise in the exhaust air temperature resulted in nonuniform drying of the
product besides resulting in an inefﬁcient process.

6. PROCESS AND VARIABLES IN GRANULATION
6.1. Process
As with any granulating system, in ﬂuid bed granulation processing, the goal is toform agglomerated particles through the use of binder bridges between the particles.
To achieve a good granulation, the particles must be uniformly mixed, and the liquid
bridges between the particles must be strong and easy to dry. Therefore, this system
is sensitive to the particle movement of the product in the unit, the addition of theliquid binder, and the drying capacity of the air. The granulation process in the ﬂuid
bed requires a binary nozzle, a solution delivery system, and compressed air to atomize the liquid binder. Figure 23 shows the equipment setup for granulation using
the ﬂuid bed processor.
Thurn (49), in a 1970 thesis, investigated the details of the mixing, agglomerating, and the drying operations, which take place in the ﬂuid bed process. Results
indicated that the mixing stage was particularly inﬂuenced by the airﬂow rate and the
air volume. It was suggested that the physical properties of the raw materials, such ashydrophobicity, might exert a strong inﬂuence on the mixing stage. At the granulation stage, particular attention was paid to the nozzle, and it was concluded that a

Figure 23 A typical ﬂuid bed processor setup for ﬂuid bed granulation.
© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

269

binary design (two-ﬂuid) nozzle gave a wide droplet size distribution, yielding ahomogenous granule. The need for strong binders was recommended to aid granuleformation and it was suggested that the wettability of the raw materials required
particular attention. Several research papers have been published, on the inﬂuenceof raw material (47–65), binder type (5,8,47,49,59,61,66–76), binder concentration,and binder quantity (8,52,57,61,63,66,68–70,73–75,77–93). Recently, researchers
granulated various products using foam instead of solution and found that ﬂuid
bed granulation using foams of aqueous solutions of low molecular weight Methocel
hypromellose polymers (E3PLV and E6PLV) or conventional solution did not havean effect on the physical properties of granules or tablets compressed from these
granules. However, they found that due to foam, the granule formation is achieved
more efﬁciently. It was further claimed that variables associated with nozzles were
eliminated by using foam, and water requirement was reduced along with shorterproduction time (94).
Each phase of the granulation process must be controlled carefully to achieve
process reproducibility. When the binder liquid is sprayed into a ﬂuidized bed, theprimary particles are wetted and form together with the binder, relatively loose andvery porous agglomerates. Densiﬁcation of these agglomerates is brought about,almost solely by the capillary forces present in the liquid bridges. It is therefore
important that the liquid binder sprayed into the bed should be relatively large inquantity, compared with that used in high- or low-shear granulation processes. During spraying, a portion of the liquid is immediately lost by evaporation, so the system
has little tendency to pass beyond the liquid bridge phase. The particle size of theresulting granule can be controlled to some extent by adjusting the quantity of binder liquid and the rate at which it is fed, i.e., the droplet size. The mechanicalstrength of the particles depends principally on the composition of the primary product being granulated and the type of the binder used. Aulton et al. (83) found thatlower ﬂuidizing air temperature, a dilute solution of binder ﬂuid, and a greater sprayrate produced better granulation for tableting.
6.2. Variables
Factors affecting the ﬂuid bed granulation process can be divided into three broad
categories:
1. Formulation related variables
2. Equipment related variables
3. Process related variables
6.2.1. Formulation Related Variables
6.2.1.1. Properties of Primary Material. Ideally, the particle properties
desired in the starting material include a low particle density, a small particle size,a narrow particle size range, the particle shape approaching spherical, a lack of particle cohesiveness, and a lack of stickiness during the processing. Properties such as
cohesiveness, static charge, particle size distribution, crystalline or amorphous nature, and wettability are some of the properties which have an impact on the properties of granules formed. The cohesiveness and static charges on particles present
ﬂuidization difﬁculty. The same difﬁculties were observed when the formulation contained hydrophobic material or a mixture of hydrophilic and hydrophobic materials.
The inﬂuence of hydrophobicity of primary particles has been shown by Aulton and© 2005 by Taylor & Francis Group, LLC

270

Parikh and Mogavero

Banks (17) where they demonstrated that the mean particle size of the product was
directly related to wettability of the primary particles expressed as cos y (where y is
the contact angle of the particles). It was also reported that as the hydrophobicity ofthe mix is increased, a decrease in granule growth is observed. Aulton, Banks, andSmith, in a later publication, showed that addition of a surface-active agent, suchas sodium laurel sulfate, improves the ﬂuidized bed granulation (57). In a mixture
containing hydrophobic and hydrophilic primary particles, granule growth of hydrophilic materials takes place selectively, creating content uniformity problems. Formulating a controlled release granulation can be accomplished by using ﬂuid bed
granulation. A controlled release matrix formulation of Naproxen was successfully
developed using ﬂuid bed granulation (95).
6.2.1.2. Low-Dose Drug Content. Wan et al. (96) studied various methods ofincorporating a low-dose drug, such as chlorphenirmine maleate, in lactose formulation with Povidone (PVP) as the granulating binder. They concluded that the randomized movement of particles in the ﬂuid bed might cause segregation of the drug andthat uniform drug distribution was best achieved by dissolving the drug in the granulating solution. The mixing efﬁciency of drug particles with the bulk material was
found to increase, in the proportion of the granulating liquid used to dissolve thedrug. The optimum nozzle atomizing pressure was deemed to be important to avoid
spray drying the drug particles or overwetting, which creates uneven drug distribution. Higashide et al. (97) studied the ﬂuidized bed granulation using 5-ﬂuorouracil
in a concentration of 0.3% in 1:1 mixture of starch and lactose. Hydroxy propyl cellulose (HPC) was used as the binder. The ratios of starch and lactose contained in
the granules were measured gravimetrically. The researchers found that a larger
amount of the drug and starch was found in larger granules than in smaller granules.
The results were attributed to the hydrophobicity of the 5-ﬂuorouracil, starch, andthe hydrophilicity of lactose.
6.2.1.3. Binder. A more general discussion on the types of binders used in
the pharmaceutical granulations and their inﬂuence on the ﬁnal granule properties
was presented in a previous chapter of this book. Different binders have different
binding properties, and the concentration of the individual binder may have to bechanged to obtain similar binding of primary particles. Thus, the type of binder, binder content in the formulation, and concentration of the binder have a major inﬂuence on granule properties. These properties include friability, ﬂow, bulk density,
porosity, and size distribution.
Davies and Gloor (98,99) reported that the types of binder such as povidone,
acacia, gelatin, and HPC, all have different binding properties that affect the ﬁnal
granule properties mentioned above. Hontz (91) investigated microcrystalline cellulose concentration, inlet air temperature, binder (PVP) concentration, and binder
solution concentration effects on tablet properties. Binder and microcrystalline cellulose concentration were found to have a signiﬁcant effect on tablet properties.
Alkan and Ulusoy (76) studied binder (PVP) addition in solution and as a dry powder in the powder mix. They found a larger mean granule size when the dry binder
was granulated with ethanol. However, when the binder was in solution, the granules
produced were less friable and more free-ﬂowing. A similar ﬁnding was conﬁrmed byother researchers (92,93). Binder temperature affects the viscosity of the solution,and in turn affects the droplet size. Increased temperature of the binder solution
reduces the viscosity of the solution, reducing the droplet size, and hence producing
smaller mean granule size. Binder solution viscosity and concentration affect the
droplet size of the binder. Polymers, starches, and high molecular weight PVP cause© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

271

increased viscosity, which in turn creates a larger droplet size and subsequently a larger mean granule particle size (68).
Diluted binders are preferred because they facilitate ﬁner atomization of thebinder solution, provide control of the particle size, reduce friability, and increase thebulk density, even though the tackiness or binding strength may suffer (8,69,79,83,99).
6.2.1.4. Binder Solvent. In most instances, water is used as the solvent. The
selection of solvent, such as aqueous or organic, depends on the solubility of the binder and the compatibility of the product being granulated. Generally, organic solvents, due to their rapid vaporization from the process, produce smaller granules
than the aqueous solution. Different solvents have different heats of vaporization
as shown in Table 1. Incorporating the binder or a mixture of binders of low melting
point with the drug substance in the dry form can eliminate the requirement of a solvent for the binder. The temperature of the incoming air is sufﬁcient to melt the binder and form the granules. Seo et al. (100) studied ﬂuid bed granulation using
meltable polymers such as polyethylene glycol (PEG) 3000, or esters of polyethylene
glycol and glycerol (Gelucire 50/13). They showed that melt agglomeration by atomization of a melted binder in a ﬂuid bed occurs by initial nucleation followed bycoalescence between nuclei. The nuclei are formed by immersion of the solid particles
in the binder droplets, provided that the droplet size is larger than the size of thesolid particles. The agglomerate growth rate is supposed to be practically independent of the droplet size, if the binder viscosity is so low that the droplets are able
to spread over the agglomerate surface. If the droplets are unable to spread, becauseof high viscosity, the growth rate is supposed to be inversely proportional to the droplet size. These effects of droplet size are different from those seen in aqueous ﬂuid
bed granulation, probably because the aqueous process is affected by the evaporation of the binder liquid.
6.2.2. Equipment Related Variables
6.2.2.1. Design. To ﬂuidize, and thus granulate and dry the product, a certain quantity of process air is required. The volume of the air required will vary
based on the amount of material that needs to be processed. The ratio of drying
capacity of the process air to the quantity of the product needs to be maintained constant throughout the scaling-up process. However, some suppliers of the equipment
provide higher drying capacity for their laboratory unit, but cannot maintain thesame ratio for the production units. This lack of proportionality reduces the drying
capacity per unit volume of the process air, resulting in a longer process time in the
production units. The current design of the ﬂuid bed is a modular one, where multiple
Table 1 Heats of Vaporization for Commonly Used Solvents
Solvent
Methylene chloride
AcetoneMethanol
Ethanol
Isopropanol
Water© 2005 by Taylor & Francis Group, LLC

Solvent boiling point( C)

Density(g/mL)Heat of vaporization(kcal/g)

40.0
56.2
65.0
78.5
82.4
100.0

1.327
0.790
0.791
0.789
0.786
1.000

77
123.5
262.8
204.3
175.0
540.0

272

Parikh and Mogavero

processes such as drying, granulating, Wurster coating, rotary ﬂuid bed granulatingor coating, etc., can be carried out by changing the container specially designed forthe individual process.
6.2.2.2. Air Distributor Plate. The process of agglomeration and attrition
due to random ﬂuidization requires control of the particle during the granulation
process. This is a complex phenomenon due to the prevailing ﬂuidizing conditions
and a particle size distribution, which undergoes changes during the process. As
the conditioned air is introduced through the lower plenum of the batch ﬂuid bed,
the ﬂuidizing velocity of a given volume of air determines how ﬂuidization will beachieved.
Perforated air-distributor plates covered with the 60–325-mesh ﬁne stainlesssteel screen, described previously, provide an appropriate means of supplying air
to the product. These plates are identiﬁed by their percentage of open area. Air distributor plates that have 4–30% open area are normally available. These interchangeable plates provide a range of loading capacities, so that batches of various sizes canbe produced efﬁciently and with uniform quality. To prevent channeling, an operator
can select a plate with optimum lift properties. For example, a product with low bulk
density requires low ﬂuidizing velocity. A distributor plate having a small open area
to give a large enough pressure drop may provide uniform ﬂuidization of such a product without reaching entraining velocity and impinging the process ﬁlters. Alternatively, a product with higher bulk density can be ﬂuidized and processed using a platewith a larger open area. The air distributor plate consists of a perforated plate and aﬁne mesh screen. This arrangement sometimes causes problems like product leakage,due to a torn screen, and difﬁculty in cleaning without separating the perforated plate
and the ﬁne mesh screen. To overcome these deﬁciencies, various air distributor
design have been recently introduced. These distributor designs were discussed earlier
in the chapter.
6.2.2.3. Pressure Drop. The blower creates ﬂow of air through the ﬂuid bed
processor, or a fan located downstream from the process chamber. This fan imparts
motion and pressure to air using a paddle-wheel action. The moving air acquires aforce or pressure component in its direction of motion, because of its weight and inertia. This force is called velocity pressure and is measured in inches or millimeters ofwater column. In operating duct systems, a second pressure that is independent of
air velocity or movement is always present. Known as static pressure, it acts equallyin all directions. In exhaust systems such as ﬂuid bed processors, a negative static pressure exists on the inlet side of the fan. The total pressure is thus a combination of staticand velocity pressures. Blower size is determined by calculating the pressure drop (DP)created by all the components of the ﬂuid bed processing system. Proper selection of
the blower is essential in ﬂuid bed design. A blower with appropriate DP will ﬂuidize
the process material adequately. However, a blower without enough DP will not allow
proper ﬂuidization of the product, resulting in longer process time and improper granulation. A similar effect can be seen when a product with unusually high bulk density
is processed in place of normal pharmaceutical materials, or an air distributor offers
high resistance due to its construction. This creates a pressure drop that the blower
was not designed to handle. A properly sized blower or fan should develop sufﬁcient
DP so that the exhaust damper can be used in the 30–60% open position. Any additional components such as scrubbers, exhaust HEPA, police ﬁlters, or additional components in the air handling unit would require a larger blower/static pressure which
can be recommended by the supplier of the ﬂuid bed processor.
© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation273

6.2.2.4. Shaker/Blow Back Cycle Mechanism. To retain entrained particles
of a process material, process ﬁlters are used. To maintain these ﬁlters from building
up layers of ﬁne process material, and causing a higher pressure drop and thus
improper ﬂuidization, these ﬁlters are cleaned during the granulation process. Whenbag ﬁlters are used, mechanical means are used to clean them. This mechanical cleaning of the bag ﬁlters requires a cessation of airﬂow and thus the ﬂuidization during
the ﬁlter cleaning process. In units with a single-bag house, this results in a momentary dead bed, where no ﬂuidization takes place. This interruption in the processextends the process time. To avoid process interruptions, a multishaking ﬁlter bag
arrangement is desired, where the granulation process is continuous. Using bag ﬁlters with a blowback or using cartridge ﬁlters where air under pressure is pulsed
through the ﬁlters also achieves the continuous process. Generally, ﬁlters should
be cleaned frequently during the granulation step, to incorporate the ﬁnes back in
the granulation. This is possible if the cleaning frequency is high and the period
between the ﬁlter cleaning is short. Rawley (101) reported the effect of bag-shake/interval cycle. He discussed the possibility of improving particle size distribution
by optimizing the shake time and the corresponding interval between bag shakes.
The following general guidelines for ﬁlter cleaning frequency and duration arerecommended:
Single-bag shaker unit: Frequency, 2–10 min between ﬁlter cleaning, 5–10 sec
for shaking. This may vary as the ﬁne powders form granules, and thefrequency between the shakes or duration of shaking interval, can beextended. In any case, the occurrence of a collapsed bed should be kept
at a minimum in a single-shaker unit.
Multiple bags shaker unit: Since this is a continuous process, frequency of shaking for each section is approximately 15–30 sec between ﬁlter cleanings,
and about 5 sec for shaking the ﬁlters. If a low-pressure blow back system
is used for the bags, the frequency of cleaning is about 10–30 sec.
Cartridge ﬁlters: These offer continuous processing and require cleaning frequency of 10–30 sec.
The cleaning frequency and cleaning duration are now offered as an automatedsystem, where instead of having to base the cleaning frequency on time, the trigger
point for ﬁlter cleaning is the buildup of a pressure drop across the ﬁlters. This automates the process and eliminates operator input.
6.2.2.5. Other Miscellaneous Equipment Factors. Granulator bowl geometry
is considered to be a factor that may have an impact on the agglomeration process.
The ﬂuidization velocity must drop from the bottom to the top rim of the bowl by
more than half to prevent smaller, lighter particles from being impinged into the ﬁlter, creating segregation from heavier product components in the bowl. Generally,
the conical shape of the container and expansion chamber is preferred, where theratio of cross-sectional diameter of the distributor plate to the top of the vessel is 1:2.
Most of the suppliers of this equipment offer units with a multiprocessor concept
where a single unit can be used for drying, agglomerating, air suspension coating,or rotary ﬂuid bed processing by changing the processing container, while the restof the unit is common. This approach does eliminate the concerns about the geometry of the processor, because of the way these units are constructed.
© 2005 by Taylor & Francis Group, LLC

274

Parikh and Mogavero

6.2.3. Process Related Variables
The agglomeration process is a dynamic process where a droplet is created by a twoﬂuid nozzle, and deposited on the randomly ﬂuidized particle. The binder solvent
evaporates, leaving behind the binder. Before all of the solvent is evaporated, otherrandomized particles form bonds on the wet site. This process is repeated numerous
times to produce the desired agglomerated product. There are a number of process
variables that control the agglomeration. Process variables, most important to consider are listed as follows:
1.
2.
3.
4.
5.
6.
7.
8.

Process inlet air temperature
Atomization air pressure
Fluidization air velocity and volume
Liquid spray rate
Nozzle position and number of spray heads
Product and exhaust air temperature
Filter porosity and cleaning frequency
Bowl capacity

These process parameters are interdependent and can produce the desired product if this interdependency is understood. Inlet process air temperature is determined by the choice of binder vehicle, whether aqueous or organic, and the heatsensitivity of the product being agglomerated. Generally, aqueous vehicles will
enable the use of temperatures between 60 C and 100 C. On the other hand organic
vehicles will require the use of temperatures from 50 C to below room temperature.
Higher temperatures will produce rapid evaporation of the binder solution and willproduce smaller, friable granules. On the other hand, lower temperatures will produce larger, ﬂuffy, and denser granules.
Figure 24 shows the relationship of inlet and product air temperature, and outlet air humidity during the granulation process.
The process of drying while applying spraying solution is a critical unit operation. This mass transfer step was previously discussed. The temperature, humidity,
and volume of the process air determine the drying capacity. If the drying capacityof the air is ﬁxed from one batch to the next, then the spray rate can also be ﬁxed. If
the drying capacity of the air is too high, the binder solution will have a tendency tospray dry before it can effectively form bridges between the primary particles. If on
the other hand, the drying capacity of the air is too low, the bed moisture level will
become too high and particle growth may become uncontrollable. This will result in
unacceptable movement of the product bed.
As previously discussed, the appropriate process air volume, inlet air temperature, and binder spray rate are critical for achieving proper and consistent particle
size distribution and granule characteristics. There are many ways to arrive at theproper operating parameters. The following procedure was found by the authors
to be one of the ways one can set the operating parameters when granulating withﬂuid bed processors.
1. Determine the proper volume of air, to achieve adequate mixing and particle movement in the bowl. Avoid excessive volumetric airﬂow so as toentrain the particles into the ﬁlters.
2. Choose an inlet air temperature that is high enough to negate weather
effects (outside air humidity or inside room conditions). The air temperature should not be detrimental to the product being granulated. (To© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

275

Figure 24 Temperature and humidity changes during the granulation process.

achieve consistent process year round, a dehumidiﬁcation/humidiﬁcation
system is necessary, which provides the process air with constant dew
point, and hence constant drying capacity).
3. Achieve a binder solution spray rate that will not dry while spraying (spraydrying) and will not overwet the bed. This rate should also allow the nozzle
to atomize the binder solution to the required droplet size.
4. As stated earlier, a typical air velocity used for spray granulation is from
1.0 to 2.0 m/sec. Table 2, which is based on the psychometric chart, gives
a ﬁrst guess at determining the proper spray rate for a spray granulation
process in a ﬂuid bed processor.
The presence of variables in the ﬂuid bed granulation process, and their impact
on the ﬁnal granulation, was summarized by Davies and Gloor (102), where theystate that the physical properties of granulation are dependent on both the individual
formulations and the various operational variables associated with the process. The
solution spray rate increase and subsequent increase in average granule size, resulted
in a less friable granulation, a higher bulk density, and a better ﬂow property for alactose/corn starch granulation. Similar results were obtained by an enhanced binder solution, decreasing nozzle air pressure, or lowering the inlet air temperatureduring the granulation cycle. The position of the binary nozzle with respect to theﬂuidized powders was also studied. It was concluded that by lowering the nozzle,
binder efﬁciency is enhanced, resulting in average granule size and a corresponding
decrease in granule friability.
© 2005 by Taylor & Francis Group, LLC

276

Parikh and Mogavero

Table 2 Calculation of Fluid Bed Spray Rate
Given process data
Air volume range:
Minimum (1.2 m/sec)
Maximum (1.8 m/sec)
Inlet air temperature and humidity to be used:% Solids in sprayed solution:_________________ m3/hr_________________ m3/hr_______  C _______ %RH_________________ % solids

From psychrometry chart
Air density at point where air volume is measured:___________
m3/kg air
Inlet air absolute humidity (H):___________ g H2O/kg air
Maximum outlet air absolute humidity (H):___________ g H2O/kg air(Follow line of constant adiabatic conditions)Use 100% outlet RH for spray granulator or 30–60% RH (as required for column coating)Calculations for spray rate
Step 1 Convert air volumetric rate to air mass rate
Minimum ________
m3/hr  (60  ________
m3/kg air) ¼ ________ kg air/min
3
Maximum _________ m /hr  (60  ________ m3/kg air) ¼ ________ kg air/min
Step 2 Subtract inlet air humidity from outlet air humidity___________________ (g H2O/kg air) Hout ___________________ (g H2O/kg air) Hin¼ ____________________________________________________ g H2O removed/kg air
Step 3 Calculate (minimum and maximum) spray rate of solution
This will provide range of generally acceptable spray rates based on the airﬂow usedin the unit
Step 1 (minimum) _________  step 2 ________
 [1  ( ________ % solids  100)]¼ _______________________ spray rate (g/min) at minimum airﬂow
Step 2 (maximum) ________  step 2 ________
 [1  ( ________ % solids  100)]¼ _______________________ spray rate (g/min) at minimum airﬂow

The signiﬁcant process parameters and their effect on the granule properties
are summarized in Table 3.
Maroglou (43) listed various parameters affecting the type and rate of growthin batch ﬂuidized granulation (Table 4) and showed the inﬂuence of process parameters and the material parameters on the product.

7. PROCESS CONTROLS AND AUTOMATION
The agglomeration process is a batch process, and accurate repeatable control of all
critical process parameters is necessary for a robust system. Earlier designs of theﬂuid bed processor used pneumatic control, which provided safe operation in ahazardous area but relied heavily on human actions to achieve repeatable productquality and accurate data acquisition. Current designs use PLCs and personal computers (PCs) to achieve sophisticated control and data acquisition. The operating
conditions are controlled to satisfy parameters of multiple user-conﬁgured recipes,
and critical data are collected at selected time intervals for inclusion in an end-ofbatch report. Security levels protect access to all user-conﬁgured data with passwords permitting access only to selected functions. With the appropriate security
level, not only are operating conditions conﬁgured, but also identiﬁcation of each© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

277

Table 3 Signiﬁcant Variables and Their Impact on the Fluid Bed Granulation Process
Process parameter

Impact on process

References(74,85)
Inlet air temperature Higher inlet temperature produces ﬁner
granules and lower temperature produces
larger stronger granules
Humidity
Increase in air humidity causes larger(39)
granule size, longer drying times(17,20,74)
Fluidizing airﬂow
Proper airﬂow should ﬂuidize the bed
without clogging the ﬁlters. Higher airﬂow
will cause attrition and rapid evaporation,
generating smaller granules and ﬁnes
(59)
Nozzle and position A binary nozzle produces the ﬁnest droplets
and is preferred. The size of the oriﬁce has
an insigniﬁcant effect, except when bindersuspensions are to be sprayed. Optimum
nozzle height should cover the bed surface.
Too close to the bed will wet the bed fasterproducing larger granules, while too higha position will spray dry the binder, create
ﬁner granules, and increase granulation time.
(39,59,87,94)
Liquid is atomized by the compressed air. This
Atomization air
mass-to-liquid ratio must be kept constant tovolume andcontrol the droplet size and hence the granule size.
pressure
Higher liquid ﬂow rate will produce larger droplet
and larger granule and the reverse will produce
smaller granules. At a given pressure an increasein oriﬁce size will increase droplet size
(17,56,73,74,94)
Binder spray rate
Droplet size is affected by liquid ﬂow rate, andbinder viscosity and atomizing air pressure andvolume. The ﬁner the droplet, the smaller the
resulting average granules

valid recipe and operator is entered. The identiﬁcation is veriﬁed before any operator
actions are permitted and is included with the end-of-run report. The use of computer related hardware requires some additional validation, but with coordination
between the control system provider and the end user, the validation of software
can be managed. Figure 25 shows the pneumatic control panel and Fig. 26(A) and(B) shows a PLC-based control panel with a typical operator screen.
The most important sensors for control of the drying process are product, inlet
and exhaust air temperature, and sensor for airﬂow measurement, located in the airtransport system. Other sensors for the spray agglomeration process are atomization
air pressure and volume, pressure drops (across the inlet ﬁlter; the product container
with the product being processed, and outlet process air ﬁlter), inlet air humidity or
dew point, process ﬁlter cleaning frequency and duration, spray rate for the binder
solution, and total process time.
All of these sensors provide constant feedback information to the computer.
These electronic signals may then be stored in the computer’s memory and thenrecalled as a batch report. With this ability to recall data analysis, a greater insightcan be gained into the process.
© 2005 by Taylor & Francis Group, LLC

278

Parikh and Mogavero

Table 4 Inﬂuence of Operating and Material Parameters on the Granulated ProductOperating parameters
Droplet size

Bed moisture content

Binder solution/suspension Concentration
Material parameters
Binder solution/suspension Concentration
Type of binder
Wettability

Material to be granulated

NARa
Atomization air velocity
Rheology
Surface tension
Nozzle position
Nozzle type
Solution type and feed rate
Bed temperature
Fluidization velocity
Aspect ratio
Nozzle position and atomization velocity
Air distributor design
Jet grinding
Bridge strength and size
Rheology
Bridge strength and size
Rheology
Molecular length and weight
Particle-solvent interaction
Surface tension
Viscosity
Average particle size
Size distributiona
Shape and porosity
Drying characteristics
Density and density differencesba

NAR is the ratio of air to liquid ﬂow rates through the nozzle of a twin ﬂuid atomizer expressed either inmass units or in volume units (air at STP).
b
Especially important relative to elutriation and segregation.

7.1. Advances in Process Control and Automation
The degree of the instrumentation of pharmaceutical unit operations has increased.
This instrumentation provides information on the state of the process and can beused for both process control and research. A central part of optimizing production
is increasing the level of automation. Besides monitoring the process parameters,
a number of approaches are being developed for measuring the moisture of the
product to determine the end point of the process, and consequently the in-process
particle size analysis. A number of publications discuss the on-line moisturemeasurement and process end point determination using near-infrared (NIR).
7.1.1. Near-Infrared
The nondestructive character of vibrational spectroscopic techniques, such as NIR,
makes them novel tools for in-line quality assurance (103). NIR has been widely used
for the measurement of water in various applications (28). NIR can be applied bothfor quantitative analysis of water and for determining the state of water in solidmaterial. This gives a tool for understanding the physicochemical phenomena during
manufacture of pharmaceutical granulation.
© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

279

Figure 25 Pneumatic control panel. (Courtesy of the Glatt Group.)

The history of NIR dates back to the studies, by Herschel, in 1800. The modern
NIR analysis was developed in 1950 by the works of a group at United States
Department of Agriculture (USDA), headed by Karl Norris (28).
Other branches of chemical industry have also applied for various applications.
One feature of NIR is that the applications have been ahead of theoretical aspects.
This has hindered the general approval of NIR in the pharmaceutical industry. However, the pharmacopoeias have deﬁned some characteristics of analysis with NIR(104,105). The NIR spectrum is just above the visible region of electromagnetic spectrum (EMS). The NIR region covers the interval between 4000 and 12,500 cm1
(0.8–2.5 mm). Molecules that absorb NIR energy vibrate in two fundamental modes:
stretching and bending. Stretching is a continuous change in the interatomic distance, along the axis between two atoms, and it occurs at lower wavelengths thanbending vibration. A bending vibration is a change in the bond angle between diatomic molecules. A band observed at 1940 nm is known to be caused by O–H stretching and bending vibrations, and is the most used analytically (106,107). It has
recently been reported, from measurements on silica gel layers, that water content
has an effect on NIR absorption at all wavelengths, even where water is absorbed
minimally (108). Usually, for a solid sample, the reﬂected light is the parameter measured in NIR spectroscopy, known as diffuse reﬂectance. The reﬂected light consistsof two components: specular and diffuse. The specular, or mirror-like, component in
the boundary between two media occurs at the sample surface, and it contains little
information about the chemical composition of the substance. The NIR spectroscopy
is particularly based on the diffused component of the reﬂected light, and it can beaffected by particle size and shape distribution, bulk density surface characteristics,
and temperature (109,110). This portion of the Electro Magnetic Spectrum (EMS)
has, for the last 30 years, been studied and investigated in great detail as an analytical
tool for the analysis of many natural and man-made materials (109,111–114).
Developing a functional automation system requires new measuring techniques; new in-line measuring devices are needed (115–119). Solid–water interactions
are one of the fundamental issues in the pharmaceutical technology. The state of© 2005 by Taylor & Francis Group, LLC

280

Parikh and Mogavero

Figure 26 (A) PLC based system. (Courtesy of Niro Pharma Systems.) (B) Production unit
with a PLC control panel. (Courtesy of the L.B. Bohle Group.)water in the solid material may be characterized using x-ray diffraction, microscopic
methods, thermal analysis, vibrational spectroscopy, and nuclear magnetic resonancespectroscopy (120). Traditionally, the control of ﬂuidized bed granulation has been
based on indirect measurements. These control methods applied utilize the properties of process air by Schaefer and Worts (47). Frake et al. (121) demonstrated theuse of NIR for in-line analysis of the moisture content in 0.05–0.07 mm pellets during spray granulation in ﬂuid bed processor. Rantanen et al. (122,123) described asimilar approach for moisture content measurement using a rationing of three tofour selected wavelengths. He and his coworkers reported that the critical partof in-line process was the sight glass for probe positioning, which was continuously© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

281

blown with heated air. They also reported spectra baselines caused by particle size andrefractive properties of the in-line samples; they analyzed several data pretreatments
to eliminate these effects on their ﬁxed wavelength setup. Solvents other than water
have also been evaluated for real-time quantiﬁcation.
On-line measurement has also been possible enabling the monitoring of ﬁlm
coating on pharmaceutical pellets, in an industrial manufacturing process. Andersson et al. (124) conducted measurements on solid coated tablets using ﬁber-optic
probe positioned in the ﬂuid bed processor. In this case, they secured a representative
sampling during processing, by using a sample collector that was emptied with compressed air inside the processor. Vázquez recently provided comprehensive review of
FT-NIR application in measuring ﬂuid bed drying end (125). Rantanen et al. (126)used NIR to monitor the moisture as well as airﬂow. Using in-line multichannel NIR
the multivariate process data collected were analyzed using principal component
analysis (PCA). The authors showed that robust process control and measurement
system combined with reliable historical data storage can be used for analyzing
the ﬂuid bed granulation process. PCA modeling proved a promising tool to handle
multidimensional data that were collected, and for reduction of the dimensionality ofprocess data. FT-NIR spectra gave useful information for understanding the phenomenon during granulation. Rantanen et al. (127) further studied the applicationof NIR for ﬂuid bed process analysis. The authors used NIR to study moisture measurement combined with temperature and humidity measurements. By controllingthe water during the ﬂuid bed granulation, the granulation process was controlled.
They concluded that the varying behavior of formulations during processing canbe identiﬁed in a real-time mode. Thus, they found that NIR spectroscopy offeredunique information of granule moisture content during all phases of granulation.
7.1.2. Other Approaches for Process Control
7.1.2.1. Self-Organizing Maps. On-line process data are usually multidimensional, and it is difﬁcult to study with traditional trends and scatter plots. Rantanen
et al. (128) has suggested a new tool called ‘‘self-organizing maps’’ (SOM), fordimension reduction and process state monitoring. As a batch process, granulation
traversed through a number of process states, which was visualized by SOM as a
two-dimensional map. In addition, they demonstrated how the differences between
granulation batches can be studied.
7.1.2.2. At-Line Measurement. Laitinen et al. presented a paper at a recent
conference (129) proposing at-line optical techniques to study particle size. Usinga CCD camera with optics and illumination units, with stabilized collimated lightbeams, authors took two images of 36 granule samples by illuminating the samples
alternatively. Two digital images, with matrices of their gray scale values, wereobtained and the differences between the two matrices were calculated. This method
provided very rapid (1 min per sample) measurement of particle size, with a verysmall sample size (<0.5 g).
7.1.2.3. Focused Beam Reﬂectance Measurement. This device uses a focused
beam of laser light that scans, in a circular path, across a particle or particle structure
passing in front of the window. Upon hitting the particle, light is scattered in all
directions. The light scattered back toward the probe is used to measure the chord
length or the length between any two points on a particle. Such devices are suppliedcommercially and claim to be useful for monitoring on-line measurement of particle
size in the ﬂuid bed granulation process.
© 2005 by Taylor & Francis Group, LLC

282

Parikh and Mogavero

7.1.2.4. Artiﬁcial Neural Network. Neural networks have been used by scientists for optimizing formulations as an alternative to statistical analysis because of its
simplicity for use and potential to provide detailed information. The neural networkbuilds a model of the data space, which can be consulted to ask ‘‘what if’’ kinds ofquestions. Recently, there has been interest in using artiﬁcial neural network (ANN)for process control. Similar to the human brain, an ANN predicts events or information based on learned pattern recognition. ANNs are computer systems developed to
mimic the operations of the human brain, by mathematically modeling its neurophysiological structure (i.e., its nerve cells and the network of interconnections betweenthem). In ANN, the nerve cells are replaced by computational units called neurons,
and the strengths of the interconnections are represented by weights (130). This
unique arrangement can simulate some of the neurolocal processing ability of thebrain, such as learning and drawing conclusions from experience (131). Using theprocess control system, quality assurance results, or energy usage data, an ANN
develops supervisory set points for the system. When ANN and process control systems are used together, they form a product control system. Product control occurs
when a system measures deﬁned product attributes in real time, and uses the knowledge to adjust the control system. While process control system runs the process (i.e.,fans, motors, heaters, etc.), the ANN controls the product (moisture level, consistency). The ﬂuidized bed processor’s process control system includes an operator interface, sensing elements, and ﬁnal control elements. The inputs in that case are inlet air
temperature, outlet air temperature, airﬂow rate, and energy consumption. Additional
contributing factors are the fouling coefﬁcient of the dryer bags, the quantity of product in the processor, and the type of product with its unique characteristics.
Watano et al. (132) described a practical method for moisture control in ﬂuid bed
granulation by means of neural network. Wet granulation of pharmaceutical powder
was conducted using an agitation ﬂuidized bed, and the moisture content was continuously measured by IR moisture sensor. A neural network system for moisture control
was developed using moisture content and its changing rate as input variables, and the
moisture control characteristics were investigated by the neural network system with aback propagation learning. Good response and stability without overshoot wereachieved by adopting the developed systems. This system also maintained favorable
stability under various operating conditions. Several researchers have publishedpapers, detailing the use of ANN for different applications (133–135).

8. PROCESS SCALE-UP
8.1. Regulatory
Scale-up is normally identiﬁed with an incremental increase in batch size, until adesired level of production is obtained. In 1991, American Association of Pharmaceutical Scientists (AAPS) with US FDA held a workshop on scale-up (136), where
several speakers presented scale-up issues from an industrial and regulatory perspective. For example, Shangraw divided scale-up problems into two general categories:
those related to raw materials or formulation and those related to processing
equipment. He also indicated that it is essential to ascertain whether or not changes
in raw materials have occurred, before one looks at processing/equipment changes
as a source of any problem. The workshop report, as it pertains to the process
and equipment, is reproduced below:© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation283

It is generally recognized that many NDAs and ANDAs contain provision for
multiple manufacturers of the drug substance(s), and that not all drug substance
suppliers, a priori, produce equivalent material. There is then a need for material
quality control to assure the performance and reproducibility of the ﬁnishedproduct. Particle size and distribution, morphology, and intrinsic dissolution of
the drug substance are important considerations. Polymorphism, hygroscopicity,
surface area, wettability, density (bulk and tapped), compressibility (for dry
blending), and powder ﬂow effects should be controlled.
Additionally, the process should be controlled by employment of a validation
protocol, which deﬁnes the critical parameters and also establishes the acceptancecriteria for the granulation or blend; which may include sieve analysis, ﬂow,
density, uniformity, and compressibility, moisture content, etc.
In the milling, blending, granulating and or drying processes, the operating
principles of the equipment employed should be deﬁned, and the variables determined. The impact and mechanism of measurement on in-process variables should
be deﬁned. Time, temperature, work input of equipment, blend/granulation
volume, and granulating rate should be determined. . . . The parameters selectedshould be appropriate for the process, . . . In those cases where the manufacturing
process has been controlled and validated as speciﬁed in the foregoing discussion;
batch scale-up, changes in site of manufacture, allowance for equipment change(where the operating principle is the same), minor formulation changes, etc.,
should be determined on the basis of the comparability of both the blend/granulation and the ﬁnal product; as assured by: a) appropriate tests; b) speciﬁcations; c)process validation; and d) comparative accelerated stability.

Regulatory guidelines for scale-up and postapproval changes (SUPAC) IR
were released in 1995 (137) and are discussed in another chapter of this book.
8.2. Scale-Up and Equipment Design
The scale-up from the laboratory equipment to production size units is dependent onequipment design, which may or may not have been scalable as far as its dimensionalfeature or components selection is concerned. The importance of scalability is wellunderstood and accepted by the manufacturers of ﬂuid bed processors. Various sizes
in their product line are logically designated and manufactured. Airﬂow in the ﬂuid
bed process is a critical parameter. The design and selection of the processor is very
important for the laboratory and production unit. Because airﬂow is one of the components of the drying capacity of a ﬂuid bed system, the ratio of air volume per kilogram or liter of the product is very critical to achieve a scale-up that is linear. The
other design feature is the cross-sectional area of the product container, and how
it has been designed throughout the various sizes that a manufacturer supplies.
The relationship between various sizes of the process containers can be utilized to
calculate the scale-up of binder spray rate, and if the cross-sectional area is designed
linearly, then the spray rate scale-up can be linear.
8.3. Scale-Up and Process Factors
The ﬂuid bed agglomeration process is a combination of three steps, namely, dry
mixing, spray agglomeration, and drying to a desired moisture level. These process
steps are equally important. But the quality of the granules is really determined
during the spraying stage, when constant building of granules and evaporation of© 2005 by Taylor & Francis Group, LLC

284

Parikh and Mogavero

binder solvent are taking place. Granule size is directly proportional to the
bed humidity during granulation (47) and hence, control of this humidity during
scale-up is essential.
Gore et al. (138) studied the factors affecting the ﬂuid bed process during scale
up. The authors found that processing factors that affected granule characteristics
the most, were process air temperature, height of the spray nozzle from the bed, rateof binder addition, and the degree of atomization of the binder liquid.
The atomizing air pressure and the wetness of the bed are two of the mostimportant elements of ﬂuid bed granulation. A higher atomizing air pressure yields
a ﬁner droplet of binder solution. Therefore, granule growth (as described earlier inthis section) is affected by the atomizing air pressure. A major factor which must be
considered during the scale up of ﬂuid bed granulation process is maintaining thesame droplet size of the binder for assuring successful scale-up. A recent study(139) conﬁrmed the inﬂuence of spray nozzle setup parameters on the drying capacity of the air. The study concluded that more attention should be paid to the easily
overlooked nozzle atomizing air pressure and volume. When considering the atomizing
air pressure, attention must be paid to ensure that enough air is delivered to the nozzle
tip. This can be ensured by placing air pressure and volume measurement devices at thenozzle. The data also show that the drying capacity of the process air inﬂuences theﬁnal granulated particle size.
Jones (140) has suggested various process related factors that should be considered during the scale-up of a ﬂuid bed processing. The suggestions are listed in thefollowing paragraphs.
Due to the higher degree of attrition in the larger unit compared to the smaller
unit, the bulk density of the granulation from the larger ﬂuid bed is 20% higher
than the smaller unit. He also re-emphasized the importance of keeping the bed
moisture level below the critical moisture level, to prevent the formation of larger
agglomerates. Since the higher airﬂow along with the temperature (drying capacity)
in a larger unit provide higher evaporation rate, one must maintain the drying capacity in the larger unit, such that the bed temperature is similar to the smaller-unit bed
temperature. This can be accomplished, either by increased spray rate, increased airtemperature, and increased airﬂow, or by the combination of these variables toobtain suitable results. Since the ratio of bed depth to the air distributor increases
with the size of the equipment, the ﬂuidization air velocity is kept constant by
increasing the air volume. In the past, the scale-up was carried out by selecting best
guess process parameters. The recent trend is to employ the factorial and modiﬁed
factorial designs and search methods. These statistically designed experimental plans
can generate mathematical relationships between the independent variables, such asprocess factors, and dependent variables, such as product properties. This approachstill requires an effective laboratory/pilot scale development program and an understanding of the variables that affect the product properties.
In summary, when scaling up, the following processing conditions should be
similar to the pilot scale studies:
1. Fluidization velocity of the process air through the system
2. The ratio of granulation spray rate to drying capacity of ﬂuidization air
volume3. Droplet size of the binder spray liquid.
© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

285

Each of these values must be calculated based on the results of the operation of
the pilot size unit. Pilot size equipment studies should also be conducted in a wide
range to determine the allowable operating range for the process.
Another chapter of this book provides ﬂuidized bed scale-up and should be
reviewed.
8.4. Case Study
The following case study illustrates how a product is scaled up from 15 to 150 kg in
the equipment supplied by Aeromatic, when one understands the critical processparameters used when scaling up.
A spray granulation process was developed for a common pharmaceuticalcompound. The granulation process involved spraying of a 5% w/w binder solution
onto the ﬂuidized powder. Table 5 shows the data from the 15 kg run and the resulting successful 150 kg run condition for a spray agglomeration process.
8.4.1. Airﬂow Calculations
To maintain the same ﬂuidization velocity, the air volume in a larger unit must be
increased, based on the cross-sectional area of the product bowl. In this case, thecross-sectional area of the base of the larger container was 0.77 m2 and that of thesmaller was 0.06 m2. The correct airﬂow should be calculated as 300  (0.77/0.06) ¼ 3850 CMH. This number was further modiﬁed after considering the increase
in bed depth in a larger unit to 4000 CMH.
8.4.2. Spray Rate Calculations
To maintain the same particle size, the triple-headed nozzle could spray three times
the pilot unit spray rate at a 2.5 atomization air pressure. However, this could resultin a longer process time. Another approach to maintain a similar droplet size is tomaintain the mass balance of spray rate and the atomization pressure. Thus, byincreasing the atomization pressure to 5 bar, the spray rate was increased to 800 g/
min, keeping the same droplet size, and hence obtaining granulation with the desired
characteristics.
8.4.3. Temperature Calculations
Finally, the required inlet temperature was recalculated based on the change in theratio of the air volume to the spray rate. Because the air volume was increased over
13 times but the spray rate was only increased eight times, the inlet temperature was
reduced to 50 C. This adjustment in drying capacity was necessary to avoid spraydrying of the spray solution. (A three-headed nozzle used in this scale-up can be
Table 5 Scale-Up Process Parameters from a 15 to a 150 kg Batch
Process parameters

15 kg

150 kgAirﬂow (m3/hr)
Inlet air temperature ( C)
Spray rate (g/min)Nozzle air pressure (bar)Container cross-sectional area of the base (m2)
Number of nozzles

300
55
100
2.5
0.06
1

4000
50
800
5
0.77
3

© 2005 by Taylor & Francis Group, LLC

286

Parikh and Mogavero

replaced by a six-headed nozzle. This would have resulted in the ability to increase
the spraying rate 13 times above the pilot size unit to match the airﬂow. The maintenance of droplet size and temperature could have been achieved with thesix-headed nozzle. The end result would be reduced process time.) Figure 27 shows
the particle size distribution produced, using 15 and 150 kg units.
Recently, Matharu and Patel (141) presented a scale-up case study, where alow-dose multiple-strength product (0.5–5% w/w/ active) was spray granulated
and scaled up from a pilot scale ﬂuid bed processor up to production size equipment.
Their approach was based on matching air velocity between the two scales of operation. The impact of droplet size was determined by varying the independent parameters. Based on their study, authors have suggested an equation, which takes into
account, material and equipment parameters. Rambali (142) scaled up granulation
process from small (5 kg) to medium (30 kg) to large (120 kg) with an aim to obtainthe target geometric mean granule size of 400 mm. The scaling up was based on therelative droplet size and the powder bed moisture content at the end of the spraying
cycle. Authors found that the effect of the change in relative droplet size on the granule size was different for each ﬂuid bed. They applied the experimental design on thesmall- and medium-scale unit, and regression models for the granule size were proposed in order to scale up the granulation process on the small to medium scale.
Using only the relative droplet size, authors were able to scale up the process to
the larger unit.
9. SAFETY IN FLUID BED
For an explosion to occur, three conditions must exist: an ignition source, a fuel, andoxygen. With an explosion, oxygen reacts with the fuel, releasing heat and gases. If a
dust explosion occurs in free space, a ﬁreball of considerable extent arises. If the dust
explosion occurs in a closed container, there is a sudden pressure rise that is mainly
decided by the following factors: type of dust, size of the dust, dust/oxygen ratio,
turbulence, precompression, temperature, shape of the container, and ignition
source. In a container without precompression and with an organic dust of sufﬁcientﬁneness, the pressure inside the container can rise to over 10 bar overpressure.

Figure 27 Scale-up case study and resultant particle size distribution.
© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

287

The ﬂuid bed process handles a large amount of air. This air, in the presence ofﬁne product dust, poses potential for an explosion. This hazard can be enhanced
when using ﬂammable solvents. If sufﬁcient ignition energy (static charge) is introduced, an explosion within the processor can take place. In order to contain thesedust or ﬂammable solvent induced explosions, ﬂuid bed processors are normally constructed to withstand an overpressure of 2.0 bar. In this case, the ﬂuid beds are provided with explosion relief ﬂaps, to release the pressure as soon as it starts to build up
inside the processor. The explosion ﬂaps, mounted either horizontally or vertically(Fig. 28), are designed to vent the pressure buildup as low as 0.06 bar. The explosion
protection valve, shown in Figure 29, acts to cut off the airﬂow to the blower andisolates the overpressure within the processor. The 2 bar vented design shows the
propagation of the overpressure (Fig. 30). The explosion ﬂaps open up to the outsideof the building. These panels are gasketed, and sealed so that normal ﬂuid bed operation is not affected. It was an accepted practice to have the production unit with
2 bar pressure shock integrity; however, the cleaning of the gasket area around theﬂaps is always difﬁcult. To avoid having the product exposed to the outside during
such an event, a suppression system is used to contain the possible overpressure front
from leaving the unit (Fig. 31). The suppression system consists of low-pressure sensors located within the processor. These sensors are designed to trigger a series of ﬁreextinguishers (containing ammonium phosphate), as soon as a preset level (generally,
0.1 bar) of pressure is set within the processor.

Figure 28 Processor with horizontal and vertical relief.
© 2005 by Taylor & Francis Group, LLC

288

Parikh and Mogavero

Figure 29 Explosion protection valve.

With the introduction of potent and costly drug substances, the 2 bar design isbeing replaced with a 10 bar design and higher, based on the speciﬁc mixtures of the
product(s) being processed. These units can withstand explosions up to 10 bar. Mostof the pharmaceutical dust explosions studied (143) show the overpressure reaching

Figure 30 Vented design (2 bar unit). (Courtesy of the Glatt Group.)© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

289

Figure 31 Explosion suppression system.

9 bar, with a Kst value (constant of explosion speed) of 200. An explosion in a 10 bar
unit is contained within the unit. A 10 bar designed unit does not require any explosion relief panels or gaskets. This eliminates the concerns about cleaning of the gaskets and panels. Another advantage of a 10 bar unit is that, in case of explosion, theprocessor containing the potent drug substance is contained inside the unit, and explosion does not pose an environmental problem as with the 2.0 bar unit. Figure 32(A)and (B) shows the Ventex-ESI valve for passive control of the explosion. The VentexESI valve requires less maintenance than the active valve shown in Figure 29. An explosion force (pressure wave), moving ahead of the ﬂame front, hurls the poppet forward to
the valve seat providing an airtight seal. The poppet, once seated, is locked in by amechanical shut-off device, which retains the seal until manually reset. The three basic
versions of the standard mechanical Ventex valve are available with a set pressure of
1.5 psi and a maximum pressure of 150 psi. The Ventex-ESI valve closes by the explosion
pressure wave, without external power for horizontal or vertical operation. Figure 33
shows the various types of Ventex valves installed in a ﬂuid bed system.
In case of granulation requiring ﬂammable solvents, process air and nozzle atomization air are replaced by an inert gas such as nitrogen and the system is designed
as a closed cycle with a solvent recovery capability (144). A number of approaches
can be taken to handle solvent from the process. Table 6 summarizes various methods for solvent emission control systems.
Kullingand Simon (18) reported the closed loop system shown in Figure 34.
¨
The inert gas used for ﬂuidization circulates continuously. An adjustable volume ofgas is diverted through the bypassed duct, where solvent vapors are condensed andsolvent collected. The circulating gas passes through the heat exchanger to maintainthe temperature necessary for evaporation of the solvent from the product bed. During© 2005 by Taylor & Francis Group, LLC

290

Parikh and Mogavero

Figure 32 (A) Schematic of the Ventex valve. (B) Ventex valve. (Courtesy of Rico-Sicherheitechnik AG, Switzerland.)the agglomeration and subsequent drying process, the solvent load in the gas stream
does vary. The bypass valve controls the ﬂow of the gas to the heat exchanger andthe condenser. By controlling the gas stream in this manner, the drying action is continued until the desired level of drying is reached. Even though the cost of ﬂuid bed
processor with the solvent recovery is generally double the cost of a regular single-pass
ﬂuid bed processor, such a system offers effective measures for both explosion hazard
reduction and air pollution control.
In 1994 European parliament issued the ATEX directive (145) on the approximation of the laws of the member states, concerning equipment and protective systems
intended for use in potentially explosive atmospheres. The scope, these regulations speciﬁcally require ‘‘protective systems,’’ intended to halt incipient explosions immediately© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

291

Figure 33 Setup of ﬂuid bed with different Ventex valves. (Courtesy of Rico-Sicherheitechnik AG, Switzerland.)and to limit the effective range of explosion ﬂames and explosion pressures. All manufacturers of ﬂuid bed processors in Europe must comply with this directive.

10. MATERIAL HANDLING OPTIONS
The transfer of materials to and from the ﬂuid bed processor is an important consideration. The loading and unloading of the processing bowl can be accomplishedeither by manual mode or by automated methods.
Table 6 Comparison of Different Solvent Emission Control System
Water scrubbing

Catalytic burning

Carbon absorption

Open cycle

Open cycle

Open cycle

High capital cost
High energy
requirement
External installation
Medium spacerequirement
Medium ﬂexibility
Waste treatment
requiredLow capital cost
Low energy
External installation
High spacerequirement
Medium ﬂexibility
CO2/H2O emission
waste treatment© 2005 by Taylor & Francis Group, LLC

Condensation

Closed cycle withnitrogen
Moderate capital cost Low capital cost
Low energy
Low energy
External installation
Moderate spacerequirement
Low ﬂexibility
Waste treatment

Internal installation
Small spacerequirement
Good ﬂexibility
Concentrated waste
treatment

292

Parikh and Mogavero

Figure 34 Schematic of closed loop solvent recovery system.

10.1. Loading
The contemporary method for loading the unit is by removing the product bowl
from the unit, charging the material into the bowl, and then placing the bowl backinto the unit. This loading is simple and cost-effective. Unfortunately, it has thepotential of exposing the operators to the product and contaminating the working
area. To avoid the product from having a dust and cleaning hazard, a dust collection
system should be installed to collect the dust before it spreads. A manual process also
depends on the batch size, the operator’s physical ability to handle the material, andthe container full of product. Furthermore, this can be time consuming, since thematerial must be added to the product container, one material at a time.
The loading process can be automated and isolated to avoid worker exposure,minimize dust generation, and reduce loading time. There are two main types ofloading systems. These systems are similar because both use the ﬂuid bed’s capability
to create a vacuum inside the unit. Here, the product enters the ﬂuid bed through a
product in-feed port, on the side of the unit. This is done by having the fan runningand the inlet air control ﬂap set, so that minimum airﬂow may pass through the product container and the outlet ﬂap is almost fully open. Typically, when the highshear granulated material needs to be charged into the ﬂuid bed, this approach helps(Fig. 35). Once the material has been charged to the ﬂuid bed, the product in-feedvalve is closed and the granulating process started. This transfer method uses someamount of air to help the material move through the tube. Loading can be done
either vertically from an overhead bin, or from the ground. Less air is required
through the transfer pipe when the material is transferred vertically because gravity
is working to help the process. Vertical transfer methods do require greater available
height in the process area. Loading by this method has the advantages of limited
operator exposure to the product, allows the product to be ﬂuidized as it enters
the processor, and reduces the loading time. The disadvantage of this type of systemis the cleaning required between different products.
© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

293

Figure 35 Loading of ﬂuid bed from high-shear mixer. (Courtesy of the Glatt Group.)

10.2. Unloading
As with loading, the standard method for unloading is by removing the productbowl from the unit. Once the bowl is removed, the operator may scoop the material
from the bowl, which is the most time consuming and impractical method, becauseof its potential of exposure to the product. Alternatively, the product can be vacuumtransferred to a secondary container or unloaded by placing the product bowl into
bowl dumping discharge device, as shown in Figure 36(A) and (B).
This hydraulic device is installed in the processing area. The mobile productcontainer of the ﬂuid bed processor is pushed under the cone of the bowl dumperand coupled together by engaging the toggle locks. Subsequently, the container islifted hydraulically, pivoted around the lifting column, and rotated 180 for discharging. Use of the bowl dumping device or vacuum unloading device still requires thatthe product bowl be removed from the unit. There are contained and automatedmethods for unloading the product, while the product bowl is still in the ﬂuid bed
processor. The product may be unloaded either from the bottom of the productcontainer or from the side. Until recently, the most common contained method
is to unload the material from the bottom of the unit. This requires a ceilingheight high enough to accommodate it, or the installation becomes multistoried
installation.
There are two types of bottom discharge options, gravity or pneumatic.
Gravity discharge (Figs. 37 and 38) allows for collection of the product into container, which is located below the lower plenum. If the overall ceiling height limitation prevents discharge by gravity, the gravity/pneumatic transfer combination canbe considered. The gravity discharge poses cleaning problems, since the process air
and the product discharge follow the same path; assurance of cleanliness is always ofprime concern.
The desire to limit the processing area and the development of the overlap gillair distributor mentioned earlier in the chapter has prompted the consideration of
the side discharge as an option. The product bowl is ﬁtted with the discharge gate,
as shown in (Fig. 39A and B).
© 2005 by Taylor & Francis Group, LLC

294

Parikh and Mogavero

Figure 36 (A) Product discharge system. (B) Bowl inverter. (Courtesy of Niro Pharma
Systems.)

Most of the product, being free-ﬂowing granules, ﬂows through the side
discharge into a container. The remainder of the product is then discharged bymanipulation of the airﬂow through the overlap gill air distributor. The discharged
product can be pneumatically transported to an overhead bin if the dry milling of the
granulation is desired.
The contained system for unloading the product helps to isolate the operator
from the product. The isolation feature also prevents the product from being
contaminated due to exposure to the working environment. Material handling consideration must be thought of early in the equipment procurement process. Fluid bed
processing, whether used as an integral part of high-shear mixer/ﬂuid bed dryer or asa granulating equipment option, production efﬁciency, and eventual automation canbe enhanced by considering these loading and unloading options.

11. FLUID BED TECHNOLOGY PROGRESS
The ﬂuid bed processor was used as an efﬁcient way to dry a product due to suspension of particles in the hot air stream. However, over the last 35 years, the development in the pharmaceutical industry and the proliferation of the batch ﬂuid bed
processing technology in other industries as food, polymer, detergent, etc., hasprovided the opportunity to use the batch ﬂuid bed processor for granulation,
coating of particles, and pelletization. The advances in the ﬂuid bed can be attributed
to several factors. The needs of formulators, the requirements of the regulators,
and technological innovations from the manufacturers of these equipments are© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

295

Figure 37 Loading and unloading setup with bottom discharge. (Courtesy of the Vector
Corporation.)

responsible for these advances. The result of these changes provided units that are
paint free, modular, safer, in compliance with the cGMPs, and are capable of performing various processes that were not thought of before.
11.1. Developments in Equipment and Process Applications
Parikh (146) has presented a review of all of the equipment developments. Among
various advances, the development of production units that can withstand more than
10 bar pressure shock resistance is a very signiﬁcant development. These units do not
require pressure relief duct and associated cleaning problems. Units are now equippedwith the air handler that can provide designated humidity and dew point air, throughout the year and at any geographical location. The ﬂuid bed CIP became a reality with
the introduction of the overlap gill air distributors and the stainless steel cartridge ﬁlters
described earlier in this chapter. The coating of the particles is carried out mostfrequently using Wurster column (Fig. 40A and B). The Wurster process is the most© 2005 by Taylor & Francis Group, LLC

296

Parikh and Mogavero

Figure 38 Bottom discharge. (Courtesy of the Glatt Group.)

popular method for coating particles. The Wurster based coating process does notcontain any ﬂuid bed regions in the traditional sense, as it is a circulating ﬂuid bed
process. Four different regions within the equipment can be identiﬁed: the upbed
region, the expansion chamber, the downbed region, and the horizontal transport
region. The coating process consists of three phases: the start-up phase, the coatingphase, and the drying and cooling phase. During the coating phase, several processes
take place simultaneously. They are atomization of the coating solution or suspension,transport of the atomized droplets of the coating solution to the substrate, and dryingof the ﬁlm. In 1993, the design was modiﬁed as in Wurster HS (147).
However, the technology has certain disadvantages, such as nozzle accessibility, prolonged process time, minimum volume requirement, and difﬁculty of loading
and unloading. In 1995, to address these shortcomings of the Wurster system, thePrecision CoaterÕ incorporating modiﬁed air suspension technique was introduced(148). It was designed to allow removal of the nozzles for cleaning, faster process
time because of the patented particle accelerator, good utilization of thermal andkinetic energies, and scalability from a single-column to a multicolumn setup.
Recently, Glatt organization introduced the STRATOS2 system for applying sustained release tablet coating, using bottom spray. The modiﬁcation of the bottom
spray setup offers better efﬁciency than Wurster HS for coating tablets (149). The
Wurster setup for granulating was presented by Walter et al. (150). Authors claimthat the quality of granulation is superior to the top spray granulation.
Researchers have discussed the incorporation of microwave in the laboratory
ﬂuid bed processor (151,152). Fluid bed process using organic solvent requires aninert gas such as nitrogen to replace the air used for ﬂuidization, as discussed earlier
in the chapter. It is accompanied by the solvent recovery system. In 1989, a vacuum
ﬂuid bed system was presented by Luy et al. (153). The main feature was the generation and sustaining of a ﬂuidized bed under vacuum, thereby eliminating the use ofinert gas. Several advantages are claimed by the authors, such as emission reduction,
increased recovery rate of solvent, and an application for oxygen sensitive materials.
© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

297

Figure 39 (A) Side discharge. (Courtesy of the Glatt Group.) (B) Side discharge. (Courtesyof Niro Pharma Systems.)

11.2. Rotary Fluid Bed
The other advance of signiﬁcance is the development of a rotary ﬂuid bed for producing denser granulation. Modules were introduced by various manufacturers, andthe technology is discussed below. The 1972 patent (154) for the rotor technology
was awarded for the equipment and coating of the granular material. The subsequent patents (155,156) were awarded for the coating of the spherical granules.
An advantage of rotary ﬂuid bed processing to produce granules over the conventional top-spray granulation technique was reported by Jager and Bauer (155). In
this unit, the conventional air distributor is replaced by the rotating disk. The material to be granulated is loaded on the rotating disk. The binder solution is added
through the atomization nozzle, located tangentially to the wall of the bowl. The centrifugal force creates a dense, helical doughnut-shaped pattern. This type of motion
is caused by the three directional forces.
The vertical movement is caused by the gap or slit air around the rotating disk,
the gravitational force folds back the material to the center, and the centrifugal force
caused by the rotating disk pushes the material away from the center. The granulation produced in the rotary ﬂuid bed processor shows less porosity, compared to the© 2005 by Taylor & Francis Group, LLC

298

Parikh and Mogavero

Figure 40 (A) Wurster Coater schematic. (B) Wurster Coater. (Courtesy of the Vector
Corporation.)conventionally agglomerated product in the ﬂuid bed processor. There are essentially
two designs of this rotary ﬂuid bed module which are available: the single-chamber
design and the double-chamber design (Fig. 41). In the single-chamber design, theconventional air distributor is replaced by the rotating disk, which has variable size
slit opening between the bowl wall and the rotor disk. The ﬂuidizing air enters the
mixing zone in the bowl through the slit. The single-chamber design is manufactured
by Glatt (W.Glatt GMBH, Binzen, Germany), as Glatt Rotor GranulatorÕ , and by© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

299

Figure 41 Various rotary ﬂuid bed inserts.

Freund (Freund Industrial Co. Ltd., Tokyo, Japan), as a Spir-a-ﬂowÕ granulator.
The double-chamber design was patented and manufactured by Aeromatic-Fielder
AG (Aeromatic-Fielder AG–now Niro Pharma Systems, Bubendorf, Switzerland)(158). An inner stainless steel wall, encompassing the area called the forming zone
is surrounded by an annular drying zone. The forming zone has a rotating disk.
The gap air around the rotating disk allows the free movement of the disk. The stainless steel wall separating the forming zone and drying zone can be raised, so that therotating product transfers in the drying zone through the gap created during the drying
mode between the stationary and movable walls. The process air ﬂuidizes the productthrough the annular drying zone. As the partially dried product reaches the upperboundary of the forming zone, the particle velocity slows down due to the design of
the unit and the particles fall back in the forming zone. These partially dried particles,
eventually, go through the same path in a cyclic pattern, until the desired moisture content is reached. The rotary ﬂuid bed, with its different designs listed above, do provide
granules which have less porosity, and higher bulk density compared to the granulation produced by the typical top spray granulated ﬂuid bed process.
Türkoglu et al. produced Theophylline granulation using a rotary ﬂuid bed(159). The formulation contained lactose, starch, and microcrystalline cellulose,© 2005 by Taylor & Francis Group, LLC

300

Parikh and Mogavero

along with Theophylline. They reported that the granules produced were sphericaland dense. Three different drug level formulations were evaluated. The authors concluded that the rotary ﬂuid bed, as a wet granulator, has the potential to obtain abetter drug content uniformity for tablets even at low active levels such as 1% incomparison with conventional ﬂuidized beds. The use of rotary ﬂuid bed to produce
spherical granules for modiﬁed release application is reported by a number ofauthors. Rotary ﬂuid bed technology was reviewed by Li et al. (160), and its usefulness was described to produce the pellets. The comparison of the rotary ﬂuid bed
processing with the multiple-step extrusion and spheronization was reported byRobinson et al. (161). The authors manufactured acceptable immediate release acetaminophen pellets, using both of these techniques. The quality of the pellet produced
improved as the minimum quantity of product was increased in the rotary ﬂuid bed
processor. The advantage of using a single unit, such as the rotary ﬂuid bed, over themultiple-unit process involving several pieces of equipment was described.
The rotary ﬂuid bed is used for producing a pellet by layering the active drug
suspension or solution on to nonpareil cores, and subsequently coating them withpolymers to impart modiﬁed release properties (162) Hileman et al. (163) reported
the manufacture of immediate spheres of a poorly water-soluble drug in a rotary
ﬂuid bed by layering the active drug suspension on to nonpareil cores. These immediate release spheres were then overcoated with an ethylcellulose/HPMC hydroalcoholic solution in the same unit, eliminating the need for additional process andhandling steps. Iyer et al. evaluated layering of aqueous solution of phenylpropanolamine hydrochloride with different binders (164). The layered beads were coated in
the rotoprocessor and the Wurster Coater to compare the utility of the rotoprocessor
as an equipment, not only to produce pellets, but to coat them as well. Various
equipment manufacturers have promoted powder layering on the pellets, in a rotary
ﬂuid bed. In 1992, Jones et al. received a patent for such a process (165). The process
claims to have advantages of layering a drug substance with a relatively small
amount of liquid, thus making this layering process more efﬁcient. The commercial
application of this process has not been reported in the literature. Korakianiti et al.
(166) studied the preparation of pellets using rotary ﬂuid bed granulator. The
authors concluded that the rotor speed and the amount of water signiﬁcantly
affected the geometric mean diameter of the pellets, and they proposed an equation
to show that correlation. Piśek et al. (167) studied the inﬂuence of rotational speed
and surface of rotating disk on pellets produced by using rotary ﬂuid bed. They useda mixture of pentoxifylline and microcrystalline cellulose to produce pellets, using asuspension of EudragitÕ NE 30 D as a binder. The results showed that both the surface and the rotational speed of the disk have an inﬂuence on the shape, surface, andsize of the pellets, while there was less effect on the density, humidity content, andyield. They found that the textured surface of the disk produced pellets with arougher surface when the rotational speed was increased compared to the smoothsurface, where increased rotational speed produced more spherical pellets with alarger diameter. Jan Vertommen (168) has summarized the use of rotary ﬂuid bed
processor to produce pellets.
11.3. Integrated Systems
The ﬂuid bed technology is used for drying, agglomerating, coating, and pelletization. The trend in the industry is toward integrating various steps currently used
to produce the solid dosage products. In an attempt to minimize the number of steps© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

301

involved, ﬂuid bed granulation and drying is increasingly planned in the following
three ways:
1. Fluid bed processor for granulation and drying
2. Integration of high-shear mixer and a ﬂuid bed dryer
3. Integration of high-shear mixer with ﬂuid bed dryer for containment ofpotent compounds.
11.3.1. The Granulation and Drying Carried Out in a Single Unit
To minimize material handling steps, the ﬂuid bed units are loaded by gravity or by
vacuum, as described previously. Discharge of the product from the unit is accomplished by either side or bottom discharge, by employing pneumatic transportsystem. The CIP of such a unit can be accomplished by using stainless steel cartridgeﬁlters and an overlap gill air distributor, if desired.
11.3.2. Integration of a High-Shear Mixer and a Fluid Bed Dryer
Figures 42 and 43 show a typical integrated system, where containment is considered
for controlling dust and cross-contamination. When these two-unit operations areintegrated as a single unit, a number of points must be considered. The following is alist of some of the questions that the reader may want to consider:
1. Engineering layout and the footprint, ceiling height requirements.
2. How will the high-shear mixer be loaded—by gravity, vacuum, or
manually?

Figure 42 Integrated system. (Courtesy of the Glatt Group.)© 2005 by Taylor & Francis Group, LLC

302

Parikh and Mogavero

Figure 43 Integrated system. (Courtesy of the Glatt Group.)

3.
4.
5.
6.
7.
8.
9.
10.

How will the binder solution be prepared and delivered to the mixer?
How will the granulation end point be determined and reproduced?
How will the discharge from the high-shear mixer be accomplished?
Are the process parameters for granulation and ﬂuid bed drying established and reproducible, indicating a robust process?
How will the product, discharged from the ﬂuid bed dryer be handled?
Does it require sizing, blending with the lubricants?
Is this system dedicated for a single product or multiple products?
How will this system be cleaned?
Will the control of a process be done individually for each unit or by an
integrated control system?

For the potent compound processing, requiring high-shear granulation andﬂuid bed drying, all the questions mentioned previously must be considered. In
addition, the operator safety, special sampling valves, isolated room air handlingsystems, and CIP must be considered. Such an integrated system can be dedicatedfor a single product.
Figure 44 shows a system where a potent compound is processed. After the raw
materials are dispensed, operating personnel do not have to handle the product during the granulation drying steps. Such a system is costly and does require an enormous amount of time for process and cleaning validation.
The ﬂuid bed process, like other granulation techniques requires understandingof the importance of characterization of the raw materials, especially of a drug substance, the process equipment, limitations of the selected process, establishment of
in-process control speciﬁcations, characterization of the ﬁnished product, and clean© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

303

Figure 44 Integrated system for potent compound. (Courtesy of Niro Pharma Systems.)

ing and process validation. It is equally important that the formulation and development scientists do not lose sight of the fact that the process being developed will begoing on the production ﬂoor and should be robust enough.

ACKNOWLEDGMENTMy sincere thanks to Ms. Christine Budny, my assistant at Synthon Pharmaceuticals
Inc., for her help in preparing this chapter.
© 2005 by Taylor & Francis Group, LLC

304

Parikh and Mogavero

REFERENCES
1. Kunii D, Lvenspiel O. Fluidization Engineering. New York: John Wiley & Sons, Inc.,
1968.
2. Wurster DE. J Am Pharm Assoc Sci Ed 1960; 49:82.
3. Wurster DE. J Am Pharm Assoc Sci Ed 1959; 48(8):451–454.
4. Scott MW, Liberman HA, Rankell AS, Battista JV. J Pharm Sci 1964; 53(3):314–319.
5. Rankell AS, Scott MW, Liberman HA, Chow FS, Battista JV. J Pharma Sci 1964;
53(3):320.
6. Contini S, Atasoy K. Pharm Ind 1966; 28:144–146.
7. Wolf G. Drugs Made Germany 1968; 11:172–180.
8. Liske T, Mobus W. The manufacture and comparative aspects of ﬂuidized layer spraygranulation. Drugs Made Germany 1968; XI:182–189.
9. Sherrington PJ, Oliver R. Granulation monograph (chapter 3). In: Goldberg AS, ed.
Powder Science and Technology. London: Heyden, 1981.
10. Pietch WB. In: Fayed ME, Otten L, eds. Handbook of Powder Science and Technology.
New York: Van Nostrand Reinhold, 1984.
11. Hersey JA. Fluidized bed technology—an overview. Int J Pharm Tech Prod Manuf
1981; 2(3):3–4.
12. Thiel WJ. The theory of ﬂuidization and application to the industrial processing ofpharmaceutical products. Int J Pharm Tech Prod Manuf 1981; 2(5):5–8.
13. Thiel WJ. Solids mixing in gas ﬂuidized beds. Int J Pharm Tech Prod Manuf 1981;
2(9):9–12.
14. Littman H. An overview of ﬂow in ﬂuidized beds. Pharm Technol 1985; 9(3):48.
15. Whitehead AB. Behavior of ﬂuidized bed systems. Pharm Technol 1981; 2(13).
16. Story MJ. Granulation and ﬁlm coating in the ﬂuidized bed. Pharm Technol 1981;
2(19):19–23.
17. Aulton MJ, Banks M. Fluidized bed granulation; factors inﬂuencing the quality of the
product. Pharm Technol 1981; 2(24):24–27.
18. Kulling W, Simon EJ. Fluid bed technology applied to pharmaceuticals. Pharm Technol
1980; 4(1):79–83.
19. Gomezplata A, Kugelman AM. Processing systems. In: Marchello JM and Gomezplata A,
eds. Gas–Solid Handling in the Process Industries, Chemical Processing and Engineering
Vol. 8. New York: Marcel Dekker, Inc., 1976:chap 4.
20. E. Räsänen et al. AAPS PharmSci, 3(3) Abstract, AAPS Annual Meeting 2001.
21. Parikh DM. Airﬂow in batch ﬂuid-bed processing. Pharm Technol 1991; 15(3):100–110.
22. Row PN, et al. Trans Inst Chem Eng 1965; 32T:271.
23. Davis L, et al. Trans Inst Chem Eng 1966; 44T:293.
24. Gorrodnichev VI, et al. Pharm Chem J (USSR) 1974; 8:298.
25. Thiel WJ. The theory of ﬂuidization and application to the industrial processing ofpharmaceutical products. Int J pharm Tech Prod Manuf 1981; 2(5).
26. Zenz FA. In: Kirk-Othmer, ed. Fluidization: Encyclopedia of Chemical Technology,
Vol. 10, 3rd ed. New York: Wiley-Interscience Publication, 548–581.
27. Ennis BJ, Tardos GI, Pfeffer R. A micro-level–based characterization of granulation
phenomena. Powder Technol 1991; 65:257–272.
28. Osborne BG, Fearn T, Hindle PH. In: Practical NIR Spectroscopy with Applications inFood and Beverage Industry Analysis. 2nd ed. Harlow, U.K.: Longman, 1993:227.
29. Long GE. Spraying theory and practice. Chem Eng 1978:73–77.
30. Masters K. Spray Drying, an Introduction to Principles, Operational Practice andApplication. 2nd ed. New York: John Wiley & Sons Inc., 1976.
31. Japanese Patent Application 61–259696, 1986.
32. Swiss Patent 0176/93, 1993, U.S. Patent 5,444,892, 1995, European Patent 0572356A1.
33. Guidance for Industry, Part 11, Electronic Records; Electronic Signatures—Scope andApplication, February 2003.
© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

305

34. Newitt DM, Conway-Jones JM. A contribution to the theory and practice of granulation. Int J Pharm Tech Prod Manuf 1958; 36:422.
35. Record PC. A review of pharmaceutical granulation technology. Int J Pharm Tech Prod
Manuf 1980; 1:32.
36. Rumpf H. In: Krepper W, ed. Agglomeration. New York: Interscience, 1962:374.
37. Tardos GI, Khan MI, Mort PR. Critical parameters and limiting conditions in binder
granulation of ﬁne powders. Powder Technol 1997; 94:245–258.
38. Iveson SM. Granule coalescence modeling: including the effects of bond strengthening
and distributed impact separation forces. Chem Eng Sci 2001; 56:2215–2220.
39. Schaefer T, Worts O. Control of ﬂuidized bed granulation I. Effects of spray angle, nozzle height and starting materials on granule size and size distribution. Arch Pharm
Chem Sci Ed 1977; 5:51–60.
40. Smith PJ, Nienow AW. Chem Eng Sci 1983; 38(8):1223–1231, 1323–1240.
41. Aulton ME, Banks M. Int J Pharm Tech Prod Manuf 1981; 2(4):24–29.
42. Maroglou A, Nienow AW. 4th Symposium on Agglomeration, Toronto, Canada, Iron
& Steel Society Inc., June 1985:465–470.
43. Maroglou A, Nienow AW. Fluidized bed granulation technology and its application totungsten carbide. Powder Metall 1986; 29(4):195–291.
44. McCabe WL, Smith JC. In: Lachman L, Liberman HA, Kanig JL, eds. Unit Operationsof Chemical Engineering. New York: McGraw-Hill, 1956:Inc.
45. Green Don W, ed. In: Perry’s Chemical Engineer’s Handbook. New York : McGrawHill, Inc., 1984:section 20.
46. Rankell RS, Liberman HA, Schiffman RF. Drying. In: The Theory and Practice ofIndustrial Pharmacy. 3rd ed. Philadelphia, PA: Lea & Feabiger, 1986.
47. Schaefer T, Worts O. Control of ﬂuidized granulation III, effects of the inlet air temperature, and liquid ﬂow rate on granule size and size distribution. Control of moisture
content of granules in the drying phase. Arch Pharm Chem Sci Ed 1978; 6(1):1–13.
48. Gao JZH, et al. AAPS PharmSci, 1(4) Abstract (Tech Note), AAPS Annual Meeting
2000.
49. Thurn U. Dissertation, Eidgenossischen Technischen, Hochschule, Zurich, 1970.
50. Liske T, Mobus W. Drugs Made Germany 1968; 11(4):182–189.
51. Schaefer T, Worts O. Control of ﬂuidized bed granulation, I. Effects of spray angle,
nozzle height and starting materials on granule size and size distribution. Arch Pharm
Chem Sci Ed 1977; 5:51–60.
52. Schaefer T, Worts O. Control of ﬂuidized bed granulation V, factors affecting granule
growth. Arch Pharm Chem Sci Ed 1978; 6:69–82.
53. Ormos Z, Pataki K. Hung J Ind Chem 1979; 7:89–103.
54. Ormos Z, Pataki K. Hung J Ind Chem 1979; 7:105–117.
55. Banks M. Ph.D. Thesis, C.N.A.A., Leicester Polytechnic, 1981.
56. Galmen MJ, GreerW. Paper 2. Fluid Technology and Pharmaceutical Manufacturing
International Conference, 1982.
57. Aulton ME. Paper 3. Fluid Technology and Pharmaceutical Manufacturing International Conference, Powder Advisory Center, London, 1982.
58. Veillard M, et al. Int J Pharm Tech Prod Manuf 1982; 3(4):100–107.
59. Georgakopoulos PP, et al. Pharmazie 1983; 38(4):240–243.
60. Jinot JC, et al. STP Pharm 1986; 2(13):126–131.
61. Shinoda A, et al. Yakuzaigaku 1976; 36(2):83–88.
62. Aulton ME, et al. J Pharm Pharmacol 1977; 29(suppl):59.
63. Schepky G. Acta Pharm Technol 1978; 24(3):185–212.
64. Aulton ME, et al. Proceedings of the International Conference on Powder Technology
in Pharmacy, Powder Advisory Center, Basel, Switzerland, June 1979.
65. Kocova El-Arini S, et al. Drugs Made Germany 1983; 26(4):205–211.
66. Davies WL, Gloor WT. J Pharm Sci 1972; 61(4):618–622.
67. Rouiller M, et al. Acta Pharm Technol 1975; 21(2):129–138.
© 2005 by Taylor & Francis Group, LLC

306

Parikh and Mogavero

68. Schaefer T, Worts O. Control of ﬂuidized bed granulation II, estimation of droplet sizeof atomized binder solution. Arch Pharm Chem Sci Ed 1977; 5:178–193.
69. Ormos Z, et al. Hung J Ind Chem 1979; 7:131–140.
70. Ormos Z, et al. Hung J Ind Chem 1979; 7:141–151.
71. Ormos Z, et al. Hung J Ind Chem 1979; 7:153–163.
72. Ormos Z, et al. Hung J Ind Chem 1979; 7:221–235.
73. Kocova El-Arini S. Pharm Ind 1981; 43(7):674–679.
74. Jager KF, Bauer KH. Acta Pharm Technol 1984; 30(1):85–92.
75. Nouh ATI. Pharm Ind 1986; 48(6):670–673.
76. Alkan H, et al. Doga Tu J Med Pharm 1987; 11(1):1–7.
77. Bank A, et al. Proc 2nd Conf Appl Phys Chem 1971; 2:687–692.
78. Davies WL, Gloor WT. J Pharm Sci 1973; 62(1):170–172.
79. Ormos Z, et al. Hung J Ind Chem 1973; 1:307–328.
80. Ormos Z, et al. Hung J Ind Chem 1973; 1:463–474.
81. Johnson MCR, et al. J Pharm Pharmacol 1975; suppl:80.
82. Schaefer T, Worts O. Control of ﬂuidized bed granulation IV. Effects of binder solution
and atomization on granule size and size distribution. Arch PharmChem Sci Ed 1978;
6:14–25.
83. Aulton ME, et al. Mfg Chem Aerosol News 1978; 12:50–56.
84. Gorodnichev VI, et al. Pharm Chem J (USSR) 1980; 14(10):72–77.
85. Ceschel GC, et al. II Farm Ed Prat 1981; 36(6):281–293.
86. Rangnarsson G, et al. Int J Pharm 1982; 12:163–171.
87. Meshali M, El-Banna HM, El-Sabbagh H. Pharmazie 1983; 38(5):323–325.
88. Hajdu R, Ormos Z. Hung J Ind Chem 1983; 12:425–430.
89. Devay A, et al. Acta Pharm Technol 1984; 30(3):239–242.
90. Alkan MH, Yuksel A. Drug Dev Ind Pharm 1986; 12(10):1529–1543.
91. Hontz J. Assessment of Selected Formulation and Processing Variables in Fluid Bed
Granulation, Ph.D. Thesis, University of Maryland, Baltimore, MD, 1987; Dissertation
Abs Int 1987; 6:1655-B.
92. Wan LSC, Lim KS. STP Pharm 1988; 4(7):560–571.
93. Wan LSC, Lim KS. STP Pharm 1989; 5(4):244–250.
94. Sheskey P, Keary C, Inbasekaran P, Deyarmond V, Balwinski K. Foam technology: thedevelopment of a novel technique for the delivery of aqueous binder systems in highshear and ﬂuid-bed wet-granulation applications. Poster at AAPS Annual Meeting,Oct 26–30, 2003.
95. Dahl TC, Bormeth AP. Naproxen controlled release matrix tablets: ﬂuid bed granulation feasibility. Drug Dev Ind Pharm 1990; 16(4):581–590.
96. Wan Lucy SC, Heng Paul WS, Muhuri G. Incorporation and distribution of a low dose
drug in granules. Int J Pharm 1992; 88:159–163.
97. Higashide F, Miki Y, Nozawa Y, Ishibashi K. Dependence of drug content uniformity
on particle sizes in ﬂuidized bed granulation. Pharm Ind 1985; 47(11):1202–1205.
98. Davies WL, Gloor WT Jr. Batch production of pharmaceutical granulationin ﬂuidized
bed II: effects of various binders and their concentrations on granulations and compressed tablets. J Pharm Sci 1972; 61:618.
99. Davies WL, Gloor WT Jr. Batch production of pharmaceutical granulation in ﬂuidized
bed III: binder dilution effects on granulation. J Pharm Sci 1973; 62:170.
100. Seo A, Holm P, Schaefer T. Effects of droplet size and type of binder on the agglomerate growth mechanisms by melt agglomeration in a ﬂuidized bed. Eur J Pharm Sci 2002;
16:95–105.
101. Rawley FA. Effects of the bag shaking cycle on the particle size distribution of granulation. Pharm Technol 1989; 13(9):78–82.
102. Davies WL, Gloor WT Jr. Batch production of pharmaceutical granulation in ﬂuidized
bed I: effects of process variables on physical properties of ﬁnal granulation. J PharmSci 1971; 60(12):1869–1874.
© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

307

103. Workman J Jr. A review of process near infrared spectroscopy: 1980–1994. J. Near
Infrared Spectrosc 1993; 1:221–245.
104. U.S. Patent USP XXVII 2004.
105. Near Infra Red Spectrometry. European Pharmacopoeia June 2004:59.
106. Choppin G, Buijs K. Near infrared studies of structure of water-II. Ionic solutions.
J Chem Phys 1963; 39:2042–2050.
107. Osborne BG, Fearn T, Hindle PH. In: Practical NIR Spectroscopy with Applications inFood and Beverage Industry Analysis, 2nd ed. Harlow, U.K.: Longman, 1993.
108. Fong A, Hieftje GM. Near infrared measurement of relative and absolute humidity
through detection of water adsorbed on a silica gel layer. Anal Chem 1995; 67:
1139–1146.
109. Siesler HW, Ozaki Y, Kawata S, Heise HM. Near-Infrared Spectroscopy: Principles,
Instruments and Applications. Weinheim, Germany: Wiley, 2002.
110. Wetzel DL. Near infrared reﬂectance analysis: sleeper among the spectroscopic techniques. Anal Chem 1983; 55(12):1165A–1175A.
111. McDonald BF, Pebble KA. Some application of near-infrared reﬂectance analysis in thepharmaceutical industry. J Pharm Biomed Anal 1993; 11(11–12):1077–1085.
112. Sinsheimer J, Poswalk N. Pharmaceutical applications of the near infrared determination of water. J Pharm Sci 1968; 57:2007–2010.
113. Wetzel DL. Near infrared reﬂectance analysis: sleeper among the spectroscopic techniques. Anal Chem 1983; 55(12):1165A–1175A.
114. Workmann JJ. Review of process and non-invasive near-infrared and infrared spectroscopy 1193–1999. Appl Spectrosc Rev 1999; 34:1–89.
115. Callis J, Illman D, Kowalski B. Process analytical chemistry. Anal Chem 1987;
59:624A–637A.
116. Beebe K, Blaser W, Bredeweg R, Chauvel J, Harner R, LaPack M, Leugers A, Martin D,
Wright L, Yalvac E. Process analytical chemistry. Anal Chem 1993; 65:199R–216R.
117. Blaser W, Bredeweg R, LaPack M, Leugers A, Martin D, Pell R, Workman J, Wright L.
Process analytical chemistry. Anal Chem 1995; 67:47R–70R.
118. Hassel D, Bowman E. Process analytical chemistry for spectroscopists. Appl Spectrosc
1998; 52:18A–29A.
119. Workman J Jr, Veltkamp D, Doherty S, Anderson B, Creasy K, Koch M, Tatera J,
Robinson A, Bond L, Burgess L, Bokerman G, Ullman A, Darsey G, Mozayeni F,
Bamberger J, Greenwood M. Process analytical chemistry. Anal Chem 1999;
71:121R–180R.
120. Brittain H. Methods for the characterization of polymorphs and solvates in polymorphism in pharmaceutical solids. In: Brittain H ed. 1st ed. New York: Marcel Dekker Inc.,
1999:227–278.
121. Frake PD, Greenhlgh SM, Grierson JM, Hempenstall, Rudd DR. Process control andend-point determination of ﬂuid bed granulation by application of near-infrared spectroscopy. Int J Pharm 1997; 151:75–80.
122. Rantanen JO, Antikanen JP, Mannermaa, Yliuusi J. Use of near-infrared reﬂectancemethod for measurement of moisture content during granulation. Pharm Dev Technol
2000; 5(2):209–217.
123. Rantanen J, Lehtola S, Rämet P, Mannermaa JP, Ylirussi. On-line monitoring of moisture content in an instrumented ﬂuidized bed granulator with multi-channel NIR moisture sensor. Powder Technol 1998; 99:163–170.
124. Andersson M, Folestad S, Gottﬁres J, Johansson MO, Josefson M, Wahlund KG.
Quantitative analysis of ﬁlm coating in a ﬂuidized-bed process by in-line NIR spectroscopy and multivariate batch calibration. Anal Chem 2000; 72:2099–2108.
125. Vazquz ER. Optimization of Drying-End-Points Measurements for the Automation of
a Fluidized-Bed Dryer Using FT-NIR Spectroscopy. M.S. Thesis, University of Puerto
Rico, 2004.

© 2005 by Taylor & Francis Group, LLC

308

Parikh and Mogavero

126. Rantanen J, Känsäkoski M, Tenhunen J, Lehtonen S, Rajalahti T, Mannermaa J,
Yliruusi J. Next generation ﬂuidized bed granulator automation. AAPS PharmSciTech
2000; 1(2):article 10.
127. Rantanen JA, Jørgensen E.Räsänen,Luukkonen P, Airaksinen S, Raiman J, Hänninen K,
Antikainen O, Yliruusi J. Process analysis of ﬂuidized bed granulation. AAPS Pharm
SciTech 2001; 2(4):article 21.
128. Rantanen J, Sampsa JL, Osmo KA, Jukka-Pekka M, Olii ES, Jouko KY. Visualizationof ﬂuid bed granulation with self organizing maps. J Pharm Biomed Anal 2001;
24(3):343–352.
129. Laitinen N, Antikainen O, Airaksinen S, Yliuusi J. At-line particle size analysis with anovel optical technique during a ﬂuidized-bed granulation process. Poster at AAPS
Annual Meeting, 2002.
130. Jha BK, Tambe SS, Kulkarni BD. Estimating diffusion coefﬁcients of a micellar systemusing an ANN. J Coll Interface Sci 1995; 170:392–398.
131. Bourquin J, Schmidi H, Van Hoogevest P, Leunberger H. Basic concepts of ANN modeling in the application to pharmaceutical development. Pharm Dev Technol 1997;
2(2):95–109, 111–121.
132. Watano S, Takashima H, Miyanami K. Control of moisture content in ﬂuidized bed
granulation by neural network. J Chem Eng Jpn 1997; 30(2):223–229.
133. Leane MM, Cumming I, Corrigan OI. The use of artiﬁcial neural networks for the selection of the most appropriate formulation and processing variables in order to predict
the in vitro dissolution of sustained release minitabs. AAPS PharmSciTech 2003;
4(2):article 26.
134. Vandel DA, Davari, Famouri P. Modeling of ﬂuidized bed neural networks. Proceedings of 32nd IEEE SSST, Tallahassee, FL, March 2000, FAMU-FSU.
135. Quantrille TE, Liu YA. In: Artiﬁcial Intelligence in Chemical Engineering. San Diego:
Academic Press, 1991.
136. AAPS/FDA. Scale-up of Oral Solid Dosage Forms, December 11–13, 1991.
137. Food and Drug Administration. Immediate Release Solid Dosage Forms. Scale-up andPost Approval Changes: Chemistry, Manufacturing and Control, In-vitro Dissolution
Testing and In-Vivo Bioequivalence Documentation. Rockville, MD: FDA Center for
Drug Evaluation and Research, November 30, 1995.
138. Gore AY, McFarland DW, Batuyios NH. Fluid bed granulation: factors affecting theprocess in laboratory development and production scale-up. Pharm Technol 1985;
9(9):114.
139. Bonck JA. Spray granulation. Presented at the AIChE Annual Meeting, November,
1993.
140. Jones DM. Factors to consider in ﬂuid bed processing. Pharm Technol 1985; 9(4):50.
141. Matharu AS, Patel MR. A new scale-up equation for ﬂuid bed processing. Poster at
AAPS Annual Meeting, 2003.
142. Rambali B, Baert L, Massart DL. Scaling up of the ﬂuidized bed granulation process.
Int J Pharm 2003; 252(1–2):197–206.
143. Simon EJ. Fluid bed processing of bulk solids. In: Third International Powder Technology and Bulk Solids Conference, February 20, 1975. Harrogate, U.K.: Heyden & Sons
Publisher, 1975:63–73.
144. Kulling W. Method and Apparatus for Removing a Vaporized Liquid from Gas for Use
in a Process Based on the Fluidized Bed Principle. U.S. Patent 4,145,818, March 27,
1979.
145. ATEX Directive 94/9/EC of the European Parliament and the Council, March 23,
1994.
146. Parikh DM. Fluid bed processing in the 1990s. In: Tabletting and Granulation Yearbook. Pharm Technol 1996; suppl:40–47.
147. International Patent WO 93/08923, 1993.
148. International Patent WO 95/20432, 1995.
© 2005 by Taylor & Francis Group, LLC

Batch Fluid Bed Granulation

309

149. Glatt Brochure on STRATOS2.
150. Walter KT, et al. Fluidized bed precision granulation with real time process determination. Poster at AAPS Annual Meeting, 2003.
151. Doelling MK, et al. The development of a microwave ﬂuid bed processor I: construction
and qualiﬁcation of a prototype laboratory unit. Pharm Res 1992; 9(11):1487–1492.
152. Doelling MK, Nash RA. The development of a microwave ﬂuid bed processor II: drying
performance and physical characteristics of typical pharmaceutical granulations. Pharm
Res 1992; 9(11):1493–1501.
153. Luy B, Hirschfeld P, Leuenberger H. Granulation and drying in vacuum ﬂuid-bed system. Pharm Ind 1989; 51:89.
154. U.S. Patent 3,671,296, June 20, 1977.
155. U.S. Patent 4,034,126, July 5, 1977.
156. U.S. Patent 4,542,043, Sep 17, 1985.
157. Jäger KF, Bauer KH. Effect of material motion on agglomeration in the rotary
ﬂuidized-bed granulator. Drugs Made Germany 1982; 25:61–65.
158. U.S. Patent 4,740,390.
159. Türkoglu M, He M, Sakr A. Evaluation of rotary ﬂuidized-bed as a wet granulationequipment. Eur J Pharm Biopharm 1995; 41(6):388–394.
160. Li Shun P, Kowarski CR, Feld KW, Grim WM. Recent advances in microencapsulation technology and equipment. Drug Dev Ind Pharm 1988; 14(2,3):353–376.
161. Robinson RL, Hollenbeck G. Manufacture of spherical acetaminophen pellets: comparison of rotary processing with multiple-step extrusion and spheronization. Pharm Technol 1991; 15(5):48–56.
162. Parikh DM. Layering in rotary ﬂuid bed a unique process for the production of spherical pellets for controlled release. Interphex, New York, May 18, 1991.
163. Hileman GA, Sarabia RE. Manufacture of immediate and controlled release spheres ina single unit using ﬂuid bed rotor insert. Poster PT 6167 at AAPS Annual Meeting,1992.
164. Iyer RM, Augsburger LL, Parikh DM. Evaluation of drug layering and coating: effectof process mode and binder level. Drug Dev Ind Pharm 1993; 19(9):9891–9998.
165. U.S. Patent 5,132,142, 1992.
166. Korakianti ES, Rekkas DM, Dallas PP, Choulis NH. Optimization of the pelletization
process in a ﬂuid bed rotor granulator using experimental design. AAPS PharmSciTech
2000;1(4):article 35.
167. Piśek R, Planinśek O, Tuś M, Srčič S. Inﬂuence of rotational speed and surface of rotating disc on pellets produced by direct rotor pelletization. Pharm Ind 2000; 62:312–319.
168. Vertommen J. Pelletization in a rotary processor using the wet granulation technique.
In: ACTA Biomedica Lovaniesia Leuven. Belgium Leuven University Press, 1998:166.

© 2005 by Taylor & Francis Group, LLC

10Single-Pot Processing
Harald Stahl
Niro Pharma Systems, Muellheim, Germany

Griet Van VaerenberghCollette N.V., Wommelgren, Belgium

1. INTRODUCTION
Single-pot processing was developed to provide the means for mixing, granulating,drying, and blending pharmaceutical granulations in a single apparatus. Althoughequipment design varies from manufacturer to manufacturer (Figs. 1–3), this category of processors consists of a high- or low-shear mixer–granulator (similar to conventional granulators) and outﬁtted with a variety of drying options. Initially,
vacuum was combined with a heat-jacketed bowl to provide the means for drying
in the single pot. Today, processors are available that provide vacuum drying withmicrowaves or that percolate gas under low pressure into the vacuum chamber(i.e., processing bowl). Another very interesting improvement is the use of swinging
processing bowls (1).
Single-pot processors for the pharmaceutical industry have been available foryears. They received renewed interest in the mid-1980s when microwaves were
coupled with vacuum to enhance the drying operation. Microwaves applied to drying pharmaceutical granulations became synonymous with single-pot processing,and there was anticipation that this technology would eventually become the norm
for granulation processing. Several major pharmaceutical companies purchased production-scale units following successful trials conducted at vendors’ pilot facilities.
In the ensuing years, when the technology did not become as popular as expected,
there were rumors that microwave systems could not be validated and suffered fromexcessive regulatory hurdles. The reality is neither, and single-pot technology has
continued to evolve during the last decade. It has de-emphasised its association withmicrowave drying while continuing to demonstrate its appropriate role in granulation technology (2).
In a production setting, single-pot processing may offer a number of advantages. By integrating granulating and drying capabilities into a single unit, capital
investment in equipment and good manufacturing practice ﬂoor space may be lower
than the other alternatives. The number of material-handling steps is decreased; consequently, the total processing time may be shorter while maintaining a high yield
311© 2005 by Taylor & Francis Group, LLC

312

Stahl and Van Vaerenbergh

Figure 1 UltimaProTM 600 microwave/vacuum single-pot processor with swinging bowl.
(Courtesy of Collette NV, Belgium.)and keeping production support to a minimum. Environmental variables, such as
humidity, are eliminated from the manufacturing process, which may offer advantages for processing moisture-sensitive formulations. State of the art is to outﬁt a single-pot processor with clean-in-place systems, thereby enhancing operator safety byminimizing exposure to the product both during manufacturing and during cleaning

Figure 2 L.B. Bohle single-pot processor. (Courtesy of the L.B. Bohle Group, Germany.)© 2005 by Taylor & Francis Group, LLC

Single-Pot Processing

313

Figure 3 Zanchetta single-pot processor. (Courtesy of Zanchetta, Italy.)(3). Requirements for solvent recovery systems are lower for single-pot processors
compared with ﬂuid-bed driers. Single-pot processors outﬁtted with vacuum are
attractive for evaporating events that are explosive or for containing drug substanceswith low-exposure limits.
The versatility and compactness of small-scale (3–25 L) single-pot processors
also make the technology attractive for development and pilot laboratory facilities.
Within the last few years, equipment manufacturers began offering single-pot processors that can accommodate the batch sizes required during early development(0.3 g–10 kg). The processors can be used as mixer–blenders for direct compression
formulations, or as mixer–granulators to prepare wet granulations for ﬂuid-bed drying, or utilized for their full range of capabilities as a single-processing unit for all thesteps required for granulation preparation. Some vendors offer the option of upgrading their small-scale processors. For example, a user can initially purchase a singlepot processor with vacuum-drying capabilities and add a microwave drying system
at a later time. Consequently, single-pot processors should be given strong consideration when equipping a development laboratory or a pilot plant intended to offer
a variety of processing options to the pharmaceutical formulator.
The following text is intended to expose the reader to the drying methods, thecapabilities, and the applications of single-pot processing to pharmaceutical granulations. Fluid-bed technology, which can also be used to mix, to granulate, and fordrying alternative wet granulation technologies in a single unit, will not be addressedin this chapter because it is discussed elsewhere in this book.
2. TYPICAL SINGLE-POT PROCESSThe steps and sequence of manufacturing pharmaceutical granulations using singlepot processing are the same as those that use alternative technologies, except that© 2005 by Taylor & Francis Group, LLC

314

Stahl and Van Vaerenberghseveral of the steps are performed in the same product chamber. The majority of production installations make use of its mixing, granulating, and drying capabilities during the processing of a single batch. Important to note is the absence of a milling stepin between granulation and drying. The advantage of a reduced number of process
steps is obvious while the drawback is that there is no possibility of breaking lumps
generated during granulation. Single-pot operations therefore require excellent control of the granulation to prevent the formation of oversized material.

2.1. Dry Mixing
Powders are loaded into the single pot either manually (for development-and pilotscale units) or by a conveying system (for production-scale units). Vacuum pump(s)used for the drying operation can also be used to charge the processor. Pneumaticand vacuum-conveying systems contribute to minimizing operator exposure to thedrug product. The powders are mixed in the dry state until the desired degree of uniformity is obtained. Depending on the geometry of the processing bowl and the efﬁciency of its mixing blades, optimal mixing for most processors generally occurs
when the bowl is charged to 50–75% of its capacity. Batch size, impeller speed,
and mixing time are the variables that affect the desired degree of blend homogeneity
before the addition of the binder solution.
2.2. Addition of Binder Solution
Once dry mixing is completed, the binder solution is added through a spray lance
connected to a solvent delivery system (such as a pressure pot or peristaltic pump).
For highly viscous binder solutions it is of advantage to use the vacuum system of
the processor for sucking into the processor. Because the single-pot processor isoperating as a granulator at this point, all variables considered during the manufacture of wet granulations in conventional high-or low-shear mixer–granulators areapplicable. Those variables include the rate of binder action, droplet size, and spraypattern (the last two being determined by the selection of the spray nozzle and the
distance between the nozzle tip and granulation bed). The speed of the main impeller
and the granulating tool (e.g., high-intensity chopper bar), as well as the jacket temperature should also be controlled during binder addition.
2.3. Wet Massing
Following binder addition, additional energy may be imparted to the granulation
until the desired consistency is obtained. The speeds of the main impeller and granulating tool, wet-massing time, and jacket temperature are variables that can affectthe physical attributes of the granulation. Like the bowl shape the impeller design
will also affect the amount of shear imparted to the granulation. Granulation end
point may be controlled by process time, temperature of the product bed, and theenergy consumption or torque of the main impeller.
2.4. Drying
After granulation, the material is dried using one of three approaches: (a) vacuum
drying, (b) gas-assisted vacuum drying, or (c) microwave vacuum drying. Details© 2005 by Taylor & Francis Group, LLC

Single-Pot Processing

315of each drying method are summarized in Drying Methods for Single-Pot
Processors. The product bed is usually stirred at low intensity during the drying process to facilitate solvent removal and promote uniform drying, as well as to prevent
caking of the granulation on the chamber’s walls. Agitation may be applied byslowly tilting the bowl or operating the impeller at low speed, either continuously
or intermittently, throughout the drying stage. Caution must be exercised to avoid
granule breakdown during drying, which may result in unfavorable compression
characteristics (4). Variables for vacuum drying include the level of vacuum maintained in the bowl, the jacket temperature, and the degree of agitation. In addition
to the parameters listed for vacuum drying, gas-assisted vacuum drying must also
consider the type of drying gas used and its rate of delivery. When microwave
vacuum drying is used, all of the variables used for vacuum drying are applicable,
as well as the level of microwave power used to dry the granulation. If yield is ofgreater importance than process time, a very interesting process option is to follow
with the wall temperature very closely the product temperature and use as a sourceof drying energy only the introduced microwave energy. This mode of operation
minimizes the amount of material sticking to the walls for the price of a prolonged
drying operation resulting in a reduced throughput. This option is of special interestfor the processing of highly expensive materials.
If required, cooling can be conducted at the conclusion of the drying operation.
The heated water or steam in the bowl jacket, which supplied conductive heat during
the drying process, can be replaced with a glycol–water solution to provide a contact
surface as low as 10 C. Another approach to cool the granulation is by purging
a cooling gas into the single pot while agitating the granulation bed.

2.5. Sizing and Lubrication
Once the granulation is dried, it is usually necessary to size it. This may be accomplished by discharging the material through an in-line mill into a receiving vessel,
where it may be blended with any remaining excipients (e.g., lubricant and ﬂavors).
This process design maintains the containment beneﬁts of the single-pot process.
Alternatively, the remaining excipients may be added to the single-pot processor
and blended with the granulation before discharging and milling. This approachrequires that the lubricant be adequately distributed during milling and materialtransfer during the compression operation.

3. DRYING METHODS FOR SINGLE-POT PROCESSORS
3.1. Conductive Drying
The bowls of single-pot processors are generally jacketed for temperature control,
which minimizes condensation of the granulating solvent and assists in solvent evaporation during drying. As a result, conductive heating provided by the heatjacketed lid and the walls of the single pot contributes to the drying process. Its
dependence on the transfer of heat through pharmaceutical powders, which are poor
conductors of heat, prevents its use as the sole mode of drying in single-pot processors. Eq. 1 addresses the conductive drying component for solvent removal.
© 2005 by Taylor & Francis Group, LLC

316

Stahl and Van VaerenberghHeat transfer from the vessel walls to the granulation bed is governed by
Q ¼ hSDT

ð3:1Þ

where Q ¼ the energy exchange, h ¼ the exchange coefﬁcient, S ¼ the contact surfaceof the heated wall, and DT ¼ the temperature difference between the contact walland the granulation.
The rate of drying can be facilitated either by increasing the contact area
between the granulation and the vessel walls (which can be achieved by agitating
the product or utilizing a tilting bowl) or by maximizing the temperature differential
between the vessel walls and product (either through increasing the jacket temperature or through maintaining the temperature of the product as low as possible during
processing).
Eq. 2 is a simple relation that may be of some value for the scaling-up of processes using conductive heating (5)tb =ta ¼ ðA=V Þa ðA=V Þbð3:2Þ

where t ¼ drying time, A ¼ heat transfer surface (m2), V ¼ vessel working volume(m3), a ¼ refers to pilot scale, and b ¼ refers to production scale.
This relation accounts for the ratio of the surface area of the jacketed bowl andthe volume of the product requiring drying.

3.2. Vacuum Drying
Single-pot processors using vacuum drying may be considered if the product must be
dried at low temperature (<40 C), if solvent recovery is required, or if the potential
for explosion is high. A vacuum is maintained within the vessel, thereby lowering
the temperature at which the granulating solvent evaporates. Because vapors are
removed from the processing bowl, vacuum drying provides a convenient means
for solvent recovery.
De Smet (6) has discussed the theory, advantages, and limitations of vacuum
drying. Aqueous granulations require a large amount of energy during drying, whichis generally supplied by the transfer of heat through conduction from the jacketedbowl to the product. The amount of energy required for water removal is dependent
on the level of vacuum applied to the vessel and the osmotic pressure of dissolved
substances. As additional material dissolves in the water, the osmotic pressure
increases and additional energy is necessary to drive off the water. Therefore, as
the material becomes drier, the amount of energy necessary to evaporate the water
increases, and the rate of evaporation slows down. Processing times in vacuum driers
are often long, owing to the limited contact of the granulation with the heat from thejacketed walls, and the slow rate of evaporation of the solvent from the interior of
the granules.
The drying rate of the vacuum component is dependent on the following relation:
V ¼ ksDP

ð3:3Þ

where V ¼ evaporation rate, k ¼ rate coefﬁcient, s ¼ total surface of granules,
and DP ¼ the vapor pressure difference between the granules and the surrounding
space.
© 2005 by Taylor & Francis Group, LLC

Single-Pot Processing

317

Figure 4 Typical curve for vacuum drying. (Courtesy of Manufacturing Chemist).

The rate of drying can be facilitated by increasing the level of vacuum (i.e.,decreasing the pressure within the bowl) to increase the differential between granuleand bowl vapor pressure. Figure 4 is a typical drying curve for a vacuum-drying
process. When moisture content in the granulation is high, the rate of drying isconstant because evaporation of solvent from the product surface readily occurs.
As the level of moisture on the granule surface decreases, water must migrate fromthe interior of the granule before evaporation. As a result, the rate of evaporation
progressively decreases.
During vacuum-drying processes, one should be aware of various problems
that could arise. For example, granule damage may occur owing to excessive
attrition as the bed is agitated during drying. Vacuum systems should contain adequate ﬁltering or blowback to prevent the loss of granulation ‘‘ﬁnes’’ through thevacuum line, which may compromise the drug uniformity within the processedbatch.
A condenser positioned between the processor and vacuum pump, should
always be used, especially for granulations manufactured using organic solvents.
The condensate must be sufﬁciently cooled to prevent it from being released into
the atmosphere. Also, ﬁlters may become blocked owing to condensation formingon the ﬁlter or the entrapment of solid particles. Blockage of the ﬁlters reduces
the level of vacuum that can be pulled on the bowl and excessively strains the pumpitself.
3.3. Gas-Assisted Vacuum Drying
Accelerating the drying process in vacuum driers is often limited by characteristics ofthe product or equipment. Bowl temperature is generally limited by the physicochemical stability of the product, which can limit the use of higher temperatures
to expedite drying. Increasing the contact area between the product and the vessel
is difﬁcult without signiﬁcantly altering the design of the equipment. Excessive agitation of the product can lead to considerable granule attrition, which can lead to poor
granulation ﬂow and compression properties.
© 2005 by Taylor & Francis Group, LLC

318

Stahl and Van Vaerenbergh

Figure 5 Gas-assisted vacuum-drying principle. (Courtesy of Collette NV, Belgium.)Gas-assisted vacuum drying improves the efﬁciency of single-pot processorsthat use vacuum drying by continuously introducing a small stream of gas throughthe granulation to facilitate solvent removal. Drying continues to be performed atlower temperatures (compared with tray and ﬂuid-bed drying), but at shorter-processing times than vacuum drying alone.
The gas may be introduced into the unit through openings in the bottom of thevessel or through the mixing blades (Fig. 5).
Compressed air or nitrogen (mixed with or without air) is the commonly used
gas for these units. The rate of gas ﬂow and the level of vacuum applied to the bowl
can be adjusted for a speciﬁc product to produce optimal drying conditions.
The introduction of gas into a vacuum chamber facilitates the drying process
through several actions. The constant ﬂow of gas through the product improves
the transport of moisture from the product to the vacuum-solvent recovery system(7). Introducing gas into the bowl also increases the vapor pressure driving force(8). The pressure gradient across the vessel is increased, resulting in a reductionin the rate at which water molecules recombine, producing a net increase in therate of evaporation. This causes the product temperature to be reduced, which
increases the temperature differential between the granules and the bowl wall.
The gas also reduces drying time by increasing the heat transfer coefﬁcient fromthe bowl to the bed. In addition to improving the heat transport through thebed, the gas can reduce or eliminate product sticking to the sides of the vessel walls
because it improves ﬂow and dries the particle surfaces more quickly. As the vessel
wall is the only notable source of drying energy this technology is best used in thecase of:© 2005 by Taylor & Francis Group, LLC

Single-Pot Processing319

 Small batch sizes (good surface volume ratio) Heat-insensitive materials (allows to operate a higher wall temperature) Organic solvents (requires only a fraction of the energy water needs for evaporation).
Additionally, the boiling temperature corresponding to the actual vacuum levelis much lower for organic solvents than for water, generating a larger temperature
difference between product bed and vessel.

3.4. Microwave Vacuum Drying
High-shear granulators with microwave vacuum-drying capabilities provide the fastest drying rates in the family of single-pot processors. Microwave drying is based on
the absorption of electromagnetic radiation by dielectric materials, the theory ofwhich has been extensively described (9–11). Microwaves are a form of electromagnetic energy similar to radio waves, the frequencies of which fall between 300 and3000 MHz (between radio and optical waves, (Fig. 6). The two frequencies allocatedfor domestic, scientiﬁc, medical, and industrial purposes are 915 and 2450 MHz.
Pharmaceutical processors generally use 2450 MHz, because this frequency is moredesirable when used in conjunction with vacuum. Single-pot processors incorporating microwave drying are constructed of stainless steel because metal is a common
reﬂector of microwave energy and contains the energy within the processing chamber. Teﬂon is essentially inert to microwaves, making it a suitable material for components required in the processing bowl (e.g., spray lance and temperature probe).
Energy absorption of materials exposed to microwaves is described by Eq. 4(10,11):P ¼ 2pfV 2 E0 Er tan dð3:4Þ

where P ¼ the power density of the material (W/m3), f ¼ frequency (Hz), V ¼ voltage
gradient (V/m), E0 ¼ dielectric permissivity of free space (8.85  1012 F/m), Er ¼
dielectric constant of the material, and tan d ¼ loss tangent.

Figure 6 The electromagnetic spectrum.
© 2005 by Taylor & Francis Group, LLC

320

Stahl and Van Vaerenbergh

For a constant electric ﬁeld strength V the term (2pfV2E0) is constant. Therefore, the power absorbed is proportional to the term (Er tan d), called the loss factor,
which is a relative measure of how easily a material absorbs microwave energy.
Various materials commonly used in pharmaceutical formulations have low
loss factors and only absorb microwave energy at high ﬁeld strengths. Solvents usedin the granulation process (water, ethanol, isopropanol, and such), however, possesshigh loss factors relative to the pharmaceutical powders (10). The dipolar componentof the solvents couples with the high-frequency electromagnetic ﬁeld producing highheating rates for the solvent, resulting in its evaporation and subsequent removalfrom the processing chamber. Table 1 lists the loss factors for various components
in a typical pharmaceutical granulation (12).
Lucisano and Moss (13) performed a study in which a microwave drying process was conducted in two different processors, one using ﬁxed-output magnetrons
and the other using a variable-power magnetron. The unit using ﬁxed-output magnetrons had difﬁculty obtaining low moisture levels (<0.3%) because the E-ﬁeld
safety set point was exceeded when the moisture was <1%. This problem did notoccur for the unit using the variable-power magnetron because forward power was
reduced as the E-ﬁeld increased. During the late stages of drying, the unit was primarily functioning as a vacuum dryer, as the amount of microwave energy being
introduced into the bowl was minimal. Nowadays, most microwave driers use thevariable output magnetrons.
The use of vacuum during microwave drying lowers the temperature at which
the solvent volatilizes, thereby limiting the temperature to which the material is
exposed. For example, at a vacuum of 45 mbar, water-based granulations will dryat 31 C. Once most of the water is removed from the process, the temperatureof the material will rise as components in the mixture with lower loss factors start
to absorb the microwaves. If too much vacuum is applied to the system, there is apotential for granule breakdown owing to the excessive pressure between the core
and the surface of the granules. Microwaves are typically applied in a vacuum rangeof 30–100 mbar. Introducing microwave into a vacuum <30 mbar risks ignition of
the surrounding atmosphere, a condition known as ‘‘arcing.’’
Control of the drying process is achieved through the simultaneous measurement of product temperature, forward power, and reﬂected power. Figure 7 depicts
the level of microwave forward power, microwave reﬂected power, and product temperature at various times during the drying process. During the initial stage, the product temperature remains relatively constant as the free solvent is preferentially
evaporated, and the reﬂected power remains relatively low. The amount of vacuum
applied to the bowl, and to a lesser extent the bowl jacket temperature, will affect theactual product temperature observed. As drying progresses at a constant rate of forward power, the amount of absorbed energy decreases as the material dries, thereby
increasing the amount of free energy. As the free energy increases, a corresponding
increase in the reﬂected power is also observed.
The rise in reﬂected power is accompanied by an increase in product temperature, which is simultaneously monitored while the magnetron output power isreduced. This is necessary because the loss factors for some pharmaceutical components are so small that very low moisture can be achieved before the temperaturerises. For such materials, the reﬂected power can rise sharply once most of the solvent has evaporated, resulting in signiﬁcant temperature gains.
The rise in temperature and reﬂected power signiﬁes that the end of the drying
process is approaching. Several factors, such as the loss factors of the formulation© 2005 by Taylor & Francis Group, LLC

Single-Pot Processing

321

Figure 7 Relationship between microwave forward power, microwave reﬂected power, andproduct temperature during microwave vacuum drying.

components, the microwave power, and the solvent retention properties of the solids
inﬂuence the point at which the previous relation will occur.
For example, lactose has a low loss factor and shows a sharp rise in reﬂected
power, followed by a slow temperature rise. Conversely, starch has a high loss factor
and demonstrates a fast temperature rise followed by a slow rise in reﬂected power.
4. OTHER PROCESSES AND APPLICATIONS
Because of the different technologies incorporated into a single-pot processor, it iscapable of executing many different processes, apart from the standard wet granulation and drying process, while small modiﬁcations or additional options can extend
the ﬂexibility even further.
This chapter discusses some of the possible ‘‘special’’ processes and applications in a single-pot processor. Although many of these processes are used in thepharmaceutical industry, scientiﬁc literature on them is rare. The main reason forthis is that many of these processes were developed by the pharmaceutical industry
as product-speciﬁc solutions. This does not imply, however, that these processes cannot be used more widely.
4.1. Melt Granulation
Melt granulation is a process in which the binder solution of the standard wet granulation process is replaced with a meltable binder such as a wax or polyethylene glycol (PEG), which is generally added in solid form, and melted during the process byadding the necessary energy.
The most common production technique for melt granulation uses extruders,
but melt granulation in a high-shear mixer has also been extensively described in
the literature.
© 2005 by Taylor & Francis Group, LLC

322

Stahl and Van VaerenberghIn this process, the necessary energy to melt the binder is provided either
by the mixer arm (mainly in laboratory-scale equipment) or by a heated jacket(14–16).
If the meltable binder used absorbs microwaves, however (such as PEG for
example), using a single-pot processor equipped with microwave drying can present
major time-savings to the production process.
Providing the melting energy by the impeller or the heated jacket can be a very
time-consuming process, especially in production-scale equipment. Microwaves (asexplained earlier) are an instant source of energy that penetrates into the productand can provide the energy faster and immediately where needed.
In a comparison between the use of the heated jacket to melt the binder and theuse of the heated jacket supplemented with microwaves, the latter method not only
proved to be more than twice faster in melting the binder used (PEG 3000), but also
the granulation step was reduced threefold (17).
At this moment, there is no literature available about other meltable binders incombination with microwaves.
However, the results from the previously mentioned study show that it is worthwhile to consider a single-pot processor for the production of melt granulations.
Another step where a single-pot processor can present a major advantage compared to the standard production techniques, and especially compared to the process
in a high-shear mixer, is the cooling step. To achieve a stable ‘‘dry’’ granule from amelt granulation process, the product needs to be cooled down to room temperature.
In a high-shear mixer, the cooling process is done by circulating cold water or a glycol–water mixture in the bowl jacket. As the contact surface between the product andthe jacket is limited, the cooling process generally takes a long time. If the process is
executed in a single-pot processor equipped with a gas-assisted vacuum-drying system, this system can be used to pass cold air or even liquid nitrogen through the product to aid the cooling process and reduce the cooling time considerably. If liquid
nitrogen is used, even a ﬁvefold reduction of the cooling time is achievable (17).
A related chapter in this book should be consulted to gain more understanding ofmelt granulation.

4.2. Pellet Production
For the production of spheres or pellets, in most cases an extrusion/spheronization
process is used.
There are, however, many references in scientiﬁc literature detailing the production of pellets using a high-shear mixer, most of which concern melt pelletization(15–21). Taking into account the explanations given earlier on melt granulation, asingle-pot processor can, of course, also be used for this process for the same
reasons.
Also, for other pelletization processes, not using meltable binders, the use of asingle-pot processor can be advantageous. In scientiﬁc literature, there are somereferences describing the use of a high-shear mixer for such processes (22,23), but
so far none can be found about single-pot processors. Nevertheless, a standard pellet
formulation often contains microcrystalline cellulose, which needs high water content to obtain a good granule/pellet quality. Drying the pellets is always a part ofthe production process. The advantage of a single-pot processor is that the wholeprocess of pelletization and drying can be executed in the same equipment, making© 2005 by Taylor & Francis Group, LLC

Single-Pot Processing

323

Figure 8 Example of a special pelletizing mixer arm. (Courtesy of Collette NV, Belgium.)product transfers redundant and thereby reducing the risk of product loss and contamination and enhancing containment and operator safety.
To enhance the pelletization/spheronization process, many vendors of highshear mixers/single-pot processors offer special mixing tools for producing pelletlike granules. Depending on the geometry of the equipment, this special mixing tool
has either more (up to six) or less (up to two) mixing blades than a standard mixing
tool, which generally has three mixing blades (Fig. 8). All special pellet-mixing tools
have, however, the same purpose: to simulate the product behavior in a spheronizer
and enhance the spheronization process that occurs in the mixer.

4.3. Effervescent Production
The production of effervescent tablets is ﬁrst of all a conventional solid dosage form
manufacturing process, which has to be taken into consideration, due to the special
characteristics of the product and some unusual features.
For granulation of effervescent products, many different production techniques can be used, ranging from dry granulation methods over two-step granulation(granulating acid and alkali phase separately) to one-step granulation using water ororganic solvents.
For the one-step granulation methods, the use of a single-pot processor offers
many beneﬁts. Apart from the overall beneﬁt of eliminating product transfer between
a granulator and a dryer, a single-pot processor allows easy solvent recovery by condensation in case organic solvents are used as granulation liquid, compared to thequite complex system for the exhaust gas treatment required for a ﬂuid-bed dryer.
When water is used as granulation liquid for effervescents, the effervescent
reaction will start and cause a chain reaction. The critical point in such a process
is to stop this reaction at the correct time by evaporating the water created by thisreaction. In a single-pot processor, this can be very easily and accurately achievedby switching on the vacuum-drying system (possibly supplemented with gas-assisted
drying or microwave drying) (24).
© 2005 by Taylor & Francis Group, LLC

324

Stahl and Van Vaerenbergh

4.4. Crystallization
Although a high-shear mixer/single-pot processor is mainly intended for powder
processing, there is a possibility of executing crystallization or recrystallization processes in this type of equipment as well. Starting either from a solution or from apowder, which is dissolved in a suitable solvent, the speed of the drying process
can be controlled to achieve the desired crystallization process. Using vacuum drying
only, the drying process will be slow and gradual. Temperatures during this process
will remain low, creating an environment for slow crystal growth. When microwaves
are used for drying, the process will be considerably faster and the temperature of the
product will most likely be higher then under ‘‘pure’’ vacuum conditions. The crystals that result from such a crystallization process will have different characteristics
from those from the vacuum-drying process. When choosing the appropriate settings
for the drying/evaporation process, combining vacuum and microwave drying, crystals with speciﬁc properties can thus be obtained.
The main advantage of executing a (re) crystallizing process in a single-pot processor is that the possibility exists of granulating the product at the same time byvarying the mixer speed during the drying process. The resulting product will be suitable for tableting without the necessity of executing other processing steps (apartfrom lubrication).

5. SCALE-UP OF DRYING PROCESSES
Because the rate of solvent removal during vacuum drying is dependent on a favorable surface area/volume ratio, the drying time in a vacuum processor often increases
substantially during scale-up as described by Formula (3.2). Microwave vacuum
drying is relatively insensitive to the surface area/volume ratio and does not suffer
the same inefﬁciency as vacuum drying during transition from pilot to production
scale. Pearlswig et al. reported successfully scaling a microwave vacuum-drying
process for a moisture-sensitive formulation that required a drying end point of< 0.2% (25). The drying time remained within a 30–45 min range throughout thescale-up from 15 kg (Vactron.75) to 300 kg (Vactron.600), whereas the time forvacuum drying increased threefold. After additional scale-up to 600 kg in a
Vactron.1200, the drying time rose slightly to a 50–55 min range. Poska also
reported attaining equivalent drying times when scaling up in Spectrum processors
ranging from 65 to 300 L bowl size (26). Figure 9 compares typical drying curves
for lactose–starch granulation prepared in single-pot processors using vacuum
drying, gas-assisted vacuum drying, or microwave vacuum drying. Although not
as rapid as microwave vacuum drying, gas-assisted vacuum drying can decrease
the drying time by up to 50% compared with that of vacuum drying alone. As thewall of the vessel is the only source for drying energy, also in this case the scale isof major importance for the drying time (27).
When performing feasibility trials on a development- or pilot-scale single-pot
processor, it is important to be aware of the maximum energy input capacity of
the corresponding production-scale processor. In Figures 9 and 10, the drying times
for each drying method in a pilot- and production-scale single-pot processor are
shown. While for processors equipped with microwaves, the drying time is relatively
independent of the scale, a signiﬁcant increase in drying time is observed for vacuumand gas-assisted vacuum-drying processes.
© 2005 by Taylor & Francis Group, LLC

Single-Pot Processing

325

Figure 9 Comparison of drying curves for different modes of drying in a 75 L UltimaProTM.
(Courtesy of Collette NV, Belgium.)

Figure 10 Comparison of drying curves for different modes of drying in a 600 L UltimaProTM. (Courtesy of Collette NV, Belgium.)© 2005 by Taylor & Francis Group, LLC

326

Stahl and Van Vaerenbergh

6. CLEANINGAs a single-pot processor is often used for highly potent products, or more generally
for contained production, it is important that also cleaning of the machine can be
executed in a contained, automated fashion to eliminate the risk of operator exposure to the active product.
All single-pot processors on the market nowadays are equipped with a more orless extensive clean-in-place system. Vendors have made a great effort to optimize
their design enabling easy cleaning in place, which can be validated (3). The focus
has been to eliminate any dead spots in the equipment where the cleaning water cannot reach and including cleaning spray balls in critical product contact areas such as
the product ﬁlter and discharge valve.
Drying of the single-pot processor after the cleaning cycle to prepare the equipment for the next batch can be done using the system’s own vacuum-drying system
and jacketed bowl, making a separate drying unit redundant.
A nice case study of an evaluation of a clean-in-place system on a pilot-scale
single-pot processor is given in Ref (3). In this study it was proved that a completechangeover from one product to the next can take place in <2 hr.

7. PRODUCT STABILITY
The stability of pharmaceutical granulations dried by microwaves is comparable withthat provided by alternative methods. Microwaves are nonionizing and do notpossess the amount of energy required for the formation of free radicals or theliberation of bound water conditions that foster product instability (Fig. 6).
Since the introduction of microwave drying at the end of the 1980s, numerous
new and supplemental drug applications that include the use of microwave vacuum
drying of wet granulations have been approved by the Food and Drug Administration (FDA). We are unaware of any instance in which the FDA required additional
stability or analytical testing beyond that normally required for other methods ofmanufacture. Mandal (28), Moss (29), and others (26,30) have also published or presented data showing the comparability of the physicochemical characteristics ofgranulation dried in microwave processors vs. tray driers and ﬂuid-bed driers.
When microwaves were ﬁrst introduced, some authors (31) concluded thatmicrowave drying could not be generally recommended because of the inability tocontrol the microwaves after they enter the drying cavity and the risk of unacceptable thermal damage to active substances with high loss factors (i.e., high dielectric
constants). The routine production of pharmaceutical products by several installations of single-pot processors using microwave vacuum drying indicates that theirgeneral concerns can be addressed by the proper selection of formulation components and process parameters.

8. REGULATORY CONSIDERATIONSSingle-pot processors combine established technologies into a single piece of equipment and, in general, deserve no special regulatory consideration when using them todevelop a new product or to manufacture an approved product. Robin and colleagues (4) surveyed eight European regulatory agencies in 1992 to determine the© 2005 by Taylor & Francis Group, LLC

Single-Pot Processing

327

implications of converting from ﬂuid bed drying to microwave vacuum drying within
a single-pot processor. The majority of the agencies required only process validation
data and three suggested limited stability data (up to 6 months of accelerated data).
These requests were no different from those expected for similar types of manufacturing changes (i.e., change in process or equipment).
Manufacturers considering converting to a single-pot process for an immediaterelease, solid oral dosage form (tablets, capsules, or the like) with an approved
manufacturing process should consult their appropriate regulatory agencies
governing the practices they use to manufacture their products. For drug products
sold in the United States, manufacturers should refer to FDA’s SUPAC IR
Guidance document (32), which addresses scale-up and postapproval changes formarketed products. This document describes the levels of change that may be madein a manufacturing process and equipment. It outlines the chemistry, manufacturing,and control tests and documentation for each level of change as well as the appropriate regulatory ﬁling (Annual Report, Prior Approval Supplement, or other).
For example, a tablet formulation is currently granulated using a high-shear
granulator and dried in a tray drier. A drug manufacturer wishes to replace this process with a single-pot processor that incorporates high-shear granulation and gasassisted vacuum drying. This conversion would be viewed as a change in equipment
to a different design and different operating principles (deﬁned as a Level 2 Equipment Change in the SUPAC IR Guidance document). Such a change requires the
manufacturer to submit a Prior Approval Supplement with up to three batches with
3-months accelerated stability data (depending on the duration of commercial
experience with the product). The submission would also require updated batchrecords including the new equipment, and the generation of multipoint dissolution
proﬁles. The requirements for this conversion are, however, the same as those fora conversion of a tray drier to a ﬂuid-bed drying process.

9. VALIDATION OF SINGLE-POT PROCESSORS
Because single-pot processors combine standard engineering approaches into a single
processor, their validation should pose no special problems. Other sources adequately describe the validation of granulating and drying processes (33), althoughvalidation of the microwave drying system and the approach to process control ofdrying end point deserves special mention.
For operational qualiﬁcation of microwave components, such as forward andreﬂected power, and arc detection, we suggest that customers contact the vendors
because of the specialized nature of microwave systems. The cost associated withthe calibration equipment is difﬁcult to justify, and microwave systems should operate reliably following proper setup and qualiﬁcation and require no more periodic
maintenance than other granulation approaches.
When microwave processors were ﬁrst introduced, there was the expectationthat E-ﬁeld would be a reliable indicator of the drying end point. With experience,
users found that the E-ﬁeld tends to be too variable, and now view it primarily asa safety feature monitoring the microwave ﬁeld within the drying cavity. Most
microwave driers on the market today do not even include E-ﬁeld monitoring any
more, because of the difﬁculties with validation of this system.
Product temperature, time, cumulative forward power, and reﬂected power areproving to be more reliable indicators of drying end point with veriﬁcation by some© 2005 by Taylor & Francis Group, LLC

328

Stahl and Van Vaerenberghin-process control that directly measures the moisture content of a product sample.
The industrial processes in operation today all use one of these approaches for endpoint determination.
With the pharmaceutical industry moving toward the use of process analyticaltechnology (PAT), however, the equipment vendors are also investigating the possibility of applying this technology to single-pot processors and thereby eliminating
the necessity of taking product samples. The ﬁrst single-pot processors with PAT willundoubtedly be introduced into the market shortly.
10. CONTROL SYSTEMS AND DATA ACQUISITION SYSTEMS
Users of single-pot processors may use one or all of its processing features (mixing,
granulating, drying, or other). The accompanying data acquisition system must collect, display, and record the relevant processing conditions and granulation behavior
for each cycle. The degree of sophistication of the system may depend on the venue
in which the processor is used.
In a development setting, the sequence of cycles is often interrupted to collectsamples for analysis, and the user is interested in capturing as much information as
possible to assist in deﬁning a suitable processor for a particular formulation. In
many cases, the control system for a development environment can be limited to amanual control system. The data acquisition system, however, needs to be moresophisticated to allow registration of all relevant processing data.
In production, the manufacturing sequence and process parameters are predeﬁned and validated, and information needs are reduced to monitoring critical parameters. In these settings, an automatic control system with recipes to reduce operator
interventions is indispensable. The data acquisition system may or may not be as
sophisticated as for the development settings, depending on the requirements fordata in the batch records.
For the purposes of trouble-shooting and trend analysis of production
operations, however, the information requirements of development and production
converge, and data acquisition systems for single-pot processors should seek toaddress the needs of both types of users.
All data acquisition systems are considered to generate electronic records. If
these electronic records are used as batch documentation, the acquisition systemneeds to be compliant with FDA 21 CFR part 11.
Most vendors have addressed these issues by including password control, audit
trails, and point veriﬁcation systems (Fig. 11).
11. SAFETY
The primary safety concern during the granulation and drying processes is the prevention of explosions. Bulk powder, dust clouds, and ﬂammable vapors, all have thepotential to explode. Adequate grounding and ventilation during loading and discharging of the vessel and controlling the various processing conditions can reduce
the risk of explosion.
In Europe, all equipment used in a potentially explosive atmosphere needs tobe compliant with the ATEX guidelines (34).
Two approaches are generally taken toward explosion protection in single-pot
processors. One consists in removing oxygen from the processing chamber and© 2005 by Taylor & Francis Group, LLC

Single-Pot Processing

329

Figure 11 Screen of a typical control system for a single-pot processor. (Courtesy of ColletteNV, Belgium.)

replacing it with an inert gas (e.g., nitrogen) before any mixing action can take place.
The removal of oxygen reduces the risk of explosion by eliminating one of the elements
necessary to create an explosion. The other approach is to design the equipment inorder to contain the explosion. Executions of 10 or even up to 16 bar of high-shear
granulators and single-pot processors are now becoming available on the market.
Apart from the measures taken to avoid or contain explosions within the processing chamber, the electrical, electronic, and mechanical parts of single-pot processors that will be used in potentially explosive atmospheres also need to be explosion
protected.
The leakage of microwave energy is a concern for single-pot processors that use
this drying approach. Industrial microwave processors are expected to meet theguidelines for microwave leakage speciﬁed by the Center for Devices and Radiological Health within FDA and by the American National Standards Institute (35,36).
The guideline is 5 mW/cm2 maximum exposure at a frequency of 2450 MHz at a
distance of 5 cm from any surface of the microwave cavity. Survey meters for thedetection of microwave leakage are relatively inexpensive and should be purchasedby users of single-pot processors that incorporate microwave drying. The survey
meters are calibrated before shipment and returned to the supplier for recalibration
at periodic intervals. Their use should be incorporated in standard operating procedures for the equipment. Operator readings that exceed the guideline limit are often
indicative of deteriorating seals around the lid cavity.
In addition to energy leakage standards, microwave processors are designedwith safety interlocks to prevent accidental exposure. For example, the magnetrons
can be activated only if the microwave cavity (i.e., bowl of the processor) is operating
under vacuum, usually 30–100 mbar. If the vacuum falls outside this range, as in theunlikely event that an operator inadvertently tries to open the lid during microwave
vacuum drying, the magnetrons are disabled. Vendors also incorporate additionalsafeguards to ensure that the microwave power is disabled with access to the bowl.
Because of popular misconceptions about the use of microwave ovens (e.g.,
stainless steel should not be used in a microwave cavity) and electromagnetic radiation (e.g., all types cause biological effects), a training program should be instituted© 2005 by Taylor & Francis Group, LLC

330

Stahl and Van Vaerenberghin any facility that uses microwave drying. This will demystify any unfounded concerns about the technology and foster a rational approach to a sound safety andmaintenance program.

12. CONCLUSION
Over the last 30 years since its introduction, single-pot processing has developed intoa mature and generally accepted production technique.
Even if the technique historically was often used because of its speciﬁc advantages for effervescent production, potent compounds, organic solvents, or multiproduct facilities, practice has shown that single-pot processing is also attractive forstandard pharmaceutical solid dosage production.

REFERENCES
1. Van Vaerenbergh G. The inﬂuence of a swinging bowl on granulate properties. Pharm
Technol 2001; 13(3):36–43.
2. Lucisano LJ, Poska RP. Microwave technology-fad or the future. Pharm Technol 1990;
14:38–42.
3. Van Vaerenbergh G. Cleaning validation practices using a one-pot processor. Pharm
Technol. Europe. Feb 2004.
4. Robin P, Lucisano LJ, Pearlswig DM. Rationale for the selection of a single pot manufacturing process using microwave/vacuum drying. Pharm Technol 1994; 18:28–36.
5. Bellini G, Pellegrini L. Non adiabatic drying. In: Goldberg E, ed. Handbook of Downstream Processing, Chapman & Hall, 1993.
6. De Smet P. Vacuum drying. Manuf Chem Mar 1989; 37–39.
7. LB Bohle, Inc. Technical Report. Granulation and Drying with SYSTEM-VAGAS.
Bristol, PA: LB Bohle, Inc.
8. Niro-Fielder Ltd. Technical Report. AEROVAC System, Accelerated Vacuum Drying.
Eastleigh, Hampshire, U.K.: Niro-Fielder Ltd.
9. Metaxas AC, Meredith RJ. Industrial Microwave Heating. London: Peter Peregrines,
1983.
10. Doyle C, Cliff MJ. Microwave drying for highly active pharmaceutical granules. Manuf
Chem Feb 1987; 23–32.
11. Waldron MS. Microwave vacuum drying of pharmaceuticals: the development ofa process. Pharm Eng 1988; 8:9–13.
12. Poska RP. Microwave processing: the development experience revisited. Proceedings ofInternational Society of Pharmaceutical Engineers Congress, September, 1992.
13. Lucisano U, Moss RA. Vacuum drying vs. microwave-vacuum drying in three pilot-scale
single pot processors using sodium acid pyrophosphate as the model granulation. AAPS
Annual Meeting, San Antonio, TX, Nov 15, 1992.
14. Schaefer T. Melt Agglomeration with Polyethylene Glycols in High Shear Mixers. Ph.D.
thesis, The Royal Danish School of Pharmacy, Copenhagen, 1996.
15. Schaefer T, Holm P, Kristensen HG. Melt pelletisation in a high shear mixer. I. Effects ofprocess variables and binder. Acta Pharm Nordica 1992; 4:133–140.
16. Schaefer T, Mathiesen C. Melt pelletisation in a high shear mixer. IX. Effects of binder
particle size. Int J Pharm 1996; 139:139–148.
17. Van Vaerenbergh G. Melt granulation with polyethylene glycol in a one-pot processor.
Pharma. In press.

© 2005 by Taylor & Francis Group, LLC

Single-Pot Processing

331

18. Heng PW, Wong TW, Chan LW. Inﬂuence of production variables on the sphericity ofmelt pellets. Chem Pharm Bull (Tokyo) 2000; 48:420–424.
19. Hamdani J, Moës AJ, Amighi K. Development and evaluation of prolonged releasepellets obtained by the melt pelletization process. Int J Pharm 2002; 245:167–177.
20. Thies R, Kleinebudde P. Melt pelletisation of a hygroscopic drug in a high shear mixer.
Part 1. Inﬂuence of process variables. Int J Pharm 1999; 188(2):131–143.
21. Voinovich D, Moneghini M, Perisutti B, Franceschinis E. Melt pelletization in high shear
mixer using a hydrophobic melt binder: inﬂuence of some apparatus and process variables. Eur J Pharm Biopharm 2001; 52(3):305–313.
22. Vonk P, Guillaume CPF, Ramaker JS, Vromans H, Kossen NWF. Growth mechanismsof high-shear pelletisation. Int J Pharm 1997; 157(1):93–102.
23. Ramaker JS, Albada Jelgersma M, Vonk P, Kossen NWF. Scale-down of a high-shear
pelletisation process: ﬂow proﬁle and growth kinetics. Int J Pharm 1998; 166(1):89–97.
24. Stahl H. Manufacturing effervescent tablets. Pharm Technol 2003; 15(4):25–28.
25. Pearlswig DM, Robin P, Lucisano LJ. Simulation modeling applied to the developmentof a single-pot process using microwave/vacuum drying. Pharm Technol 1994; 18:44–60.
26. Poska R. Integrated mixing granulating and microwave drying: a development experience. Pharm Eng 1991; 11:9–13.
27. Stahl H. Single pot systems for drying pharmaceutical granules. Pharm Technol Eur
2000; 12(5):23–34.
28. Mandal TK. Evaluation of microwave drying for pharmaceutical granulations. Drug
Dev Ind Pharm 1995; 21:1683–1688.
29. Moss RA. Demonstration-microwave/vacuum drying of pharmaceuticals. AAPS
Annual Meeting, Washington, DC, Nov 17, 1991.
30. Van Scoik K. Microwave vacuum processing in the Vactron 300. AAPS Annual Meeting,Washington, DC, November 1991.
31. Duschler G, Carius W, Bauer KH. Single-step granulation method with microwaves:preliminary studies and pilot scale results. Drug Dev Ind Pharm 1995; 21:1599–1610.
32. Food and Drug Administration. Immediate release solid oral dosage forms: scale-up andpostapproval changes: chemistry, manufacturing, and controls; in vitro dissolution testing; in vivo bioequivalence documentation; guidance. Fed Reg 1995; 60:61638–61643.
33. Berry IR, Nash eds. Pharmaceutical Process Validation. New York: Marcel Dekker,
1993.
34. Directive 94/9/EC of the European Parliament and the Council of 23 March 1994 on theapproximation of the laws of the Member States concerning equipment and protective
systems intended for use in potentially explosive atmospheres.
35. Performance Standards for Microwave and Radio Frequency Emitting Products. 21
Code of Federal Regulations, Part 1030. Washington, DC: General Services Administration, April 1, 2003.
36. IEEE Standard for Safety Levels with Respect to Human Exposure to Radio Frequency
Electromagnetic Fields, 3 kHz to 300 GH—Supplement 1999 (IEEE C95.1–1999). New
York: Institute of Electrical and Electronics Engineers.

© 2005 by Taylor & Francis Group, LLC

11
Extrusion/Spheronization as a Granulation
Technique
Ketan A. Mehta
RÖHM Pharma, Degussa Corp., Piscataway, New Jersey, U.S.A.

Gurvinder Singh Rekhi
Elan Drug Delivery Inc., Gainesville, Georgia, U.S.A.

Dilip M. Parikh
Synthon Pharmaceuticals Inc., Research Triangle Park, North Carolina, U.S.A.

1. INTRODUCTION
Extrusion/spheronization is a multiple step process capable of making uniformly
sized spherical particles. The process is now being widely utilized in the pharmaceutical industry. This is the revision of the original chapter written by D. Erkoboni(1). As a pharmaceutical dosage form, pellets are deﬁned as small, free ﬂowing,
spherical, or semispherical units made up of ﬁne powders or granules of bulk drugs
and excipients by variety of processes, extrusion and spheronization being one. It
is primarily used as a method to produce multiparticulates for immediate and controlled release applications. The major advantage over other methods of producing
drug-loaded spheres or pellets is the ability to incorporate high levels of actives without producing an excessively large particle. Mehta and Kislalioglu in their study
demonstrated the incorporation of a poorly soluble drug in a pellet matrix up to
40% loading via extrusion/spheronization for controlled drug delivery (2).
Though the process is more efﬁcient than other techniques for producing
spheres, it is more labor and time intensive than the more common granulation techniques. Therefore, it should be considered as a granulating technique when thedesired particle properties are essential and cannot be produced using more conventional techniques. However, more recently, pharmaceutical scientists worldwide havebeen able to use this method more easily due to advances in extrusion/spheronizationequipment engineering, thus making it simple to use. Pellets offer scientists a great
deal of development ﬂexibility. Chemically incompatible ingredients, for instance,
can be incorporated into single capsule using two pellet types each containing
one of the incompatible ingredients. Pellets of different release characteristics canbe combined to achieve the desired release pattern of the active ingredients. Pellets
are characterized by a low surface area-to-volume ratio compared with powder or333© 2005 by Taylor & Francis Group, LLC

334

Mehta et al.

granules, which provides excellent coating substrate. Typically, pellets range in diameter between 0.25 and 1.5 mm. Pellets are normally ﬁlled into hard gelatin capsules, or eventually compressed into tablets which disintegrate into individual
pellets after oral intake.
Spheronization is a process invented by Nakahara in 1964. The patentdescribes a ‘‘Method and Apparatus for Making Spherical Granules’’ from wet powder mixtures (3). The equipment described in the patent was commercialized by Fuji
Denki Kogyo Co. under the trade name MarumerizerÕ . The process went widely
unnoticed in the pharmaceutical industry until 1970 when two articles were published by employees of Eli Lilly and Co. Conine and Hadley described the steps
involved in the process including (a) dry blending, (b) wet granulation, (c) extrusion,(d) spheronization, (e) drying, and (f) screening (optional) (4). Reynolds went on tofurther describe the equipment and the mechanics of the process including the movement of the particles within the spheronizer (5). Both publications cite desirable
product attributes that can be achieved, including good ﬂow, low dusting, uniform
size distribution, low friability, high hardness, ease of coating, and reproducible
packing. Additionally, the resulting pellets offer not only technological advantages
as mentioned before but also therapeutic advantages such as less irritation of the gastrointestinal tract and a lowered risk of side effects due to dose dumping and reproducibility of the drug blood levels (6). From the publication of these articles throughpresent day the interest in extrusion/spheronization has continued to grow. The process has recently become established in industry but was primarily driven by academia
in the interim. The increased popularity in recent years is, in part, due to a growing
understanding of the effects of process parameters and material characteristics.
In recent times, hot-melt extrusion (HME) has gained subsequent industry andacademic attention and is in the phase of further process maturity for ultimately
gaining wide spread popularity. HME is somewhat widespread in the plastics industry for the production tubes, pipes, wires, and ﬁlms. For pharmaceutical systems,
this method has been used to prepare granules, sustained release tablets, and transdermal drug delivery systems (7). The advantage of HME is that it does not require
the use of solvents and water and few processing steps are needed making the process
somewhat simpler, efﬁcient, and continuous. The disadvantage of HME is that it
may use complicated know-how and typically employs high temperatures aroundand over 100 C as a processing requirement. However, it has been used as a method
to increase the solubility of a poorly soluble drug, to taste mask a bitter drug andoverall for controlled release dosage form purposes. The bioavailability of the drug
substance has been demonstrated to improve when it is dispersed at the molecularlevel in hot-melt extruded dosage forms. Several examples of melt-extruded molecular dispersions were presented by Breitenbach and Mägerlein (8).
A recent patent (9) describes melt- extrusion process as being used to produce
improved controlled release characteristics. The authors described the process which
includes mixing together a therapeutically effective agent, a water-insoluble retardant, and a binder to form a homogeneous mixture, heating the mixture and thereafter extruding the mixture into strands. The strands are then cooled, reduced to thedesired sizes.
The number of hot-melt extrusion patents issued for pharmaceutical systems
has increased more than sixfold annually since the early 1980s, with the UnitedStates, Germany, and Japan leading the ﬁeld. The ﬁeld of melt extrusion technology
is growing very rapidly and its use to produce ﬁlms for transmucosal and transdermal drug delivery applications was presented by McGinity and Repka (10).
© 2005 by Taylor & Francis Group, LLC

Extrusion/Spheronization as a Granulation Technique335

2. APPLICATIONS
Potential applications are many including both immediate and controlled release. Ina paper by Sood et al., extrusion/spheronization method was used to develop controlled release dosage forms for diltiazem hydrochloride (11). Two or more actives
can easily be combined in any ratio in the same unit. These combination products
can contain actives that are incompatible or have varying release proﬁles. Spheres
can be used as a method to limit drug migration. Physical characteristics of the active
ingredients and excipients can be modiﬁed to improve physical properties and downstream processing. As an example, a low-density, ﬁnely divided active can be pelletized to increase density, improve ﬂow, and limit dusting (12). Mehta et al. showedthat this technique can be used for the development of zero order controlled releasedrug delivery of poorly soluble drugs (13). Functional coatings can be applied easily
and effectively. Dense multiparticulates disperse evenly within the gastrointestinal
tract and can be used to prolong gastrointestinal transit times (14,15) or to improve
tolerance of some compounds. Regardless of the application, care must be taken toachieve the required sphere or granule properties.
Spheres for controlled release coating applications will likely have signiﬁcantly
different physical requirements than granules for compression. A product to becoated for controlled release should have a uniform size distribution, good sphericity
and surface characteristics as well as low friability. Once coated, the sphere shouldhave the desired release characteristics. Additionally, if the coated spheres are to
be compressed into tablets, they will require sufﬁcient strength to withstand theforces of compression. Upon disintegration of the tablet, the individual spheres mustretain their original release proﬁle. Physical properties such as ﬂow, density, friability, porosity, and surface area become important for granules intended for compression into tablets. The granules should have good deformation and bonding
characteristics to form tablets having desirable physical properties. Drug releasefrom the ﬁnal dosage form must meet the target speciﬁcation.
Product produced using extrusion/spheronization can range from barely
shaped, irregular particles with physical properties similar to a conventional granule
to very spherical particles having properties that are drastically different (16). Tableting characteristics can be modiﬁed by altering the composition of the spherical particles (17), granulating ﬂuid (18), or the process conditions used to produce them(19). Compaction studies conducted on spheres similar to those used for controlled
release applications show the bonding and densiﬁcation that occur during extrusion/
spheronization can alter the deformation characteristics of some materials (18).
Microcrystalline cellulose (MCC), which deforms plastically in the dry powder state,exhibits elastic deformation followed by brittle fracture once spheronized (17). The
deformation characteristics, coupled with the larger size particles result in reduced
bonding sites and the production of weak compacts. A compaction proﬁle of
MCC and spheres prepared from MCC is shown in Figure 1.
The point is not to dwell on the properties required for each application, butrather to reinforce the fact that each application will have very speciﬁc requirements.
One must ﬁrst understand the properties required and then tailor the process toyield the desired effects. The effects of process and formulation variables will be
discussed next.
A review of the literature shows that most investigators have tried to understand small components of this process isolated from other effects. They havefocused on particular formulation or process parameters. It is valuable to have
© 2005 by Taylor & Francis Group, LLC

336

Mehta et al.

Figure 1 Compaction proﬁles of microcrystalline cellulose powder and spheres. (From Ref. 17.)a detailed understanding of the main variables; however, this approach fails to take
into consideration the high degree of interaction that exists between the variables.
The use of statistical experimental design is a valuable tool to understand not
only the main effects but also the interactions that can have a profound effect on
the characteristics of the resulting particles (20–22). Additionally, these techniques
are extremely useful during product/process development to understand the effectof variables and control them to produce product having desired attributes (23).
After pointing out the beneﬁts of design methodology in this application, it should
be understood that, for simplicity, much of the discussion to follow will address thevarious topics individually. In reality, however, they truly cannot be isolated fromone another. This chapter will review and discuss the general process, equipment
types, and the effect of process and formulation variables on the properties ofspherical granules.

3. GENERAL PROCESS DESCRIPTION
Extrusion/spheronization is a process requiring at least ﬁve units of operation with
an optional sixth screening step. First, the materials are dry mixed (i) to achieve ahomogeneous powder dispersion and then wet granulated (ii) to produce a sufﬁciently plastic wet mass. The wet mass is extruded (iii) to form rod-shaped particles
of uniform diameter that are charged into a spheronizer and rounded off (iv) into
spherical particles. The spherical particles are then dried (v) to achieve the desired
moisture content and optionally screened (vi) to achieve a targeted size distribution.
The process ﬂow diagram, shown in Figure 2, has been used to show each of the process steps along with critical variables associated with them (24). The end productfrom each of the steps is shown in Figure 3.
© 2005 by Taylor & Francis Group, LLC

Extrusion/Spheronization as a Granulation Technique

337

Figure 2 Process ﬂow chart of the extrusion/spheronization process showing the process
variables for each individual step. (From Ref. 24.)

4. EQUIPMENT DESCRIPTION AND PROCESS PARAMETERS
4.1. Dry Mixing
During the ﬁrst step, powders are dry mixed to achieve a uniform dispersion prior to
wet granulation. It is generally carried out in the same mixer used for the granulation;

Figure 3 Product produced by the ﬁrst four extrusion/spheronization process steps.
(A) Powder from dry mixing; (B) granules from granulation; (C) extrudate from extrusion;and (D) spheres from spheronization.
© 2005 by Taylor & Francis Group, LLC

338

Mehta et al.

however, if a continuous granulator is used, a separate mixer is required for thedry mix. This step is typically taken for granted because wet massing follows.
The uniformity of the dry mix, however, can have a signiﬁcant effect on the qualityof the granulation and, in turn, the spherical particles produced. An uneven distribution of materials having wide differences in properties such as size and solubility
can result in localized over wetting, at least initially, during the granulation step.
The more soluble and ﬁnely divided components can also dissolve and become partof the granulating ﬂuid. The ﬂuids, rich in soluble compounds, can either remain
as overwet regions or, with continued wet massing, can be redistributed (25).
Sphere uniformity (size and shape) is very much dependent on the uniform distribution and composition of the granulating ﬂuid which include not only the solvent
but also any dissolved ingredients.
4.2. Granulation
The second step is granulation, during which a wet mass having the requisite plasticity or deformation characteristics is prepared. With a few exceptions, this step issimilar to conventional granulation techniques used to produce product for compression. It is typically carried out in a batch type mixer/granulator; however, any
equipment capable of producing a wet mass, including the continuous type, canbe used. Batch type processors include planetary mixers, vertical or horizontal highshear mixers, and sigma blade mixers. Examples of continuous mixers include the
Nica M6 instant mixer (26) and high shear twin screw mixer/extruders (27). The highshear twin screw mixer/extruders have mixer/feeders that are capable of shearing
and kneading the feed materials. Dry powders and ﬂuids are fed in through separate
ports and mixed by the action of the extruder blades and screws. The mixer/extruder
is capable of being conﬁgured to customize the amount of shear and energy used in
the process by changing the conﬁguration of the mixing blades. This can have an
impact on the properties of the extrudate produced (28). As with the batch processors it is critical to achieve a uniform level of ﬂuid within the wet mass. The proper
ﬂuid/solids ratio is accomplished by maintaining a steady powder and ﬂuid feed into
the mixer/extruder. Both are critical; however, the powder feed is the mostproblematic. Small variations in feed rates can cause signiﬁcant shifts in the moisture
content of the granulation and, therefore, the quality of the spherical particles produced.
The two major differences in the granulation step, as compared to typicalgranulations for compression are the amount of granulating ﬂuid required and theimportance of achieving a uniform dispersion of the ﬂuid. The amount of ﬂuid neededto achieve spheres of uniform size and sphericity is likely to be greater than that fora similar granulation intended for tableting. Instruments such as a ram extruder (29)
and a torque rheometer (30) have been used to characterize the ﬂow characteristics
of granulations for use in extrusion/spheronization. They are useful tools in quantifying the rheological effect of formulation and process variations in the granulation.
The ram extruder has been used to characterize the ﬂow of wet masses through a die,which has been divided into stages. They are: (a) compression, where the materials
are consolidated under slight pressure, (b) steady-state ﬂow, where the pressure
required to maintain ﬂow is constant, and (c) forced ﬂow, where an increase in force
is required to maintain ﬂow. The three stages are shown in the force vs. displacement
proﬁle in Figure 4.
The change from steady state to forced ﬂow is caused by the movement of ﬂuid
under pressure. Extrusion in a ram extruder is continuous, and this phenomenon is© 2005 by Taylor & Francis Group, LLC

Extrusion/Spheronization as a Granulation Technique

339

Figure 4 A force–displacement proﬁle for a microcrystalline cellulose–lactose–water mixture
showing the three stages of extrusion on a ram extruder: Compression, steady-state ﬂow, andforced ﬂow (ram speed, 4 mm/sec; die diameter, 1.5 mm; L/R ratio, 12). (From Ref. 31.)

less likely to be seen in extruders that are discontinuous such as gravity-feed models(32). A diagram of a ram extruder is shown in Figure 5.
Regardless of the mixer used, one must remember that the downstream process
steps of extrusion and spheronization are very dependent on the level of water contained in the granulation and the quality of its dispersion. High-energy mixers suchas high shear mixers and high shear twin screw mixer/extruders can cause a signiﬁcant rise in temperature. It may be necessary to use a jacket to guard against heatbuild-up. High temperatures can result in a greater than tolerable level of evaporation (33) or an increase in the solubility of some of the solids. A reduction in ﬂuid
will reduce the plasticity of the granulation, while an increase in solubility will
increase the weight ratio of granulating ﬂuid since the solute is then part of that ﬂuid(34). The water solubility of the drug in the granulation plays a key role in determining granulation end point for extrusion/spheronization process. A highly water soluble drug will dissolve in the granulation whereas a highly insoluble drug will havewetting problems during the granulation step. Upon extrusion and during spheronization step a granulation containing a highly insoluble drug at a high dose will havea higher tendency to release moisture due to which the moisture will migrate to thesurface of the extrudates, which might cause interpellet sticking. In order to avoid
this Mehta et al. in their work demonstrated the use of small quantities of talc toadsorb the surface moisture which helped in the spheronization step without altering
the drug release from the resulting pellets (2).

4.3. Extrusion
The third step is the extrusion step which forms the wet mass into rod-shaped particles. The wet mass is forced through dies and shaped into small cylindrical particles
having a uniform diameter. The extrudate particles break at similar lengths under© 2005 by Taylor & Francis Group, LLC

340

Mehta et al.

Figure 5 Schematic diagrams of extruder types used in extrusion/spheronization.

their own weight. The extrudate must have enough plasticity to deform but not somuch to adhere to other particles when collected or rolled in the spheronizer.
Extruders come in many varieties but can generally be divided into three classes
based on their feed mechanism. They include those that rely on a screw, gravity or apiston to feed the wet mass into the extrusion zone (35). Examples of extruders fromeach class are shown in Figure 5. Screw feed extruders include the (a) axial or end
plate, (b) dome, and (c) radial type, while gravity-feed extruders include (d) cylinder,(e) gear, and (f) radial types. The screw and gravity-feed types are used for development and manufacturing with the radial varieties being the most popular for pharmaceutical applications. The piston feed or ram extruder is primarily used inresearch as an analytical tool.
© 2005 by Taylor & Francis Group, LLC

Extrusion/Spheronization as a Granulation Technique

341

Screw extruders have either one (single) or two (twin) augers that transport the
wet mass from the feed area to the extrusion zone. During the transport process, thescrews compress the wet mass removing most of the entrapped air. Studies have been
conducted on the ram extruder to understand this compression or consolidation
stage. They have shown the apparent density of the wet mass plug prior to extrusion
is approximately equal to the theoretical apparent particle density, indicating thatnearly all of the voids were eliminated (31). Twin screw extruders generally have ahigher throughput than single screw models, while single screw extruders compress
and increase the density of the extrudate more. Other features that can affect thedensity of the extrudate are the spacing of the turnings on the screw and the space
between the end of the screw and the beginning of the die (36). Turnings that arewide and regularly spaced minimize the amount of compression during materialtransport. Screws with closer or progressively closer spacing between the turnings
will result in more compression and produce a denser extrudate. Space between
the screw and the die results in a void into which material is deposited and compressed. The greater the space, the more compression takes place prior to extrusion.
As material builds up, pressure increases and causes the material to be forced, underhydraulic pressure, to ﬂow through the die. When space between the screw and thedie is at a minimum, extrusion takes place as material is compressed in the nip,
between the extruder blade and the die.
The primary difference between the various types of screw extruders is in the
extrusion zone. An axial or dome extruder transports and extrudes the wet massin the same plane. Axial extruders force the wet mass through a ﬂat, perforated
end plate, typically prepared by drilling holes in a plate. The thickness of the plate
can be more than four times the hole diameter, resulting in high die length to radius(L/R) ratios. An axial extruder is shown in Figure 6(A).
Dome extruders use a dome or half sphere shaped screen as the die. It is prepared by stamping holes in metal stock having a similar thickness as the hole diameter. This results in a die L/R ratio close to 2, however, variations in screen
thickness are possible resulting in a slightly higher or lower ratio. A dome extruder
is shown in Figure 6(B).
Unlike axial and dome extruders, radial extruders extrude the wet mass perpendicular to the plane of transport. Material is transported to the extrusion zone where
it is wiped against the screen die by an extrusion blade. The mass is forced throughthe die by pressure generated at the nip. A screw feed radial extruder is shown in
Figure 6(C).

Figure 6 Types of extruders. (A) Axial; (B) dome and (C) radial. (Courtesy of the LCI
Corporation.)© 2005 by Taylor & Francis Group, LLC

342

Mehta et al.

As with dome type extruders the die is a stamped screen. Due to the shorter die
lengths and the increase number of holes or dies, dome and radial extruders have theadvantage of higher throughput as compared to the axial type.
As with almost every step in extrusion/spheronization, heat build-up during
extrusion is a signiﬁcant concern. This is especially true of the screw fed extruders.
Axial extruders generate heat due to their long die lengths. Radial extruders can havea signiﬁcant heat differential over the width of the screen. Materials fed into the
extrusion zone will have the lowest temperature. However, as material moves tothe front of the zone, the temperature increases due to the longer residence timeof material. Of the screw feed extruders, the dome type has the highest rates andis least likely to generate signiﬁcant heat over an extended period.
Gravity-feed extruders include a cylinder, gear, and radial type. The cylinderand gear both belong to a broader class referred to as roll extruders. Both use tworollers to exert force on the wet mass and form an extrudate. The cylinder extruder
has rollers in the form of cylinders, one solid and one hollow with drilled holes toform the dies. The wet mass is fed by gravity into the nip area between the two cylinders and forced through the dies into the hollow of the cylinder. Gear type extruders
have rollers in the form of hollow gears. The dies are holes drilled at the base of each
tooth. Wet mass is forced through the holes and collected in the hollow of the gears
as the teeth and the base areas mesh. The last type of gravity-feed extruder to be discussed is the radial type. One or more arms rotate to stir the wet mass as it is fed bygravity. Rotating blades wipe the wet mass against the screen, creating localized
forces sufﬁcient to extrude at the nip. There is no compression prior to extrusion
which is the major difference between the gravity and screw feed radial extruders.
A gravity-feed extruder is shown in Figure 7.
The primary extrusion process variables are the feed rate, die opening, and die
length. The water content of the granulation is also very critical, since the propertiesof the extrudate and resulting spheres are very dependent on the plasticity and cohesiveness of the wet mass. The process variables and water content have been thefocus of many studies. Harrison, Newton, and Rowe studied the ﬂow of the wet mass
as it is forced through a die (29,31,37,38). They determined that steady-state ﬂow(described earlier and shown in Fig. 4) was essential to produce a smooth extrudate,
which results in uniformly sized spherical particles having good sphericity and surface characteristics. Materials and processes that did not result in steady state, acondition referred to as forced ﬂow, produced extrudate having surface impairments.
In moderate cases, the surface is rough, while in more severe cases, a phenomenoncommonly referred to as shark-skinning occurs. Examples of smooth extrudate
and shark-skinned extrudate are shown in Figure 8(A) and (B), respectively.
Force–displacement proﬁles of microcrystalline cellulose (MCC) and water atvarious ratios, MCC, lactose, and water at a 5:5:6 ratio, and lactose and water at a
8:2 ratio, developed by Harrison et al., are shown in Figure 9.
Steady state was possible with the MCC and MCC:lactose samples but notwith lactose alone. As can be seen with the MCC samples, the duration of the compression stage was water level dependent with no effect seen on the steady state stage.
Additional studies indicated the effect of ram speed (extrusion speed) and die L/Rratio. An increase in ram speed increased duration of the steady-state stage withno effect on the compression stage. The L/R ratio had no effect on either compression or steady state. Wet mass composition, therefore, inﬂuenced the ability
to achieve steady state while the water level and ram speed inﬂuenced duration.
Higher water levels decreased the force to produce steady-state ﬂow but increased© 2005 by Taylor & Francis Group, LLC

Extrusion/Spheronization as a Granulation Technique343

Figure 7 (A) Gravity-feed rotary extruder; (B) close-up showing the extrusion zone;(C) operating principle of gravity-feed extruder. (Courtesy of Niro Pharma Systems.)

Figure 8 Scanning electron micrographs showing an example of (A) smooth extrudate and(B) extrudate having surface impairment, or shark-skinning.
© 2005 by Taylor & Francis Group, LLC

344

Mehta et al.

Figure 9 Force–displacement proﬁles at various moisture contents of mixtures of microcrystalline cellulose and water: (a–d) microcrystalline cellulose–lactose–water (5:5:6);(e) lactose–water (8:2); (f) at a ram speed of 4 mm/sec, die diameter of 1.0, and a L/R ratioof 12. Percentage of moisture content of microcrystalline cellulose–water mixture: a, 59.4;
b, 51.1; d, 45.0. (From Ref. 29.)

the duration. Faster ram speeds (extrusion rates) increased the duration of steadystate and increased the force. As discussed in the following text, other investigators
have reported the correlation between extrusion force and sphere quality.
Fechner et al. indicated that for an optimum extrusion process, a mixture ofspongelike and gel-like behavior might be desirable which are possible by the useof MCC and powder cellulose (39).
Harrison et al. also indicated that a uniform lubricating layer at the die wallinterface must occur to eliminate the slip-stick phenomenon responsible for forced
ﬂow. Development of a lubricating layer was dependent on the length of the die(a minimum length required), wall shear stress and upstream pressure loss. They
represent the frictional forces at the die wall interface and the estimated pressure loss
at zero die length in the barrel of the ram extruder. The method for deriving thesevalues is described in Ref. 27. These parameters allow for a quantitative comparison
between formulations and process; however, no speciﬁc values can be targeted since
they vary with materials.
Pinto et al. also showed that, at slow ram speeds, water moves toward the diewall interface and acts as a lubricant resulting in reduced extrusion forces. At higher
speeds water is unable to move rapidly through the mass resulting in higher forces(40). They indicated that the water content and its distribution are critical in determining the particle size and sphericity of the product. Lower water content andhigher speed will reduce the size and sphericity of the particles. The extrusion speed
and water content should be adjusted to achieve the desired effect. Other researchers
have investigated the effect of die length using gravity-feed radial extruder. Hellén
et al. indicated the extrudate became smoother and more bound as the L/R ratio© 2005 by Taylor & Francis Group, LLC

Extrusion/Spheronization as a Granulation Technique345

of the die was increased (41). Vervaet et al. reported that a higher L/R ratio enables
the use of lower water levels to achieve a more bound extrudate (42). This also
increased the range (drug loading and water level) over which quality spheres could
be produced. They attributed the increased latitude and capability to increased densiﬁcation and resulting well-bound extrudate. The average pore diameter and bulk
density reported for extrudate prepared from various MCC:DCP:water ratios at
two L/R ratios are shown in Table 1.
Baert et al. also indicated a similar increase in latitude when a cylinder extruder
having an L/R ratio of 4 was compared to a twin screw extruder having a L/R ratioof close to 1.8 (43). Other studies have shown that there is an optimal pressure range
over which extrudate capable of yielding acceptable spheres can be produced. Shahet al. demonstrated the correlation between screen pressure yield and density (44).
A high yield of spheres within a targeted narrow size distribution was produced aslong as the screen pressure was maintained within a given range. The relationshipbetween yield and screen pressure is shown in Figure 10.
While many of the researchers have indicated a need for a more cohesive extrudate, few have expressed a need to remove all surface impairments. Some researchers
have indicated that spheres having acceptable characteristic can be produced fromextrudate having shark-skinning. O’Connor and Schwartz have found the presenceof shark-skinning to be advantageous in facilitating the breakage of the extrudate
during the spheronization step (45).
Experimental design studies conducted to concurrently investigate the effect of
extrusion as well as other process and formulation variables have indicated the extrusion variables to be less signiﬁcant than granulating ﬂuid level or variables of thespheronization step. Hasznos et al. determined that extruder speed had little effecton the size distribution of the ﬁnal product or moisture change during processing
as compared to the spheronization variables (46). Hilemann et al. indicated that,when water/MCC ratios are held constant, a change in screen size results in a significant change in the size distribution (47). However, in a study where water level was
included as a variable, Erkoboni et al. have shown that the effect of screen size on
size distribution is small compared to the effect of a change in water level. A change
in water level can shift the mean size and still result in an acceptable distribution (21).
This is in agreement with earlier work by Malinowski and Smith who also showed
the mean particle size is typically smaller than the size of the screen itself due toshrinking during the drying step (12). Vervaet et al. have presented an excellent
review of extrusion spheronization (48).
Table 1 Average Pore Diameter and Bulk Density of Extrudate Composed of DCP–Avicel
PH-101–Water Mixture, Extrudated Using Screens with Different L/R Ratios
Composition DCP–
Avicel–water (w/w)

L/R ratio of screen

Average pore
diameter (mm)Bulk density (g/mL)

4
4
2
2

0.982
0.992
1.249
1.292

1.132
1.211
0.949
0.947

150:380:470
150:400:450
150:380:470
150:400:4502
Source: From Ref. 42.
© 2005 by Taylor & Francis Group, LLC

346

Mehta et al.

Figure 10 The effect of extruder screen pressure on the yield of particles within an acceptable
distribution. (From Ref. 44.)4.4. Spheronization
The fourth step in the extrusion/spheronization process is the spheronization step. It
is carried out in a relatively simple piece of equipment. The working parts consist of
a bowl having ﬁxed sidewalls with a rapidly rotating bottom plate or disk. The
rounding of the extrudate into spheres is dependent on frictional forces. The forces
are generated by particle-to-particle and particle-to-equipment interactions. For thisreason the disk is generally machined to have a grooved surface which increases theforces generated as particles move across its surface. Disks having two geometricpatterns are produced, a cross-hatched pattern with the grooves running at rightangles to one another and a radial pattern with the grooves running radially fromthe center. The two varieties are shown graphically in Figure 11.
Some studies have shown the rate of spheronization to be faster with the radial
pattern; however, both plates will result in acceptable product (35).
During the spheronization step, the extrudate is transformed from rod-shapedpellets into spherical particles. This transition occurs in various stages. Once charged

Figure 11 Spheronizer disks having two geometric patterns: (A) a cross-hatched patternwith the groves running at right angle to one another and (B) a radial pattern with the groves
running radially from the center.
© 2005 by Taylor & Francis Group, LLC

Extrusion/Spheronization as a Granulation Technique347

into the spheronizer, the extrudate is drawn to the walls of the extruder due to centrifugal forces. From here what happens is very much dependent on the properties ofthe extrudate. Under ideal conditions, the extrudate breaks into smaller, more uniform pieces. Within a short period of time, the length of each piece is approximately
equal to the diameter, due to attrition and rapid movement of the bottom plate or
disk. The differential in particle velocity as they move outward to the walls, begin
to climb the walls and fall back onto the rotating bed, along with the angular motionof the disk results in a rope-like formation (5). Figure 12 shows the rope-like formation of the extrudates.
This formation can be a critical indicator of the quality of the granulation or
extrudate. As pointed out by Reynolds (5), the disk rotating without movement of
the product indicates an over wet condition. The condition is caused either froma granulation that was initially over wet or migration of water or a ﬂuid ingredientto the surface of the extrudate during extrusion or spheronization.
As mentioned, the transformation from cylinder-shaped extrudate to a sphereoccurs in various stages. Two models have been proposed to describe the mechanism
and are shown graphically in Figure 13.
The model proposed by Rowe in 1985 describes a transition whereby thecylindrical particles (Fig. 13-2A) are ﬁrst rounded off into cylindrical particles withrounded edges (Fig. 13-2B), then form dumbbell-shaped particles (Fig. 13-2C), ellipsoids (Fig. 13-2D), and ﬁnally spheres (Fig. 13-2E) (35). The second model proposedby Baert et al. in 1993 suggests that the initial cylindrical particles (Fig. 13-1A) are
deformed into a bent rope-shaped particle (Fig. 13-1B), then form a dumbbell with atwisted middle (Fig. 13-1C). The twisting action eventually causes the dumbbell to
break into two spherical particles with a ﬂat side having a hollow cavity (Fig. 131D). Continued action in the spheronizer causes the particles to round off into
spheres (Fig. 13-1E). When the sphere is fractured a hollow particle is revealed(49). The exact mechanism is likely to be composition dependent. If the extrudate
is overwet, particle growth will occur resulting in a broad size distribution. Under
wet extrudate will not have enough plasticity to further round off in the spheronizer;
the result is the formation of dumbbells. The scanning electron micrographs in Figure 14 show an example of good spheres produced from a sufﬁciently plastic massand dumbbells that would not deform further.

Figure 12 A characteristic rope-like formation in a spheronizer bowl during operation.
© 2005 by Taylor & Francis Group, LLC

348

Mehta et al.

Figure 13 A graphic representation of the two models proposed to describe the mechanismof spheronization. The model proposed by Baert et al. (38) describes a transition from initialcylindrical particles (1A) into a bent rope (1B), dumbbell (1C), two spherical particles with ahollow cavity (1D), and spheres (1E).The model proposed by Rowe (25) describes a transition
from cylindrical particles (2A) into cylindrical particles with rounded edges (2B), dumbbells(2C), ellipsoids (2D), and spheres (2E). (From Refs. 35,49.)

Of the two process steps unique to extrusion/spheronization, the ﬁrst, extrusion, is a continuous process while the second, spheronization, is a batch process.
To make the process viable for commercial operations, two systems have been developed to enable the extruder to continuously feed material to the spheronizer(s). The

Figure 14 An example of (A) good spheres produced from a sufﬁciently plastic mass and(B) dumbbells that would not deform further produced from underwet extrudate.
© 2005 by Taylor & Francis Group, LLC

Extrusion/Spheronization as a Granulation Technique349

ﬁrst system is a semicontinuous shuttle system and the second is a cascade system.
The shuttle system is typically used when uniform particles are required, such as
for controlled release coating applications. The cascade system, however, can be used
for applications where less size and shape uniformity is required, such as granulations intended for compression.
The shuttle system uses two spheronizers in parallel. It is designed to ﬁll one
spheronizer while the second is in the middle of its cycle, continue to collect extrudate in a shuttle receptacle while they are both full and operational, and ﬁll the second after it empties and the ﬁrst unit is in the middle of its cycle. The shuttle system
operation is shown graphically in Figure 15.
A picture of a spheronizing system having twin spheronizers is also shown in
Figure 16.
The cascade operation uses one or more spheronizers that are modiﬁed to havethe disks some distance below the discharge chute (36). This results in a spheronization zone having a ﬁxed volume. The product is continually fed from either the
extruder or a previous spheronizer. As the charge volume grows from incoming
material some product is discharged. The residence time is dictated by the feed rate.
The reduced size and shape distributions are due to the percentage of material that
does not reside in the spheronization zone for the intended period of time. The number of spheronizers placed in sequence depends on the desired outcome. However, if
only a slight rounding with minimal densiﬁcation is required, one spheronizer witha short residence time will be sufﬁcient.
A commercial manufacturing of pellets using the extrusion/spheronization
process can be accomplished by discharging the formed pellets from the spheronizer
in a continuous ﬂuid bed unit. This provides the semiautomatic commercial setup.
Figure 17 illustrates a typical setup in such an equipment conﬁguration.
Variables in the spheronization step include spheronizer size, charge, disk
speed, and residence time. A number of studies have shown each of the variables

Figure 15 A graphic representation of twin spheronizer shuttle system using two spheronizers
in parallel and shuttle receptacle. (A) When both units are full the shuttle receptacle collects the
extrudate. (B) After one empties, (C) the shuttle box ﬁlls it. (D–F) The cycle repeats itself forthe second unit. (From Ref. 36.)
© 2005 by Taylor & Francis Group, LLC

350

Mehta et al.

Figure 16 Twin spheronizer with extruder. (Courtesy of Niro Pharma Systems.)

has the potential to play a signiﬁcant role in inﬂuencing the physical characteristicsof the resulting product. Hasznos et al. (46) showed that a higher disk speed andlonger residence time increased the coarse fraction and mean diameter and decreased
the ﬁne fraction. The faster speed and longer time also increased the moisture loss
during the process. Since the moisture loss can reduce the plasticity of the particle,
it can have the same effect as an underwet granulation. The particles may not round
off into spheres and stay as deformed cylinders or dumbbells. Higher spheronizer

Figure 17 Typical semicontinuous pellet production setup. (Courtesy of LCI Corporation.)© 2005 by Taylor & Francis Group, LLC

Extrusion/Spheronization as a Granulation Technique351

charges reduced the moisture loss. They also suggested that an interaction between
spheronizer speed and residence time indicated the total number of revolutions of thedisk was critical. A change in one of the variables could be offset by an oppositechange of the other, as long as the total number of revolutions remained constant(46). Hellén et al. showed a similar moisture loss during spheronization. In addition,
they indicated that the major factors inﬂuencing the shape of the spheres were thedisk speed and residence time. High speed and long time produced more sphericalparticles (26). Wan et al. indicated that a minimum disk speed and residence time
was required to round the cylinder-shaped extrudate. Furthermore, an increase in
speed or time, up to a limit, increased the median diameter of the spheres while
higher speeds and longer times caused a reduction in size. Short residence times athigh disk speeds resulted in small but round particles (50).
A number of investigators have reported the effect of disk speed and residence
time on density. Woodruff and Neussle reported the variables to have no effect on
the density of the spheres as compared to the density of the granulation and extrudate (16). These results are in conﬂict with most of the other studies; however, they
are likely due to the use of mineral oil in the formulation. The oil can reduce the frictional forces at the die wall during extrusion and between particles and equipment
surfaces during spheronization. A number of investigators including Malinowski
and Smith reported that an increase in either disk speed or residence time resulted
in an increase in density (20,21,26,47). Mehta et al. studied the effect of spheronization time on the pellet hardness and drug release (2). It was concluded that pellet
hardness changed with spheronization time until about 10 min after which the hardness decreased until the 20 min point. No signiﬁcant difference in pellet hardness
from 20 to 40 min thereafter was observed. Mehta et al. explained this by the densiﬁcation process occurring during the spheronization step. As spheronization time
progresses from time zero to a certain time point ‘‘t’’ the extrudates are cut into uniform particles and shaped into spheres by the centrifugal and frictional forces present in the spheronizer during the operation. These forces act on each and every
particle, making them denser and more spherical with time. However, after a critical
period, no further densiﬁcation occurs with an increase in spheronization time. In
another study, Mehta et al. showed the effect of spheronization time on the porosity
parameters of the pellets (51). It was summarized that a processing period of
2–10 min increased the number of pores and the total pore surface area anddecreased the pore diameter. Beyond this time, for up to 20 min of spheronization
time, the porosity was unchanged.
O’Connor et al. indicated that the friability of placebo spheres decreased withincreasing residence time while the mean particle diameter decreased (24). Erkoboni
et al. showed an increase in extruder screen size resulted in reduced friability (21).
4.5. Drying
Drying is the ﬁnal step in the process. This can be accomplished in any dryer that canbe used for conventional type granulations, including tray dryers, column type ﬂuid
beds, and deck type vibratory ﬂuid beds. Each of the drying techniques has advantages; however, the major differences are based on the rate of water removal. Tray
drying is the slowest of the processes. Fluidized bed dryers result in a much more
rapid drying rate because of the higher air volumes and the potential use of higher
inlet temperatures. Column ﬂuid beds are batch dryers, while the deck type dryers
offer the advantage of a continuous process. Both have been used successfully in© 2005 by Taylor & Francis Group, LLC

352

Mehta et al.

drying product produced by extrusion spheronization. The drying process must be
chosen based on the desired particle properties. For example, pellets to be dried in
ﬂuid bed equipment will have to withstand ﬂuidization process, resist attrition,and maintain its integrity.
Tray drying is a slow process in a static bed. Because of this, it can offer thegreatest opportunity for a drug to migrate toward the surface and recrystallize(52). The more rapid rate in a ﬂuid bed will likely minimize the effects of migration.
This phenomenon can have an effect on a number of particle properties. The increased
active concentration at the surface of the particle can increase the rate of dissolution.
This recrystallization, however, can cause a problem for applications requiring ﬁlm
coating since the smooth surfaces developed by the spheronization process would bedamaged. Additionally, the crushing strength of tray dried particles will likely begreater than their ﬂuid bed counterparts. The slow recrystallization in the static
bed allows for crystal bridges to develop as the ﬂuid is removed and the soluterecrystallizes.

5. FORMULATION VARIABLES
The composition of the wet mass is critical in determining the properties of theparticles produced. This is clearly understood if we look at what material behaviors
are required during each of the process steps. During the granulation step, a plastic
mass is produced—a simple enough task if ended there. The materials must forma plastic mass, deform when extruded and break off to form uniformly sized cylindrical particles. A minimal amount of granulating ﬂuid should migrate to the surface
during extrusion and the particles should stay discrete during collection. During
spheronization the particles must round off to form uniformly sized spheres. They
must not dry out due to temperature or air volume or grow in size due to agglomeration. The fact is that a lot is expected from materials used in this process. Thisis especially true of formulations containing high percentages of active where lowlevels of excipients are used to impart the desired properties to the mass.
The importance of using sphere-forming excipients was noted early on. Conineand Hadley cited the necessity of using microcrystalline cellulose (4). Reynolds went
on to indicate the need for either adhesive or capillary type binders (5). He cited cellulose gums, natural gums, and synthetic polymers as adhesives and microcrystalline
cellulose, talc, and kaolin as capillary type binders. Since then much work has been
conducted in an attempt to understand the signiﬁcance of material properties. Someof the studies are discussed in the following text.
O’Connor et al. studied the behavior of some common excipients in extrusion/
spheronization. The materials were studied as single components using water as the
granulating ﬂuid in an attempt to understand their application in the process. Of thematerials tested, only MCC or MCC with Na-CMC (Na-caboxymethyl cellulose)
was capable of being processed. Others including dicalcium phosphate, lactose,
starch, and modiﬁed starch did not process adequately (24).
In an additional study, they investigated the effect of varying drug, excipient,and excipient:drug ratios. At low drug levels they found the spheronizing excipient
played the most signiﬁcant role in determining sphere properties. They found that,for low dose applications, MCC was the best excipient to use since it formed themost spherical particles. At moderate drug loading (50%), MCC as well as thetwo products consisting of MCC coprocessed with Na-CMC (AvicelÕ RC-581 and© 2005 by Taylor & Francis Group, LLC

Extrusion/Spheronization as a Granulation Technique

353

Avicel CL-611) resulted in acceptable spheres. At higher loading levels, however, theMCC did not yield acceptable spheres and the coprocessed materials did. The
spheres produced using Avicel CL-611 were the most spherical. In addition, theyfound dissolution to be dependent on the type of excipient used, the solubility,
and concentration of the active. Spheres containing MCC remained intact andbehaved as inert matrix systems, while those containing the coprocessed products
formed a gel plug in the dissolution basket and were described as water-swellablehydrogel matrix systems. The release proﬁles for spheres containing each of the excipients and theophylline in a 50:50 ratio are shown in Figure 18.
Release proﬁles for spheres containing different drug loads are shown in
Figure 19.
An increase in drug load resulted in an increased release rate. Release proﬁlesfor spheres containing actives having different solubilities, including chlorpheniramine maleate, quinidine sulfate, theophylline, and hydrochlorothiazide are shownin Figure 20. An increase in drug solubility resulted in an increased release rate (53).
Mehta and Kislalioglu demonstrated the use of polymethacrylate type polymers such as Eudragit L 100–55 and Eudragit S 100 via extrusion/spheronizationin the development of controlled release pellets (13,54). They theorized that forthe development of zero-order controlled release pellets of a poorly soluble drug,
MCC would not be a good choice to form a pellet system via extrusion/spheronization. This would be due to the fact that MCC being insoluble would form a nondisintegrating matrix from which it would be difﬁcult for an insoluble drug to bereleased. In their work they showed that Eudragit L100–55 and Eudragit S 100
can be used as pellet forming and release rate governing polymers for developing
a controlled release drug delivery system with out the use of MCC in the matrix.
Zhou and Vervaet produced matrix pellets by combining microcrystalline
waxes, pregelatinized starches, and hydrolyzed starches with model drugs such as
Ibuprofen, chloroquin phosphate, and others (55). They concluded that the combination of microcrystalline waxes and pregelatinized starches or maltodextrins is a
ﬂexible system for the production of matrix pellets, even with a high drug concentration. Additionally, they concluded that the drug release with such a system could be

Figure 18 Dissolution proﬁles of spheres containing 50% theophylline in different Avicel
MCC types  Avicel PH-101; G, Avicel RC-581; &, Avicel CL-611. (From Ref. 53.)
© 2005 by Taylor & Francis Group, LLC

354

Mehta et al.

Figure 19 Dissolution proﬁles of spheres containing different concentrations of drug in
Avicel CL-611: , 10%; &, 59%; `, 80%. (From Ref. 53.)

modeled by varying the type and the concentration of the wax and the starch. Tapia
et al. described factors inﬂuencing the mechanism of release from sustained releasematrix pellets, produced by the extrusion/spheronization process (56).
Kleinebudde and Jumaa concluded that during the extrusion process, watercontent in the extrudate and pellet porosity were increased as the degree of polymerization of MCC and powder cellulose in the matrix was increased (57).
Millili and Schwartz demonstrated the effect of granulating with water andethanol at various ratios. The physical properties of the spheres changed signiﬁcantly
as the ratio of the two ﬂuids was varied. Spheres could not be formed with absoluteethanol but were possible with 5:95 water:ethanol. An increase in the water fraction
resulted in a decrease in porosity, friability, dissolution, and compressibility and anincrease in density. The porosity of spheres granulated with 95% ethanol was 54%

Figure 20 Dissolution proﬁles of spheres containing 10% drug in Avicel PH 101: , chlorphenarimine maleate; , quinidine sulfate; , theophyline; & hydrochlorothiazide. (From Ref. 53.)
© 2005 by Taylor & Francis Group, LLC

Extrusion/Spheronization as a Granulation Technique355

while the water granulated product had a porosity of 14%. When greater than 30%
water was used, spheres remained intact throughout the dissolution test. As previously discussed, water granulated spheres were very difﬁcult to compress while
spheres granulated with 95% ethanol were signiﬁcantly more compressible than those
prepared using water (18). In contrast, Mehta et al. showed that an increase in granulation water level increased the total number of pores in the pellet matrix withoutchanging the pore diameters (51). Additionally they concluded that this direct
increase in porosity increased the dissolution contact angle due to which dissolutionof the poorly soluble drug was increased. Jerwanska et al. concluded that the rate of
drug release increased with increased levels of granulation liquid because of a greater
degree of porosity obtained after drying (58). They also correlated these results withdifferences in hardness of the pellets. This was similar to the ﬁndings by Mehta et al.
Jerwanska et al. proposed that for a continuous extrusion process, adequate water isrequired to bridge the particles together until liquid saturation in the granulation isachieved. This strategy is necessary to deform the granulation to form extrudates
and consequently shape them into spheres by spheronization. If the granulation waterlevel is below the liquid saturation point, then the spheres obtained will be hard andless porous, thereby leading to decreased drug release rates. Above the liquid saturation point, the hardness and porosity of the pellets are not signiﬁcantly decreased.
A tablet hardness vs. compression forces proﬁle is shown in Figure 21.
In a later study, Millili et al. proposed a bonding mechanism, referred to as
autohesion, to explain the differences in the properties of spheres granulated withwater and ethanol. Autohesion is a term used to describe the strong bonds formedby the interdiffusion of free polymer chain ends across particle–particle interfaces(59).
Using a ram extruder, Harrison et al. demonstrated that steady state ﬂow could
not be achieved with lactose. Additionally, they demonstrated the reduced sensitivityof MCC to small changes in moisture as determined by the force required to induce
plug ﬂow in a cylinder. Comparing MCC to a MCC/lactose blend and 100% lactose,

Figure 21 The effect of varying compression force on the hardness of compacted 16/30mesh spheres of 10% theophylline–Avicel PH101: `, spheres prepared by water; &, spheres
prepared by 95% ethanol granulation. (From Ref. 18.)
© 2005 by Taylor & Francis Group, LLC

356

Mehta et al.

they found that, with lactose, small changes in moisture caused large changes in force
while with MCC, larger changes in moisture were required to have similar effects on
the force (29).
Baert et al. used mixtures of microcrystalline cellulose and coexcipients at various ratios to demonstrate the effect of solubility and the total ﬂuid on extrusion
forces. They showed that if the coexcipient was insoluble, such as dicalcium phosphate, the force required to extrude increased with increasing levels of coexcipient.
When a soluble excipient such as lactose was used, the force required to extrude
decreased with the addition of the initial amounts of lactose. After a certain level,
however, the reduction in force stopped and began to increase. This was due tothe initial solubilization of lactose and the resulting increase in the total ﬂuid level.
Once the ﬂuid was saturated the remaining lactose was not soluble and the force
began to increase. The increase began at about 10% lactose level for a-lactose and
20% for b-lactose. This was due to the difference in solubility between the two materials (33). The effects of dicalcium phosphate and various lactose grades on extrusion
force are shown in Figure 22.
Funck et al. showed that low levels of common binders could be used to produce high drug loaded spheres with microcrystalline cellulose. Materials such as carbomer, Na-CMC, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose(HPMC), povidone (PVP), and pregelatinized starch were used. All materials werecapable of producing spheres of acceptable quality. Dissolution testing showedspheres containing HPC and HPMC remained intact during testing while spheres
containing starch, PVP, and Na-CMC disintegrated (60).
Lender and Kleinebudde reported that spheres produced with powdered cellulose had higher porosity and faster dissolution than those made using microcrystalline cellulose. Spheres could not be produced using only powdered cellulose anddrug; a binder was required. The higher porosity of the spheres prepared from powdered cellulose may be beneﬁcial for applications requiring compression (61).

Figure 22 Inﬂuence of the amount of lactose or dicalcium phosphate dehydrate (% total
weight) on the extrusion forces (N) for mixtures of lactose or dicalcium phosphate dehydrate–Avicel PH 101–water after granulation with a planetary mixer. Each end point is themean of six values. The SD is lower than 3% for each point. Six different types of lactose wereused: &, a-lactose monohydrate 80 mesh; , a-lactose monohydrate 200 mesh; , a-lactose
monohydrate 325 mesh; &, spray dried lactose DCL 11; , anhydrous b-lactose DCL 21; ,anhydrous a-lactose DCL 30. One type of dicalcium phosphate dehydrate was used, G. (FromRef. 33.)© 2005 by Taylor & Francis Group, LLC

Extrusion/Spheronization as a Granulation Technique

357

Feilden et al. showed that increasing the particle size of lactose resulted in forced
ﬂow and high extrusion forces, which resulted in poor quality extrudate and spheres having a wide size distribution. This was attributed to the increased pore diameter of the mixture containing the coarse lactose which allowed greater movement of water (62).
Chien and Nuessle (63) showed the use of a surfactant, such as sodium laurylsulfate, reduced the migration of drug to the surface of the sphere during drying by
reducing the surface tension of the granulating ﬂuid. The reduction in surface tension
also made it difﬁcult to produce a cohesive extrudate in some cases.
Some miscellaneous observations include the following. Reynolds reported
that excess extrudate friability can be overcome by incorporating more MCC, binder, or water in the granulation (5). Erkoboni et al. indicated that sphere hardness
was most affected by the level of MCC in the formulation and the level of granulating ﬂuid used (21). Hileman et al. showed that MCC had a narrower water range
over which quality spheres could be made than MCC coprocessed Na-CMC (47).
Hellén et al. showed that the surface characteristics were inﬂuenced by the waterlevel with higher water levels giving smoother surfaces (26). Mehta et al. showed thatwhen concentrations of pellet forming and release rate governing polymers in thematrix were changed, it altered the dissolution kinetics of a poorly soluble drug (2).

6. COMPRESSION OF PELLETS
Typically, pellets are produced for administering in a capsule dosage form after manufacturing with desired modiﬁed release properties. These pellets can be compressed
into tablets as well. The tablets are normally intended to disintegrate into discretepellets in the gastrointestinal tract and the drug should be subsequently be released
in a controlled manner from the individual pellets. One challenge in the productionof such tablets is maintaining the desired drug release after compaction, as the application of a compaction pressure can lead to structural changes in the ﬁlm coating
and consequently, altered drug release. Numerous investigations have been madeinto the compaction of pellets, coated or uncoated. It is imperative that the coatedpellets do not lose their release properties during the compression stage. Pellets havebeen shown to react differently to compaction and consolidation than powders of thesame material. Wang et al. reported compression of various lactose/microcrystalline
cellulose compositions in powder or pellet form (64). Schwartz et al. (17) demonstrated the compaction characteristics of MCC processed into spheres are signiﬁcantly different than the original powder. The powder material forms hardcompacts at low compression forces, while the spheres are not compressible andform soft compacts, even at high forces. They indicated that spheres prepared from
MCC showed a high degree of viscoelasticity over the entire compression range.
Inclusion of coexcipients such as lactose and dicalcium phosphate increase the compactability by decreasing the viscoelastic resistance or pressure range over which thespheres behave elastically. A reduction in viscoelastic resistance was seen withspheres containing both lactose and dicalcium phosphate; however, dicalcium phosphate had a greater effect. Compaction proﬁles of spheres containing 10% theophylline with MCC, MCC/DCP, or MCC/lactose in a 22.5/67.5 ratio are shown in
Figure 23.
A similar phenomenon was reported by Maganti and Celik when pellets produced by rotor granulation were compressed (65). They compared the compaction
behavior of pellet formulations, mainly consisting of MCC, to that of the powders© 2005 by Taylor & Francis Group, LLC

358

Mehta et al.

Figure 23 The effect of excipients on the compaction proﬁle of spheres. Compaction proﬁlesof spheres containing 10% theophylline with either MCC, MCC–DCP, or MCC–lactose ina 22.5:67.5 ratio using the Leunberger model. (From Ref. 17.)from which they were formed and also found signiﬁcant differences. The powders
examined were found to compact by plastic deformation and produced strong compacts, while the pellets exhibited elastic deformation and brittle fragmentation,
resulting in compacts of lower tensile strength. This can be explained by the fact thatthe pellets, which are large and spherical in shape as compared to the small, irregularpowder particles they are composed of, have a low surface-to-volume ratio, whichmight result in a decreased area of contact between the particles as they consolidate.
Nicklasson (66) investigated the compression behavior of pellets consisting of MCC,
with or without other excipients such as polyethylene glycol and DCP. Deformationof the aggregates was found to depend on three deformation characteristics, namely,
the capacity for, the mode of and the resistance to deformation. High surface deformation refers to the great ability of the pellets to conform to the surface of the surrounding pellets. In pellets containing the soft component, the primary particles canreposition within the agglomerate and the ability to ﬁll the intragranular pore spaceis increased. For pellets containing hard materials, the compaction stress may give
local failure at pellet surfaces. Thus, the material properties of the primary particles
constituting the pellets are important for the compression behavior of pellets. In
number of studies (67,68) various soft materials have been incorporated in pellets
to modify their deformability and compatibility. Nicklasson and Alderborn (69) studied the modulation of the tableting behavior of pellets through the incorporation ofpolyethylene glycol and found that these soft pellets had an increased propensity to
deform and altered mode of deformation to the relatively hard MCC pellets. Iloañusi
et al. (67) found MCC-based bead formulations incorporating wax to be more compressible than those made without wax. Salako et al. (68) found that pellets containing theophylline and MCC were hard and less brittle than the ones containing
glyceryl monostearate which were soft pellets. The soft pellets were found to fracture
under low compression pressures and were able to form a coherent network of
deformable material in the tablets at higher pressures. The hard pellets were unable© 2005 by Taylor & Francis Group, LLC

Extrusion/Spheronization as a Granulation Technique359

to form such a network at high pressures and found to reduce more in volume
without bond formation than soft pellets.
The size of the pellets can also have a bearing on their compression behavior.
Small pellets have been shown to be less affected than larger ones by the compaction
process (70,71). Smaller beads were signiﬁcantly stronger, relative to their size, thanlarger ones. Researchers also found that larger pellets were much more readily
deformed (71). The application of coating to the pellet core can inﬂuence their compression characteristics. Magnati et al. (72) added a water-based ethyl cellulose coating (Surelease) to the MCC-based pellets previously used (65) and thereby altered
their deformation characteristics, introducing plastoelastic properties whereas previously they had been brittle and elastic. The overall ability of the pellets to deform,
both plastically and elastically, increased with an increasing coating level. Miller et al.
(73) investigated the mechanical properties of tablets compressed from pellets coatedwith Surelease to that of uncoated pellets and found them to be comparable with the
exception of the diametrical strain, which increased on coating. This was attributed
to the ﬂexibility of the plasticized ethyl cellulose, allowing greater deformation of thecompact to occur before failure.
It has been found that coated pellets can be compressed into tablets while
retaining controlled release of the drug, provided that the effect of excipients andcompression force is considered and determined. The protective effect of an excipientis dependent on the particle size and the compaction characteristics of the material.
In general, materials that deform plastically, such as MCC and PEG, give the bestprotective effect (74–77). Yuasa et al. studied the protective effect of 14 different
excipients and were able to correlate the plastic energy percentage to the release rate,that is, materials that deform plastically were shown to protect the coating best (78).
However, Stubberud et al. found that lactose, a fragmented material, gives better
protection than MCC (79). The compressed induced changes in the structure of aﬁlm coating may depend on formulation factors, such as the type and the thicknessof the coating, the properties and the structure of the substrate pellets, and theincorporation of excipient particles.
The optimum amount of excipients incorporated in the tablet formulation was
concluded to be 30% (80). Palmieri et al. (81) showed that tablets consisting of maximum 40% coated granules had acceptable release proﬁles, using MCC as the tablet
excipient. Wagner et al. (82) concluded that a tablet content of 70% (w/w) of pellets,
approximately 1 mm diameter, is a critical level resulting in pronounced damage tothe coating. On reducing the pellet proportion to 60% (w/w), tablets fulﬁlling thecompendial dissolution requirements for enteric-coated products can be prepared.
Tunón (83) investigated factors that inﬂuence the preparation of modiﬁed releasepellets, its compression behavior, inﬂuence of inter- and intragranular factors andrelease of drug release of pellets. The most frequently encountered explanation forthe loss of modiﬁed release upon compaction, in terms of an increased drug releaserate, is the occurrence of cracks in the coating. However, knowledge of why and how
cracks are formed in the coating and techniques to avoid them is highly valuable inthe development of multiple unit tablets containing pellets.

7. CONCLUSIONS
Extrusion/spheronization is a versatile process capable of producing granules or
spheres having unique physical properties. Since it may be more labor and time© 2005 by Taylor & Francis Group, LLC

360

Mehta et al.

intensive than the more common granulation techniques, it should be considered
as a granulating technique when the desired properties cannot be produced using
more conventional techniques. Potential applications are many including both
immediate and controlled release. Regardless of the application, care must be taken
to understand the desired properties and the formulation and process variables capable of achieving them. The use of statistical experimental design for formulationand process development is strongly recommended due to the high degree of interactions between the variables. Lastly, new technologies such as hot melt extrusionand spheronization (HME) are gaining considerable interest in the pharmaceutical
drug delivery arena for solving speciﬁc problems such as enhancing taste masking,improving solubility and drug bioavailability and in general for controlled releasedrug delivery. Compression of pellets into modiﬁed release multiple unit dosage form
is now possible once the proper understanding of the formulation of the core pellets,
type of coating, and protective excipients to maintain the coating integrity of thepellets is understood.

REFERENCES
1. Erkoboni D. Extrusion–spheronization for granulation. Parikh DM, ed. Handbook of
Pharmaceutical Granulation Technology. New York: Marcel Dekker, 1997.
2. Mehta KA, Kislalioglu MS, Phuapradit W, Malick AW, Shah NH. Effect of formulationand process variables on matrix erosion and drug release from a multiunit erosion matrix
of a poorly soluble drug. Pharm Technol 2002; February:26–34.
3. Nakahara, US Patent 3,277,520, October 1966.
4. Conine JW, Hadley HR. Preparation of small solid pharmaceutical spheres. Drug Cosmet Ind 1970; 106:38–41.
5. Reynolds AD. A new technique for the production of spherical particles. Manuf Chem
Aerosol News 1970; 41:40–43.
6. Mehta KA, Kislalioglu MS, Phuapradit W, Malick AW, Ke J, Shah NH. In vivo release
performance of nifedipine in dogs from a novel Eudragit based multi-unit erosion matrix.
Drug Deliv Technol 2002; 2(2):38–42.
7. Young CR, Koleng JJ, McGinity JW. Production of spherical pellets by a hot-melt extrusion and spheronization process. Int J Pharm 2002; 242:87–92.
8. Breitenbach J, Mägerlein M. Melt extruded molecular dispersions. Ghebre-Sellassie I, ed.
Pharmaceutical Extrusion Technology. New York: Marcel Dekker, 2003.
9. Oshlack B, et al. US Patent 6,706,281, issued March 16, 2004.
10. McGinity J, Repka M. Hot melt extruded ﬁlms. Drug Deliv Technol 2004; 4(7):40–47.
11. Sood A, Ashokraj Y, Panchagnula R. Use of extrusion spenronization to develop controlled release dosage forms for diltiazem hydrochloride. Pharm Tech 2004; April:62–85.
12. Jalal IM, Malinowski HJ, Smith WE. Tablet granulations composed of spherical-shaped
particles. J Pharm Sci 1972; 61:1466–1468.
13. Mehta KA, Kislalioglu MS, Phuapradit W, Malick AW, Shah NH. Release performanceof a poorly soluble drug from a novel Eudragit based multi-unit erosion matrix. Int
J Pharm 2001; 213:7–12.
14. Clarke, GM, Newton JM, Short MB. Comparative gastrointestinal transit of pellet systems of varying density. Int J Pharm 1995; 114:1–11.
15. Devereus JE, Newton JM, Short MB. The inﬂuence of density on the gastrointestinal
transit of pellets. J Pharm Pharmacol 1990; 42:500–501.
16. Woodruff CW, Nuessle NO. Effect of processing variables on particles obtained by
extrusion-spheronization. J Pharm Sci 1972; 61:787–790.
© 2005 by Taylor & Francis Group, LLC

Extrusion/Spheronization as a Granulation Technique361

17. Schwartz JP, Nguyen NH, Schnaare RL. Compaction studies on beads: compression andconsolidation parameters. Drug Dev Ind Pharm 1994; 20:3105–3129.
18. Millili GP, Schwartz JB. The strength of microcrystalline cellulose pellets: the effect of
granulating with water/ethanol mixtures. Drug Dev Ind Pharm 1990; 16:1411–1426.
19. Malinowski HJ, Smith WE. Effect of spheronization process variables on selected tablet
properties. J Pharm Sci 1974; 63:285–288.
20. Malinowski HJ, Smith WE. Use of factorial design to evaluate granulations prepared byspheronization. J Pharm Sci 1975; 64:1688–1692.
21. Erkoboni DF, Fiore SA, Wheatley TA, Davan T. The effect of various process and formulation variables on the quality of spheres produced by extrusion/spheronization. Poster presentation, AAPS National Meeting, 1991.
22. Chariot M, Francès J, Lewis GA, Mathieu D, Phan Tan Luu R, Stevens HNE. A factorial approach to process variables of extrusion-spheronization of wet powder masses.
Drug Dev Ind Pharm 1987; 13:1639–1649.
23. Hileman GA, Goskonda SR, Spalitto AJ, Upadrashta SM. Response surface optimization of high dose pellets by extrusion and spheronization. Int J Pharm 1993; 100:71–79.
24. O’Connor RE, Holinez J, Schwartz JB. Spheronization I: processing and evaluation of
spheres prepared from commercially available excipients. Am J Pharm 1984; 156:80–87.
25. Ojile JE, Macfarlane CB, Selkirk AB. Drug distribution during massing and its effect ondose uniformity in granules. Int J Pharm 1982; 10:99–107.
26. Hellén L, Yliruusi J, Merkku P, Kristoffersson E. Process variables of instant granulator
and spheronizer: I. Physical properties of granules, extrudate and pellets. Int J Pharm
1993; 96:197–204.
27. Kleinebudde P, Lindner H. Experiments with a twin screw extruder using a single-stepgranulation/extrusion process. Int J Pharm 1993; 94:49–58.
28. Lindberg NO, Tufvesson C, Holm P, Olbjer L. Extrusion of an effervescent granulation
with a twin screw extruder, Baker Perkins MPF 50 D. Inﬂuence on intragranular porosityand liquid saturation. Drug Dev Ind Pharm 1988; 14:1791–1798.
29. Harrison PJ, Newton JM, Rowe RC. The characterization of wet powder masses suitablefor extrusion/spheronization. J Pharm Pharmacol 1985; 37:686–691.
30. Landı́n M, Rowe RC, York P. Characterization of wet powder masses with a mixer torque rheometer. 3. Nonlinear effects of shaft speed and sample weight. J Pharm Sci 1995;
85:557–560.
31. Baert L, Remon JP, Knight P, Newton JM. A comparison between the extrusion forces
and sphere quality of a gravity feed extruder and a ram extruder. Int J Pharm 1992;
86:187–192.
32. Baert L, Fanara D, De Baets P, Remon JP. Instrumentation of a gravity feed extruder
and the inﬂuence of the composition of binary and tertiary mixtures on the extrusion
forces. J Pharm Pharmacol 1991; 43:745–749.
33. Ku CC, Joshi YM, Bergum JS, Jain NB. Bead manufacture by extrusion/spheronization—a statistical design for process optimization. Drug Dev Ind Pharm 1993;
19:1505–1519.
34. Rowe RC. Spheronization: a noval pill-making process? Pharm Int 1985; 6:119–123.
35. Harrison PJ, Newton JM, Rowe RC. The application of capillary rheometry to the extrusion of wet masses. J Pharm 1987; 35:235–242.
36. Hicks DC, Freese HL. Extrusion and spheronization equipment. Ghebre-Sellassie I, ed.
Pharmaceutical Pelletization Technology, Chap. 4. New York: Marcel Dekker, 1989:71–
100.
37. Harrison PJ, Newton JM, Rowe RC. Flow defects in wet powder masses. J Pharm Pharmacol 1984; 37:81–83.
38. Harrison PJ, Newton JM, Rowe RC. Congergent ﬂow analysis in the extrusion of wet
powder masses. J Pharm Pharmacol 1984; 37:81–83.
39. Fechner P, Wartewig S, Fueting M, Heilmann A, Neubert R, Kleinebudde P. Propertiesof microcrystalline cellulose and powder cellulose after extrusion/spheronization as© 2005 by Taylor & Francis Group, LLC

362

40.

41.

42.
43.
44.

45.

46.

47.

48.
49.
50.

51.

52.
53.

54.
55.

56.
57.
58.
59.
60.

Mehta et al.
studied by Fourier transform Raman spectroscopy and environmental scanning electron
microscopy. AAPS PharmSci 2003; 5(4):Article 31.
Pinto JF, Buckton G, Newton JM. The inﬂuence of four selected processing and formulation factors on the production of spheres by extrusion and spheronization. Int J Pharm
1992; 83:187–196.
Hellén L, Ritala J, Yliruusi P, Palmroos A, Kristoffersson E. Process variables of theradial screen extruder: I. Production capacity of the extruder and the properties of the
extrudate. J Pharm Tech Int 1992; 4:50–60.
Vervaet C, Baert L, Risha PA, Remon JP. The inﬂuence of the extrusion screen on pellet
quality using an instrumented basket extruder. Int J Pharm 1994; 107:29–39.
Baert L, Remon JP, Elbers JAC, Van Bommel EMG. Comparison between a gravity feed
extruder and a twin screw extruder. Int J Pharm 1993; 99:7–12.
Shah R, Kabadi M, Pope DG, Augsberger LL. Physico-mechanical characterization of
the extrusion/spheronization process. Part I. Instrumentation of the extruder. Pharm
Res 1994; 11:355–360.
O’Connor RE, Schwartz JB. Extrusion and spheronization technology. Ghebre-Sellassie
I, ed. Pharmaceutical Pelletization Technology, Chap. 9. New York: Marcel Dekker,
1989:187–216.
Hasznos L, Langer I, Gyarmathy M. Some factors inﬂuencing pellet characteristics madeby an extrusion/spheronization process. Part I. Effects on size characteristics and moisture content decrease of pellets. Drug Dev Ind Pharm 1992; 18:409–437.
Hileman GA, Goskonda SR, Spalitto AJ, Upadrashta SM. A factorial approach to highdose product development by an extrusion/spheronization process. Drug Dev Ind Pharm
1993; 19:483–491.
Baert L, Remon JP. Inﬂuence of amount of granulating liquid on the drug release ratefrom pellets made by extrusion spheronization. Int J Pharm 1993; 95:135–141.
Wan LSC, Heng PWS, Liew CV. Spheronization conditions on spheroid shape and size.
Int J Pharm 1993; 96:59–65.
Mehta KA, Kislalioglu MS, Phuapradit W, Malick AW, Shah NH. Effect of formulationand process variables on porosity parameters and release rates from a multi unit erosion
matrix of a poorly soluble drug. J Control Release 2000; 63:201–211.
Dyer AM, Khan KA, Aulton ME. Effect of the drying method on the mechanical anddrug release properties of pellets prepared by extrusion. Drug Dev Ind Pharm 1994;
20:3045–3068.
O’Connor RE, Schwartz JB. Spheronization II: Drug release from drug–diluent mixtures. Drug Dev Ind Pharm 1985; 11:1837–1857.
Mehta KA, Kislalioglu MS, Phuapradit W, Malick AW, Shah NH. Multi-unit controlled
release systems of nifedipine and nifedipine: Pluronic F-68 solid dispersions: characterization of release mechanisms. Drug Dev Ind Pharm 2002; 28(3):275–285.
Zhou F, Vervaet C, Remon JP. Matrix pellets based on the combination of waxes,
starches and maltodextrins. Int J Pharm 1996; 133:155–160.
Kleinebudde P, Jumaa M, El Saleh F. Inﬂuence of degree of polymerization on behaviorof cellulose during homogenization and extrusion/spheronization. AAPS PharmSci 2000;
2(2):Article 21.
Jerwanska E, Alderborn G, Newton JM, Nystrom C. The effect of water content on theporosity and liquid saturation of extruded cylinders. Int J Pharm 1995; 121:65–71.
Millili GP, Wigent RJ, Schwartz JB. Autohesion in pharmaceutical solids. Drug Dev Ind
Pharm 1990; 16:2383–2407.
Maganti L, Celik M. Compaction studies on pellets I. Uncoated pellets. Int J Pharm
1993; 95:29–42.
Funck JAB, Schwartz JB, Reilly WJ, Ghali ES. Binder effectiveness for beads with highdrug levels. Drug Dev Ind Pharm 1991; 17:1143–1156.
Linder H, Kleinebudde P. Use of powdered cellulose for the production of pellets byextrusion/spheronization. J Pharm Pharmacol 1994; 46:2–7.

© 2005 by Taylor & Francis Group, LLC

Extrusion/Spheronization as a Granulation Technique363

61. Fielden KE, Newton JM, Rowe RC. The inﬂuence of lactose particle size on the spheronization of extrudate processed by a ram extruder. Int J Pharm 1992; 81:205–224.
62. Vervaet C, Baert L, Remon JP. Extrusion–spheronization: a literature review. Int
J Pharm 1995; 116:131–146.
63. Tapia C, Buckton G, Newton JM. Factors inﬂuencing the mechanism of release fromsustained release matrix pellets, produced by extrusion/spheronization. Int J Pharm
1993; 92:211–218.
64. Chien TY, Nuessle NO. Factors inﬂuencing migration during spheronization. Pharm
Technol 1985; 4:44–48.
65. Wang C, Zhang G, Shah NH, Infeld MH, Malick AW, McGinity JW. Compaction properties of spheronized binary granular mixtures. Drug Dev Ind Pharm 1995; 21:753–779.
66. Nicklasson F. Compression Mechanics of Pharmaceutical Aggregates—Studies on the
Tabletting of Spheronized Aggregates with Varying Composition and Porosity Ph.D.
Thesis, Uppsala University, Sweden, 2000.
67. Iloañusi NO, Schwartz JB. The effect of wax on compaction of microcrystalline cellulose
beads made by extrusion and spheronization. Drug Dev Ind Pharm 1998; 24:37–44.
68. Salako M, Podczeck F, Newton JM. Investigations into the deformability and tensile
strength of pellets. Int J Pharm 1998; 168:49–57.
69. Nicklasson F, Alderborn G. Modulation of the tableting behavior of microcrystalline cellulose pellets by the incorporation of polyethylene glycol. Eur J Pharm Sci 1999; 9:57–65.
70. Haslam JL, Forbes AE, Rork GS, Ripkin TL, Slade DA, Khossravi D. Tableting of controlled release multiparticulates, the effect of millisphere size and protective overcoating.
Int J Pharm 1998; 173:233–242.
71. Johansson B, Nicklasson F, Alderborn G. Effect of pellet size on degree of deformationand densiﬁcation during compression and on compactability of microcrystalline cellulose
pellets. Int J Pharm 1998; 163:35–48.
72. Maganti L, Celik M. Compaction studies on pellets II. Coated pellets. Int J Pharm 1994;
103:55–67.
73. Miller RA, Leung EMK, Oates RJ. The compression of spheres coated with an aqueous
ethylcellulose dispersion. Drug Dev Ind Pharm 1999; 16:1411–1426.
74. Béchard SR, Leroux JC. Coated palletized dosage form: effect of compaction on drug
release. Drug Dev Ind Pharm 1992; 18:1927–1944.
75. Torrado JJ, Augsburger LL. Effect of different excipients on the tableting of coated particles. Int J Pharm 1994; 106:149–155.
76. Beckert TE, Lehmann K, Schmidt PC. Compression of enteric-coated pellets to disintegrating tablets. Int J Pharm 1996; 143:13–23.
77. Haubitz H, Mehnert W, Frömming KH. Preparation of theophylline multiple units
tablets. Pharm Ind 1996; 58:83–86.
78. Yuassa H, Takashima Y, Omata T, Kanaya Y. Studies on stress dispersion in tablets III.
Suppression of fracture of coated ﬁlm by an excipients during the preparation of tablets
containing particles. STP Pharm Sci 2001; 11:221–227.
79. Stubberrud L, Eriksson M, Kordnejad K, Graffner C. Water–solid interactions. IV.
Inﬂuence of moisture sorption on the compaction of ﬁlm-coated particles. Pharm Dev
Technol 1998; 3:141–151.
80. Lehmann K, Petereit HU, Dreher D. Scnellzerfallende Tabletten mit gesteuerter Wirkstoffabgabe. Pharm Ind 1993; 55:940–947.
81. Palmieri GF, Wehrlé P, Martelli S. Drug release from compressed Eudragit RS 30D
coated beads. STP Pharm Sci 1996; 6:118–121.
82. Wagner KG, Krumme M, Beckert TE, Schmidt PC. Development of disintegrating multiple-unit tablets on a high-speed rotary tablet press. Eur J Pharm Biopharm 2000;
50:285–291.
83. Tunón Å. Preparation of Tablets from Reservoir Pellets with an Emphasis on the Compression Behavior and Drug Release. Ph.D. Thesis, Uppsala University, Sweden, 2003.

© 2005 by Taylor & Francis Group, LLC

12
Effervescent Granulation
Guia Bertuzzi
IMA S.p.A, Solid Dose Division, Bologna, Italy

1. INTRODUCTION
Effervescent granulation is an important step in the production of ﬁzzy dosage forms
that, most of the time, cannot be avoided to achieve the desired characteristics of theeffervescent tablets. It is also very critical because it can affect the stability of the
ﬁnal dosage forms.
The ﬁrst effervescent preparations were described over two centuries ago in theofﬁcial compendia; they were in powder form for use as cathartic salts. Later, in
1815, a patent described ‘‘a combination of neutral salt or powder which possesses
all the properties of the medicinal spring of Seidlitz in Germany, under the nameof Seidlitz Powders,’’ which contains sodium potassium tartarate, sodium bicarbonate, and tartaric acid, in the proportions 3:1:1, respectively (1). Effervescentgranules and tablets have become more and more popular as the dosage form
because they are readily soluble and easy to consume just by drinking the glass ofwater where they are dissolved.
To state the growing interest in such forms, in the 1980s—when electronic
bibliography searching was not available yet—the results of a literature search about
effervescent forms were published so as to help scientists working on new
developments (2).
According to the 4th edition of the European Pharmacopoeia, the effervescentforms are deﬁned as those granules or tablets that are to be dissolved in water before
administration to patients. Effervescent tablets or granules are uncoated and generally contain acidic substances and carbonate or bicarbonate which reacts rapidly torelease carbon dioxide when dissolved in water. Disintegration of the tablets usuallyoccurs within 2 min or even less, due to the evolution of carbon dioxide.
Effervescent forms have many advantages over conventional pharmaceuticalforms. They substitute liquid forms when the active ingredient is less stable in liquid
form because they can be administered only by ﬁrst dissolving the tablet in water.
Active ingredients that are not stable in liquid form are often more stable in theeffervescent form. Their administration is easy and is particularly helpful to patients,
for instance, children, who are not able to swallow capsules or tablets. They havea pleasant taste due to carbonation, which helps to mask the bad taste of certain drugs.
365© 2005 by Taylor & Francis Group, LLC

366

BertuzziThis could help to avoid the gastric side effect of certain drugs. In certain cases they
can shorten drug absorption rate in the body when compared to traditional tablets,with a quicker therapeutic effect (3). They are easy to use and appeal to consumers
more than the traditional dosage forms because of their color and ﬁzzy appearance.
Disadvantages of such solid dosage forms are more related to production technology even if processing methods and equipment are the same as the conventional
ones. The general product requirements are similar to conventional granules: particle
size distribution and shape, uniformity of active distribution, to produce satisfactoryfree-ﬂowing granules, capable of being tableted using high-speed rotary tablet press.
However, it is also necessary to focus attention on some aspects of the procedure,
including compression and packaging because effervescent dosage forms—irrespectiveof whether it is a sachet or a tablet—are larger and consequently difﬁcult to produce.
The pharmaceutical industry has faced many problems, especially in the preparation of effervescent tablets as it is certainly the application for which the choiceof the processing equipment is at least as important as the formulation design.

2. THE EFFERVESCENT REACTION
Effervescence is the evolution of gas bubbles from a liquid, as the result of a chemical
reaction. The most common reaction for pharmaceutical purpose is the acid–basereaction between sodium bicarbonate and citric acid:
3NaHCO3 ðaqÞ þ H3 C6 H5 O7 ðaqÞ ) 3H2 OðaqÞ þ 3CO2 þ 3Na3 C6 H5 O7 ðaqÞ252gð3molÞ

192gð1molÞ

54gð3molÞ

132gð3molÞ

258gð1molÞThis reaction starts in presence of water, even with a very small amount as catalyzing agent, and because water is one of the reaction products, it will accelerate therate of reaction, leading to difﬁculty in stopping the reaction. For this reason thewhole manufacturing and storage of effervescent products has to be planned byminimizing the contact with water. Looking at the stechiometric ratios in the reaction it is quite easy to understand the reason why effervescent tablets are so large.
Recently, some effervescent systems have been prepared that act as penetration
enhancers for drug absorption, not only in oral forms but also in some topical forms,
such as skin or vaginal applications. In these cases the reaction takes place directly
after administration, in the mouth due to saliva (4), upon the wounds due to blood
serum (5), or when formulated in a suppository. The effervescence can be provokedby the moisture of the vaginal mucosa to treat vaginal infections or by simply adjusting the pH.
There are other forms in which effervescence is based on a reaction different
from carbon dioxide formation. Effervescence is due to reactants that evolve oxygenor other gases, which are safe for human consumption even if they are not suitablefor oral administration but can be employed in preparations for external use such as
antibacterial for dental plate cleaning.

3. FORMULATIONThe criteria to choose the raw materials for effervescent products are not very different from those for conventional tablets, since in both cases good compressibility andcompactability are the targets to be achieved.
© 2005 by Taylor & Francis Group, LLC

Effervescent Granulation

367

The intrinsic characteristics of effervescent forms bring some considerations
that limit the choice of the raw material, including the selection of the active ingredient. Moisture content of the raw material is a very signiﬁcant aspect, because it
affects compressibility and stability of the tablets. To avoid premature effervescent
reaction during the process or once the tablets are formed, raw materials with very
low moisture content have to be used.
Since an effervescent tablet is required to dissolve within 2 min or less in a glassof water (about 100 mL), the solubility of raw materials and their rate of solubility
are other signiﬁcant parameters. The active ingredient must be soluble, water dispersible, or at least solubilized by salt formation during the dissolution in the glass ofwater. The rest of the excipients, such as additives like sweeteners, coloring agents,
ﬂavors, also have to be water soluble.
For all the above considerations the list of the excipients has not changed since
many years. However, the physical properties of these raw materials have recently
improved. Many different grades for each material are now commercially available,
also including also some preformulated grades, which are highly recommended for
direct compression. Formulators must choose the excipient grade on the basis of
the active ingredient, tablet size, and the process technology available. Therefore,
the ultimate use of the effervescent granules or tablets mainly affects the choiceof the raw materials.
To design an effervescent formula it is necessary to consider the stechiometricratios in the reaction, and the carbon dioxide solubility in water, which is 90 mg/
100 mL of water (in STP conditions). The suggested ratio between acid and alkaline
components is about 0.6 but sometimes it might be required to increase the acidsource to get a pleasant taste. In fact, the alkali–acid ratio controls both the effervescence capacity and the taste of the solution to be administered.
When the solubility of the active ingredients is not pH dependent, the alkali–acidratio can be optionally selected. This ratio can also be determined according to the pHthat is required for dissolving the active ingredient. In fact, when the active solubility
increases at the acid side, the pH of the solution is lowered by adding an excess of
the acidic agent. Conversely, an excess of alkaline source must be added when the active
ingredient is more soluble at higher pH (6). However, another approach that can beused to increase the active ingredient solubility is to increase the volume of carbon
dioxide to be generated by increasing the alkaline component in the formulation.
As far as other excipients, such as diluents or binders, are concerned there is avery little freedom for the formulator to experiment, because of the large dimensionof the tablet required for effervescent systems. In addition, compressibility cannot beenhanced by additional binders for effervescent dosage form, because of the larger
size of the tablet.
In the latest development in effervescent forms, some formulations have been
designed to control the rate of effervescence, so to obtain a rapid, intermediate, or
slow rate. The rate control is strictly related to the acid–alkaline components ratio,
but the chemical properties of the effervescent excipients or their combinations canhave inﬂuence on it, especially when a slow rate of effervescence is required.

4. RAW MATERIALS
Because of the nature of the effervescence reaction, additional excipients are sparingly used as the alkaline and acid ingredients also act as ﬁllers to get a tablet bulk.
© 2005 by Taylor & Francis Group, LLC

368

Bertuzzi

They are in a so large an amount that effervescent tablets are much larger than conventional ones. In case it is necessary to add a ﬁller, sodium bicarbonate is the material of choice due to its lower cost and because it does not inﬂuence ﬁnal pH of thesolution and it also increases the effervescence effect. Sodium chloride and sodium
sulfate are other possible ﬁllers. They are high-density crystalline powders that arevery compatible with the other ingredients.
Additives are added in a small amount to obtain tablets that are more attractive
to users. Flavors, colors, and sweeteners are used as usual in all the formulations.
4.1. Acid Materials
Necessary acidity for effervescence can be provided by three main sources: foodacids, acid anhydrides, and acid salts. Citric acid, tartaric acid, and ascorbic acidare the most commonly used food acids because they are odorless, have a nice taste,
are not expensive, and are easy to handle.
4.1.1. Citric Acid
Citric acid is the more often used acidic ingredient because of its good solubility andpleasant taste. It is commercially available in powder form and is either colorless orexist as white crystals. The particle-size grades are: coarse, medium, ﬁne, powder(only anhydrous). It is very soluble in water and soluble in ethanol (7). It can be used
as monohydrate or anhydrate, depending on the selected equipment, technology,
and process conditions. It is very hygroscopic; however, the anhydrous form is lesshygroscopic than the monohydrate (8). However, caking of the anhydrous may
occur upon prolonged storage at humidity >70%. The monohydrate melts at
100 C, and releases the water of hydration at 75 C. For this reason, it can be used
as a binder source in hot melt granulation.
4.1.2. Tartaric Acid
It is very soluble in water and very hygroscopic compared to citric acid. In the effervescence reaction with sodium bicarbonate it behaves like citric acid in producing anevident effervescence. It must be used in a higher amount to get the proper stoichiometric proportions, because it is a diprotic acid, while citric acid is a triprotic one.
In terms of compressibility it is comparable to citric acid (8).
4.1.3. Ascorbic Acid
It is white in crystalline form and light yellow in ﬁne powder. It is not hygroscopic
and this may be helpful in production because it is easier to handle. It is freely soluble in water (1 g in about 3 mL) and absolute ethanol (9). If exposed to light, it gradually darkens. Its behavior in the effervescent reaction with sodium bicarbonate iscomparable to the other acids (citric and tartaric) in terms of release rate of carbon
dioxide.
4.1.4. Acid Anhydrides
Anhydrides of food acids are potential acid source as they are precursors of the corresponding acid on hydrolyzation. The effervescent effect is strong and sustained by
the continuous production of acid in the solution. Water has to be avoided during© 2005 by Taylor & Francis Group, LLC

Effervescent Granulation369

the whole process when anhydrides are part of a formulation. Otherwise they would
be hydrolyzed to the corresponding acid before their use in the product (10).
4.1.5. Acids Salts
Sodium dihydrogen phosphate and disodium dihydrogen pyrophosphate are acidsalts that have been used in effervescent formulation. They are soluble in water, producing acid solution and react quickly with alkaline sources. They are commerciallyavailable either as granules or powder.
4.1.6. Other Less Frequent Sources of Acid
 Fumaric and nicotinic acids, which are not hygroscopic, but have low watersolubility.
 Malic acid has recently been introduced in effervescent formulations becauseof its smooth and light taste. It is highly hygroscopic and soluble but hasless acid strength than tartaric or citric acids.
 Acetylsalicylic acid, though an active ingredient that is very commonly administered in effervescent preparations, cannot be used as an acid source becauseof its low water solubility.
 Adipic acid deserves to be mentioned even if it does not function as an acidsource because of its low water solubility. It has given good results as
a lubricant for effervescent calcium carbonate tablets (11).
4.2. Sources of Carbon Dioxide
Solid carbonates salts are the most popular source for effervescents; bicarbonate
forms are more reactive than carbonates.
4.2.1. Sodium Bicarbonate
Sodium bicarbonate is the major source of carbon dioxide in effervescent forms andis able to provide a yield of 52% of carbon dioxide. It is commercially available inﬁve grades according to particle size, from free-ﬂowing uniform granule to ﬁne powder, which are odorless and slightly alkaline in taste. When heated, the bicarbonate isconverted into anhydrous sodium carbonate. This reaction is time and temperaturedependent. Ninety percent of the conversion is achieved within 75 min at 93 C, but
dehydration starts at 50 C, which must be considered as a critical temperature inprocessing (12).
Being a nonelastic material sodium bicarbonate has a very low compressibility
but this issue has been overcome since its production by spray-drying technique.
Direct compressible grades are now available but contain some additives such as
polyvinylpyrrolidone (PVP) or silicone oil.
4.2.2. Sodium Carbonate
Sodium carbonate is commercially available in three different forms, all very soluble
in water: anhydrous, monohydrate, or decahydrate (13). It is more resistant to theeffervescent reaction and in some formulations can be used as a stabilizing agent
in amounts not exceeding the 10% of the batch size. It is used as a stabilizing agent
in certain effervescent formulas because it absorbs moisture preferentially, preventing the effervescent reaction from starting. Of course the anhydrous form is the© 2005 by Taylor & Francis Group, LLC

370

Bertuzzi

preferred choice for this purpose. Recently, a particular grade of sodium bicarbonate
has been produced as round-shaped particles, coated with a carbonate layer toincrease bicarbonate stability (14).
4.2.3. Potassium Bicarbonate and Potassium Carbonate
They substitute the sodium salts when sodium ion is not required (15). They are lesssoluble than the corresponding sodium salts and are more expensive.
4.2.4. Calcium Carbonate
Precipitated calcium carbonate occurs as ﬁne, white, odorless, and tasteless powder
or crystals. Its water solubility is very poor, and it is not soluble in ethanol or isopropanol. It is a high density powder, and thus not suitable for compression. It is
normally used as a drug in effervescent tablets for patients who suffer from calcium
deﬁciency. It can also be used as alkaline source because it provides stability to theeffervescent system (16).
4.2.5. Sodium Glycine Carbonate
Sodium glycine carbonate provides a light effervescence reaction, but causes rapid
disintegration of the tablets, so it has been applied in the preparation of fastdissolving sublingual tablets. It is much more compressible than the other alkaline
compounds and has been found suitable for direct compression (17).
4.3. Binders
The use of a binder in effervescent formulations is limited by the fact that any binder,
even if water soluble, will retard the tablet disintegration. Therefore, the amount ofbinder in a given formula will be a compromise between desired granule strength anddesired disintegration time.
As will be described in Section 5.1.2, water itself is an effective binder for effervescent granules when granulated with all the components together. A small amountof water, very ﬁnely distributed on the powder bed, acts as a binder by partially dissolving the raw materials so that they can be agglomerated. Other solvents, ethanol
and isopropanol are not binders themselves, but can be used as granulating liquids todissolve dry binders.
Binders for dry granulation, such as lactose, mannitol, dextrose, are almost
inappropriate, because they would be effective only in larger amount than thatallowed by an effervescent formulations. The binder choice in wet granulation is also
limited by the method of production and consequently by the amount of granulating
liquid.
In case of granulation of both the alkaline and acid components together withwater, it would not make sense to put a binder in the formulation because the small
water amount will never be able to dissolve the binder.
The most popular binder for effervescent tablets is polyvinylpyrrolidone(PVP). Types K25 and K30 are preferred for their water solubility and dissolution
rate which is an important parameter for the ﬁnal purpose of effervescent tablets.
PVP is effective at low percentage in the formula, starting from 2% and over. It is
feasible either for dry or wet granulation. It is soluble in water, alcohols, andhydroalcoholic liquids (18).
© 2005 by Taylor & Francis Group, LLC

Effervescent Granulation

371

4.4. Lubricants
Because tableting is a critical step in effervescent production, selecting the lubricant
is one of the most important issues. Lubrication of the effervescent mixture is quite
problematic because of the chemical–physical nature of the lubricants. Most of the
lubricants, because of their low water solubility, inhibit the tablet disintegration,
which, as already said, must be very rapid in case of effervescent tablets. The effervescent tablets—mainly for marketing reasons—are often required to provide a clear
transparent solution, that is, without any insoluble ‘‘scum’’ forming on the water
surface, or any residue left. In selecting a lubricant, proper attention must be given
to its solubility in water along with its compatibility with the active ingredient.
Many different lubricants have been tested for a long time to establish the mostappropriate one for effervescent tablets (19), including the opportunity to carry out
external lubrication of the granules directly in the dies of the tablet-press.
Lubricant substances which are reported in literature as suitable for effervescent manufacturing because they are water soluble are: sodium benzoate, sodium
acetate, L-leucine, and Carbowax 4000. A very recent application is a combinationof calcium and potassium sorbates, micronized polyethylene glycol with calcium
ascorbate or trisodium citrate (20). Combination of spray-dried L-leucine and polyethylene glycol 6000 has been reported as a successful lubricant in the literature(21). Other less soluble lubricants have been used in formulating effervescent tablets,
however, a balance should be found between compression efﬁciency and watersolubility. Magnesium stearate is also employed but the most suitable, commerciallyavailable type is its combination with sodium lauryl sulfate, a surface-active agent
that helps in its dispersion (22).
4.5. Additives: Sweeteners, Coloring Agents, and Flavors
Coloring agents can include all the dyes soluble and suitable for food, such as thosethe F.D.&C. ones and all the natural coloring substances in amounts varying in therange of 0.1–3.5% of the total weight of the formulation.
Flavors can be selected from synthetic ﬂavors or natural extracts. Lemon,orange, and other fruit essences are particularly suitable to obtain organoleptic
requirement in amounts varying from 0.5% to 3.0% of the total weight of theformulation.
5. MANUFACTURING OF EFFERVESCENT FORMS
Manufacturing conditions are crucially important even with regards to stability ofthe products after they have been packed. Almost all the raw materials used for effervescent tablet manufacturing are hygroscopic, and hence moisture absorption fromthe air must be prevented to avoid the effervescent reaction prior to use of thetablets.
The whole production process as shown in Figure 1 (dosing of the ingredients,
mixing or granulating, lubricating, tableting, and packaging) can be carried out incompletely closed and integrated handling system, consisting of intermediate bulk
containers (IBCs), tumblers for IBCs, docking and dosing stations.
In this case only the packaging area will be ventilated with low moisture content of air. Otherwise traditional open handling systems can be employed but thewhole facility has to be conditioned with air at minimum level of moisture content© 2005 by Taylor & Francis Group, LLC

372

Bertuzzi

Figure 1 Integrated production plant.

(23). In fact, the suggested conditions throughout the plant are: relative humidity(RH) below 20% and uniform temperature at 21 C. It is known, however, that
25% RH at controlled room temperature (25 C) is enough to avoid instability causedby atmospheric moisture (24).
Manufacturing effervescent drugs on a large scale is usually done using a semicontinuous procedure, by paying attention to synchronize all the process steps, inorder to achieve the largest production throughput. A continuous process ﬂow, with
continuous feeding of raw materials and collection of granules, can be performed by
extrusion of the wet mass and drying in a continuous ﬂuid bed dryer. Granulation ofeffervescent mixtures must, most of the times, be executed in batches and is deﬁnitely
the most critical step of this particular kind of pharmaceutical manufacturing, as itstrongly inﬂuences the characteristics of the ﬁnal forms, granules or tablets, and consequently the following steps of production. Lubrication of the granulation,© 2005 by Taylor & Francis Group, LLC

Effervescent Granulation

373

compression of tablets, and packaging of effervescent tablets should be carefullyplanned to produce a suitable effervescent product.
The critical issues discussed earlier, for the compression of effervescent granules, are related to the low compressibility of the majority of the raw materials,
large dimensions of the tablets, poor content of binder in the formulation, and difﬁculties of lubricating the mixture. For all these reasons the tableting phase has to be
carried out carefully, and even the choice of the tablet press is of great importance.
To overcome lubrication difﬁculties, some suppliers of tablet press have developed
equipment that is capable of carrying out external lubrication of the granules. Antiadherent materials are sprayed directly into the dies of the tablet press, during thepause phase of compression, so as to prevent sticking of granules upon dies andpunches. External lubrication is not as good a method as using lubricant substances
to disperse in the granules. It is not considered the best solution for lubrication
because it is considered less compliant to the standard GMP (good manufacturing
practices) rules; In addition, the assembling and disassembling of the tablet press
is complex. An alternative method to obtain better tablets, facilitating the compression, is to tablet the granules while they are still slightly wet, or not dried yet as weare still considering very low moisture content of <1%. Tablets are then dried andstabilized by means of a process step in a static ventilated oven.
Packaging operations for both granules and tablets must be done, as alreadymentioned, in a low humidity environment. The critical aspects about packaging
of effervescent drugs are obviously related to stability of the tablets and granules
and the main objective is to protect them, as much as possible, not only during
packaging operations but also after they are packed, so as to impart a reasonableshelf-life. The oldest packaging method for effervescent preparations consisted ofwrapping the acid and alkaline components separately, to avoid the premature effervescent reaction until use. All the effervescent drugs can be packed in individual dose
units, in airtight containers made of protective aluminum foil or plastic laminates.
Tablets can also be packed by stacking them one by one in plastic or metal tubes,
which have almost the same diameter of the tablets so as to minimize the air which
remains in contact with the tablets. The tubes must be resealed every time, after taking out each tablet.
Certain tablets are also wrapped in an aluminum foil before packaging in the
tube and this seems to be the best solution for long-term stability. Patented types oftubes containing silica-gel in the internal side of the cap are the most recent invention(25).
For tablets that are packed in strips, it is essential that the packaging machine
has a ﬁne control over the temperature of the welding unit, so that an accurate sealing of the strips can be obtained and overheating phenomenon that could provoke
release of residual water from the tablets can be avoided (24).
5.1. Granulation Methods
Two main granulation methods have been known for a long time. The 1911 editionof the British Pharmacopoeia reported a detailed description of the manufacturing
procedure (26).
Effervescent granules are made by mixing citric and tartaric acids with the
medicament, and the sodium bicarbonate with the sugar when present; and thenthoroughly mixing the one with the other, and granulating the resulting mixture
by stirring in a pan heated to between 93 and 104 , passing through sieves of© 2005 by Taylor & Francis Group, LLC

374

Bertuzzi
a suitable size, and drying at temperature not exceeding 54 . This method for
preparing the granules yields satisfactory results but the following alternative
method has also been suggested: Mix the sodium bicarbonate, the sugar, andthe medicament, pass the mixture through a No 20 to No 30 stainless steel sieve,
subject the mixed acids to the same process, and thoroughly mix the two sifted
powders. Place the mixed powders in layers on suitable dish, pan or glass tray,heated to 75 to 85 , if required but not exceeding the higher temperature. Whenthe mass, after being suitably kneaded and compressed, has assumed a uniform
plastic condition, suitable for granulation, rub it to a No 5 to No 10 stainlesssteel sieve, according to the size of granules desired, and dry the granules at
a temperature not exceeding 50 .

Only a few aspects have substantially changed in the modern methods. Twomain methods can be executed with various types of granulation equipment:a. Single-step method. All the components of an effervescent formula are
granulated together, handled with care, running the process in an contained manner to maintain the stability of the mixture until the step iscompleted. This single-step method is normally carried out using dry
granulation, hot-melt granulation, and certain wet granulation processes.
b. Multistep method. The alkaline and the acid components are granulated
separately, then mixed together, just before the tableting or packaging
step. Usually these are also typical applications of wet granulation technologies.
5.1.1. Dry Granulation
Dry granulation by roller compactor is deﬁnitely the most appropriate method for its
simplicity, low costs, and higher product throughput. The number of operations andspace required are less and consequently, air ventilation is reduced. On the other
hand, not all the excipient grades are suitable for such a technology. More sophisticated grades, and thus expensive, pre-prepared by raw material bulk suppliers are
required.
An alternate process to dry granulation is direct compression of the blend of all
the raw materials, in the attempt to avoid operating and stability problems. It would
be the ideal process for effervescent tablet manufacturing, but its application is limited to a few cases, for example, when the active ingredient cannot be granulated(e.g., when it is already included in a complex like with a cyclodextrine), or contains
some water of crystallization.
5.1.2. Wet Granulation
Despite some disadvantages, wet granulation is still the most preferred method foreffervescent granulation. As required for conventional tablets, this method assures
homogeneous granules, suitable for compression, and is able to provide uniform
tablets either in terms of weight or active ingredient content.
For this technique, it is necessary to use a granulating liquid that might interact
with the powders initiating the effervescent reaction. Hence it is essential to handle
the process with great care.
A wet granulation process in two separate steps is mostly recommended andsuitable for conventional equipment like high-shear granulator-dryer and ﬂuid bed
processor. Acidic and alkaline ingredients are granulated separately. The two granules are then mixed together, just before adding the lubricant for tableting. Water,© 2005 by Taylor & Francis Group, LLC

Effervescent Granulation

375

Figure 2 Alternative granulation processes.

alcohols, or hydroalcoholic solutions can be used as a binding liquid because thisprocess is a standard wet granulation process. The usual procedure is to granulate
only one of the effervescent sources and add the other one in powder in the ﬁnal
blending. All these possibilities are illustrated in Figure 2.
In certain cases only the acid components of the formulation are granulated
and then mixed with the sodium bicarbonate, preferably when it is of ﬁne granular
grade. Other additives such as ﬂavors and lubricants can then be added and mixed.
This approach increases productivity and reduces costs since one granulation stephas been eliminated.
The peculiar process that distinguishes effervescent granulation consists in asingle-step granulation of all the components of the formulation, which can be performed either with nonreactive or reactive liquids with reference to the effervescence
reaction.
5.1.3. Single-Step Granulation
Single-step granulation process provides dry effervescent granules directly by granulating the acid and the alkaline materials together. It is possible to use only water
as the granulating liquid, thus controlling the effervescent reaction to granulate.
A nonreactive liquid like absolute ethanol or isopropanol can also be used, but inthis case it is necessary to use a binder to agglomerate the raw material particles.
5.1.3.1. Process with Water. A very small amount of water, less than 1% of
the batch size, can be used to initiate the effervescent reaction. Some carbon dioxide
is released, but some water too, which acts as the binding liquid as well. It takes a few
minutes (from 5 to10 min) to obtain wet granules. The effervescent reaction rate
rapidly increases and becomes difﬁcult to stop; it must however be terminated very
quickly otherwise no product will remain. An immediate start of the drying of the
granules will control and stop the effervescent reaction. For single-step technology,
both ﬂuid bed granulator and high-shear granulator-dryer are suitable.
© 2005 by Taylor & Francis Group, LLC

376

Bertuzzi

In high-shear granulator-dryer technology it is possible to suddenly switch to
drying phase by creating vacuum inside the bowl, just after the granulation phasewhen wet granules are well massed. Vacuum is created in a few seconds, which
immediately provokes the decrease of the water boiling point down to about
20 C. At the same time the bowl is heated up to provide more energy for water
evaporation. The water released on the granules surface is removed within a few
seconds and the effervescent reaction stops.
The application of microwave radiation, combined with vacuum inside thebowl of the high-shear granulator (27), can also be used to stop the effervescent reaction and to dry the effervescent granules (28).
Drying of effervescent granules is a shorter process than drying conventional
granules granulated with water, because of the very small amount of water involvedin the process. However, drying still remains a critical step since it is very hard to
remove, even the small quantity of water, from hydrophilic or hygroscopic materials.
Typical drying time is about 50 min for 20 kg batch of effervescent granulation undervacuum. See Figure 3 for comparison of drying of conventional and effervescentgranules by vacuum technology.
Drying rate for effervescent granules is lower because the moisture content tobe removed is in a range below 2% of the batch size. Consequently, the drying time,
passing from pilot scale to industrial scale, does not increase as much as for conventional granules (Fig. 4).
The great advantage of this method for effervescent tablet preparation lies in
the installation of equipment that does not require explosion-proof systems. An
example of effervescent aspirin produced in 600 L high-shear granulator-dryer
equipped with vacuum and tilting bowl (29) is shown in Figure 5.
The formulation consists of:Anhydrous citric acid
Sodium bicarbonate
Sodium carbonate
Acetylsalicylic acid116.6 kg
154.2 kg
39.2 kg
50 kg

Figure 3 Drying rate of effervescent granules, compared to conventional granules.
© 2005 by Taylor & Francis Group, LLC

Effervescent Granulation

377

Figure 4 Drying time scale up for high-shear granulator-dryer.

First, the effervescent system is granulated with very small amounts of water(2–4 mL/kg) and sprayed in very ﬁne droplets. The acetylsalicylic acid is added
later, in the ﬁnal blending, after granulation is completed. The results of threebatches are reported in Table 1.

Figure 5 ‘‘Rotocube’’ high-shear granulator-dryer equipped with vacuum and tilting bowl.
© 2005 by Taylor & Francis Group, LLC

378

Table 1 Granules Produced with Single-Step Technology in a High-Shear Granulator-Dryer
Results of samples
Yield

Acid
neutralizing power(185 mL
0.1 N acid/tablet)pH(6.0–6.4)

244.6

6.1

6.4

Batch
size (kg)kg%

Batch #1
granulated with
720 mL of water(2 mL/kg)

360

352.2

97.80

30

0.048%

93.44

60
90
30

< 0.01%< 0.01%< 0.01%< 0.015%< 0.01%

244.6

89.86

60
After
discharge
60

0.075%

229.8

After
discharge< 0.01%

245.5

Batch #3
granulated with
1440 mL of water(4 mL/kg).
Note: no tiltingof the bowl while
drying© 2005 by Taylor & Francis Group, LLC

360

360

336.4

323.5

6.25

Bertuzzi

Batch
code

Batch #2
granulated with
1440 mL of water(4 mL/kg)

Sampling
time (min)Moisturecontent(0.1%)

Effervescent Granulation

379

The lower yield of the third batch is due to product sticking to the walls of thebowl, which could not be discharged. The reason why it happened is related to theset parameters during drying phase: in batch #3, drying was performed by keeping
the bowl static, instead of tilting it as in the other batches. The batch size in actual
production was then increased to 644 kg in 1400 L equipment.
All the components of an effervescent mixture can be granulated together ina single-step process in a conventional ﬂuid bed granulator-dryer. Granulation occurs
when water is sprayed on the ﬂuidized bed, initiating the effervescent reaction. The
reaction is stopped when water is not sprayed anymore and drying phase is carriedout with warm dry air. It is quite understandable that this method is difﬁcult tocontrol and reproduce (30). A subsequent patent application (31) describes animprovement of the method reproducibility, which can be achieved by controllingthe air humidity (it has to be less than 1 g/m3), using an hydroalcoholic solution
instead of water. Even better results in controlling the effervescent reaction areachieved when spraying and drying phase are combined together.
It is, however, very difﬁcult to reproduce such a process. Therefore, an alternative procedure to manufacture effervescent granules has been invented using a rotor
ﬂuid bed spray-granulator (32).
Warm air, which is the only method available for drying in ﬂuid bed technology, is not capable of stopping the reaction all at once as it happens by applying
vacuum inside the processing bowl. Therefore, the only way to proceed is tominimize in some way the contact between the two components of the effervescentsystem. An intelligent and brilliant hypothesis put forward by Professors P. Gautierand J.M. Aiache (32) is to alternate the granulation of the acid materials with that ofalkaline materials while still using a single equipment such as a rotary ﬂuid bed system. In the literature a vitamin C formulation is reported to explain this technique
but other active ingredients can also be used (33).
The process consists of two or three continuous steps to produce effervescentspheres by layering the acid components over alkaline spheres or vice versa. The
binding liquid is, however, a hydroalcoholic solution in which PVP the binder must
be previously dissolved.
The ﬁrst step is the granulation of alkaline components in the rotary ﬂuid bed.
In the second step, the granulating solution is sprayed in combination with the acidic
powders, which deposit on the alkaline spheres creating an external acid layer separated by a neutral layer of the binder. When agglomeration is completed, drying
phase with hot air starts with no interruptions (32).
5.1.3.2. Process with Alcohol or Hydroalcoholic Solution. As reported in theprevious example, it is sometimes preferable to granulate with a hydroalcoholic solution to initiate a lighter effervescence so as to keep the reaction under better control
during the process. Use of alcohols is indispensable in case a binder like PVP is
included in the formulation. In fact, the amount of water required to dissolve
PVP to obtain the binding action will be too high, and it will not be possible to keep
the effervescent reaction under control.
As already suggested for a conventional granulation process that requires theuse of an inﬂammable liquid, it is convenient to install fully explosion-proof equipment with an accessory solvent-recovery utility that will limit the emission of vapors
in the atmosphere. Solvent recovery will be more advantageous while drying undervacuum than with a ﬂuid bed.
© 2005 by Taylor & Francis Group, LLC

380

Bertuzzi

Certain high-shear granulator-dryers are equipped to achieve 99% of solvent
recovery by installing a tank to collect the condensate, and by bringing down thepossible residual exhaust with a shower of water.
5.1.4. Hot Melt Granulation
Hot melt process is an alternative technology to wet granulation (which is discussed
in detail in another chapter of this book). Agglomeration of the particles of a powder
mixer can be achieved by melting hydrated citric acid so as to release the hydrationwater which acts as the granulating liquid. Once granules are formed it is necessary
to cool them to achieve the proper hardness and mechanical stability. There are twodifferent techniques: Surface hot melt granulation (SHMG), which consists of mixing all the raw
materials together in a blender and then drying the mix in a tray oven at
90 C. Water is then released from citric acid and other ingredients to form
granules (34). Unfortunately, batch reproducibility of this method is verylow.
 Hot melt granulation is normally carried out in high-shear granulator-dryer
with the capability to heat up the bowl. In certain cases the released waterof hydration of citric acid initiates the effervescent reaction to produce
additional water which acts as the binding liquid. However, this process
for obvious reasons is difﬁcult to control. The same process has been
applied to ﬂuid bed spray-granulator where low melting point polymers,
like polyethylene glycols (PEGs) or polyoxyethylene glycols can also be
used as binders (35).
5.1.4.1. Hot Melt Extrusion. Hot melt extrusion is a recent patented method
to produce effervescent granules, especially dedicated to produce granules having acontrollable rate of effervescence (36). The formulations for this technology must
contain a hot-melt extrudable binder. Preferred binders are the polyethylene glycols
with molecular weight in the range 1000–8000 Da, but some other polymers havebeen investigated. Binder percentage varies according to the formulation in a rangeof 20–40% of the total weight. There are two main extrusion techniques to carry out
in extruders that must be equipped with a solid conveying zone, multiple separate
temperature controllable heating zones, and an extrusion die:a. A blend of all the ingredients, including the active ingredient of the formulation, is hot-melt extruded at high temperature, in order to melt orsoften the binder. The extrudate is then ground or chopped to obtaineffervescent granules.
b. The acidic agent and the hot-melt binder are formulated in the right proportions to obtain an eutectic mixture that has decreased the melting
point temperature. This binary mixture is separately melted, the alkaline
agent is added as powder in the next step. The melted mixture is thenextruded, chopped, or ground as in the previous method.
To control the effervescence rate of the ﬁnal dosage form, it is possible toadjust some parameters like the temperature and the rate of extrusion. The temperature range selected can be critical because degradation of the active agent may occur
alongside decomposition of the effervescent components. This range is usually fromabout 50 C to about 120 C.
© 2005 by Taylor & Francis Group, LLC

Dry granulation
Slugging or
laminating

Process
Equipment
Numberof steps
Estimatedtime (h)Advantages

Disadvantages

DirectCompression

Granulation by heating

Wet granulation
Granulation þ drying(two steps)

Granulation þ drying(one step)

Surface hot
melt granulation

Hot melt
granulation
Single-pot mixergranulator-dryer
5

Mixer þ ﬂuid
bed dryer
6

Single-pot
mixer-granulator-dryer
4

Blender þ tablet
press compactor
6

Blender
3

Blender þ tray
dryer
6

23

10

22

14

15

12

Fast process

No producttransfers
No granulation

No granulating
liquidTotally closed

No producttransfers
No granulating
liquidBatch
reproducibility

Batch
reproducibility

Loss ofeffervescence

Difﬁcult tocarry out

Difﬁcult
to cleanDifﬁcult
to clean

Dusty process

Long time

Difﬁcult
to cleanHigh manpower
required

Dusty process

No producttransfers
No granulation
Raw materials
at low residual
moisture

Note

Short time
Raw materials
for direct compression
at low residual
moisture (moreexpensive)

Obsolete

Effervescent Granulation

Table 2 Manufacturing Process for Effervescent Tablets

High manpower
required
Rarely applied381© 2005 by Taylor & Francis Group, LLC

382

Bertuzzi

The rate of extrusion is related to the time of materials exposure to high temperature which is usually less than 5 min.
The hot-melt extrusion technology in some cases can be run as a continuous
process, having a higher throughput than batch hot-melt granulation process perbatches.
All the previous sections provided an overview of all the possible technologies
to manufacture effervescent granules but how to choose the most appropriate technique for a certain formulation. An interesting study to ﬁgure out the best production method for effervescent tablets was presented by Laugier and Rona (Table 2)(37).
Three technologies were evaluated: dry granulation, hot melt granulation, andwet granulation. The choice of the process technology was strictly related to the physical properties of the raw materials, namely particle size, density, ﬂowability, andmoisture content. Moisture content is deﬁnitely the most signiﬁcant parameter since
the powder mixture has less than 0.2–0.3% of moisture content. It would be stable
but difﬁcult to tablet and pointing such a situation, a wet granulation process isrequired.
The use of high-shear granulator-dryer has been found as the more economic
and ﬂexible production method by other researchers (38) as well. This technology
allows us to use a wider range of excipient grades, avoiding problems related toparticle size or moisture content of the raw materials. Even if the granules producedby this technology appear ﬁner, their ﬂow properties are good despite the large
fraction of ﬁne-sized particles. Tableting properties are always in line within thespeciﬁcations.

REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.

Homan P. Pharm J 2001; 267:911–936 (http://www.pharmj.com).
NCF. December 1984 pp. 19–22; May 1985 pp. 21–23.
Moller PL, Norholt et al. J Clin Pharmacol 2000; 40(4):370–378.
US Patent 6,200,604, 1999.
Rapp M. PCT Int Appl 2000.
US Patent 6,077,536, 1998.
Handbook of Pharmaceutical Excipients. Washington/London: The American Pharmaceutical Association/The Pharmaceutical Society of Great Britain, 1986:78–80.
Schmidt PC, Brögmann B. Dtsch Apoth-Ztg 1987; 127:991–997.
Handbook of Pharmaceutical Excipients. Washington/London: The American
Pharmaceutical Association/The Pharmaceutical Society of Great Britain, 1986:6–8.
Repta AJ, Higuchi T. J Pharm Sci 1969; 58:1110–1113.
Romaco Zanchetta R&D Laboratory archive.
Handbook of Pharmaceutical Excipients. Washington/London: The American Pharmaceutical Association/The Pharmaceutical Society of Great Britain, 1986:263–265.
Handbook of Pharmaceutical Excipients. Washington/London: The American
Pharmaceutical Association/The Pharmaceutical Society of Great Britain, 1986:436–438.
SPI Pharma Group. Fall 2001.
Duvall RN, Gold, G. Miles, Inc., USA, 1990, 6 pp.
US Patent 6,242,002, 1999.
US Patent 6,284,272, 1999.
Handbook of Pharmaceutical Excipients. Washington/London: The American Pharmaceutical Association/The Pharmaceutical Society of Great Britain, 1986:234–239.

© 2005 by Taylor & Francis Group, LLC

Effervescent Granulation

383

19. Strickland WA Jr, Higuchi T, Busse L. J Am. Pharm. Assoc. (Sci. Ed.), 1956; 45:51–55.
20. Daher LJ. Bayer Corporation, USA. US Patent 1999, 6 pp.
21. Rotthaeuser B, Kraus G, Schmidt PC. Pharmazeutisches Institut, Eberhard-Karls-Univ.,
Tuebingen, Germany. Pharmazeutische Industrie 1998; 60(6).
22. Rudnic E, Schwartz JB. Oral Solid Dosage Forms, Chapter 45, Tablets, 861, Remington.
23. Armandou J-P, Mattha AG. Pharm Acta Helv 1982; 57:287–289.
24. Mohrle R. Effervescent tablets. Lieberman HA, Lachman L, eds. Pharmaceutical Solid
Dosage Forms. Vol. 1. New York: Marcel Dekker, 1980:225–258.
25. http://www.desiccantcity.com/CASE_HISTORIES/History11.htm.
26. The British Pharmaceutical Codex. Published by direction of the Council of the Pharmaceutical Society of Great Britain, 1911 (http://www.scocca.org/herbmed/eclectic/
bpc1911/granulae.html).
27. Collette News Vol. 2, Issue 1, May 2001, GEA Powder Technology Division.
28. Aiache JM, Cardot JM. Utilisation des micro-ondes dans la fabrication des formes
pharmacutiques. Conf. INSA Roeuen, 1999.
29. Romaco Zanchetta R&D Laboratory Archive.
30. Coletta V, Kennon L. J Pharm Sci 1964; 53:1524–1525.
31. Patent EP 673,644.
32. Gauthier P, Aiache J-M. Pharm Technol Eur 2001; 13(10):32 (see also p. 34 andpp. 36–37).
33. US Patent 6,210,711, 1999.
34. Yanze FM, Duru C, Jacob M. Laboratoire de pharmacie galenique, pharmacotechnie
et de Biopharmacie, Universite Montpellier I, UFR de Sciences Pharmaceutiques,
Montpellier, France, Die pharmazie 12/2000.
35. Yanze FM, Duru C, Jacob M. Drug Dev Ind Pharm 2000; 26(11):1167–1176.
36. US Patent 6,488,961, 1999.
37. Laugier M, Rona R. PMPS Spring 2002:26–28.
38. Pearlswig DM. Simulation Modeling Applied to the Single Pot Processing ofEffervescent Tablets. Master’s Thesis, North Carolina State University, Raleigh, NC.

© 2005 by Taylor & Francis Group, LLC

13Melt Granulation and Pelletization
T. W. Wong
Faculty of Pharmacy, University of Technology MARA, Selangor, Malaysia

W. S. Cheong and P. W. S. Heng
National University of Singapore, Singapore

1. INTRODUCTION
Melt granulation and melt pelletization are agglomeration processes that havegathered increasing interest in the pharmaceutical industry for the concept of utilizing a molten liquid as a binder. Unlike the conventional use of aqueous or organic
solvents as binders, the binding liquid in melt processes remains as a constituentof the formulation. However, the basic principles in melt agglomeration processes
are relatively similar to those of wet agglomeration processes with solvents exceptthat the interpretation of the melt agglomeration processes is not complicated byan evaporation of the molten binding liquid.
1.1. Overview of Agglomeration
Agglomeration is one of the key pharmaceutical manufacturing processes concerning
the conversion of ﬁne solid particles into larger entities by agitating the ﬁne solid particles in the presence of a binding liquid using equipment such as tumbling drum,
ﬂuid bed granulator, and high-shear mixer. The agglomeration is considered asa wet process because a binding liquid is required for the wetting of solid particles
prior to agglomeration. The agglomerates formed have a speciﬁc mean size andshape, improved ﬂowability and mechanical strength, narrow bulk density and porosity values, as well as, a modiﬁed drug release rate (1,2). Agglomerates can be classiﬁed into two types: granules and pellets, based on their physical characteristics.
Granules are irregularly shaped agglomerates which have a rather wide size distribution, typically within the range of 0.1–2 mm. Pellets are spherical agglomerates witha narrow size distribution, within the range of 0.5–2 mm. Traditionally, the binding
liquid required for agglomeration of ﬁne solid particles is aqueous or organic solvent. The solid particles are held together by the binding liquid which provides
temporary binding force by means of liquid bridges, and subsequently by solid
bridges of the residual solute after the removal of solvent by evaporation. The hardness of solid bridges largely determines the strength of the dried agglomerates (3).
385
© 2005 by Taylor & Francis Group, LLC

386

Wong et al.

The solid bridges can also be formed by the resolidiﬁcation of molten material. Thisis the basis by which meltable materials can be used as a binder in agglomeration.
1.2. Development of Melt Processes
The concept of using molten binding liquid for agglomeration instead of the conventional binding liquid prepared from aqueous or organic solvent that has to be evaporated off after agglomeration is completed was reported in some researchﬁndings in the late 1970s and early 1980s (4–6). However, the concept was not widely
studied until more than a decade later and the period thereafter, using high-shear
mixer and ﬂuidizing granulator as the processors for melt agglomeration (7–27).
High-shear mixer has gained greater popularity for use in melt agglomeration thanother equipment such as coating pan (4), drum granulator (28,29) or extruder(30–34) for it provides intense shear forces from the high-speed rotation of theimpeller. The impeller mixing action facilitates a more homogenous distribution ofmolten binding liquid, leading to the formation of agglomerates with narrower size
distribution and uniform drug content. In addition, the meltable binder can bebrought to melting by the frictional heat generated from the high shearing forcesof the impeller, without external heat supply (8). Highly spherical pellets can be produced by a continuous agglomeration and rounding effect of the high-speed impeller
rotation in a high-shear mixer.
The characteristics of melt agglomerates such as size, size distribution, andshape change progressively with variations in processing and formulation parameters. The melt agglomeration process can be broadly classiﬁed as melt granulation
or melt pelletization, based on the physical properties of the formed agglomerates(35). For simplicity of presentation, melt agglomeration will be used as the term
representing both melt pelletization and melt granulation, and melt agglomerates
as the term for their resultant products in this discussion.
1.3. Requirement of Melt Agglomeration
Melt agglomeration is carried out by adding the binder to the ﬁne solid particles
either in the form of a molten liquid or in the form of a solid that melts during
the process. Generally, an amount of 10–30% w/w of binder, with respect to thatof ﬁne solid particles, is used. The melting temperature of solid binder can beachieved by external heat supply or heat generated from interparticulate friction during high-speed mixing in the processor. A meltable binder suitable for melt agglomeration has a melting point typically within the range of 50–100 C. Meltable binders
with melting point lower than 50 C are generally unsuitable as the end products areliable to melting, softening, or sticking during handling and storage. On the other
hand, binders of high melting temperatures are not desirable due to greater risksof thermal instability to the drugs used when very high heat is required for the melting of the binders. The meltable binder can be classiﬁed as hydrophilic or hydrophobic. Examples of hydrophilic binders include polyethylene glycols and poloxamers.
Hydrophobic binders include fatty acids, fatty alcohols, waxes, and glycerides.
Hydrophilic meltable binders are used to prepare immediate-release dosage forms
while the hydrophobic meltable binders are preferred for prolonged-release formulations. One or more meltable binders may be employed in the formulation of a batchof melt agglomerates. The binding action of meltable binders can be manifested
through liquid bridges formed by the molten liquid. Alternatively, a softened© 2005 by Taylor & Francis Group, LLC

Melt Granulation and Pelletization

387

semisolid can act as a binder (6,36). The local melting zone on the surface of asemisolid binder could promote particle aggregation and subsequently agglomerate
growth. Nonetheless, a higher binder content up to 50% w/w was possible as there
was less binding liquid available for agglomerative action for a given weight of meltable binder (6). Furthermore, the process of melt agglomeration is less sensitive
to the level of binder when softened semisolid is used as a binder. Frequently, theprocess of agglomeration which employs softened semisolid binder is termed asthermoplastic agglomeration.
The ﬁne solid particles can be organic or inorganic in origin and in melt
agglomeration studies, inert substances commonly employed are lactose and dicalcium phosphate. The melting point of ﬁne solid particles should be at least 20 C
higher than that of the maximum processing temperature. This prevents excessive
softening of the solid particles as they form the support for the molten binding liquid
during the building-up process of agglomerate structure. The ﬁne solid particles may
be constituted by one or more components. The physicochemical characteristics ofboth meltable binders and nonmeltable ﬁne solid particles have crucial effects on
the outcome of a melt agglomeration and will be discussed in Section 3.
1.4. Advantages of Melt Agglomeration
The growing interest in melt agglomeration has largely been attributed to various
advantages of melt agglomeration which are not attainable using the conventional
wet agglomeration techniques. With an appropriate selection of meltable binders,both immediate-and prolonged-release agglomerates can be prepared using a onestep, one-processor approach (14,37–42). Melt agglomeration is applicable for processing of water-sensitive materials such as effervescent excipients and hygroscopic
drugs, thus omitting the use of either aqueous or organic solvent (43,44). With melt
methods, organic solvent, ﬂame-proof facilities, and solvent recovery equipment are
not required, giving rise to lower cost of operation, and reduced ecological and toxicological hazards. In addition, the formative process of melt agglomerates does not
require a drying phase and this shortens the total processing time. Melt agglomeration is an ideal model for the elucidation of an agglomeration process as the processof particle binding is not complicated by an evaporation of molten binding liquid
unlike the aqueous and nonaqueous wet agglomeration. Moreover, the physicochemical properties of the molten binding liquid are potentially modiﬁable by incorporating an additive (45).
Despite the various advantages offered by melt agglomeration, the technique is
not suitable for processing of heat-labile materials due to the involvement of elevatedtemperatures. Nonetheless, successful agglomeration of volatile substances withalmost complete prevention of material loss by vaporization has been reported (46).
The probable reason is that the agglomerate surfaces was covered by layers of solidiﬁed molten binder and loss of volatile substances was further avoided since themelt process was in a closed chamber. In addition, Lactobacillus acidophilus bacteria
were found to have a higher survival rate in formulations prepared by continuous
melt technology than in formulations prepared using conventional wet techniques,in spite of the molten mass’ temperature rising to more than 100 C (47). Clearly,
the detrimental effects of heat were considerably reduced by the absence of moisture
in melt agglomeration.
The growth processes of melt agglomerates are highly sensitive to formulation, processing, and equipment variables. Uncontrollable melt agglomeration is© 2005 by Taylor & Francis Group, LLC

388

Wong et al.

frequently encountered when such variables are not optimally adjusted. In view ofchallenges in controlling the melt agglomeration process, melt agglomeration has
remained an interesting ﬁeld of research with the potential for practical and wider
application in the pharmaceutical industry.
1.5. Characterization of Melt Agglomerates
Over the past decade, many researchers have examined the effects of formulation,
processing, and equipment variables on melt agglomeration process through physicochemical characterization of the formed agglomerates. This has contributed toa better understanding of the formation and growth processes of melt agglomerates.
Similar to agglomerates produced by wet techniques, the most common method
employed for the characterization of melt agglomerates is the determination of mean
agglomerate size and size distribution by sieving. The size and size distribution ofmelt agglomerates generally ﬁt a log-normal mathematical model. They can be represented by geometric weight mean diameter (dgw) and geometric standard deviation(sg), respectively, as described by Schæfer and Worts (48):Pwi  log diPlog dgw ¼
ð1:1Þ
wi
sP
ﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃﬃ
Pwi ðlog di Þ2  ð wi  log di Þ2
P
log Sg ¼wið1:2Þ

where di is the mean diameter and wi is the weight of agglomerates of sieve
fraction i.
Alternatively, the size and size distribution of melt agglomerates can be
expressed as the model independent mass median diameter and span, respectively.
The mass median diameter is deﬁned as agglomerate size corresponding to the50th weight percentile of the cumulative agglomerate size distribution and spanbeing the quotient of difference between the agglomerate sizes corresponding to
the 90th and 10th weight percentiles of cumulative size distribution to mass median
diameter. The percentages of ﬁnes and lumps, generally described with respect toagglomerate fractions smaller than 90–250 mm and larger than 2000–4000 mm,
respectively, are also reported as an indirect quantitative input on size distributionof melt agglomerates.
Apart from size and size distribution of melt agglomerates, shape, surface morphology, speciﬁc surface area, moisture content, density, porosity, tensile strength,
friability, ﬂow, and packing properties have often been determined in elucidationof the mechanism and kinetics of melt agglomeration. The distribution of binder
content in melt agglomerates has a strong bearing on the homogeneity of melt
agglomerate growth. The actual binder content in melt agglomerates has also beenmeasured directly through experiments or estimated indirectly via the applicationof mathematical modeling. A direct measurement of polyethylene glycol content
was determined using near-infrared spectrophotometry (20). The content of binder
in melt agglomerates was also determined with the aid of the high-performanceliquid chromatography analytical method (49). The polyethylene glycol content
was indirectly measured from the true density values of milled agglomerate fraction
determined by means of a gas displacement pycnometer (50) and the polyethylene© 2005 by Taylor & Francis Group, LLC

Melt Granulation and Pelletization389

glycol content was calculated using Eq. 1.3 as follows:ð1  xÞ x
1
þ ¼
rl
rb ra

ð1:3Þ

where x is the fraction of polyethylene glycol, rl, rb, and ra are true density values oflactose, binder, and melt agglomerates, respectively. The content of polyethylene glycol can also be determined through gravimetric analysis whereby the weight of binder is obtained by weight subtraction of nonbinder fraction from that of the melt
agglomerates (51,52). In the case of complexation and crystallite behavior of drug,binder, and ﬁne solid particles, the melt agglomerates have often been subjected toevaluation by differential scanning calorimetry and x-ray diffractometry. In vitro
dissolution studies have been conducted to examine the drug release characteristics
of melt agglomerates. El-Shanawany (53) and Voinovich et al. (39) found that thein vivo drug release attributes of melt agglomerates were in accordance with thein vitro ﬁndings. Nonetheless, a quantitative relationship between the in vivo and invitro performances of melt agglomerates is still generally lacking.
Another important feature of melt agglomerates is their performance stability
during storage. It was found that the melt agglomerates could maintain their dissolution proﬁle after a year of storage at 25 C and 60% relative humidity (40). The
release of sulfamethazine from tablets made of melt granules remained unchanged
after 2 years of storage at 25 C in closed containers (37). Nevertheless, the rateand extent of drug release were found to increase with agglomerates stored at anelevated temperature of 40 C and at a relative humidity of 75%, probably owing
to the softening of the melt matrices (41,54). On the basis of the meltable natureof agglomerates, stability testing is preferred to be conducted at an appropriate
choice of storage temperature which will not bring about marked alterations to
the physicochemical state of the agglomerates.

2. MECHANISM OF MELT AGGLOMERATION
The mechanism of melt agglomeration is similar to that of wet agglomeration,
except that the formation and growth processes of melt agglomerates are not complicated by binding liquid losses via evaporation during the agglomeration process.
The growth process of melt agglomerates is dependent on the interplay between thesize enlargement and size reduction processes. The likelihood of an agglomerate togrow in size or experience breakages is a result of the balance between externallyapplied mechanical forces and agglomerate strength. The agglomerates will growin size if they have sufﬁcient strength to withstand the impact of externally applied
forces or vice versa. The strength of agglomerates is affected by the relative magnitude of capillary, frictional, and viscous forces. The capillary forces aid agglomerate consolidation by pulling the solid particles together while the viscous andfrictional forces resist both consolidation and dilation of the solid particle assembly. The mechanisms involved in the formation and growth of melt agglomerates
have been categorized into different stages and will be discussed in the following
sections.
© 2005 by Taylor & Francis Group, LLC

390

Wong et al.

2.1. Stages of Agglomerate Growth
The mechanism of wet agglomeration has traditionally been subdivided into nucleation, coalescence, layering, abrasion transfer, crushing, and other concomitant
events such as snow balling and onion skinning, based mainly on the elementary
growth mechanism suggested by Sastry and Fuerstenau (Fig. 1) (55). An alternativedescription of the agglomeration mechanism has also been proposed (2,56). The process of agglomeration consists of a combination of three phases: wetting and nucleation, consolidation and growth, together with the steps of attrition and breakage(Fig. 2).

2.1.1. Wetting and Nucleation
Nucleation is the initial phase of agglomeration in which nuclei or small agglomerates of loose and porous structure are formed after the primary particles are wetted
by a binding liquid droplet. The primary particles are bound by liquid bridges in the

Figure 1 Elementary agglomerate growth mechanisms. (Adapted from Ref. 55.)
© 2005 by Taylor & Francis Group, LLC

Melt Granulation and Pelletization

391

Figure 2 A recent approach in describing the agglomeration mechanism. (Adapted from
Ref. 2.)

pendular state. The degree of liquid saturation of an agglomerate can be increased
either by continuous addition of liquid or through the consolidation of the agglomerate. Two nucleation mechanisms, namely immersion and distribution, are proposed by Schæfer and Mathiesen (50), based on the process of melt agglomeration(Fig. 3). The dominance of either mechanism in the nucleation process of melt
agglomeration is a function of the ratio between the sizes of primary particles andmolten binder droplets (25,50,52).
Nucleation by immersion occurs when the size of the molten binder droplets isgreater than that of the ﬁne solid particles. Immersion proceeds by the deposition ofﬁne solid particles onto the surfaces of molten binder droplets. The propensity of
nucleation by immersion method is promoted by large binder droplet size, high binder viscosity, and low shearing forces. High binder viscosity and low shearing forces
reduce the opportunity of molten binder droplets to break down, thus keeping theirsize comparatively large and several times the size of the ﬁne solid particles.
In nucleation by distribution method, a molten binding liquid is distributed
onto the surfaces of ﬁne solid particles. The nuclei are formed by the collision
between the wetted particles. The formed nuclei have a loose structure withentrapped air unlike those produced by the immersion method. Generally, small binder droplet size, low binder viscosity, and high shearing forces are favorable conditions for nucleation by the distribution method.
The nucleation phase is characterized by the disappearance of ﬁnes (35), asa consequence of coalescence between the wetted primary particles or the primaryparticles with the formed nuclei. The resultant nuclei would undergo consolidation
under the impact of the externally applied mechanical forces and acquire sufﬁcient© 2005 by Taylor & Francis Group, LLC

392

Wong et al.

Figure 3 Modes of nucleation mechanism: (A) distribution and (B) immersion. (Adaptedfrom Ref. 50.)

strength to resist further breakdown by impact forces and will be able to grow into
bigger agglomerates.
2.1.2. Consolidation and Growth
Agglomerate growth refers to progression in the size of the formed nuclei, typicallyby binary coalescence and layering. The number of nuclei is progressively reducedwith an increase in size of the resultant agglomerates by coalescence. In contrast,
the number of agglomerates remains largely unchanged when size enlargement proceeds by layering. The layering growth stage generally takes place after the agglomerates have attained a certain size and rigidity and is associated with the reduced rateof coalescence (57).
The probability of successful fusion between the collided nuclei is dependent on
the liquid saturation state of nuclei. During the process of agglomeration, the agglomerates are consolidated by the agitation forces. The reduction in agglomerate pore size
and number promotes the migration of binding liquid from agglomerate core to surfaces, thus enhancing the surface plasticity and propensity of agglomerate growth bycoalescence. The rate and extent of consolidation of an agglomerate is governed byinterparticulate frictional, capillary, and viscous forces. The interparticulate frictionaland viscous forces resist the consolidation process of agglomerates. Conversely, thecapillary forces promote the consolidation of agglomerates by pulling the particles
together (58). The net extent of consolidation for an agglomerate is dependent on
the relative magnitude of these forces, which is a function of agglomerate size, viscosity,and surface tension of binding liquid, as well as the physicochemical properties of ﬁne
solid particles (17,20,45,52,59,60).
The degree of liquid saturation of an agglomerate may be increased throughconsolidating the agglomerates by agitation. Alternatively, it is attainable by adding
an additional volume of binding liquid to the existing agglomerates, making the liquid
bridges of nuclei progress from pendular to funicular and followed by the capillarystate where the level of liquid saturation can be as high as 80–100%. The degree of© 2005 by Taylor & Francis Group, LLC

Melt Granulation and Pelletization393

liquid saturation reaches and probably exceeds 100% prior to agglomeration when acohesive powder, highly viscous binding liquid, or an excessive amount of binding
liquid is employed. At the droplet state when excessively high liquid saturation is
attained, there is considerable risk of agglomerate overwetting and uncontrollable
agglomerate growth may result. In contrast to the conventional wet agglomeration
processes, the level of liquid saturation of melt agglomerates cannot be reduced via
the evaporation of solvent. The effects of excess surface wetness are counteracted
by the application of a very high impeller speed which aids in the dispersion of lumps
and large agglomerates or through the use of porous ﬁne particles which could
accommodate binding liquid in pores and crevices, away from the agglomeratesurfaces.
2.1.3. Attrition and Breakage
Attrition and breakage refer to the phenomenon of agglomerate fragmentation in thedry and wet states respectively (2). In melt agglomeration, the formed agglomerates
are solidiﬁed by tray cooling to ambient temperature without the need for drying by
a tumbling process. Consequently, breakage is known to have a more essential rolein affecting the resultant properties of the melt agglomerates during the agglomerative phase.
The propensity of agglomerate breakage is largely governed by the strength of
the agglomerates. Rumpf (61) described the strength of moist agglomerates in theirstatic funicular and capillary states as follows:
st ¼ SC

1eg
cos y
e d

ð2:1Þ

where st is the tensile strength, S is the liquid saturation, C is a constant, e is theagglomerate porosity, g is the surface tension of binding liquid, d is the surface mean
particle diameter, and y is the contact angle between the solid particles and the binding liquid. The strength of moist agglomerates is promoted by an elevation in surface
tension of the binding liquid, liquid saturation, and wetting state of solid particles, aswell as a reduction in agglomerate porosity and mean size of solid particles.
The application of a binding liquid with low viscosity and surface tension
values increases the propensity of agglomerates to breakage (17). This deters theagglomerates from consolidation. The regular breakdown of agglomerates aids inthe distribution of binding liquid across the solid particle bed ensuring homogenous
agglomerate growth. Nevertheless, it prevents a complete buildup of structure which
is needed for size enlargement process. In the case of spheronization, the regularbreakdown of agglomerates is translated to the absence of a plastically deformablecoalesced structure which is needed for rounding through shaping of agglomeratesurfaces by particle rearrangement.

3. FACTORS AFFECTING MELT AGGLOMERATION
The formation and growth processes of melt agglomerates are governed by formulation, processing, and equipment variables to a greater extent than those of conventional wet agglomerates as a result of the involvement of high impeller speeds andhigh shearing forces for agglomeration and viscous molten binding liquid. Many
© 2005 by Taylor & Francis Group, LLC

394

Wong et al.

researchers had studied the inﬂuences of these variables, through the characterization of melt agglomerates as previously illustrated, for a better understanding andcontrol of the melt agglomeration processes.
The effects of processing variables such as mixing time, mixing speed, mixerload, jacket temperature, and method of binder addition on melt agglomeration havebeen extensively investigated (8,11,13,43,52,62–67). Typically, an increase in mixing
time or mixing speed promotes agglomerate growth through squeezing the molten
binding liquid from agglomerate core to surfaces by means of a densiﬁcation process,thus increasing the degree of liquid saturation of agglomerates and their propensity
to grow by binary coalescence following the collision between two or more plastically deformable surfaces. Under the continuous stirring action of impeller rotation,
the deformable surfaces of these agglomerates can be rounded via intra-agglomerate
rearrangement of particles leading to the formation of spherical pellets.
The inﬂuences of equipment variables on melt agglomerate growth are moremarked with high-shear mixers than with low-shear mixers and ﬂuid bed granulators. One main reason is that the intensity of shearing forces is greater in high-shear
mixers. The high shearing forces promote a more even distribution of molten binding
liquid making the size distribution of melt agglomerates becoming narrower. The
level of shearing forces generated in a high-shear mixer is dependent on the geometryof impeller blade, design of processing chamber, and relative dimension between theblade and chamber. The construction of both impeller blade and processing chamber
can have a signiﬁcant impact on the ﬂow pattern of processing material. The use of atruncated cone-shaped lid (11) and an inner wall lining made of polytetraﬂuoroethylene (68) reduced the adhesion of mass undergoing agglomeration onto the wall of
the processing chamber. Variation in the curvature of impeller blade and the distancefrom its base to the ﬂoor of the chamber likewise brought about changes in the ﬂow
pattern of the wet mass (12,18). The pattern of material ﬂow is related to themechanical force distribution and homogeneity of melt agglomeration. It has
a strong bearing on the disparity in size and shape of the formed agglomerates.
In the case of formulation variables, the effects of size, size distribution, shape,density, and packing properties of ﬁne solid particles have been reported (10,69,70).
The use of solid particles of mean size smaller than 10 mm is usually problematic inmelt agglomeration because a very high level of liquid saturation is needed to overcome the high agglomerate strength resulting from the cohesiveness of small particles
in order to provide sufﬁcient agglomerate deformability for growth. This, in turn,can lead to a potentially uncontrollable melt agglomerative process. Generally, solid
particles with size ranges between 20 and 25 mm are preferable for the production ofmelt agglomerates (10). Excessively large solid particles, with a mean size of over
100 mm, produce mechanically weak agglomerates or ﬁnes. The excessively large orsmall solid particles will tend to produce irregularly shaped melt agglomerates assuch aggregates are susceptible to breakdown under the inﬂuence of shear forces
or have rigid particle linkages within the agglomerate which inhibit particle deformation and rearrangement. The effects of size, size distribution, shape, density, andpacking property of ﬁne solid particles on melt agglomeration are interdependent.
Size, size distribution, shape, and density affect the packing geometry of solid particles, bound by molten binding liquid, within the agglomerate. The strength of particulate interlocking, state of liquid distribution, and saturation of agglomerates canbe altered via the modiﬁcation in these properties of ﬁne solid particles.
The effects of binder volume, binder rheology, binder surface property, andbinder particle size on melt agglomeration have largely been reported in relation© 2005 by Taylor & Francis Group, LLC

Melt Granulation and Pelletization395

to the inﬂuences of other formulation or processing variables (15,17,20,36,45,70). The
growth of melt agglomerates is promoted predominantly by an increase in viscosity,
tack, and speciﬁc volume as well as a decrease in surface tension of the molten binding
liquid. The viscosity, tack, speciﬁc volume, and surface tension govern the intraagglomerate mobility of molten binding liquid and state of liquid saturation of melt
agglomerates. The inﬂuences of viscosity, tack, and surface tension of molten binding
liquid on melt agglomeration are affected by product temperature, mixing speed, andphysicochemical properties of the ﬁne solid particles. The effect of binder particle sizeon melt agglomeration is less marked except when high-viscosity binder is used and at
early agglomerative phases (50). At the early agglomerative phase, the dimension ofdroplets of a very viscous molten binding liquid can remain large and unreduced by
the high shearing forces, resulting in larger agglomerates for further growth.

4. CONTROL OF MELT AGGLOMERATION
The growth processes of melt agglomerates are sensitive to formulation, processing,and equipment variables. A better understanding of the mechanism of melt agglomerate formation aids in the development of methods to control and monitor the inprocess changes of product attributes. In conventional wet agglomeration process,the instrumentation of equipment to monitor and control the operation has been studied by several investigators. The incorporation of sensors and suitable instrumentation of the equipment enables changes in agglomerate properties during theagglomeration process to be monitored such that the end point of the process canbe accurately predicted.

4.1. Image Processing/Infrared Spectroscopy/Bed HeightIn ﬂuid bed agglomeration process, the control of agglomerate growth through monitoring agglomerate moisture content using infrared spectroscopy (71–73) or agglomerate size and shape using an image processing system (74,75) has been investigated.
The application of bed height control to monitor agglomerate growth in ﬂuid bed
agglomeration process has also been studied (76,77). Of all instrumentation techniques, the image processing system can potentially be adopted as a tool to control themelt agglomeration process. Such a system requires a heat-resistant optic device capable of withstanding the processing temperatures associated with the melt agglomeration process of up to as high as 120 C. The infrared spectroscopy or equivalenttechniques are less suitable for use in monitoring the melt agglomerate growth process. Unlike the wet agglomeration process, the meltable binder is incorporated withthe processing material prior to mixing and shearing in the melt processor to bring
the binder to its melting temperature. Practically, there is no need for monitoring thechanges of binding liquid content added. Melt agglomeration in high-shear mixer
proceeds by the active centrifugal massing of the processing materials. In contrast
to the ﬂuid bed agglomerator, the bed height of powder particles in the processing
chamber is less affected by gravitational forces and the upward air ﬂow velocity
required for particle suspension. For a given material load, the bed height is expected
to have minimal effects on the changes in product attributes. It is envisaged that themeasurement of bed height would not be useful in reﬂecting the in-process productattributes.
© 2005 by Taylor & Francis Group, LLC

396

Wong et al.

4.2. Torque/Current/Power Consumption
For wet agglomeration in high- or low-shear mixers, the popular method for instrumentation involves an indirect measurement based on the changes in rheologicalproperties of moistened mass which are related to the growth propensity of agglomerates. The process of extrusion in extrusion–spheronization had been monitored
using the measurement of power consumption of the extruder motor or extrusion
force on the screen (78–84). Low-shear mixers had employed torque (85–90), power
consumption (85,91–93), or current (94) measurements as the tool for end-point
determination. The instrumentation technique for high-shear mixers involved themeasurement of torque on impeller shaft (95,96), power consumption (80,95–110),current (111,112) or motor slip (113–116). Technically, power and current consumption are the simpler techniques for monitoring the agglomerate growth in a highshear mixer. It was easier to equip a high-shear mixer with a power consumption
meter than a sensor for torque or slip measurement (117). Torque generated had
been reported to provide a more descriptive proﬁle of the agglomeration process
than power consumption. Nevertheless, there were only small differences between
the two methods for process monitoring (95,96,117). The measurement of torqueis a more expensive method and technically more difﬁcult due to problems associatedwith the transmission of signals from the sensor (118). Holm et al. (98) showed thatthe power consumption proﬁle of an agglomeration process was related to plasticity
and liquid saturation of the processing material in addition to that of the interparticulate friction within the agglomerates. Since plastic deformation is important for
agglomerate growth, power consumption may then be related to the agglomeration
propensity.
A slow and continuous binding liquid addition is a prerequisite for obtaining
a power consumption that is suitable for use in process control of wet agglomeration(118). Five characteristic phases of power consumption are identiﬁable (Fig. 4). In
the ﬁrst phase, a wetting of powder mixture takes place without any observable risein the power consumption.
The subsequent addition of binding liquid brings about particle agglomeration
and a sharp rise in the magnitude of power consumption. The power consumption of
the agglomeration process levels off as the agglomerates gradually become dense andsaturated with the binding liquid. During the fourth phase, the power consumption
rises due to overwetting and excessive growth of agglomerates by coalescence. The
power consumption falls in the ﬁfth phase and it is associated with the formationof a suspension upon the addition of an excessive amount of the binding liquid.
The optimum end point of the process lies within the third phase of the power consumption tracing. In the case of melt agglomeration process, the addition of meltablebinder is almost instantaneous. This lack of the typical power consumption proﬁlemakes power consumption measurement less suitable for monitoring melt agglomeration end point as in the case of the wet agglomeration process. In laboratory
high-shear mixers, an increase in melt agglomerate size is not reﬂected in the power
consumption signals except at an excessively high impeller speed (11,69). The
deformability of the agglomerates produced by a molten binding liquid is relatively
low in comparison to that of agglomerates formed when using an aqueous binding
liquid. The sensitivity of power consumption measurement is not sufﬁciently discriminating to reﬂect small changes in the plasticity of melt agglomerates.
During the premelt agglomeration phase of the powder mixture, the level ofpower consumption is low and with minimal ﬂuctuations in its magnitude (Fig. 5).
© 2005 by Taylor & Francis Group, LLC

Melt Granulation and Pelletization

397

Figure 4 Power consumption proﬁle of a wet agglomeration process. (Adapted from
Ref. 118.)

The magnitude of the power consumption falls to a value slightly below that of thevalues obtained during the premelt agglomeration phase when the binder particles
begin to melt upon the inﬂuence of frictional heat generated by the impeller rotation(9). Such observation could be related to the lubricating effect of molten binding
liquid on the solid particles undergoing agglomeration. The power consumption rises
sharply following the complete melting of the binder particles. The molten binding
liquid is distributed rapidly throughout the powder mixture. The level of power consumption becomes lower upon the complete distribution of the molten binding liquid
and increases as the agglomerate growth takes place.
Generally, a higher level of power consumption is recorded when a higher
impeller speed or a more viscous molten binding liquid is employed for the preparation of melt agglomerates. The rise in power consumption is delayed when a viscous
meltable binder is used (119). The growth process of melt agglomerates is not easilyinterpretable from the record of power consumption when the growth propensity ofmelt agglomerates is strongly governed by the viscosity of the molten binding liquid.
This is ascribed to greater difﬁculties in distributing viscous molten binding liquidand a slower rate of agglomerate densiﬁcation. A viscous binder hinders the consolidation of agglomerates as a viscous liquid resists plastic deformation and its migration from core to the surface of the agglomerate during consolidation. The power
consumption measurements are not directly comparable between high-shear mixersof different processing capacities. However, the values of power consumption can becorrelated to the changes in size of the agglomerates produced using a large-scale
high-shear mixer, albeit such relationship is not attainable when using a laboratory
scale high-shear mixer (12).
© 2005 by Taylor & Francis Group, LLC

398

Wong et al.

Figure 5 Proﬁle of power consumption at premelt and postmelt phases. (Adapted from
Ref. 19.)4.3. Energy Consumption
The applicability of both processing power and energy consumption as tools tomonitor agglomerate growth in a melt agglomeration process has been studied(19,65). Postmelt speciﬁc power consumption, postmelt speciﬁc energy consumption,
and average postmelt speciﬁc power consumption were computed. The postmelt speciﬁc power consumption was calculated by dividing the postmelt power consumption
read at speciﬁc postmelt processing time, with the total weight of processing material. The postmelt speciﬁc energy consumption was obtained by integrating the areaof postmelt speciﬁc power consumption against postmelt processing time curve. The
average postmelt speciﬁc power consumption was represented by the quotient of
postmelt speciﬁc energy consumption to that of the corresponding length of postmelt
processing time.
4.3.1. Melt Agglomerate Size
The increase in the melt agglomerate size was more closely correlated to the postmelt
speciﬁc energy consumption than that of the average postmelt speciﬁc power consumption or postmelt speciﬁc power consumption. This is because speciﬁc energy
consumption can be considered as the amount of work done for the formative
process of consolidating the primary particles into melt agglomerates. It is more indicative of the stage of melt agglomerate growth. The postmelt speciﬁc energy
consumption and postmelt processing time were linearly correlated and the formation of larger melt agglomerates at longer processing time involved a greater level© 2005 by Taylor & Francis Group, LLC

Melt Granulation and Pelletization399

of energy consumption. The postmelt speciﬁc energy consumption and melt agglomerate size were linearly related and such a relationship was not dependent on the effectof impeller speed except that of the binder concentration and size of solid particles. In
relating the inﬂuences of binder concentration and size of solid particles on the outcome of agglomeration with respect to postmelt speciﬁc energy consumption, an
equation was established. The processes of melt agglomerate formation and growth
were described using a modiﬁed macroscopic population model. The model of melt
agglomeration, under the speciﬁed processing conditions, was summarized as:
d ¼ f 1 ðsÞ½1 þ f 2 ðcÞEmelt ð4:1Þ

where d refers to mean melt agglomerate size, Emelt is the postmelt speciﬁc energy
consumption, f1(s) and f2(c) represent polynomial relationships with size of solid
particles and binder concentration as independent variables, respectively. Using
Eq. 4.1, the theoretical value of melt agglomerate size was found in good agreementwith the experimental data obtained from melt agglomeration runs employing various binder concentrations and different sizes of primary particles. Nonetheless, it
should be emphasized that the application of postmelt speciﬁc energy consumption
for the control of melt agglomeration process would be inappropriate in processes
encountering an excessive level of material adhesion or when large amounts oflumps are formed. The effective weight of processing material is markedly reducedin the presence of an excessive level of material adhesion. This will give rise to inaccuracies in computing the postmelt speciﬁc energy consumption level. With theexcessive formation of lumps, the rope-like ﬂow pattern of the agglomerates will
be affected. The movement of agglomerates, bound within the processing chamber,is expected to be variable. As a result, the predictability of the melt agglomeration
process using postmelt speciﬁc energy consumption will be substantially reduced by
the changes in product attributes from one batch to another. Practically, Eq. 4.1 isuseful for predicting the end point of an optimal or near-optimal melt agglomeration run.
Frequently, the end point of an agglomeration process is governed by the sizeof the formed agglomerates. The geometric-weight mean diameter of melt agglomerates is calculated using Eq. 1.1 described by Schæfer and Worts (48). In the case ofmelt agglomerates with size distribution which cannot be ﬁtted into a log-normal
relationship, the mass median diameter of agglomerates shall be adopted for representing of the size of melt agglomerates produced.

4.3.2. Melt Agglomerate ShapeThe shape and tensile strength of melt agglomerates may be used to characterize theagglomeration process besides the more generally used size of melt agglomerates.
Similar to the measurement of size, both shape and tensile strength can be determined using quick, simple, and accurate methods. The sphericity of melt agglomerates is best evaluated using the image analysis system. The image analyzer consists ofa computer system connected to a video camera mounted on a stereomicroscope.
The average projected area and perimeter of melt agglomerates are determined fromthe digitized images of agglomerates. By transformation of these basic parameters,
melt agglomerate sphericity is calculated. The sphericity value gives a measure ofmelt agglomerate roundness. A sphericity value, determined by Eq. 4.2, of unity© 2005 by Taylor & Francis Group, LLC

400Wong et al.

describes a perfect circle. The agglomerate sphericity is deﬁned as:
Sphericity ¼

4p  Areað4:2Þ
ðPerimeterÞ2
The melt agglomeration process can be divided into two spheronization phases,
a fast initial rate followed by a slow rate (65). The change in spheronization rate wasassociated with that of agglomerate size, porosity, and ﬂow pattern of the processing
material. The study established a biexponential mathematical model to relate theagglomerate sphericity with postmelt speciﬁc energy consumption. The relationshipof agglomerate sphericity with postmelt speciﬁc energy consumption was found to be
independent of the effect of various production variables, such as postmelt impeller
speed, binder concentration, and size of solid particles. The biexponential mathematical model has an equation as follows:
1  Sphericity ¼ ½0:4107 expð0:0118Emelt Þ þ ½0:0533 expð0:0004Emelt Þð4:3Þ
Overall, the characterization of the melt agglomeration end point using thebiexponential mathematical model is simple and without the need to consider the physicochemical properties of the processing materials used. As the process of agglomeration is aimed at making highly spherical pellets, predictive methods based on
sphericity will help to capture the ideal end point together with predictive methods
based on size.
4.3.3. Melt Agglomerate Tensile Strength
The formative process of melt agglomerates is accompanied by changes in the size,
shape, and porosity of melt agglomerates (19,65,120). The formation of a less porous
melt agglomerate is related to an increase in the size and level of sphericity of the
product. This is attributed to an enhanced molten binding liquid migration fromcore to surfaces of agglomerates upon densiﬁcation, which promotes rounding andbinary growth of melt agglomerates as previously described. The application of
agglomerate porosity as an in-process control parameter is not practical as such ameasurement requires a long experimental time and the accuracy of such a measurement is subjected to the skill of an operator. The tensile strength is an indirect
measurement of the porosity of melt agglomerates. It has an inverse relationshipwith the porosity of melt agglomerates. The tensile strength of melt agglomerates
can be determined using a tensile tester. The crushing force is usually applied at aﬁxed rate. The load required to crush each melt agglomerate is recorded. The evaluation of tensile strength of melt agglomerates is relatively simple and it is useful as an
in-process control parameter for melt agglomeration processes.

5. CONCLUSIONSOver the past decade, the properties of processing materials and their effects on melt
agglomeration have been extensively investigated. Principally, solid particle size, size
distribution, shape, density, packing property, as well as solid binder particle size,
molten binding liquid viscosity, molten binding liquid surface tension, and molten
binding liquid tack have their individual inﬂuences on the size, shape, and porosityof melt agglomerates produced. In the case of equipment and processing variables,© 2005 by Taylor & Francis Group, LLC

Melt Granulation and Pelletization

401

off-bottom clearance, impeller geometry, construction characteristics of the processing chamber, nature of wall lining, impeller speed, jacket temperature, mixing time,and mixer load are important variables affecting the kinetics of melt agglomerationand characteristics of the formed agglomerates. The reproducibility in control of amelt agglomeration process is strongly dependent on the rigid surveillance of all
critical formulation, processing, and equipment variables. Apart from the tightcontrol of formulation, processing, and equipment parameters, the application of
in-process monitoring tool and predictive mathematical model are imperative to
avoid any uncontrollable melt agglomeration.

REFERENCES
1. Tardos GI, Khan MI, Mort PR. Critical parameter and limiting conditions in binder
granulation of ﬁne powders. Powder Technol 1997; 94:245–258.
2. Iveson SM, Litster JD, Hapgood K, Ennis BJ. Nucleation, growth and breakage
phenomena in agitated wet granulation processes: a review. Powder Technol 2001; 117:
3–39.
3. Ghebre-Sellassie I. Mechanism of pellet formation. Ghebre-Sellassie I, ed. Pharmaceutical Pelletization Technology. Vol. 37. New York: Marcel Dekker, Inc., 1989:129.
4. Rubinstein MH. A new granulation method for compressed tablet. J Pharm Pharmacol
1976; 28:67.
5. Rubinstein MH, Musikabhuma P. Formulation and evaluation of paracetamol 500 mg
tablets produced by a new direct granulation method. Drug Dev Ind Pharm 1980;
6(5):451–473.
6. McTaggart CM, Ganley JA, Sickmueller A, Walker SE. The evaluation of formulationand processing conditions of a melt granulation process. Int J Pharm 1984; 19:139–148.
7. Schæfer T, Holm P, Kristensen HG. Melt granulation in a laboratory scale high shear
mixer. Drug Dev Ind Pharm 1990; 16(8):1249–1277.
8. Schæfer T, Holm P, Kristensen HG. Melt pelletization in a high shear mixer. I. Effects
of process variables and binder. Acta Pharm Nordica 1992; 4:133–140.
9. Schæfer T, Holm P, Kristensen HG. Melt pelletization in a high shear mixer. II. Powerconsumption and granule growth. Acta Pharm Nordica 1992; 4:141–148.
10. Schæfer T, Holm P, Kristensen HG. Melt pelletization in a high shear mixer. III. Effectsof lactose quality. Acta Pharm Nordica 1992; 4:245–252.
11. Schæfer T, Taagegaard B, Thomsen LJ, Kristensen HG. Melt pelletization in a highshear mixer. IV. Effects of process variables in a laboratory scale mixer. Eur J PharmSci 1993; 1(3):125–131.
12. Schæfer T, Taagegaard B, Thomsen LJ, Kristensen HG. Melt pelletization in ahigh shear mixer. V. Effects of apparatus variables. Eur J Pharm Sci 1993; 1(3):133–141.
13. Thomsen LJ, Schæfer T, Sonnergaard JM, Kristensen HG. Prolonged release matrixpellets prepared by melt pelletization. Part 1. Process variables. Drug Dev Ind Pharm
1993; 19(15):1867–1887.
14. Thomsen LJ, Schæfer T, Kristensen HG. Prolonged release matrix pellets prepared bymelt pelletization. Part 2. Hydrophobic substances as meltable binders. Drug Dev Ind
Pharm 1994; 20(7):1179–1197.
15. Eliasen H, Schæfer T, Kristensen HG. Effects of binder rheology on melt agglomeration
in a high shear mixer. Int J Pharm 1998; 176:73–83.
16. Eliasen H, Kristensen HG, Schæfer T. Electrostatic during a melt agglomeration
process. Int J Pharm 1999; 184:85–96.
17. Eliasen H, Kristensen HG, Schæfer T. Growth mechanisms in melt agglomeration witha low viscosity binder. Int J Pharm 1999; 186:149–159.
© 2005 by Taylor & Francis Group, LLC

402

Wong et al.

18. Heng PWS, Wan LSC, Wong TW. Effect of off-bottom clearance on properties ofpellets produced by melt pelletization. Pharm Dev Technol 1999; 4(1):27–33.
19. Heng PWS, Wong TW, Shu JJ, Wan LSC. A new method for the control of size ofpellets in the melt pelletization process with a high shear mixer. Chem Pharm Bull
1999; 47:633–638.
20. Wong TW, Wan LSC, Heng PWS. Effects of physical properties of PEG 6000 on pellets
produced by melt pelletization. Pharm Dev Technol 1999; 4(3):449–456.
21. Maejima T, Osawa T, Kobayashi M, Noda K. Factors effecting spherical granulation ofdrugs by tumbling granulation method. Chem Pharm Bull 1992; 40(2):488–492.
22. Maejima T, Osawa T, Nakajima K, Kobayashi M. Preparation of spherical beads without any use of solvents by a novel tumbling melt granulation (TMG) method. Chem
Pharm Bull 1997; 45:518–524.
23. Maejima T, Osawa T, Nakajima K, Kobayashi M. Effects of species of non-meltable
and meltable materials and their physical properties on granulatability in tumbling melt
granulation method. Chem Pharm Bull 1997; 45:1833–1839.
24. Maejima T, Kubo M, Osawa T, Nakajima K, Kobayashi M. Application of tumbling
melt granulation (TMG) method to prepare controlled-release ﬁne granules. 1998;
46:534–536.
25. Abberger T, Seo A, Schæfer T. The effect of droplet size and powder particle size on themechanisms of nucleation and growth in ﬂuid bed melt agglomeration. Int J Pharm
2002; 249:185–197.
26. Kidokoro M, Haramiishi Y, Sagasaki S, Shimizu T, Yamamoto Y. Application of
ﬂuidized hot-melt granulation (FHMG) for the preparation of granules for tableting;properties of granules and tablets prepared by FHMG. Drug Dev Ind Pharm 2002;
28(1):67–76.
27. Seo A, Holm P, Schæfer T. Effects of droplet size and type of binder on the agglomerate
growth mechanisms by melt agglomeration in a ﬂuidized bed. Eur J Pharm Sci 2002;
16(3):95–105.
28. Pataki K, Horváth E, Ormós Z. Rolling bed granulation with local melt forming.
Proceedings of 4th Conference on Applied Chemistry, Unit Operations and Processes,
Vol. 3. Veszprem, Hungary. 1983:361–362.
29. Litster JD, Sarwono R. Fundamental studies of ﬂuidized drum granulation. Proceedings of the 1st International Particle Technology Forum, Denver, CO, Part l, Aug
17–19, 1994; 265–270.
30. Edimo A, Leterme P, Denis J, Traisnel M, Gayot AT. Capacity of lipohilic auxiliary
substances to give spheres by extrusion-spheronization. Drug Dev Ind Pharm 1993;
19(7):827–842.
31. Miyagawa Y, Okabe T, Yamaguchi Y, Miyajima M, Sato H, Sunada H. Controlledrelease of diclofenac sodium granule. Int J Pharm 1996; 138:215–224.
32. Zhang F, McGinity JW. Properties of sustained release tablets prepared by hot-melt
extrusion. Pharm Dev Technol 1999; 4:241–250.
33. Liu J, Zhang F, KcGinity J. Properties of lipophilic matrix tablets containing phenylpropanolamine hydrochloride prepared by hot-melt extrusion. Eur J Pharm Biopharm
2001; 52:181–190.
34. Young CR, Koleng JJ, McGinity JW. Production of spherical pellets by a hot-melt
extrusion and spheronization process. Int J Pharm 2002; 242:87–92.
35. Schæfer T. Growth mechanisms in melt agglomeration in high shear mixers. Powder
Technol 2001; 117:68–82.
36. Evrard B, Amighi K, Beten D, Delattre L, Moës AJ. Inﬂuence of melting and rheological properties of fatty binders on the melt granulation process in a high-shear mixer.
Drug Dev Ind Pharm 1999; 25(11):1177–1184.
37. Evrard B, Delattre L. In vitro evaluation of lipid matries for the development ofa sustained-release sulfamethazine bolus for lambs. Drug Dev Ind Pharm 1996;
22(2):111–118.
© 2005 by Taylor & Francis Group, LLC

Melt Granulation and Pelletization

403

38. Zhou F, Vervaet C, Remon JP. Matrix pellets based on the combination of waxes,
starches and maltodextrins. Int J Pharm 1996; 133:155–160.
39. Voinovich D, Moneghini M, Perissutti B, Filipovic-Grcic J, Grabnar I. Preparation in
high-shear mixer of sustained-release pellets by melt pelletisation. Int J Pharm 2000;
203:235–244.
40. Passerini N, Albertini B, González-Rodrı́guez ML, Cavallari C, Rodriguez L. Preparation and characterization of ibuprofen-poloxamer 188 granules obtained by melt granulation. Eur J Pharm Sci 2002; 15:71–78.
41. Hamdani J, Moes AJ, Amighi K. Development and evaluation of prolonged releasepellets obtained by the melt pelletization process. Int J Pharm 2002; 245:161–177.
42. Perissutti B, Rubessa F, Moneghini M, Voinovich D. Formulation design of carbamazepine fast-release tablets prepared by melt granulation technique. Int J Pharm 2003;
256:53–63.
43. Thies R, Kleinebudde, P. Melt pelletisation of a hygroscopic drug in a high shear mixer.
Part 1. Inﬂuence of process variables. Int J Pharm 1999; 188:131–143.
44. Yanze FM, Duru C, Jacob M. A process to produce effervescent tablets: ﬂuidized bed
dryer melt granulation. Drug Dev Ind Pharm 2000; 26(11):1167–1176.
45. Heng PWS, Wong TW, Cheong WS. Investigation of melt agglomeration process witha hydrophobic binder in combination with sucrose stearate. Eur J Pharm Sci 2003;
19:381–393.
46. Ukita K, Murakami T. Preparation of essential oils loaded granule by melt granulation.
Drug Dev Ind Pharm 1994; 20(6):981–992.
47. Appelgren C, Eskilson C. A novel method for the granulation and coating of pharmacologically active substances. Drug Dev Ind Pharm 1990; 16(15):2345–2351.
48. Schæfer T, Wørts O. Control of ﬂuidized bed granulation: I: effects of spray angle, nozzle height and starting materials on granule size and size distribution. Arch Pharm
Chem Sci Ed 1977; 5:51–60.
49. Crowley KJ, Forbes RT, York P, Nyqvist H, Camber O. Drug-fatty acid salt with waxlike properties employed as binder in melt granulation. Int J Pharm 2000; 211:9–17.
50. Schaafer T, Mathiesen C. Melt pelletization in a high shear mixer. IX. Effects of binder
particle size. Int J Pharm 1996; 139:139–148.
51. Johansen A, Schæfer T. Effects of physical properties of powder particles on binder
liquid requirement and agglomerate growth mechanisms in a high shear mixer. Eur
J Pharm Sci 2001; 14:135–147.
52. Scott AC, Hounslow MJ, Instone T. Direct evidence of heterogeneity during high-shear
granulation. Powder Technol 2000; 113:205–213.
53. El-Shanawany S. Sustained release of nitrofurantoin from inert wax matrices. J Control
Release 1993; 26:11–19.
54. Brabander CD, Vervaet C, Remon JP. Development and evaluation of sustained releasemini-matrices prepared via hot melt extrusion. J Control Release 2003; 89:235–247.
55. Sastry KVS, Fuerstenau DW. Mechanisms of agglomerate growth in green pelletization. Powder Technol 1973; 7:97–105.
56. Ennis BJ, Litster JD. Particle size enlargement. Perry R, Green D, eds. Perry’s chemical
Engineers’ Handbook. 7th ed. Chapter 20. New York: McGraw-Hill, 1997:56–73.
57. Ennis BJ, Tardos G, Pfeffer R. A microlevel-based characterization of granulation
phenomena. Powder Technol 1991; 65:257–272.
58. Iveson SM, Litster JD. Fundamental studies of granule consolidation. Part 2: Quantifying the effects of particle and binder properties. Powder Technol. 1998; 99:243–250.
59. Iveson SM, Litster JD, Ennis BJ. Fundamental studies of granule consolidation. Part 1:
effects of binder content and binder viscosity. Powder Technol 1996; 88:15–20.
60. Thies R, Kleinebudde P. Melt pelletization of a hygroscopic drug in a high shear mixer.
Part 3. Effects of binder variation. Chem Pharm Bull 2001; 49(2):140–146.
61. Rumpf H. The strength of granules and agglomerates. In: Knepper WA, ed. Agglomeration. New York: Wiley-Interscience, 1962:379–419.
© 2005 by Taylor & Francis Group, LLC

404

Wong et al.

62. Knight PC. An investigation of the kinetics of granulation using a high shear mixer.
Powder Technol 1993; 77:159–169.
63. Knight PC, Instone T, Pearson JMK, Hounslow MJ. An investigation into the kinetics
of liquid distribution and growth in high shear mixer agglomeration. Powder Technol
1998; 97:246–257.
64. Knight PC, Johansen A, Kristensen HG, Schæfer T, Seville JPK. An investigation of theeffects on agglomeration of changing the speed of a mechanical mixer. Powder Technol
2000; 110:204–209.
65. Heng PWS, Wong TW, Chan LW. Inﬂuence of production variables on the sphericity ofmelt pellets. Chem Pharm Bull 2000; 48(3):420–424.
66. Heng PWS, Chan LW, Zhu L. Effects of process variables and their interactions on meltpelletization in a high shear mixer. STP Pharm Sci 2000; 10(2):165–172.
67. Voinovich D, Moneghini M, Perissutti B, Franceschini E. Melt pelletization in highshear mixer using a hydrophobic melt binder: inﬂuence of some apparatus and process
variables. Eur J Pharm Biopharm 2001; 52(3):305–313.
68. Zhou F, Vervaet C, Rernon JP. Inﬂuence of processing on the characteristics of matrixpellets based on microcrystalline waxes and starch derivatives. Int J Pharm 1997;
147(1):23–30.
69. Schæfer T. Melt pelletization in a high shear mixer. X. Agglomeration of binary
mixtures. Int J Pharm 1996; 139:149–159.
70. Johansen A, Schæfer T. Effects of interactions between powder particle size and binderviscosity on agglomerate growth mechanisms in a high shear mixer. Eur J Pharm Sci
2001; 72:297–309.
71. Watano S, Terashita K, Miyanami K. Determination of end-point with a complex granulation applying infrared moisture sensor. Chem Pharm Bull 1991; 39(4):1013–1017.
72. Watano S, Yamamoto A, Miyanami K. Effects of operational variables on the properties of granules prepared by moisture control method in tumbling ﬂuidized bed granulation. Chem Pharm Bull 1994; 42(1):133–137.
73. Frake P, Greenhalgh D, Grierson SM, Hempenstall JM, Rudd DR. Process control andend point determination of a ﬂuid bed granulation by application of near infrared
spectroscopy. Int J Pharm 1997; 151(1):75–80.
74. Watano S, Miyanami K. Image processing for on-line monitoring of granule size distribution and shape in ﬂuidized bed granulation. Powder Technol. 1995; 83(1):55–60.
75. Watano S, Sato Y, Miyanami K. Control of granule growth in ﬂuidized bed granulation
by an image processing system. Chem Pharm Bull 1996; 44(8):1556–1560.
76. Watano S, Fukushima T, Miyanami K, Murakami T, Sato T. Automation of the manufacturing process of cold remedy granules by a tumbling ﬂuidized bed applying the
fuzzy control method. Chem Pharm Bull 1994; 42(6):1302–1307.
77. Watano S, Fukushima T, Miyanami K. Application of fuzzy logic to bed height control
in agitation-ﬂuidized bed granulation. Powder Technol 1994; 81(2):161–168.
78. Baert L, Fanara D, Baets PD, Remon JP. Instrumentation of a gravity feed extruder
and the inﬂuence of the composition of binary and ternary mixtures on the extrusion
forces. J Pharm Pharmacol 1991; 43(11):745–749.
79. Baert L, Fanara D, Remon JP, Massart D. Correlation of extrusion forces, raw materials and sphere characteristics. J Pharm Pharmacol 1992; 44(8):676–678.
80. Elbers JAC, Bakkenes HW, Fokkens JG. Effect of amount and composition of granulation liquid on mixing, extrusion and spheronization. Drug Dev Ind Pharm 1992;
18(5):501–517.
81. Baert L, Down GRB. A comparison of two methods of instrumenting a small-scalebasket extruder. Int J Pharm 1994; 107(3):219–222.
82. Kleinebudde P, Sølvberg AJ, Lindner H. The power consumption-controlled extruder: atool for pellet production. J Pharm Pharmacol 1994; 46(7):542–546.
83. Vervaet C, Baert L, Risha PA, Remon JP. The inﬂuence of the extrusion screen on pellet
quality using an instrumented basket extruder. Int J Pharm 1994; 107(1):29–39.
© 2005 by Taylor & Francis Group, LLC

Melt Granulation and Pelletization

405

84. Kleinebudde P. Use of power consumption-controlled extruder in the development ofpellet formulations. J Pharm Sci 1995; 84(10):1259–1264.
85. Lindberg N-O, Leander L, Wenngren L, Helgesen H, Reenstierna B. Studies on granulation in a change can mixer. Acta Pharm Suecia 1974; 11:603–620.
86. Travers DN, Rogerson AC, Jones TM. A torque arm mixer for studying wet massing.
J Pharm Pharmacol 1975; 27(suppl):3.
87. Lindberg N-O. Studies on granulation in a small planetary mixer. II. Granulation of
lactose and an antacid mixture. Acta Pharm Suecica 1977; 14:197–204.
88. Lindberg N-O, Leander L, Nilsson PG, Reenstierna B. Studies on granulation in a small
planetary mixer. I. Instrumentation Acta Pharm Suecica 1977; 14:191–196.
89. Ghanta SR, Srinivas R, Rhodes CT. Use of mixer torque measurements as an aid to
optimizing wet granulation process. Drug Dev Ind Pharm 1984; 10:305–311.
90. Tapper G.L, Lindberg N-O. The granulation of some lactose qualities with different
particle size distributions in a domestic-type mixer. Acta Pharm Suecica 1986; 23:47–56.
91. Bier HP, Leuenberger H, Sucker HB. Determination of the uncritical quantity of
granulating liquid by power measurements of planetary mixers. Pharm Ind 1979;
41:375–380.
92. Leuenberger H. Granulation, new techniques. Pharm Acta Helv 1982; 57:72–82.
93. Paris L, Stamm A. Optimal massing liquid volume determination by energy consumption measurement: study of the inﬂuence of some physical properties of solvents andproducts used. Drug Dev Ind Pharm 1985; 11(2,3):361–385.
94. Chirkot T, Propst CW. Low shear granulators. Parikh DM, ed. Handbook of
Pharmaceutical Granulation Technology. New York: Marcel Dekker, Inc., 1997:
205–255.
95. Corvari V, Fry WC, Seibert WL, Augsberger L. Instrumentation of a high shear mixer:
evaluation and comparison of a new capacitance sensor, a watt meter, and a strain-gage
torque sensor for wet granulation monitoring. Pharm Res 1992; 9(12):1525–1533.
96. Kopcha M, Roland E, Bubb G, Vadino WA. Monitoring the granulation process ina high shear mixer/granulator: An evaluation of three approaches to instrumentation.
Drug Dev Ind Pharm 1992; 18(18):1945–1968.
97. Leuenberger H. Monitoring granulation. Manuf Chem 1984; 55:67,69,71.
98. Holm P, Schæfer T, Kristensen HG. Granulation in high-speed mixers. Part V. Powerconsumption and temperature changes during granulation. Powder Technol 1985;
43:213–223.
99. Holm P, Schæfer T, Kristensen HG. Granulation in high-speed mixers. Part VI. Effects
of process conditions on power consumption and granule growth. Powder Technol
1985; 43:225–233.
100. Ritala M, Jungersen O, Holm P, Schæfer T, Kristensen HG. A comparison between binders in the wet phase of granulation in a high shear mixer. Drug Dev Ind Pharm 1986;
12:1685–1700.
101. Terashita K, Oh’ike A, Kato M, Miyanami K. Granulation process and end-point inhigh speed mixer granulator. J Pharm Soc Jpn 1987; 107:377–383.
102. Ritala M, Holm P, Schæfer T, Kristensen HG. Inﬂuence of liquid bonding strength on
power consumption during granulation in a high shear mixer. Drug Dev Ind Pharm
1988; 14:1041–1060.
103. Werani J. Production experience with end point control. Acta Pharm Suecica 1988;
25:247–266.
104. Leuenberger H, Usteri M, Imanidis G, Winzap S. Monitoring the granulation process:granulate growth, fractal dimensionality and percolation threshold. Boll Chim Pharm
1989; 128:54–61.
105. Watano S, Terashita K, Miyanami K. Frequency analysis of power consumption inagitation granulation of powder materials with sparingly soluble acetaminophen. Chem
Pharm Bull 1992; 40(1):269–271.

© 2005 by Taylor & Francis Group, LLC

406

Wong et al.

106. Shiraishi T, Kondo S, Yuasa H, Kanaya Y. Studies on the granulation process of
granules for tableting with a high speed mixer. I. Physical properties of granules fortableting. Chem Pharm Bull 1994; 42(4):932–936.
107. Vertommen J, Michoel A, Rombaut P, Kinget R. Production of pseudoephedrine HC1
pellets in a high shear mixer-granulators. Eur J Pharm Biopharm 1994; 40(1):32–35.
108. Shiraishi T, Sano A, Kondo S, Yuasa H, Kanaya Y. Studies on the granulation processof granules for tableting with a high speed mixer. II. Inﬂuence of particle size of active
substance on granulation. Chem Pharm Bull 1995; 43(4):654–659.
109. Landin M, York P, Cliff MJ, Rowe RC, Wigmore AJ. The effect of batch size on scaleup of a pharmaceutical granulation in a ﬁxed bowl mixer granulator. Int J Pharm 1996;
134:243–246.
110. Laicher A, Proﬁtlich T, Schwitzer K, Ahlert D. Modiﬁed signal analysis system for end
point control during granulation. Eur J Pharm Sci 1997; 5(1):7–14.
111. D’Alonzo GD, O’Connor RE, Schwartz JB. Effect of binder concentration and methodof addition on granule growth in a high intensity mixer. Drug Dev Ind Pharm 1990;
16(12):1931–1944.
112. Lin K, Peck GE. Development of agglomerated talc. II. Optimization of the processing
parameters for the preparation of granulated talc. Drug Dev Ind Pharm 1995;
21(2):159–173.
113. Lindberg N-O, Jönsson C. Granulation of lactose in a recording high speed mixer,
Diosna P25. Drug Dev Ind Pharm 1983; 9(6):959–970.
114. Timko RJ, Johnson JL, Skinner GW, Chen ST, Rosenberg HA. Instrumentation ofa vertical high shear mixer with a motor slip monitoring device. Drug Dev Ind Pharm
1986; 12(10):1375–1393.
115. Cliff MJ. Granulation end point and automated process control of mixer-granulators:
part I. Pharm Technol 1990; 14(4):112–132.
116. Cliff MJ. Granulation end point and automated process control of mixer-granulators:
part II. Pharm Technol Int 1990; 18:20–23.
117. Kristensen HG, Schæfer T. Granulations. In: Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical Technology. Vol. 7. New York: Marcel Dekker, Inc., 1993:
121–160.
118. Holm P. High shear mixer granulators. Parikh DM, ed. Handbook of Pharmaceutical
Granulation Technology. New York: Marcel Dekker, Inc., 1997:151–204.
119. Schæfer T, Mathiesen C. Melt pelletization in a high shear mixer. VIII. Effects of binderviscosity. Int J Pharm 1996; 139:125–138.
120. Wong TW, Chan LW, Heng PWS. Study of the melt pelletization process focusing on
the micromeritic property of pellets. Chem Pharm Bull 2000; 48(11):1639–1643.

© 2005 by Taylor & Francis Group, LLC

14
Rapid Release Granulation
P. W. S. Heng
National University of Singapore, Singapore

Anthony Yolande and Lee Chin Chiat
International Specialty Products (ISP) Asia Pacific Pte. Ltd., Singapore

1. INTRODUCTION
Many potential drug candidates which had been screened to show therapeutic
activities could not be formulated into suitable oral dosage forms, which are themost preferred form of drug administration, due to poor aqueous solubility. These
compounds were abandoned during preformulation stage because they did not exhibit sufﬁcient solubility in the aqueous environment, implying reduced bioavailability
upon administration and the inability to attain the necessary drug levels in blood fortherapeutic effect. Figure 1 depicts the possible events that can occur upon administrating various oral dosage forms and it is obvious that there are many factors
affecting the absorption of drug.
The factors can be broadly classiﬁed into patient or dosage-form related. The
focus of the current chapter is to examine some of the dosage-form related factors
which can be controlled from the formulator’s perspective, to enhance the dissolution of the bioactive compounds in order to increase the bioavailability of poorly
water-soluble compounds through the granulation process, which is making granules
to be ﬁlled into capsules or tableted. Most of the dosage-form related factors are
outlined in Figure 2. This could be further classiﬁed into formulation-related or
granulation-related factors.
Rapid release granulation is expected to beneﬁt the class of compound whereabsorption is highly dependent on the dissolution of the drugs in the gastrointestinal
tract, termed as Class II compounds under the Biopharmaceutics Classiﬁcation
Scheme (Table 1).
1.1. Definition
Solution can be deﬁned as a mixture of at least two components forming a single
phase, which is homogenous at the molecular level. The transfer rate of molecules
or ions from solid state into solution is known as dissolution rate and the extent
to which this proceeds under a given set of conditions is known as solubility.
407© 2005 by Taylor & Francis Group, LLC

408

Heng et al.

Figure 1 Schematic illustration of the possible events upon administering various oral
dosage forms.

Thus, the rate of solution (dissolution rate) and the amount that can be dissolved(solubility) are two separate concepts but in practice, high solubility is usuallyassociated with high dissolution rate (2).

1.2. Factors Affecting Dissolution Rate
Most of the dosage-form related factors highlighted in Figure 2 can be explained by
the terms in the modiﬁed NoyesWhitney equation (3,4), which is as follows:

Figure 2 Dosage-form related factors.
© 2005 by Taylor & Francis Group, LLC

Rapid Release Granulation

409

Table 1 Biopharmaceutics Classiﬁcation SchemeClass

Solubility

Permeability

I
II
III
IV

High
Low
High
Low

High
High
Low
Low

Source: Amidon et al. (1)dC ADðCs  C Þ
¼
dt
h

ð1:1Þ

where dC/dt is the dissolution rate, A is the surface area available for dissolution, D
is the diffusion coefﬁcient of the compound, Cs is the solubility of the compound in
the dissolution medium, C is the concentration of drug in the dissolution medium attime t, and h is the thickness of the diffusion boundary layer adjacent to the surfaceof the dissolving compound (Table 2).

2. FORMULATION-RELATED FACTORS
2.1. Drug
2.1.1. Free Acid, Free Base, or Salt Form
The use of the appropriate form of drug prior to granulation is of utmost importanceto ensure the production of rapid release granules. Sodium salts of weak acids orhydrochloride salts of weak bases can cause marked increase in aqueous solubility
when compared to the corresponding free acids or bases. This is attributed to anincrease in interactions between drug and water, giving rise to a greater degree ofionic dissociation of the drug when it dissolves in water. An example of this effectis the aqueous solubilities of salicylic acid and its sodium salt, which are 1:550 and
1:1, respectively (2).
2.1.2. Particle Size
The most common approach for improving the dissolution rate (dC/dt) of drug
from rapid release granules is to increase the surface area (A) available for dissolution and this is often achieved by employing ﬁnely divided particles [Eq. (1.1)]. Size
reduction has also been shown to decrease the diffusion boundary layer (h) of
sparingly soluble drugs (5–7). Hence, the combined effects of A and h improve thedissolution rate of the drug. Griseofulvin represents a classical example of a drug
where improvement in rate of absorption can be brought about by an increase in dissolution rate due to the increase in surface area by size reduction. This drug, which
was initially marketed as coarse particles, resulted in many cases of therapeutic
failures due to low bioavailability. Kraml et al. (8) demonstrated that 0.5 g of micronized griseofulvin produced the same serum level as 1.0 g of the unmicronized form.
Subsequently, the use of micronized griseofulvin enabled a dosage reduction andcontributed not only to lower drug cost to the patient but more importantly,
a decrease in therapeutic failures caused by poor absorption (9). However, size
© 2005 by Taylor & Francis Group, LLC

410

Heng et al.

Table 2 Terms That are Being Affected by the Various Dosage-Form Related Factors
Term in modiﬁed
Noyes–Whitneyequation
A

Cs

H

D

Affected byComments

Formulation-related factors
DrugParticle size
A is inversely related to the drug
particle size
Additives
Effervescent agent
Poorly water-soluble drug particles
Hydrophilic agent
tend to form a coherent mass in the
Surface active agent
dissolution medium; the dispersibility
Superdisintegrantof these particles can be achieved
with the additives listed to enhancedissolution
Granulation-related factors
In general, these factors affect theGranulating equipment
hardness of the granules; hardness
Liquid binder
is usually associated with lower
Wet massing time
granule porosity and this will lead
Tableting force
to poorer dissolution as the
granules do not break up easily
and the penetration of dissolution
medium is impeded
Formulation-related factors
DrugFree acid, free base or Sections 2.1.1, 2.1.3, and 2.1.4
salt form
Polymorphs or solvates
Amorphous state
Additives
Complexing agent
Sections 2.2.1 and 2.2.5
Surface active agent
Formulation-related factors
DrugParticle size
The smaller the drug particle size the lower
the diffusion boundary layer (5–7)
Additives
Poorly water-soluble drug particles
Effervescent agent
tend to form a coherent mass in
Hydrophilic agent
the dissolution medium having a
Surface active agent
large resultant diffusion boundary
Superdisintegrantlayer; dispersing these particles into
individual particles decreases this value
Granulation-related factors
Granulating equipment Drug does not readily diffuse into thedissolution medium from hard
Liquid binder
granulesWet massing time
Tableting force
Blending
Section 3.4

Source: Modiﬁed from Ref. 2.

© 2005 by Taylor & Francis Group, LLC

Rapid Release Granulation

411

reduction has its practical limits as micronized particles tend to aggregate due to thehigh surface energy per unit mass. Aggregation reduced the surface area available fordissolution and lowered the drug dissolution rate (10). Wetting effect is particularly
important under such a situation as it increases the effective surface area (11). This
principle is commonly applied in interactive mixtures (Section 2.1.2.1). In a study
using rapid release granules, micronized DPC 961, which was an antiretroviral drug,
was wet granulated by high shear and the granules were subsequently tableted andfed to beagle dogs (12). It was found that for the fasted dogs, tablets made frommicronized DPC 961, which displayed higher in vitro dissolution, produced a higher
plasma drug concentration due to faster dissolution and absorption. The effect ofparticle size reduction was not obvious for the nonfasted dogs, probably because
the solubilization afforded by the nonfasted state was sufﬁcient for rapid dissolutionof drug irrespective of particle sizes. Hence, particle size of the drug is important if it
is to be consumed before meals.
There are several micronization techniques available and they can be broadlyclassiﬁed into mechanical- and solution-based micronization (Table 3) (13).
Table 3 illustrates some of the commonly established micronization techniques.
An example of a technique that could be viewed as a solution-based micronization issolvent deposition, which could be classiﬁed as a form of spray drying. The poorly
soluble drug, tolbutamide, was dissolved in aqueous ammonia, and mixed with acore material, either low-substituted hydroxypropylcellulose or partly pregelatinizedcorn starch. The suspension was subsequently spray dried leaving a thin ﬁlm of ﬁne
drug crystals on the surface of the core materials. The rapid solvent evaporation prevented the growth of large drug crystals. Using disintegrant as the core material
further improved drug release because the swelling of disintegrant would dislodge
the thin ﬁlm of ﬁne drug crystals from the core for better dissolution, thus effectively
dispersing the ﬁne drug crystals (14). This study illustrated the possibility of concurrent granulation with micronization. The concept was probably pioneered by
Monkhouse and Lach (15,16) when they loaded poorly water-soluble drugs onto
fumed silicon dioxide by dissolving the drugs in organic solvent and suspending
the fumed silicon dioxide in the drug solution, simultaneously evaporating theorganic solvent. The drugs loaded onto the fumed silicon dioxide improved the dissolution proﬁles. This improvement was attributed to particle size reduction andchanges in the crystalline structures (Section 2.1.3). The crystalline nature of the drug
has to be assessed after undergoing micronization as certain crystal forms may be
more suitable for formulation of rapid release granules (Section 2.1.3). Drug can also
be micronized with additives, usually water-soluble carriers, such that the intimate
Table 3 Mechanical-Based and Solution-Based
Micronization Techniques
Micronization technique
Mechanical-based micronization
Classiﬁcation
Comminution
Solution-based micronization
Crystallization
Spray drying
Spray freezing© 2005 by Taylor & Francis Group, LLC

412

Heng et al.

interaction between drug and additives enabled rapid drug release when in solution.
This will be discussed under Solid Dispersion (Section 4).
2.1.2.1. Interactive Mixtures. The concept of interactive mixing was ﬁrst
introduced by Hersey (17) to describe the mixing of ﬁne and cohesive particles. This
form of mixing is different from random mixing because of the adhesion of ﬁnes tocoarser particles (18). The adhesion may be due to many factors such as humidity,
adsorption, chemisorption, surface tension, friction, and electrostatic forces, unlike
random mixing where gravitational force predominates over the other types ofadhesion forces. Interactive mixtures could be viewed as ‘‘miniature granules’’ since
the ﬁne drug and coarser particles exist as agglomerates. The forces of adhesion canbe so great that it is able to resist the ﬂuidization force in a ﬂuid bed, thus facilitating
the coating of the ‘‘miniature granules’’ (19).
The basic mechanism in enhancing the dissolution rate of a poorly watersoluble drug in an interactive mixture is by reduction of drug aggregates upon mixing with highly soluble and coarse carrier particles, thus improving the wettability ofthe micronized drug. By adding carrier particles, ﬁne drug particles will adhere onto
the coarser carrier particles, thereby increasing the exposed surface area for drug
dissolution upon rapid concommitant dissolution of the carrier into the dissolution medium (20–22). Thus, the solubility of the coarse carrier particles plays animportant role in the dissolution of the adhered drug. The use of carriers having
surface active properties will further improve the dissolution rate of the drugs bysolubilization effect during dissolution.
2.1.3. Polymorphs and Solvates
Drug can exist in one or more crystalline forms. The term crystalline implies that thestructural units, known as unit cells, are repeated regularly and indeﬁnitely in threedimensional space. Crystalline forms of a drug can be further classiﬁed into polymorphs and solvates, also known as pseudopolymorphs. Crystalline polymorphs
have the same chemical composition but different crystal structures because of themanner in which molecules arrange themselves in crystal lattices during crystallization. Solvates are crystalline forms containing solvent molecules in the crystal structures in stoichiometric or nonstoichiometric proportion. The differences in crystal
packing of the polymorphs and solvates would mean that they differ in lattice energy
and entropy, thereby signiﬁcantly affecting physicochemical properties, one of whichis the solubility of the drug (23,24). This implied that the dissolution and absorptionof a poorly water-soluble drug may also be affected by the actual polymorphs orsolvates present in the oral dosage forms. Usually, only one stable polymorph exists
for a given set of environmental conditions. In terms of enhancing dissolution, it isbetter to employ metastable polymorphs of the drug. However, in processing, it isa manufacturer’s nightmare as the use of metastable polymorphs may lead tostability problems on storage unless a way is found to stabilize the polymorph.
Hence, it is always desirable to choose the most soluble and stable form of the drug
during the initial stages of product development (25).
The choice of polymorph before granulation determines the dissolution rate.
Otsuka et al. (26) found that the use of carbamazepine polymorphs I and IV, which
are the respective anhydrate and dihydrate forms, gave rise to a higher dissolution rate
than polymorphs II and III, which are the anhydride forms, when hydroxypropylcellulose solution was employed as binder. This was because the tablets made from polymorphs I and IV were not as hard and thus disintegrated faster upon contact with the© 2005 by Taylor & Francis Group, LLC

Rapid Release Granulation

413

dissolution medium. During wet granulation, forms I, II, and III were converted to form
IV. Thus, the anhydrate and the anhydrides were converted to the dihydrate form. Only
2.5% of form I was converted as compared to 80.3% of form II and 35.2% of form III.
The granulation was unsuccessful when forms II and III were employed. This was
because water from the liquid binder was used to hydrate these two polymorph forms
and little was available for wet massing. Only upon adding more water could the granuleyield be improved. Upon drying, the transformed dihydrate lost the water molecules toform polymorph III. Drying resulted in a reduction in particle size as the removal ofsolvent from solvates is a size reduction process as well. Thus, the speciﬁc surface areafor granules obtained using forms II and III were higher than forms I and IV, therefore
contributing to higher mechanical strength of the tablet and hence poorer dissolution.
The effect of the types of liquid binder on polymorphic conversion is clearly illustrated
by the work carried out by Otsuka et al. (27) when it was found that carbamazepine form
I was readily converted to the dihydrate form, which is form IV, by using 50% aqueous
ethanol solution but relatively unaffected by distilled water or ethanol. Thus, this
implies that if 50% aqueous ethanol solution is to be used, the resultant tablets would
be poorly soluble as the above-mentioned transformations would have occurred.
2.1.4. Amorphous State
Amorphous state can be deﬁned with reference to a crystalline solid. It is similar to
crystalline solid as an amorphous solid has short-range molecular arrangement withneighboring molecules, but unlike crystalline solid, an amorphous solid has no longrange order of molecular packing. The major interest in amorphous solids is in theirhigher solubilities and dissolution properties as well as better compressibility as compared to the crystalline forms. However, amorphous solids are generally not as stablephysically and chemically. Currently, many researchers are exploring various
methods to maintain the stability of drugs in their amorphous state. Methods include
stabilization of the amorphous solids by additives and storing the amorphous state
under appropriate storage temperatures (28).

2.2. Additives
2.2.1. Complexing Agent
An additive is able to improve the dissolution of a poorly water-soluble drug byforming a water-soluble intermolecular complex. The additive is called solubilizing
Table 4 Solubilizing Agents for Poorly Soluble Substances
Poorly water-soluble substanceCaffeine
Calcium theobromine
IodineMephenesin
Quinine hydrochloride
Riboﬂavin
Theobromine
Theophylline
Source: From Ref. 29.
© 2005 by Taylor & Francis Group, LLC

Solubilizing agent
Sodium benzoate, sodium salicylate
Calcium salicylate
Potassium iodide
Salicylic acid
Urethane, carbamide
Nicotinic amide
Sodium salicylate
Sodium acetate, ethylenediamine

414

Heng et al.

agent and it must be present at an optimal concentration to maximize the solubilityof a poorly water-soluble drug. Table 4 lists some of the common solubilizing agents.
One commonly used additive is cyclodextrin. Cyclodextrins are bucket-shaped
oligosaccharides produced from starch.
As a result of their molecular structures and shapes, cyclodextrins are able
to entrap poorly water-soluble drugs in the hydrophobic cavities forming watersoluble inclusion complexes with the poorly water-soluble drugs. Cavallari et al. (30)showed that complexation and granulation of piroxicam with b-cyclodextrin by steam
granulation in a single process improved in vitro drug release when compared to aphysical mixture of drug and b-cyclodextrin in the same composition. 2-Hydroxypropyl-b-cyclodextrin was employed by Uekama et al. (31) to form water-soluble
inclusion complex with nifedipine. The drug and additive were dissolved inethanol-dichloromethane and subsequently spray dried. Tablets prepared using theinclusion complexes were found to promote nifedipine in vitro release rate. Upon
feeding the test tablets to dogs, superior oral bioavailability was obtained. Storage
at 60 C and 75% relative humidity did not result in nifedipine crystal growth because
the nifedipine molecules were basically entrapped within the 2-hydroxypropylb-cyclodextrin, minimizing the opportunity for the nifedipine molecules coming
together and recrystallizing. Thus, the stability in dissolution proﬁle could beachieved throughout the entire period of study.
2.2.2. Effervescent Agent
Effervescence is deﬁned as the evolution of bubbles of gas from a liquid as the resultof a chemical reaction. The generation of gas, which is usually carbon dioxide, isusually achieved by spontaneous chemical reaction between a soluble acid source
and an alkali metal carbonate in the presence of water. The reaction can be triggeredin the presence of a small amount of water, thus moisture protection of such oral
dosage forms is paramount. This is because effervescence reaction when initiated willproceed spontaneously because one of the by-products is water.
Several researchers had found that the bioavailability of aspirin from effervescence tablet was higher than conventional or enteric-coated tablets (32–34). The reasons for this included the dramatic disintegration rate of the tablets that enabled rapid
release of the drug particles for dissolution and the increase in gastric emptying rate.
2.2.3. Hydrophilic AgentIn the formulation of rapid release granules, it is important to consider the formulation in its totality. It is always better to employ more hydrophilic agents which may
be water-soluble or water-insoluble as binders or ﬁllers in the formulation so thatwater penetration into the granules will not be impeded. Hydrophilic agentscommonly employed include hydroxylpropylcellulose, hydropropylmethylcellulose,lactose, microcrystalline cellulose, polyvinylpyrrolidone, starch, and many others.
These additives aid in wetting the poorly water-soluble drug. Polyvinylpyrrolidone
K30 was able to improve the wetting of nifedipine complexed with 2-hydroxypropyl-b-cyclodextrin, thus negating the decrease in nifedipine release brought about
by the poor wettability and good compressibility of the complex (35).
© 2005 by Taylor & Francis Group, LLC

Rapid Release Granulation

415

2.2.4. Lubricant
Lubricant is employed in a formulation to facilitate the ejection of tablets from thedie. Excessive sticking of tablets to the punches or wear of punches and dies will be
reduced. Lubricant functions by forming a thin ﬁlm at the interface of the tablet anddie, reducing the shearing force during the ejection of tablet. An optimum amount of
lubricant must be used for each formulation in order to optimize the drug dissolution. Excess lubricant interferes with both disintegration and bioavailability
by waterprooﬁng the granules and tablets. Gordon (36) found that doubling thequantity of magnesium stearate to be mixed with naproxen granules before tableting
resulted in a slower drug dissolution rate.
2.2.5. Surface Active AgentThis additive is capable of forming aggregates called micelles above the critical
micelle concentration. This is the major distinguishing feature between surface active
agent and complexing agent. In an aqueous environment, the cores of theseaggregates resemble a separate organic phase providing a suitable environment forpoorly water-soluble drugs. Solubilization results in the increase in the aqueous solubility of drugs and aids dissolution. It is also able to improve wetting of the granules.
Surfactant can also potentially disrupt the integrity of membranes to enhance drug
absorption.
Sodium lauryl sulfate was employed in the formulation of ibuprofen tablet toenhance ibuprofen dissolution. Sodium lauryl sulfate was incorporated during the
wet granulation phase and the resultant dissolution proﬁles were even better thancommercial products (37). In another study by Gohel and Patel (38), the authors
used a combination of hydrophilic and surface active agents to bring about rapid
release of nimesulide. The hydrophilic agents studied included polyethylene glycol
400, propylene glycol and polyvinylpyrrolidone K30, whereas the surface active
agents investigated were sodium lauryl sulfate and polyoxyethylene sorbitan monooleate. Aqueous solutions of the hydrophilic agents and surface active agents weremixed with the drug before the suspension was further mixed with the rest of thepowder mass during granulation. Thus, additives were incorporated as part of theliquid binder. The granules formed were shown to display enhanced dissolution ascompared to the pure drug and the improvement in drug release property was
attributed to increase in wettability and the solubilizing effects by the additives.
The solubilizing effect of sodium lauryl sulfate on griseofulvin in the griseofulvin–
polyethylene glycol 3000 system was demonstrated by Sjökvist et al. (39). At an
optimum concentration of sodium lauryl sulfate, the crystalline griseofulvin was converted into a solubilized state, which was in the molecular form. The change of phase
could be detected by x-ray diffractometry and differential scanning calorimetry.
Thus, the drug molecules existing in a molecularly dispersed state could be easily
released into the dissolution medium upon contact with the dissolution medium.
Dry granulation via slugging and roller compaction of hydroxypropylmethylcellulose with naproxen, nifedipine, or carbazepine resulted in improvement of theirdissolution proﬁles. The mechanism for dissolution enhancement was believed to bea microenvironment hydroxypropylmethylcellulose surfactant effect facilitated byplacing the hydroxypropylmethylcellulose in close proximity to the drug as simple
mixing did not result in enhanced dissolution (40). Another example was the useof polyethylene 40 hydrogenated castor oil to improve the in vitro release of hydrochlorothiazide (41). The release was dependent on the concentration of surface active© 2005 by Taylor & Francis Group, LLC

416

Heng et al.

agent and a higher concentration gave rise to better dissolution. Mehta et al. (42)managed to enhance nifedipine release from granules with copolymer of propyleneoxide and ethylene oxide as the surface active agent.
2.2.6. Superdisintegrant
The addition of disintegrant is to facilitate the breakup of tablet, thus presenting the
micronized drug to the dissolution medium. In general, for a drug having solubilityof 10 mg/mL or less, disintegration rate of the solid dosage form has a profoundeffect on the dissolution proﬁle (43). Superdisintegrants represent a subclass of
disintegrants that are associated with dramatic disintegration rates. Some of thecommon superdisintegrants are crospovidone, croscamellose sodium, and sodium
starch glycolate. Studies in the 1970s and 1980s usually used the disintegration test
to investigate the effect of incorporating superdisintegrants into formulations. Even
though tablet disintegration is often a necessary precursor for drug dissolution, it
does not ensure that the drug of interest dissolves but in practice, the two are highly
correlated. In 1993, Gordon and coworkers (44) studied the effect of superdisintegrants employed during the wet granulation process in terms of dissolution andconﬁrmed the usefulness of superdisintegrants in enhancing dissolution of p-aminobenzoic acid in tablets containing mainly lactose, dibasic calcium phosphate dehydrate, or naproxen, in order to vary the water afﬁnity of the tablet manufactured.
Bolhuis et al. (45) also veriﬁed the effectiveness of superdisintegrants in improving
the dissolution of methylprednisolone and phenylbutazone. Granules produced fromwet granulation were either ﬁlled into capsule or tableted. Both types of oral dosage
forms displayed enhanced dissolution. Superdisintegrants were found to be useful inmelt granulation as well as where the intragranular addition of crospovidone during
the melt granulation of carbamazepine, polyethylene glycol 4000, and lactose
monohydrate was able to reduce the dissolution t90% by half (46).

Figure 3 Possible factors affecting the rapid release of drug in the respective steps under dry
and wet granulation methods.
© 2005 by Taylor & Francis Group, LLC

Rapid Release Granulation

417

3. GRANULATION-RELATED FACTORS
Figure 3 refers to some of the common steps in dry and wet granulation methods andsome of the factors that may affect the ﬁnal release of drug from capsules or tablets
made from the granules.
The ﬁrst step of both methods, which is interactive mixing, plays an importantpart in improving the dissolution of poorly soluble drug because the mixing of micronized drug with the appropriate additives reduces the cohesiveness of the drug particles,
leading to better dissolution of the drug (Section 2.1.2.1). Mitchell et al. (40) processed
poorly water-soluble drugs with hydropropylmethylcellulose by dry granulation andachieved enhanced drug dissolution probably due to the reduction in cohesiveness ofthe drugs and surface active property of hydropropymethylcellulose. Levy et al. (47)reported that the dissolution rate of salicylic acid tablets increased with a decrease in
the granule size prepared by the slugging method. Gao et al. (48) improved the dissolution of an experimental drug by carrying out wet granulation in ﬂuid bed and high-shear
mixer and this could be attributed to the combined effects of employing the micronized
form of the drug, a surface active agent, a superdisintegrant, and reduction in thecohesiveness of the drug by interactive mixing.
3.1. Liquid Binder
Wet granulation offers an opportunity for the transformation of crystal forms andthe choice of the liquid binder plays an important role in determining the ﬁnal crystal
form of the drug in the granules obtained (Section 2.1.3). Transformation usuallyoccurs during the addition of liquid binder to the powder mass during wet massing
and drying of the formed granules. Addition of the binder could be viewed as suspending drug in a mixture of solvent and additives, hence, encouraging transformation of anhydrates to solvated forms. If sufﬁcient liquid binder is added, this could beviewed as a solution step and subsequent drying of granules as the recrystallization
step. Thus, close attention has to be paid to polymorph conversion during wet
granulation. An example of such a situation is theophylline. Theophylline readily
converts to the monohydrate form (II) upon exposure to water during wet granulation. The hydration process could be followed closely using near-infrared spectroscopy (49) and charge-coupled device Raman spectroscopy (50). This conversion
could not be prevented by having high water absorbing capacity additive such as
the siliciﬁed microcrystalline cellulose because the minimal amount of water for
effective wet massing was sufﬁcient to trigger this conversion (51). Theophylline
monohydrate under vacuum dehydration forms the metastable anhydrate (I). Thismetastable anhydrate on storage recrystallized to stable anhydrous form (I) and in
the process, formed solid bridges within the tablet (52). A decrease in dissolution
would result if the recrystallization process were not prevented. The use of water
as the liquid binder also affected the dissolution of naproxen sodium because of drug
hydration (53) resulting in a poorer dissolution of the drug. Thus, if wet granulation
has to be carried out for these drugs, and in order to maintain rapid dissolution,polymorphic conversion may be prevented by using ethanol as the liquid binder.
The solubility of drug in the liquid binder also affects the dissolution of theresulting capsules or tablets made from these granules. This was illustrated by astudy carried out by Wu et al. (54) who found a correlation between dissolution rate
constants of zindotrine and the solubility of zindotrine in liquid binder containing
varying ethanol concentrations. This was explained by the dissolution of a certain© 2005 by Taylor & Francis Group, LLC

418

Heng et al.

amount of zindotrine, followed by the recrystallization of ﬁne crystals during thedrying phase of the granules. The subsequent enhancement in dissolution was dueto the ﬁner crystals formed due to the recrystallization process. Thus, the drug
had effectively undergone the micronization process during wet granulation.
The quantity of liquid binder also gives rise to different dissolution proﬁles. A low
amount used would result in the production of smaller granules and the resultant tablets
formed displayed much faster dissolution as compared to granules formed using ahigher amount of liquid binder (36). Besides forming larger granules, a higher amountof liquid binder used is also expected to increase the hardness of granules. Hard tablets
will give rise to poorer dissolution because the tablets require more time to break up (55).
This observation was found to be dependent on the moisture content of the tablets. At
moisture contents of 1.6% and 2.0%, ticlopidine hydrochloride dissolution was highly
dependent on the tablet strength. However, with moisture contents of more than
3.0%, the drug dissolution was independent of tablet strength (56).
3.2. Granulating Equipment
The use of the appropriate granulating equipment also plays a part in the release rateof the drug. Acetaminophen beads made from extrusion/spheronization were compared to beads made from pan coating. Beads made from pan coating displayed
higher dissolution rates as compared to those made from the former method. This
was attributed to the disintegration of pan-coated beads and the ones made fromextrusion/spheronization were denser and less friable due to the higher energy input
during wet massing and thus did not disintegrate during dissolution. Thus, theselection of equipment for wet granulation affects the hardness of the granules
and ultimately inﬂuences drug release (57). Chowhan et al. (56,58) also reported that
granules made from high-speed shear mixer were lower in porosity as compared tothose prepared from planetary mixer. Low porosity did not facilitate solvent
penetration and, hence, caused poorer drug dissolution.
3.3. Wet Massing
Wet massing was found to play an important factor in the dissolution rate of dyphylline. Increasing the time during wet massing resulted in an increase in bulk density of
the granules. The maximum bulk density value coincided with the minimum dissolution rate indicating that the dissolution of drug required the diffusion of dissolution
medium into granules via pores to dissolve the drug (59). Thus, the duration of wet
massing affects the hardness of granules and ultimately, dissolution of the drug.
3.4. Blending
The dissolution rate is affected by the type of blending equipment employed, theduration of blending of granules with disintegrant, glidant, and lubricant. It was
found that the type of blender affected the distribution of magnesium stearate andhence, drug dissolution. High-speed blender was employed to mix interactive mixtureof theophylline with magnesium stearate before tableting. It was found that a 15 minduration was sufﬁcient to impair theophylline dissolution whereas an impairmentof dissolution was not observed for a lower-speed blender. The impairment to drug
dissolution increased with an increase in the duration of blending (60). This was© 2005 by Taylor & Francis Group, LLC

Rapid Release Granulation

419

attributed to the coating of the granules with a thin ﬁlm of lubricant, a water-repellant,
and hence, compromising the wetting of the granules.
4. SOLID DISPERSION
The term, solid dispersion, refers to a composite solid of one or more drugs in a watersoluble carrier or matrix prepared by melt (fusion), solvent, or melt–solvent method(61). Solid dispersions have been traditionally employed to enhance the dissolution rateof drug, with a view to improve bioavailability. The common approach to achieve rapid
drug dissolution is to use inert but water-soluble carriers such as polyethylene glycol or
polyvinylpyrrolidone. Solid dispersion enhances the dissolution of drugs by the formation of ﬁne drug crystals via the eutectic or monotectic systems. Hence, solid dispersion
could also be viewed as a size reduction technique (Section 2.1.2). Under certain conditions, the drug may be entrapped in the water-soluble carrier matrix without undergoingrecrystallization to form an amorphous solid solution (Section 2.1.4), a water-soluble
complex with the carrier (Section 2.2.1), or it may dissolve in the carrier to form a true
solid solution. The drug particles in solid dispersions were released as ﬁne or amorphous
colloidal entities upon dissolution of the matrix, enhancing drug dissolution rate. This
concept is deemed to be utilized for drug enhancement if the drug and water-soluble carriers have been fused prior to or during granulation via any of the three preparation
methods (Section 4.1). Table 5 lists a number of processes that employ the concept ofsolid dispersion and the ones suitable for large-scale manufacturing are further discussed under Section 4.2. Excellent reviews have been published in this area for further
reading (61,96–98).
4.1. Preparation Methods
4.1.1. Melt/Fusion Method
Early pioneers in the ﬁeld of solid dispersions were Sekiguchi and Obi (99) who utilized
the melt or fusion method to produce dispersion systems. Essentially, a physical mixtureof a drug and a water-soluble carrier was heated directly until melting occurred. The
molten mixture was subsequently solidiﬁed in an ice bath. The cooled mass was milled
and sieved. Administration of the product obtained was found to improve absorption of
the drug. Subsequent workers proposed numerous variations to this method.
4.1.2. Solvent Method
Tachibana and Nakumara (100) introduced the concept of solid dispersion preparation by a solvent method. The proposed method involved dissolving the drug andwater-soluble carrier in a common solvent and subsequent evaporation of the solvent
under vacuum. Solid dispersions produced by this manner are commonly known as
coprecipitates, a term coined by Bates (101). This term is a misnomer and should beappropriately renamed as coevaporates. In a strict sense, coprecipitates are formedby the addition of a second solvent to the original solution, which decreases the solubilities of the drug and carrier in the resultant solutions, thus coprecipitating them.
4.1.3. Melt-Solvent Method
This is a hybrid of the two methods discussed. The drug is dissolved in a suitableorganic solvent and the solution is incorporated directly into a molten carrier.
Subsequently, the organic solvent is evaporated off (61).
© 2005 by Taylor & Francis Group, LLC

420Heng et al.

Table 5 Summary of the Processes Reported in the Literature for Solid Dispersion
Production
Preparation
methodMeltmethodProcess
Compression moulding

Broman et al. (62)Extrusion/spheronization

Vervaet et al. (41), Vervaet and Remon (63),Mehta et al. (42)El-Egakey et al. (64), Hülsmann et al. (65),
Forster et al. (66), Perissutti et al. (67),
Ndindayino et al. (68)
Dittgen et al. (69)Ford and Rubinstein (70)Kinget and Kemel (71), Passerini et al. (72),Perissutti et al. (46), Gupta et al. (73–75)
Nozawa et al. (76,77)
Fini et al. (78)Melt extrusion

Hot-spin melting
In situ granulation
Melt granulation

Solvent
methodInvestigators

Roll mixing
Ultrasound-assistedcompaction
Ultrasound-assisted spray
congealing
Lyophilization
Solvent deposition
Solvent extrusion/
spheronization
Spray drying
Spray freezing into liquid
Steam granulation
Supercritical carbon dioxide

Passerini et al. (79), Fini et al. (78)Corveleyn and Remon (80–82)
Monkhouse and Lach (15,16), Kim andJarowski (83), Takeuchi (14)Deasy and Gouldson (84)Corrigan and Holohan (85), Arias et al. (86)
Hu et al. (87), Rogers et al. (13,88–91)
Cavallari et al. (30), Rodriguez et al. (92)Senčar-Božič et al. (93), Moneghini et al. (94),Corrigan and Crean (95)4.2. Processes
4.2.1. Melt Extrusion
This process originated from the plastic industry and it entails conversion of a raw
material into a product of uniform shape and density. The drug and additives areusually mixed followed by forcing the powder mass through a die under controlled
conditions. The extruded mixtures always exhibited more rapid release of drug vs. thecorresponding physical mixtures as shown by Perissutti et al. (67) using carbamazepine
as the model drug. Hülsmann et al. (65) extruded 30% of 17-b-estradiol hemihydratewith 30% polyvinylpyrrolidone K30 and 40% saccharose-monopalmitate, which, respectively, functioned as a water-soluble carrier and a surface active agent, to achievea good release of drug and this was unchanged upon tableting as the dissolution proﬁlesof the exudates and tablets were similar. Ndindayino et al. (68) used this technique to
produce hydrochlorothiazide tablets by directly extruding the melt into a tablet-shaped
cavity. The molded tablet thus formed displayed higher in vitro dissolution and relative
bioavailability in healthy volunteers. The improvement in dissolution rate is drug
speciﬁc as demonstrated by Forster et al. (66) after investigating the extrusion ofindomethacin, lacidipine, nifedipine, and tolbutamide with either polyvinylpyrrolidone© 2005 by Taylor & Francis Group, LLC

Rapid Release Granulation

421

K30 or copolymer of polyvinylpyrrolidone and vinyl acetate, both of which were acting
as water-soluble carriers. The stability of the extrudates was speculated to be dependent
on the degree of hydrogen bonding between the drug and polymer. An excellent
review by Breitenbach (102) provides an in-depth view of this process in the rapid
release of drug.
A possible modiﬁcation of this process is the extrusion/spheronization, where
the extrudates are spheronized to form pellets. Pellets are highly spherical granules
and Vervaet et al. (41) found that the use of polyethylene glycol 400 as the watersoluble carrier and polyethylene glycol 40 hydrogenated castor oil as the surface
active agent was able to enhance the in vitro release of the hydrochlorothiazide pellets produced. The pellets were subsequently ﬁlled in hard gelatin capsule and fed toeight Caucasian male volunteers. Comparison of mean serum concentration ofvolunteers between a commercial product and the pellets indicated that dissolution
and absorption from the pellets were faster (63). A slightly different method was
employed by Mehta et al. (42) for rapid drug release. They prepared a solid dispersion of nifedipine and copolymer of propylene oxide and ethylene oxide serving as
the surface active agent, and the resultant powder was mixed with other excipients
before extrusion. The nifedipine drug release was reduced to 12 h from 24 h as compared to when only micronized nifedipine powder was used.
Deasy and Gouldson (84) employed organic solvents, instead of using nonsolvent extrusion, for wet massing of the powder. The wetted mass was left aside for 12 h
for in situ formation of enteric coprecipitate of nifedipine with hydroxypropylmethylcellulose phthalate, which is a water-soluble carrier at pH 6.8. However, therelease of the nifedipine was poor as indicated by in vitro dissolution upon changing
the dissolution medium from pH 1.2 to 6.8, to simulate the passage of the pellets
through the gastrointestinal tract. Enhanced release was only achieved by the addition of sodium lauryl sulfate and sodium starch glycolate, which, respectively, acted
as the surface active agent and superdisintegrant. The combined effects of wetting,solubilization, and disintegration exposed the enteric coprecipitates for rapid
dissolution at pH 6.8.
4.2.2. Melt Granulation
Melt granulation is a process by which powders are agglomerated with the aid ofa binder, in either a molten state or solid state that melts during the process. The
apparatus of choice is a high-shear mixer, where the temperature of a powder canbe raised above the melting point of a meltable binder by either a heating jacket
or frictional forces generated by the impeller blades. Liquid binding is possible by
the molten binder, thus melt granulation does not require the use of solvents. The
choice of the meltable binder plays an important role in the process. It has to melt
at a relatively low temperature of 50–80 C. The use of hydrophilic binder that melts
at a low temperature will aid in the rapid release of drug. Passerini and coworkers(72) used a copolymer of ethylene glycol and propylene glycol as the surface active
agent, to achieve fast release ibuprofen granules. The improvement in dissolution
could be correlated to the formation of a eutectic mixture between the drug andbinder, hence utilizing the solid dispersion concept (Section 4). Polyethylene glycol
4000 and lactose monohydrate were employed as the hydrophilic meltable binderand hydrophilic ﬁller, respectively, by Perissutti et al. (46), in the formulation of
rapid release carbamazepine tablets by the melt granulation process. Dissolution© 2005 by Taylor & Francis Group, LLC

422

Heng et al.

proﬁles of the granules were found to be better than physical mixtures of the same
compositions and the pure drug.
Gupta and coworkers (73) employed a variation of the above method. Theyﬁrst formed a molten mixture of drug and polyglycolized glycerides, which was
the surface active agent employed, before adding this to a surface adsorbent suchas magnesium alumino silicate. The use of a surface adsorbent is to from granules
with good ﬂow and compressibility properties. The granules produced had enhanced
dissolution properties as compared to the physical mixtures or pure drug. Tableting
further improved the release rate. Storage under 40 C and 75% relative humidity
also improved the dissolution rate. This was attributed to an increase in the degreeof hydrogen bonding between drug and adsorbant under elevated temperatures. Thiswas mediated by the solubility of the drug in the polyglycolized glycerides matrix(74,75).
4.2.3. Roll Mixing
Roll mixing involves the feeding of the powder mix through two rollers. The powder
mass usually includes the drug with one or more water-soluble carriers. Depending
on appropriate processing conditions such as roller pressure or the use of solvent, thedrug may be converted into an amorphous state. Nozawa et al. (76) managed to
improve phenytoin in vitro dissolution release by roll mixing of the drug and polyvinylpyrrolidone K30, which served as the water-soluble carrier, as compared to thephysical mixtures and coprecipitates. The use of an organic solvent such as ethanol
would further improve the dissolution of the drug. Nozawa et al. (77) employed thissolvent during the roller mixing of nifedipine with two water-soluble carriers, polyvinylpyrrolidone K30 and polyethylene glycol 1500. They were able to achieve a 400
times higher dissolution rate as compared to nifedipine alone.
4.2.4. Lyophilization
Lyophilization, also popularly known as freeze drying, is a process whereby water issublimed from frozen solutions, frozen suspensions, or frozen emulsions; under
reduced pressure and temperature, leaving a dry porous mass of approximately
the same shape and size as the original frozen mass. Lyophilization essentiallyconsists of three steps, freezing, primary drying, and secondary drying. The materials
are cooled until they are frozen. Primary drying is accomplished under vacuum andslight heating to remove most of the water by sublimation. The last stage is toremove sorbed water, which is carried out under elevated temperature. The lyophilization technology has been applied to the formation of rapid dispersible tablets.
This type of dosage form caters mainly to the pediatric and geriatric patients who
experience difﬁculties in swallowing. This also caters to active working patients when
there is limited access to water. The ease of administration will decrease the incidenceof noncompliance. The clinical effects of some drugs are enhanced when formulated
into this dosage form as pregastric absorption from the mouth, pharynx, andesophagus will increase the bioavailability and decrease the side effects. The ﬁrstpass metabolism could also be bypassed. The most notable lyohilization process inthe pharmaceutical industry was called Zydis Technology, which was codevelopedby Wyeth Laboratories and R. P. Scherer (103). This technology essentially involved
the ﬁlling of blister pocket with a suspension of drug followed by freeze drying toform a porous tablet of sufﬁcient strength before sealing of the blister pack (104).
Thus, this technology could be viewed as a ‘‘macrogranulation’’, whereby each tablet© 2005 by Taylor & Francis Group, LLC

Rapid Release Granulation423

is considered a ‘‘macrogranule.’’ Instead of lyophilizing a suspension, Corveleyn andRemon (81) managed to lyophilize an emulsion of hydrochlorothiazide into a tablet.
Disadvantages of lyophilized tablets include poor tablet strength and tendency to be
disturbed by air currents during sealing. This problem was examined by Thapa et al.
(105) and overcome by lyophilization of sealed liquid via holes pierced throughimpermeable membrane. The lyophilization technology provides an opportunity
for the formation of amorphous solid solution and enhanced drug release by solid
dispersion concept. This technique had been successfully employed by Corveleyn
and Remon (80,82) to produce lyophilized hydrochlorothiazide tablets displaying
better in vitro dissolution as well as higher bioavailability in human volunteers.
4.2.5. Steam Granulation
Steam granulation is a derivative of wet granulation technique, which involves theuse of steam instead of traditional liquid binder. Instead of spraying the liquidbinder, steam is emitted into the wet massing chamber. The processing time is shortbecause less moisture is needed as steam has a higher diffusion rate into the powder
mass, achieving a higher distribution of the binder. Another reason is the morefavorable thermal balance during the drying step. This is because after condensationof the steam in the powder mass, water forms a hot thin ﬁlm and this requires only asmall amount of energy for vaporization as compared to evaporating the water fromroom temperature. This process was proposed by Rodriguez et al. (92) and theysuccessfully produced diclofenac-polyethylene glycol 4000 rapid release granules
whereby polyethylene glycol 4000 acted as the water-soluble carrier. The authors
compared the granules with granules manufactured from wet and melt granulation
techniques and found that the granules produced were more spherical and had alarger surface area. The larger surface area was proposed to enhance drug release.
This group of researchers also used steam to complex piroxicam with b-cyclodextrin,
as the complexing agent, forming steam granulated granules simultaneously, thus
carrying out two processes in a single step to produce granules having dissolution
proﬁles better than the original drug or a physical mixture of the two (30).

5. CONCLUSIONSThe preparation of rapid release granules for capsule or tablet preparation is a multifactorial situation whereby it has to be approached concurrently, in a number ofways in order to achieve the desired end result. This approach is dependent on anumber of factors, which could be broadly divided into formulation-related andgranulation-related, but in reality, they are closely related. This chapter aims tohighlight the key factors that the formulator has to consider in order to optimize
the dissolution properties in the preformulation stage to end product so that appropriate decisions could be made pertaining to the selection of the form of drug to bepresented, additives to be used, granulation methods employed, and processing
variables to be controlled, and the employment of solid dispersion processes.

ACKNOWLEDGMENT
The authors thank Ms. Loh Zhi Hui for assisting in the literature search.
© 2005 by Taylor & Francis Group, LLC

424

Heng et al.

REFERENCES
1. Amidon GL, Lennernäs H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classiﬁcation: the correlation of in vitro drug product dissolution and in vivo
bioavailability. Pharm Res 1995; 12(3):413–420.
2. Aulton M. Dissolution and solubility. Aulton AE, ed. Phamaceutics: The Science ofDosage Form Design. Edinburgh: Churchill Livingstone, 2000:15–32.
3. Noyes AA, Whitney WR. The rate of solution of solid substances in their own solutions.
J Am Chem Soc 1897; 19:930–934.
4. Nernst W. Theorie der reaktionsgeschwindigkeit in heterogenen systemen. Z Phys Chem
1904; 47:52–55.
5. Anderberg EK, Bisrat M, Nyström C. Physicochemical aspects of drug release VII. The
effect of surfactant concentration and drug particle size on solubility and dissolution
rate of felodipine, a sparingly soluble drug. Int J Pharm 1988; 47:67–77.
6. Bisrat M, Nyström C. Physicochemical aspects of drug release VIII. The relation
between particle size and surface speciﬁc dissolution rate in agitated suspensions. Int
J Pharm 1988; 47:223–231.
7. Bisrat M, Anderberg EK, Barnett MI, Nyström C. Physicochemical aspects of drug
release XV. Investigation of diffusional transport in dissolution of suspended, sparingly
soluble drugs. Int J Pharm 1992; 80:191–201.
8. Kraml M, Dubuc J, Gaudry R. Gastrointestinal absorption of griseofulvin: II. Inﬂuenceof particle size in man. Antibiot Chemother 1962; 12(4):239–242.
9. Levy G. Effect of particle size on dissolution and gastrointestinal absorption rates ofpharmaceuticals. Am J Pharm 1963; 135:78–92.
10. Lin SL, Menig J, Lachman L. Interdependence of physiological surfactant and drug
particle size on the dissolution behavior of water-insoluble drugs. J Pharm Sci 1968;
57(12):2143–2148.
11. Craig DQM. Polyethylene glycols and drug release. Drug Dev Ind Pharm 1990;
16(17):2501–2526.
12. Aungst BJ, Nguyen NH, Taylor NJ, Bindra DS. Formulation and food effects on theoral absorption of a poorly water soluble, highly permeable antiretroviral agent.
J Pharm Sci 2002; 91(6):1390–1395.
13. Rogers TL, Johnston KP, Williams RO. Solution-based particle formation of pharmaceutical powders by supercritical or compressed ﬂuid CO2 and cryogenic spray-freezing
technologies. Drug Dev Ind Pharm 2001; 27(10):1003–1015.
14. Takeuchi H, Handa T, Kawashima Y. Enhancement of the dissolution rate of a poorly
water-soluble drug (tolbutamide) by a spray-drying solvent deposition method anddisintegrants. J Pharm Pharmacol 1987; 39:769–773.
15. Monkhouse DC, Lach JL. Use of adsorbents in enhancement of drug dissolution I.
J Pharm Sci 1972; 61(9):1430–1435.
16. Monkhouse DC, Lach JL. Use of adsorbents in enhancement of drug dissolution II.
J Pharm Sci 1972; 61(9):1435–1441.
17. Hersey JA. Ordered mixing: a new concept in powder mixing practice. Powder Technol
1975; 11:41–44.
18. Hersey JA. Preparation and properties of ordered mixtures. Aust J Pharm Sci 1977;
6(1):29–31.
19. Thiel WJ, Sberna FJ. Fluidized bed ﬁlm coating of an interactive powder mixture to
produce microencapsulated 2-5 mm particles. J Pharm Pharmacol 1986; 38:166–171.
20. McGinity JW, Ku CT, Bodmeier R, Harris MR. Dissolution and uniformity propertiesof ordered mixes of micronized griseofulvin and a directly compressible excipient. Drug
Dev Ind Pharm 1985; 11(4):891–900.
21. Nyström C, Westerberg M. The use of ordered mixtures for improving the dissolution
rate of low solubility compounds. J Pharm Pharmacol 1986; 38:161–165.

© 2005 by Taylor & Francis Group, LLC

Rapid Release Granulation

425

22. Ibrahim H, Sallam E, Takieddin M, Shamat MA. Dissolution characteristics ofinteractive powder mixture. Part one: effect of solubility and particle size of excipients.
Drug Dev Ind Pharm 1988; 14(9):1249–1276.
23. Udupa N. Characterization of different crystal forms of ibuprofen, tinidazole andlorazepam. Drug Dev Ind Pharm 1990; 16(9):1591–1596.
24. Gul MK, Zhu J. Preparation, characterization, and evaluation of physicochemical
properties of different crystalline forms of ibuprofen. Drug Dev Ind Pharm 1998;
24(5):463–471.
25. Vippagunta SR, Brittain HG, Grant DJW. Crystalline solids. Adv Drug Delivery Rev
2001; 48:3–26.
26. Otsuka M, Hasegawa H, Matsuda Y. Effect of polymorphic forms of bulk powders on
pharmaceutical properties of carbamazepine granules. Chem Pharm Bull 1999;
47(6):852–856.
27. Otsuka M, Hasegawa H, Matsuda Y. Effect of polymorphic transformation during
the extrusion-granulation process on the pharmaceutical properties of carbamazepine
granules. Chem Pharm Bull 1997; 45(5):894–898.
28. Yu L. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv Drug Delivery Rev 2001; 48:27–42.
29. Kawashima Y. Solubility and dissolution rate. Gotoh K, Masuda H, Higashitani K,
eds. Powder Technology Handbook. New York: Marcel Dekker, 1997:217–230.
30. Cavallari C, Abertini B, González-Rodrı́guez ML, Rodriguez L. Improved dissolution
behaviour of steam-granulated piroxicam. Eur J Pharm Biopharm 2002; 54:65–73.
31. Uekama K, Ikegami K, Wang Z, Horiuchi Y, Hirayama F. Inhibitory effect of 2-hydroxypropyl-b-cyclodextrin on crystal-growth of nifedipine during storage: superiordissolution and oral bioavailability compared with polyvinylpyrrolidone K-30. J Pharm
Pharmacol 1992; 44:73–78.
32. Ekenved G, Elofsson R, Solvell L. Bioavailability studies on a buffered acetylsalicylic
acid preparation. Acta Pharm Suecica 1975; 12:323–332.
33. Mason WD, Winer N. Kinetics of aspirin, salicylic acid, and salicyluric acid following
oral administration of aspirin as a tablet and two buffered solutions. J Pharm Sci 1981;
70(3):262–265.
34. Mason WD, Winer N. Inﬂuence of food on aspirin absorption from tablets and buffered solutions. J Pharm Sci 1983; 72(7):819–821.
35. Wang Z, Hirayama F, Ikegami K, Uekama K. Release characteristics of nifedipine from
2-hydroxypropyl-b-cyclodextrin complex during storage and its modiﬁcation of
hybridizing polyvinylpyrrolidone K-30. Chem Pharm Bull 1993; 41(10):1822–1826.
36. Gordon MS. Process considerations in reducing tablet friability and their effect on invitro dissolution. Drug Dev Ind Pharm 1994; 20(1):11–29.
37. Ghosh LK, Ghosh NC, Chatterjee M, Gupta BK. Product development studies on thetablet formulation of ibuprofen to improve bioavailability. Drug Dev Ind Pharm 1998;
29(3):299–310.
38. Gohel MC, Patel LD. Processing of nimesulide-PEG 400-PG-PVP solid dispersions:preparation, characterization, and in vitro dissolution. Drug Dev Ind Pharm 2003;
29(3):299–310.
39. Sjökvist E, Nyström C, Aldén M. Physicochemical aspects of drug release XIII. The
effect of sodium dodecyl sulphate additions on the structure and dissolution of a drugin solid dispersions. Int J Pharm 1991; 69:53–62.
40. Mitchell SA, Reynolds TD, Dasbach TP. A compaction process to enhance dissolutionof poorly water-soluble drugs using hydroxypropyl methylcellulose. Int J Pharm 2003;
250:3–11.
41. Vervaet C, Baert L, Remon JP. Enhancement of in vitro release by using polyethylene
glycol 400 and PEG-40 hydrogenated castor oil in pellets made by extrusion/spheronisation. Int J Pharm 1994; 108:207–212.

© 2005 by Taylor & Francis Group, LLC

426

Heng et al.

42. Mehta KA, Kislalioglu MS, Phuapradit W, Malick AW, Shah NH. Multi-unit conÕtrolled release systems of nifedipine and nifedipine:Pluronic F-68 solid dispersions:characterization of release mechanisms. Drug Dev Ind Pharm 2002; 28(3):275–285.
43. Storey DE. The role of dissolution testing in the design of immediate release dosage
forms. Drug Inf J 1996; 30:1039–1044.
44. Gordon MS, Rudraraju VS, Rhie JK, Chowhan ZT. The effect of aging on the
dissolution of wet granulated tablets containing super disintegrants. Int J Pharm
1993; 97:119–131.
45. Bolhuis GK, Zuurman K, Wierik GHP. Improvement of dissolution of poorly soluble
drugs by solid deposition on a super disintegrant II. The choice of super disintegrants
and effect of granulation. Eur J Pharm Sci 1997; 5:63–69.
46. Perissutti B, Rubessa F, Moneghini M, Voinovich D. Formulation design of carbamazepine fast-release tablets prepared by melt granulation technique. Int J Pharm 2003;
256:53–63.
47. Levy G, Antkowiak J, Procknal J, White D. Effect of certain tablet formulation factors
on dissolution rate of the active ingredient II: granule size, starch concentration, andcompression pressure. J Pharm Sci 1963; 52(11):1047–1051.
48. Gao JZH, Jain A, Motheram R, Gray DB, Hussain MA. Fluid bed granulation of
a poorly water soluble, low density, micronized drug: comparison with high shear
granulation. Int J Pharm 2002; 237:1–14.
49. Räsänen E, Rantanen J, Jørgensen A, Karjalainen M, Paakkari T, Yliruusi J. Novelidentiﬁcation of pseudopolymorphic changes of theophylline during wet granulation
using near infrared spectroscopy. J Pharm Sci 2001; 90(3):389–396.
50. Jørgensen A, Rantanen J, Karjalainen M, Khriachtchev L, Räsänen E, Yliruusi J.
Hydrate formation during wet granulation studied by spectroscopic methods andmultivariate analysis. Pharm Res 2002; 19(9):1285–1291.
51. Airaksinen S, Luukkonen P, Jørgensen A, Karjalainen M, Rantanen J, Yliruusi J.
Effects of excipients on hydrate formation in wet masses containing theophylline.
J Pharm Sci 2003; 92(3):516–528.
52. Phadnis N, Suryanarayanan R. Polymorphism in anhydrous theophylline-implications
on the dissolution rate of theophylline tablets. J Pharm Sci 1997; 86(11):1256–1263.
53. Bansal P, Haribhakti K, Subramanian V, Plakogiannis F. Effect of formulation andprocess variables on the dissolution proﬁle of naproxen sodium from tablets. Drug
Dev Ind Pharm 1994; 20(3):2151–2156.
54. Wu P, Attarchi F, Anderson N, Carstensen JT. Effect of drug solubility in wet granulation ﬂuids on the dissolution rates of the resulting tablets. Drug Dev Ind Pharm 1989;
15(1):11–16.
55. Chowhan ZT, Amaro AA. Optimization of tablet friability, maximum attainable crushing strength, weight variation and in vitro dissolution by establishing in-process variable
controls. Drug Dev Ind Pharm 1988; 14(4):1079–1106.
56. Chowhan ZT, Yang IC, Amaro AA, Chi LH. Effect of moisture and crushing strength
on tablet friability and in vitro dissolution. J Pharm Sci 1982; 71(12):1371–1375.
57. Zhang G, Schwartz JB, Schnaare RL. Effect of spheronization technique on drug
release from uncoated beads. Drug Dev Ind Pharm 1990; 16(7):1171–1184.
58. Chowhan ZT. Moisture, hardness, disintegration and dissolution interrelationships incompressed tablets prepared by the wet granulation process. Drug Dev Ind Pharm
1979; 5:41–62.
59. Ertel KD, Zoglio MA, Ritschel WA, Carstensen JT. Physical aspects of wet granulation
IV-effect of kneading time on dissolution rate and tablet properties. Drug Dev Ind
Pharm 1990; 16(6):963–981.
60. Otsuka M, Gao J, Matsuda Y. Effects of mixer and mixing time on the pharmaceuticalproperties of theophylline tablets containing various kinds of lactose as diluents.
Drug Dev Ind Pharm 1993; 19(3):333–348.

© 2005 by Taylor & Francis Group, LLC

Rapid Release Granulation

427

61. Chiou WL, Riegelman S. Pharmaceutical applications of solid dispersion systems.
J Pharm Sci 1971; 60(9):1281–1302.
62. Broman E, Khoo C, Taylor LS. A comparison of alternative polymer excipients andprocessing methods for making solid dispersions of a poorly water soluble drug. Int
J Pharm 2002; 222:139–151.
63. Vervaet C, Remon JP. Bioavailability of hydrochlorothiazide from pellets, made by
extrusion/spheronisation, containing polyethylene glycol 400 as a dissolution enhancer.
Pharm Res 1997; 14(11):1644–1646.
64. El-Egakey MA, Soliva M, Speiser P. Hot extruded dosage forms, part I technology anddissolution kinetics of polymeric matrices P. Pharm Acta Helv 1971; 46:31–52.
65. Hülsmann S, Backensfeld T, Keitel S, Bodmeier R. Melt extrusion–an alternative
method for enhancing the dissolution rate of 17b-estradiol hemihydrate. Eur J Pharm
Biopharm 2000; 49:237–242.
66. Forster A, Hempenstall J, Rades T. Characterization of glass solutions of poorly watersoluble drugs produced by melt extrusion with hydrophilic amorphous polymers.
J Pharm Pharmacol 2001; 53:303–315.
67. Perissutti B, Newton JM, Podczeck F, Rubessa F. Preparation of extruded carbamazepine and PEG 4000 as potential rapid release dosage form. Eur J Pharm Biopharm
2002; 53:125–132.
68. Ndindayino F, Vervaet C, Van Den Mooter G, Remon JP. Bioavailability of hydrochlorothiazide from isomalt-based moulded tablets. Int J Pharm 2002; 246:199–202.
69. Dittgen M, Fricke S, Gerecke H, Osterwald H. Hot spin mixing-a new technology to
manufacture solid dispersions, part 1: testosterone. Pharmazie 1995; 50:225–226.
70. Ford JL, Rubinstein MH. Formulation and ageing of tablets prepared from indomethacin-polyethylene glycol 6000 solid dispersions. Pharm Acta Helv 1980; 55(1):1–7.
71. Kinget R, Kemel R. Preparation and properties of granulates containing solid
dispersions. Acta Pharm Technol 1985; 31(2):57–62.
72. Passerini N, Albertini B, González-Rodrı́guez ML, Cavallari C, Rodriguez L.
Preparation and characterization of ibuprofen-poloxamer 188 granules obtained bymelt granulation. Eur J Pharm Sci 2002; 15:71–78.
73. Gupta MK, Goldman D, Bogner RH, Tseng YC. Enhanced drug dissolution and bulk
properties of solid dispersions granulated with a surface adsorbent. Pharm Dev Technol
2001; 6(4):563–572.
74. Gupta MK, Bogner RH, Goldman D, Tseng YC. Mechanism for further enhancement
in drug dissolution from solid-dispersion granules upon storage. Pharm Dev Technol
2002; 7(1):103–112.
75. Gupta MK, Tseng YC, Goldman D, Bogner RH. Hydrogen bonding with adsorbent
during storage governs drug dissolution from solid-dispersion granules. Pharm Res
2002; 19(11):1663–1672.
76. Nozawa Y, Mizumoto T, Higashide F. Improving dissolution rates of practically insoluble drug phenytoin by roll mixing with polyvinyl pyrrolidone. Pharm Acta Helv 1985;
60(5,6):175–177.
77. Nozawa Y, Mizumoto T, Higashide F. Increases in dissolution rate of nifedipine by roll
mixing with polyvinyl pyrrolidone. Pharm Acta Helv 1986; 61(12):337–341.
78. Fini A, Rodriguez , Cavallari C, Albertini C, Passerini N. Ultrasound-compacted andspray-congealed indomethacin/polyethyleneglycol systems. Int J Pharm 2002; 247:
11–22.
79. Passerini N, Perissutti B, Moneghini M, Voinovich D, Albertini B, Cavallari C,
Rodriguez L. Characterization of carbamazepine-gelucire 50/13 microparticles
prepared by a spray congealing process using ultrasounds. J Pharm Sci 2002;
91(3):699–707.
80. Corveleyn S, Remon JP. Formulation and production of rapidly disintegrating tablets
by lyophilisation using hydrochlorothiazide as a model drug. Int J Pharm 1997;
152:215–225.
© 2005 by Taylor & Francis Group, LLC

428

Heng et al.

81. Corveleyn S, Remon JP. Formulation of a lyophilized dry emulsion tablet for thedelivery of poorly soluble drugs. Int J Pharm 1998; 166:65–74.
82. Corveleyn S, Remon JP. Bioavailability of hydrochlorothiazide: conventional versus
freeze-dried tablets. Int J Pharm 1998; 173:149–155.
83. Kim KH, Jarowski CI. Surface tension lowering and dissolution rate of hydrocortisonefrom solid solutions of selected n-acyl esters of cholesterol. J Pharm Sci 1977;
66(11):1536–1540.
84. Deasy PB, Gouldson MP. In vitro evaluation of pellets containing enteric coprecipitatesof nifedipine formed by non-aqueous spheronization. Int J Pharm 1996; 132:131–141.
85. Corrigan OI, Holohan EM. Amorphous spray-dried hydroﬂumethiazide-polyvinylpyrrolidone systems: physicochemical properties. J Pharm Pharmacol 1984; 36:217–221.
86. Arias MJ, Ginés JM, Moyano JR, Pérez-Martı́nez JI, Rabasco AM. Inﬂuence of the
preparation method of solid dispersions on their dissolution rate: study of triamterene-D-mannitol system. Int J Pharm 1995; 123:25–31.
87. Hu J, Rogers TL, Brown J, Young T, Johnston KP, Williams RO. Improvement ofdissolution rates of poorly water soluble APIs using novel spray freezing into liquid
technology. Pharm Res 2002; 19(9):1278–1284.
88. Rogers TL, Nelsen AC, Hu J, Brown JN, Sarkari M, Young TJ, Johnston KP, Williams
RO. A novel particle engineering technology to enhance dissolution of poorly watersoluble drugs: spray-freezing into liquid. Eur J Pharm Biopharm 2002; 54:271–280.
89. Rogers TL, Hu J, Yu Z, Johnston KP, Williams RO. A novel particle engineering
technology: spray-freezing into liquid. Int J Pharm 2002; 242:93–100.
90. Rogers TL, Johnston KP, Williams RO. Physical stability of micronized powders
produced by spray-freezing into liquid (SFL) to enhance the dissolution of an insoluble
drug. Pharm Dev Technol 2003; 8(2):187–197.
91. Rogers TL, Johnston KP, Williams RO. Enhanced aqueous dissolution of a poorly
water soluble drug by novel particle engineering technology: spray-freezing into liquidwith atmospheric freeze-drying. Pharm Res 2003; 20(3):485–493.
92. Rodriguez L, Cavallari C, Passerini N, Albertini B, González-Rodrı́guez ML, Fini A.
Preparation and characterization by morphological analysis of diclofenac/PEG 4000
granules obtained using three ifferent techniques. Int. J Pharm 2002; 242(1,2):285–289.
93. Senčar-Božič P, Srčič S, Knez Ž, Kerč J. Improvement of nifedipine dissolution
characteristics using supercritical CO2. Int J Pharm 1997; 148:123–130.
94. Moneghini M, Kikic I, Voinovich D, Perissutti B, Filipović-Grčić J. Processing of carbamazepine-PEG 4000 solid dispersions with supercritical carbon dioxide: preparation,
characterisation, and in vitro dissolution. Int J Pharm 2001; 222:129–138.
95. Corrigan OI, Crean AM. Comparative physicochemical properties of hydrocortisonePVP composites prepared using supercritical carbon dioxide by the GAS anti-solvent
recrystallization process by coprecipitation and by spray drying. Int J Pharm 2002;
245:75–82.
96. Ford JL. The current status of solid dispersions. Pharm Acta Helv 1986; 61(3):69–88.
97. Serajuddin ATM. Solid dispersion of poorly water-soluble drugs: early promises,
subsequent problems, and recent breakthroughs. J Pharm Sci 1999; 88(10):1058–1066.
98. Leuner C, Dressman J. Improving drug solubility for oral delivery using solid
dispersions. Eur J Pharm Biopharm 2000; 50:47–60.
99. Sekiguchi K, Obi N. Studies on absorption of eutectic mixture I. A comparison of the
behavior of eutectic mixture of sulfathiazole and that of ordinary sulfathiazole in man.
Chem Pharm Bull 1961; 9:866–872.
100. Tachibana T, Nakamura A. A method for preparing an aqueous colloidal dispersion oforganic materials by using water-soluble polymers: dispersion of beta-carotene bypolyvinylpyrrolidone. Koll Z Polym 1965; 203:130–133.
101. Bates TR. Dissolution characteristics of reserpine-polyvinylpyrrolidone co-precipitates.
J Pharm Pharmacol 1969; 21:710–712.

© 2005 by Taylor & Francis Group, LLC

Rapid Release Granulation

429

102. Breitenbach J. Melt extrusion: from process to drug delivery technology. Eur J Pharm
Biopharm 2002; 54:107–117.
103. Virley P, Yarwood R. Zydis—a novel, fast dissolving dosage form. Manuf Chem 1990;
61(2):36–37.
104. Seager H. Drug-delivery products and the Zydis fast-dissolving dosage form. J Pharm
Pharmacol 1998; 50:375–382.
105. Thapa P, Baillie AJ, Stevens HNE. Lyophilization of unit dose pharmaceutical dosage
forms. Drug Dev Ind Pharm 2003; 29(5):595–602.

© 2005 by Taylor & Francis Group, LLC

15Continuous Granulation Technologies
Rudolf Schroeder
L.B. Bohle Maschinen und Verfahren GmbH, Ennigerloh, Germany

Klaus-Jürgen Steffens
Department of Pharmaceutical Technology, University of Bonn, Bonn, Germany

1. INTRODUCTION
Granulation of powders is a well-known process in the pharmaceutical industry
where primary particles are made to adhere in order to form larger entities called
granules. Primarily, it is used for an improvement of the ﬂow characteristics as well
as for assuring the homogeneity and mechanical stability of the blend during further
production steps. Especially for the compaction of modern actives, granulation isoften unavoidable due to the hydrophobic characteristics of these substances. Bybinder granulation the actives are ‘‘coated’’ with a hydrophilic agent, thus establishing electrostatic interactions between the granulate particles and enabling water topenetrate the tablet in order to improve disintegration and dissolution behavior.
Also, the granulation process can be used to inﬂuence the dissolution behavior ofa tablet, e.g., to gain a drug with sustained release characteristics. In this case melt
agglomeration by hot melt extrusion is a widespread process where a particular excipient is able to melt and mechanically stabilizes the agglomerates after cooling (1,2). This
excipient embeds the active components in a so-called ‘‘matrix’’ and alters the dissolution characteristics from immediate release to a diffusion controlled sustained release.

2. COMPARISON OF DIFFERENT MODES OF PROCESSING
To be able to compare the different modes of operation like continuous, semicontinuous, and batch oriented processing it is necessary to deﬁne them and to delimit fromeach other. A ﬁrst distinction can be made by the product output per time (Fig. 1).
In the case of batch oriented processing the total product volume M is released
after the process duration T whereas for (semi) continuous processing the product output occurs gradually. The semicontinuous process arises from the division of the total

Present Address: Abbott GmbH & Co. KG, Ludwigshafen, Germany.
431© 2005 by Taylor & Francis Group, LLC

432

Schroeder and Steffens

Figure 1 Product output for batch oriented, semicontinuous, and continuous processing.

batch size M into a deﬁned number n of subbatches. The quotient of subbatch size mSand the process time for one particular subbatch tS is constant for every subbatch.
For really continuous processes neither the total batch size nor a subbatch size
is given by itself. Consecutively, the batch size M is a result of the product output mC
per time tC. The quotient of mC and tC is constant and the product output is proportional to the production time. The mathematical descriptions are displayed inTable 1. Arising from these circumstances some consequences are given, resulting
in both advantages and disadvantages in terms of process control.
For batch oriented processing always a large amount of raw materials is being
granulated; thus, it is quite stable against small deviations of single components interms of weighing. Furthermore, it is possible to equalize these deviations by adapting the process control or the total process duration. Therefore, an oos result due tothese reasons is very unlikely. In the case of continuous processing it is absolutely
unavoidable to carry out the subprocesses in a continuous way and to ensure thatthe speed of the subprocess is proportional to the process speed. Otherwise, deviations in product properties are inescapable. In most cases a correction and therebycompensation of these deviations is not possible.
The semicontinuous processing takes an intermediate position. On the one
hand, small deviations can be tolerated and equalized; on the other hand, the homogeneity from one subbatch to another has to be ensured to guarantee the homogeneity of the whole batch. From the latter point of view the semicontinuous processes
are better comparable to the batch oriented than to the continuous ones.
For pharmaceutical purposes the product properties can be ensured with the
IPC correlating to the needs of the process. Furthermore, the results of the in-processcontrol (IPC) can be used to inﬂuence the process control if speaking of batchoriented or semicontinuous processing. In the case of continuous processing one willtake care of a robust process control to avoid alterations to a maximum during theTable 1 Mathematical Descriptions of the Different Types of Processing

Batch size

Process
duration

Batch oriented

SemicontinuousM

M ¼ nmSðn ¼ 0; 1; 2; . . .ÞT

Note: For variables, see text.
© 2005 by Taylor & Francis Group, LLC

T ¼ ntS

Continuous 
M ¼ T mtCC ¼ T dm=dt
while dm=dt ¼ constant1
T ¼ M dm=dt

Continuous Granulation Technologies

433

process. Measurement of the process parameters should be for documentation only,
for instance, to show the homogeneity.
The transfer of a process from one machine to another and the simultaneous
increase of the batch size while keeping the product properties, the so-called‘‘scaling-up,’’ is a challenge in the pharmaceutical industry where most granulation
processes are batch oriented.
For instance in a high-shear granulator the product properties are inﬂuenced
by the alteration in the geometry of the bowl and the speed and shape of the impeller
as well as the not negligible inﬂuence of material load. The occurring deviations haveto be compensated with alterations in the process control.
This problem does not occur in continuous processing because the batch size
can be adjusted by the process time without interfering in the process control. For
semicontinuous processes the batch size can be adjusted by the number of subbatches resulting in identical opportunities as for continuous processes. Thisapproach is limited due to economic aspects with respect to the duration of the wholeprocess, also taking into account preceding or following process steps.
The transfer of a batch oriented process to a semicontinuous one is possible bya repetition of the process and a narrow linking of the subprocesses. The homogeneity and thereby the quality of the product can be stated if the process is always running under the same conditions. This also includes the cleanliness of the machinewith regard to material buildup arising from the former subbatches. For really continuous processes this procedure is not possible in most cases.
One big advantage of continuous processing arises from the demand for a precise
and stable process control. Hereby, the IPC can be reduced and the surveillance of theprocess can be reduced. Therefore, continuous processes have a reduced need for control
after reaching steady-state conditions (Fig. 18). Roller compaction described in anotherchapter of this book is also a good example of a continuous granulation technique.
3. FLUID BED SYSTEMS
Today there are a large number of suppliers manufacturing continuously working
ﬂuid bed systems for drying and granulation. But as the origin of these systems does
not lie in the pharmaceutical industry, few companies only designed and manufactured units corresponding to the cGMP standards.
3.1. Process Steps
Along with the traditional batch oriented ﬂuid bed systems also a continuously
working machine has to perform the following steps to produce satisfying granules:
1.
2.
3.
4.
5.
6.

Product feeding
Product preheating and mixing
Granulation (spraying)
Drying
Cooling
Discharging

But in contrast to the batch oriented processes in this case the subprocesses areto be carried out in a continuous way conjunct with all advantages and risks mentioned in Chapter 2. The zones are not necessarily mechanically and spacially separated from each other as the following explanations will show.
© 2005 by Taylor & Francis Group, LLC

434

Schroeder and Steffens

3.2. Single-Cell Systems
The ﬁrst investigations for realizing continuous ﬂuid bed systems in the pharmaceutical industry were made by adapting batch oriented ﬂuid bed units. The machines
had to be modiﬁed to allow continuous powder feeding and product reception(Fig. 2). The feeding unit could be carried out using a rotary valve. Instead of a standard product outlet the continuously working ﬂuid bed is equipped with an air
separator to lead back the ﬁne powders into the granulation area.
One major problem of single-cell ﬂuid beds is the fact that all subprocesses of a
granulation process have to take place in one reaction chamber. This means thewetted powders for granulation and the dried granules are colocated in the same
physical room and can interfere with each other.
To avoid the simultaneous presence of these conﬂicting process steps multicell
systems were developed allowing a segregation and separation of the wet process
steps from the dry ones.
3.3. MultiCell Systems
With respect to the individual features of every multicell system the general arrangement of the common aspects like air handling, product treatment, feeding, and discharging is quite similar. Therefore, the following paragraphs will give a shortoverview on the functional basics. Special properties of some exemplary systems will
be discussed later in this text.

Figure 2 Single-cell ﬂuid bed processor.
© 2005 by Taylor & Francis Group, LLC

Continuous Granulation Technologies

435

3.3.1. Air Handling and Product Flow
As the course of the inlet air conditions during a batch oriented ﬂuid bed process is
not constant, the air supply of a continuous ﬂuid bed is segmented to allow differentiated air temperatures and humidity. Usually, the number of air chambers isequal to or more than the number of process steps of a standard ﬂuid bed process.
The boundary between inlet air supply and product chamber is the air distribution plate. Often this plate is carried out as a gill-plate (Fig. 3). Because of the structure of the plate directed air jets give a forward transport of the product. But this
only affects the lowest layer of the powder bed. Above, the air stream is scatteredby the powder particles and directed upwards. Therefore, back-mixing occurs andthe ﬂow of the product is more or less based on statistical distributions. Without
any interior ﬁxtures like bafﬂes or walls the particle ﬂow can be expressed with Bateman’s function (3). Thus, the forwarding of the material is a result of the incoming
raw materials. The main advantages of the gill structure are to be seen in the emptying of the machine—as the ﬁnal residue of product is affected by the jets—and theimproved cleaning facilities compared to a ﬂat plate.
The product ﬂow can be improved by vibration or by a sloping arrangement of
the air distribution plate from the in-feed toward the product discharge. The latter
leads to a voluntary ﬂow of the particles taking advantage of the liquid-like behaviorof ﬂuidized powders.

Figure 3 Niro ContipharmTM. (Courtesy of Niro Pharma Systems, Muellheim, Germany.)© 2005 by Taylor & Francis Group, LLC

436

Schroeder and Steffens

The most important aspect of the product ﬂow is a homogenous transport
throughout the whole process without segregation of powder particles. Furthermore,
it has to be ensured that ﬁne powders can be moved as well as larger agglomerates(lumps). Consequently, the sloped design is to be seen as less favorable as it can
result in a nonhomogenous product ﬂow.
The upper boundary of the product chamber is given by a set of ﬁlter cartridges
whereas the speciﬁc design follows up different purposes like particle separation andusability for CIP (cleaning in place). In the latter case the ﬁlter cartridges are usually
made of stainless steel.
3.3.2. Spray Nozzle Arrangement
Like in batch oriented ﬂuid bed processors the spray nozzles can be arranged either
as top-spray or bottom-spray. For blends that can be hardly granulated, typicallybottom-spray arrangements are preferred to take advantage of local overwettings.
3.3.3. Feeding and Discharging
Prior to the steady-state phase of the production usually the bed has to be ﬁlled to acertain level, that is, mainly depending on the design of the equipment and the pressure drop over the bed. The constancy of the bed height can also be ensured via thepressure drop. Therefore, this value is important for the control of the powder feed
and product discharge.
3.3.4. Continuous Fluid Bed Processor: Niro ContipharmTM
The product chamber is of a round shape with a diameter of 2 m (Fig. 3). The rearboundary is ﬁxed to the wall and carried out as a torospherical head. The front
boundary of identical shape can be moved hydraulically to open the product chamber for inspection and cleaning.
The interior between the dished disks is divided horizontally into three sections. The ﬁrst section from bottom to top is the inlet air section consisting of threesubdivisions separated from each other by vertical walls. This allows adjusting theinlet air conditions for preblending, granulation, and drying corresponding to the
product characteristics and process requirements independently. The upper boundary of the inlet air chamber is given by the air distributor plate carried out as agroove-like gill-plate with a ﬂattened bottom to keep the powders in the middle ofthe plate. Additionally, it contains a set of two-component nozzles to add the granulation liquid in a bottom-spray arrangement. On the upper end the product chamber is bordered by exhaust air ﬁlters made of stainless steel. The whole rig is prepared
for CIP.
The product in-feed and discharge are carried out as rotary valves to assure a
constant material supply and bed height.
As for most continuous granulation processes the production is divided into
three major steps. In the ﬁrst step the machine is ﬁlled with 50 kg of powder. Consecutively, the granulation is started for about 1 hr in a batch-like manner with powder inlet and discharge closed. After the granulation is done the machine is switched
to continuous mode with a product throughput of about 160–240 kg/hr. When allmaterials are processed the production chamber is emptied and automaticallycleaned with the integrated CIP unit (4).
© 2005 by Taylor & Francis Group, LLC

Continuous Granulation Technologies

437

3.3.5. Heinen Continuous Fluid Bed Processes
The basic concept of the Heinen ﬂuidized bed system is based on a sectional structurewith separated inlet zones for the drying air (Fig. 4). This means, the drying or ﬂuidizing air is added section by section in multiple, separate temperature and air zones
as explained earlier.
Mostly, the air distribution plate is carried out as a rectangular gill-plate toensure the forwarding of the product, supported by integrated pneumatic vibrators.
Consecutively, it passes the different zones of the granulation process (Fig. 5).
The granulation, drying and cooling zones are physically separated from eachother by vertical walls while the oriﬁce between granulation and drying is permanently open and the cooling chamber can be closed by controllable valves. Thisshould give a more efﬁcient heat exchange and reduced back mixing of the driedgranules into the wetting area. Furthermore, it reduces the heat exchange between
the hot inlet air for drying and the cold air for cooling.
Usually, the spray nozzles are arranged in top-spray orientation. With the integrated cleaning nozzles the complete rig is prepared for CIP (Fig. 6).
Because this results in a compact system it is possible to implement widely differing process steps and temperature sequences adapted to the speciﬁc product . This
provides a variety of options for setting and optimizing process parameters.

4. MECHANICAL WET GRANULATION SYSTEMS
The variety of mechanical granulation systems is very highly justiﬁed with the manifold
requirements of the formulations on the market. The various system available on the

Figure 4 Heinen continuous ﬂuid bed processor. (Courtesy of Heinen Trocknungstechnologie
GmbH, Varel, Germany.)© 2005 by Taylor & Francis Group, LLC

438

Schroeder and Steffens

Figure 5 Continuous ﬂuid bed processor during operation. (Courtesy of Heinen Trocknungstechnologie GmbH, Varel, Germany.)market can be differentiated and classiﬁed by means of several parameters as productholding times, energy input, product loss and product hold-up, respectively.
Product holding time or dwell time and energy input cannot be seen as separated from each other. Only the combination of both enables a prediction of the
granulation characteristics of the machine. Especially in the case of hardly soluble
substances or raw materials with a need for intensive blending either a high holding

Figure 6 Exemplary PI-diagram of a granulation process. (Courtesy of Heinen Trocknungstechnologie GmbH, Varel, Germany.)© 2005 by Taylor & Francis Group, LLC

Continuous Granulation Technologies

439

time combined with an average energy input or a low holding time together withhigh energy input can lead to satisfying granules.
Product holdup (product staying inside the machine after granulation) is ofimportance during the drug development phase as it limits the minimum batch size
possible. The larger the batch size the less important is the product holdup of themachine as it is a constant value independent of the total batch size. Nevertheless,a low product holdup helps in reducing waste and thus helps in cleaning.
A lot of mechanical continuous granulation equipment can be seen as derived
from single-or twin-screw extrusion systems, mostly improved with special ﬁxturesinside like choppers or bafﬂes to fulﬁll the needs of pharmaceutical wet granulation
processes. Screw extrusion systems are treated elsewhere in this book and will not be
discussed at this point.
Other machines like the Schugi mixer–agglomerator (Hosokawa Schugi B.V.,
Lelystadt, The Netherlands) or the Nica M6 turbine mixer and granulator (Aeromatic-Fielder Ltd., Eastleigh, U.K.) were already mentioned and discussed in the lastedition of this book.
4.1. Semicontinuous Processing: Glatt MulticellTM
This machine takes an intermediate position between ﬂuid bed systems and mechanical granulation equipment (Fig. 7). The philosophy this machine is based on, is thesize reduction of the manufacturing equipment combined with the tight conjunctionof the single subprocesses (containing product loads addressed as subunits) while
each subprocess is located in a separate process chamber, in order to reduce scaleup efforts. From raw material to dried granules the product passes through the following stages:
1. Weighing system for raw materials
2. Wet granulation by small-scale plough-share blender and simultaneous
injection of granulation liquid
3. Milling of the wet granules via a rotary sieve machine
4. Predrying, ﬁnal drying, and cooling in a three-chambered ﬂuid bed dryer
5. Final milling in a second rotary sieve machine
All process chambers are linked by tubes for contained product transfer. The
transfer itself is realized pneumatically by airﬂow (5).
The minimum subunit size depends on the minimum capacity of the plough-share
blender. The manufacturer speciﬁes 1–25 kg/subunit as acceptable range, covered bythree different sizes of equipment. The throughput depends on the process and properties of the raw material. But as the system should be able to run unattended in a semicontinuous way the real throughput is less important if economic aspects are not takencare of.
The machine is prepared for automated CIP with approx. 40 cleaning nozzles
installed.

4.2. High-Throughput Mixer–Granulator: Lödige PloughshareÕ Mixers
The main elements of the plough-share blender are a horizontal drum and granulation chamber and a horizontally rotating shaft, equipped with different transporting
and blending elements, the shovels (Fig. 8). Usually, the arrangement of the shovels© 2005 by Taylor & Francis Group, LLC

440

Schroeder and Steffens

Figure 7 Multicell semicontinuous granulation processor. The dosing processor and granulation unit can be seen on the left side. (Courtesy of Glatt GmbH, Binzen, Germany.)

gives a three-segmented process. The ﬁrst part of the axle is equipped with a relatively low amount of shovels and mainly acts as a feeding section to preblend the
mixture and forward it into the granulation section where the blending elements
are carried out as blending sticks. At this point the granulation liquid is added
and forwarding of the material is less important than a sufﬁcient power intake.
Consecutively, the material is entering the postprocessing section where the granules
are formed to their ﬁnal shape and moved to the discharging oriﬁce.
The revolution speed of the axle is high enough to form a ﬂuid bed-like behavior.
Due to the shape of the blending elements and the material characteristics, nearly
spherical particles can be obtained. Due to the blending characteristic, a disadvantageof the plough-share blender is the buildup of large agglomerates. High throughputs
from 4.5 to 900 m3/hr can be achieved (6).
At an even higher revolution speed and slight alterations in the arrangement of
the blending elements, high-speed continuous mixers can be achieved (Fig. 9). The
ﬂow characteristics of the powder blend inside the machine is very different fromplough-share blenders. Due to the high speed of the axle circular layers of material
are formed, resulting in higher shearing forces and generally an increased power
input. As a result the granules are not as spherical as in plough-share blenders
and the particle size distribution is narrower. Thus, the ﬂow characteristic of the© 2005 by Taylor & Francis Group, LLC

Continuous Granulation Technologies

441

Figure 8 Continuous plough-share blender. (Courtesy of Gebr. Lödige GmbH, Paderborn,
Germany.)

product is worse but the dissolution of the granules is improved even due to the morehomogenous blending.
The throughput is comparable to the plough-share blenders and therefore
mainly suitable for the production of large batches.

5. ROLLER EXTRUSION SYSTEM
As a new system in the pharmaceutical market the function and usability of a roller
extrusion system for pharmaceutical wet granulation will be discussed in more detail.

Figure 9 High-speed continuous mixer. (Courtesy of Gebr. Lödige GmbH, Paderborn,
Germany.)© 2005 by Taylor & Francis Group, LLC

442

Schroeder and Steffens

Figure 10 Appearance of a planetary roller extruder. The arrows on the left side indicate themovements during extrusion.

Roller extrusion is a special type of extrusion not comparable to the classicalsingle- or twin-screw extrusion systems. In screw extrusion systems the main partand functional center of the machine is the combination of the screw itself and thebarrel as casing for the screw. The different aims like degassing, ventilation, blending, melting, and cooling can be made possible by the screw design—in case of atwin-screw extruder also the cooperation of both intermeshing screws—and the temperature control of the barrel. Usually, there is no temperature control for thescrews. To achieve a sufﬁcient forward transport it is necessary to take care thatthe friction between material and barrel is higher than the friction between materialand screw (14).
For roller extruders or planetary roller extruders these explanations are notapplicable. The design and shape are very different. The arrangement of the spindles
and the barrel as heart of the machine is comparable to a planetary gear but with ahelical gearing of 45 . In the center lies the central spindle attached to the main drive.
Around it are the planetary spindles ﬂoating freely in the plastic mass, varying inlength and number while they are covered by the barrel. On rotation of the central
spindle the planetary spindles roll on the central spindle and the internally toothedbarrel (Fig. 10). The plastic material ﬂoating in the gaps between the planetary spindles is rolled on the surface of the central spindle and the barrel in very thin layers.
Thus, it is blended on the whole extrusion distance while the friction heat arisingfrom the homogenization is transferred away into the coolant ﬂowing inside the central spindle and the barrel. The forward transport of the material is due to the helicalshape of the gearing. It is imaginable that the contact surface area of a planetaryroller extruder is very high (Fig. 11). Compared to a twin-screw extruder the areaof a planetary extruder is about six times larger (8).
Arising from these considerations the planetary roller extruder seems to be particularly suitable for the wet and melt agglomeration of pharmaceutical powder
blends. In the following is described a system for continuous wet granulation basedon a planetary extruder and the usage thereof.
5.1. System Description
To take advantage of the manifold opportunities of an extrusion system the machineis built up modularly to be more ﬂexible also in terms of process control. Therefore,
the subprocesses known from the classical granulation processes as weighing, blending/granulation, drying, and milling are realized as insulated procedures of an integrated process line. In addition to the classical steps a cooling step can be© 2005 by Taylor & Francis Group, LLC

Continuous Granulation Technologies

443

Figure 11 Comparison of different extrusion systems.

implemented to enable the manufacturing of granules by hot melt extrusion. The
control of these subprocesses is on the one hand separated from each other; on theother hand, all controls are integrated into a centralized control and report system.
The system is available for very different outputs from 2 up to 1,000 kg/hr,
realized by four different machine sizes only. Due to the continuous processing very
different batch sizes can be granulated with one machine size. For instance, in thecase of a granulator with a nominal output of 10 kg/hr, normally the realizable output
is about 2–20 kg/hr, leading to batch sizes from 500 g in 15 min up to 480 kg/24 hrs.
5.1.1. Feeding
It is to distinguish between feeding of the powder components and—if applicable—
the liquid components, e.g., binder solutions.
Powder components are usually added by mass-controlled twin-screw feeders
as it is standard in the pharmaceutical industry. But still there are two possible procedures for the weighing the powder components. One begins with the weighing of
the whole formulation by hand, followed up by an external blending step and ends
with the feeding of the screw feeder with a preblended mixture. The second and moreconvenient way is the usage of several screw feeders, one for each raw material inorder to completely avoid the manual weighing. This can be done for feeding rates
of 200 g/hr and more. Due to the limited space and the fact that all feeders have tofeed into a single tube the number of feeders is limited. Usually, no preblending has
to be done due to the excellent blending capabilities of the granulation system.
Depending on the ﬂow properties the raw materials immediately fall into thefeed hopper or they are force-fed inside the feeding tube by a screw or agitator ofa different shape. Subsequently, the raw materials are taken over by the feed screwof the granulation system and moved into the granulator.
The feeding of the liquid components can be done with various pumps of different outputs and pressures. As a standard a peristaltic pump is used, controlled bya ﬂow meter based on the Coriolis principle. With respect to the requirements of theformulation and process, different types of pumps can be used.
© 2005 by Taylor & Francis Group, LLC

444

Schroeder and Steffens

5.1.2. Granulation
As mentioned earlier, the granulation is realized through a planetary roller extruder.
By the feed screw the material is taken into the granulation section of the planetarysystem (Fig. 12).
In the case of binder agglomeration the powder components are plasticized by
the addition of the binder liquid at the very beginning of the granulation process.
Apart from the physical properties of the raw materials the binder liquid is the main
plasticizer and lubricant for achieving a viscosity low enough to allow extrusion. The
homogeneity and granulation are completed at the end of the ﬁrst stage of the extruder. There the material has to pass a narrow ring with the function of an intermediate die. Afterward, the mass re-expands and is—if required—blended with nitrogen
injected through the middle stop ring in extrusion direction. The gas injection leads
to an increase in product porosity and subsequently to a change of product properties as tableting and dissolution behavior. At the product outlet of the granulation
unit again the mass is pressed through a die-like ring and brought into shape througha multihole forming unit. If injection of nitrogen is not needed or not wanted, thesecond stage of the extruder can be removed reducing the extrusion length andenergy intake to one-half.
Usually, for melt agglomeration processes the addition of liquids is not necessary because the mass can be plasticized by melting one or more components. The
other facts concerning the process are identical to binder agglomerations.
5.1.3. Drying
Due to the modular design the drying process can be carried out in different ways.
For example, two different types of dryers are described as they are specially adapted
to the extrusion/granulation system.
The ﬁrst one is based on a microwave tube dryer (Figs. 12 and 13). The glass
pipe as dryer inlet is ﬂanged to the granulator directly. By the rotation of the glass

Figure 12 Overview on granulation process consisting of extruder/granulator, microwave
dryer and mill.
© 2005 by Taylor & Francis Group, LLC

Continuous Granulation Technologies

445

Figure 13 Sectional sketch of a microwave dryer.

pipe the product is cut into cylindrical pieces of 0.5–1 in. in length, the diameter
depends on the forming unit of the granulator; usual sizes are 0.08–0.2 in. As the
sticks fall into the glass pipe they roll due to the round shape. In the same way they
are blended and moved forward as an effect of the rotation of the pipe and the following material. The drying is done with low pressure of about 0.14 psi absolute
under microwave radiation and the addition of a stripping gas for improvement of
the drying time. To achieve precise drying times barriers can be mounted into theglass pipe (e.g. spirals). The product outlet is carried out as a double-valve lockdue to the vacuum inside.
If drying by microwave energy is not possible or not wanted a contact dryer
can be used instead (Fig. 14). The design is quite similar to the microwave dryer.
Due to the different drying principles the contact dryer has to be larger. The glass
pipe is replaced by a stainless steel pipe with a spiral mounted inside. Both the pipe
and the spiral can be heated. All additional features for drying improvement likevacuum and stripping gas are implemented.

Figure 14 Sectional sketch of a contact dryer.
© 2005 by Taylor & Francis Group, LLC

446

Schroeder and Steffens

In case the desired dryer is already present the extruder/granulator can be
combined with nearly every drying method imaginable.
5.1.4. Cooling
Usually, for melt agglomeration processes no drying is needed. The intermediate
product coming out of the extrusion step is warmed up and shows a soft to pastelike behavior. Therefore, milling of the warm product is not possible and a coolingstep has to be implemented in between to achieve a brittle consistency that allows
milling.
The standard cooling belt is carried out as a stainless steel conveyor while thecooling is done by pharma air (Fig. 15). The belt swings at the entry to deposit thewarm product with maximum contact surface. This allows short belts even for hightemperature differences between extrudate entry and product outlet.
5.1.5. Milling
In most processes milling can be done with a standard conical mill (Fig. 16). Fromthe behavior of the material it is to be decided whether to use a ﬂat screen or a rasping screen. The ﬂat screen allows milling with high throughput for brittle substanceswhere a higher amount of ﬁnes does not matter. If ﬁnes have to be avoided to a maximum or the material to be sieved is very hard or plastic, a rasping mill inset should
be used.
5.1.6. Raw Material Supply and Product Reception
To enable constant product ﬂow it is very important to have a look at the material
supply and its reception after granulation. The design of the supply chain depends
mostly on the process mode. This means in cases of small batches or batches witha volume of not more than one bin the realization is quite easy. With respect toFigure 15 Sketch of a cooling belt.
© 2005 by Taylor & Francis Group, LLC

Continuous Granulation Technologies

447

Figure 16 Sectional sketch of the milling unit.

the powder components the raw material bins can be docked onto the feeding unit
consisting of the screw feeders themselves and a system for the reﬁll of the feeders.
The latter can be realized by a reﬁll screw, for instance. For product reception only
one bin is needed that can be docked at the beginning of the process. It is imaginable
to connect the further production steps like ﬁnal blending and tableting immediately
instead of a material bin.
If necessary the granulation liquid can be prepared for the whole batch before
manufacturing starts.
For continuous processes over days or weeks the arrangement becomes more
complex. The bins for the raw materials have to be changed in between creating
the need for an intermediate storage of the powders. For establishing this kind of
manufacturing the feeding unit is reﬁlled from a small bin. On the other hand thesmall bins are ﬁlled from the raw material bins. This assembly gives a chance tothe operators to change the raw material bins in a certain time leading to a constantmaterial ﬂow. The same solution can be used for the granulation liquid.
During the production itself the material handling even of highly potent substances is not critical due to the total encapsulation of the single production steps
and the production line as a whole. Therefore, the only locations to take care of
are the inlet of the raw material and the product outlet. Consecutively, this meansthat at every connection designed and qualiﬁed for separation during the process
a high containment conjunction has to be implemented. With respect to total containment further modiﬁcations are not necessary.
Figure 17 shows the proposal for processing of smaller batches under high containment conditions in a building with three ﬂoors.
© 2005 by Taylor & Francis Group, LLC

448

Schroeder and Steffens

Figure 17 Sketch of a batch process with requirements for total containment.

5.2. Process Control and Automation
As in nearly every continuous production the whole process has to be seen as divided
into three phases. The ﬁrst one or start-up phase begins with the starting of themachine and the raw material supply and ends with the reaching of a stable stateof the whole production line. At that point the product reception can be started
and the production phase is reached. After the required amount of product isreceived the feeders are stopped and the process enters the end phase (Fig. 18).
From these facts it is obvious that the yield increases with the batch size.
Depending on the intended output and the process requirements a certain amountof raw materials is needed to reach the production phase. In some cases this might
be a few grams, in other cases a few kilograms are needed. But it does not depend on
the batch size. The product loss during the end phase depends on the machine size
because in most cases the yield loss is simply the material remaining inside
the machine. Therefore, the most economic way of manufacturing is the use of© 2005 by Taylor & Francis Group, LLC

Continuous Granulation Technologies

449

Figure 18 Typical course of an extrusion/granulation process with startup, production, andend phase.

a relatively small machine running in a real continuous manner; this means 24 hr a
day and 7 days a week.
Due to the fact that only a small amount of raw materials are processed at thesame time it has to be ensured that the instrumentation of the machine allows detecting of any inhomogeneities during production. And furthermore, the measurement
has to give reliable values for the product quality.
In terms of the feeding process instrumentation is very easy. As it is standard in
the pharmaceutical industry the feeders for the powdery materials are mass-controlled, recognizing any derivations from the set-point. Assuming the use of a combination of a pump and a Coriolis-based ﬂow-meter the same explanations areapplicable for the granulation liquid.
Unfortunately, it is more complicated to establish a reliable instrumentation
system for the extrusion/granulation section. As a prerequisite one has to assume
that the product properties are directly linked to the measured ambient conditions.
This means temperature, pressure, and torque. For establishing a stable process it is
not necessary to know the correct values, rather it is sufﬁcient to know that the measured values are linked with the interesting ones and do not show major ﬂuctuations.
As there will not be any measured value without ﬂuctuations it is necessary to detect
the range thereof and the inﬂuence on the product behavior at the upper and lower
limits, especially in terms of process validation.
Temperature probes are installed inside the middle and end stop ring because
these are the locations where the material has to pass a narrow oriﬁce and therefore
the highest temperatures can be expected. It is an indirect measurement of the masstemperature by measuring the ring temperature very close to the inner surface. Additionally, the coolant temperatures are detected. Because the ring temperature at theouter surface is set by the coolant the mass temperature is proportional to thedetected temperature of the ring.
Pressure probes are also installed at both rings. Due to the size and installationof the rings indirect measurements are useless at these locations. Therefore, the masspressure is being detected by strain gauges separated from the mass by a diaphragm.
© 2005 by Taylor & Francis Group, LLC

450

Schroeder and Steffens

As an average value of the mechanical power intake the torque measurement of
the extruder drive is a very important value. Any ﬂuctuation in powder or liquiddosage or speed of the extruder leads to a ﬂuctuation in torque. Additionally, theviscosity of the mass is also inﬂuenced by its temperature and pressure. Thus, thetorque measurement is also a backbone for the detection of any deviations occurring
during granulation. It is taken from the frequency converter of the main drive.
Therefore, it does not give absolute values but the possibility of recognizing a process
trend that might lead to products being out of speciﬁcation.
In case of microwave drying it is very important to have a reliable instrumentation. With a view on the needs of the product the interesting values are the holding
time of the product inside the dryer, the amount of microwave radiation, the amountof stripping gas and the pressure inside the dryer. Not all products need a very precise holding time due to the special behavior of microwaves. Normally, microwaves
affect materials that contain a minimum amount of water or other suitable liquids.
When the product is dried microwaves lose the ability to affect the material. Primarily, the drying and heating will occur where it is needed and wanted (9,11).
For security reasons and with respect to the lifetime of the magnetron the
microwave reﬂection is detected. The stripping gas can be controlled by pressure
or with a roots pump allowing determining of the gas amount very precisely.
In contrast to the microwave dryer in a contact dryer it is very important toassure constant material ﬂow and thus constant holding times. Therefore, the contact dryer is equipped with a spiral inside the drying pipe to forward the material
with a constant speed. Additionally, the temperature of the pipe is determined at
all interesting spots.
For both dryers the measurement of the product temperature at the productoutlet is a matter of course.
For a comprehensive characterization of the product properties like moisture or
active content this application gives the chance of implementing online detection instruments like NIR spectroscopy, for instance. With this powerful instrument it is possible toanalyze the complete batch in a nondestructive way. Once calibrated, the measurement
can be reduced to a detection of homogeneity that can be carried out very easily.
For automation purposes and deviation control the dependencies of temperature, pressure, and revolution speed for the granulation unit have to be understoodvery well. The inﬂuence of different temperatures can be explained quite easily.
Usually, increasing temperatures lead to decreasing viscosities and thus the pressure
and the torque will decrease. With an increasing speed of the central spindles the ﬁlling ratio inside the extruder will decrease and thereby the pressure and the torque,
not taking care of the alternations by increasing temperature caused by a higher friction inside. To make it more difﬁcult at the beginning of a speed increase the pressure
increases rapidly and then decreases slowly to a lower level due to the fact that achange of the ﬁlling ratio is a slow process.
The pressure is to be seen as a result of speed and temperature and thus notdirectly controllable. Even the product temperature can be inﬂuenced by two or
more factors, the temperature of the barrel, the speed of the central spindle, andthe physical properties of the materials, mainly the lubricant characteristics andthereby the inner friction.
Summarizing, the regulation circuits of planetary extrusion systems have to be
carried out very carefully. When the process reaches the production phase usually regulation circuits are not required if raw material supply and process control can be
maintained in a stable status as the measured values are a result thereof. If deviations© 2005 by Taylor & Francis Group, LLC

Continuous Granulation Technologies

451

occur the regulating steps have to be designed according to the intended process by
deﬁning the regulating ranges of each parameter and the dependency algorithms
describing the inﬂuences on each other.
5.3. Typical Granulation Processes
5.3.1. Wet Granulation
As there are countless variations of wet granulation processes it is possible only todemonstrate a small choice of formulations to show the feasibility and limitationsof different raw materials. During testing of the granulation unit various excipientsof higher importance for solid dosage forms were evaluated to know their behavior
under this particular treatment, concentrating more on the behavior with respect tothe extrusion system (Table 2). For these particular formulations, it was possible toachieve product temperatures below 50 C after extrusion. Compression after ﬁnal
blending led to tablets of a tensile strength of more than 1.0 MPa in the examined
range of 5–15 kN compression force. By using nitrogen injection it was possible
to improve the compression characteristics of recipe I due to an increase of the granule porosity (Fig. 19). The disintegration times of the tablets were mostly below
10 min; in some cases, it was adjustable by nitrogen pressure.
The granules of all placebo blends were of a round and compact structure,
leading to excellent ﬂowing properties at an LOD of about 2.5%, which was also
the granule moisture before compression.
A different way of evaluating the machine was the granulation of hardly wettable substances in higher concentrations as models for modern actives. As a ﬁrst
granulation, caffeine was granulated with 2.5% of povidone resulting in tablets with
Table 2 Placebo Formulations

Granules
Lactosemonohydrate
Mannitol
Corn starch
Cellulose
Providone
HPMC
Povidone,cross-linked
Final blend
Magnesium
stearate
Silicon dioxide
Providone, crosslinked
Carboxymethylcellulose
Sodium, crosslinked

I

II

III

IV

82.5

80.0

70.0

82.0

14.6

15.0

15.0
15.0

5.0
10.0
3.0

2.9

V

VI

72.0
10.0
15.0
3.0

80.0
15.0
5.0

5.0

0.5

0.5

0.5

5.0

2.0

5.0

0.5

1.0

1.0

5.0

5.0

3.0

Note: The components of the ﬁnal blend are to be seen as percentage parts of the dried granules. All values
in % (w/w).
© 2005 by Taylor & Francis Group, LLC

452

Schroeder and Steffens

Figure 19 Compression characteristics of recipe I. The second y-axis shows the inﬂuence of thenitrogen pressure on the porosity. Porosity was calculated by the quotient of upward pressure of
the coated granules in silicon oil as a measure of the apparent density and the true density. The
three different charts display the compression characteristics for three compression forces(5–15 kN).

satisfying compression and disintegration behavior and a dissolution t80 value ofabout 5 min for a tensile strength of 1.0 MPa. Hardening after 2 weeks resulted
in useless tablets with a t80 value of nearly 3 hr. This could be avoided by addition
of 5% cellulose resulting in stable tablets over a period of 6 months. The componentsof the ﬁnal blend were 3% povidone cross-linked, 0.5% silicon dioxide, and 0.5%
magnesium stearate.
Ibuprofen and mefenamic acid (12), both granulated with 3% povidone and 5%
cellulose and afterward blended with the identical substances as for caffeine, could
be easily compressed at forces of 4 kN for ibuprofen and 6 kN for mefenamic acid.
Disintegration time was 1.7 and 1.0 min for ibuprofen and mefenamic acid, respectively. The dissolution t80 value was 6.7 and 17 min, respectively, stable for the examination period of 6 months. The LOD of the granules before ﬁnal blending was 1.4%;
disintegration and dissolution behaviors were examined at a tensile strength of
1.0 MPa.
A more detailed examination of the ibuprofen granulations as factorial designs(13) showed satisfying granules for povidone concentrations of 1–4% and cellulose
concentrations of 3–13% (Figs. 20 and 21). Additionally, HPMC and a special amylose-rich starch type (EurylonÕ 7, Roquette) could be classiﬁed as suitable for the
granulation. The satisfying ranges were 1–4% of HPMC and 3–8% of starch whereas
lower concentrations gave better results in disintegration and dissolution (Fig. 22).
Gas injection resulted in worse disintegrating tablets and prolonged dissolution
due to the displacement of the hydrophilic binder from the hydrophobic active by thehydrophobic gas resulting in higher contact angles between the granules and water(Table 3).
As the results of the aforementioned granulations the following facts could befound:
 Main advantages of this process are the excellent blending quality and temperature control associated with low energy requirements for granulationand drying and a high efﬁciency of the microwave dryer.
© 2005 by Taylor & Francis Group, LLC

Continuous Granulation Technologies

453

Figure 20 Dependency of different concentrations of povidone and cellulose on the disintegration times of tablets containing ibuprofen.

 Lactose and mannitol are both suitable as ﬁller ingredients due to their slow
solubility in water.
 The necessary amount of water for granulation mainly depends on the
lubricating properties of the dry blend. In this process the main purposeof water is lubrication, which enables a very low amount of water of about
7% (w/w) for some blends.
 Ibuprofen could be granulated with active concentrations of maximum 96%(granules) and 92% (tablets); mefenamic acid could be granulated withactive concentrations of 92% (granules) and 88% (tablets) as an effect of
the excellent blending qualities.
 Cellulose can be used as disintegrant and/or hardening inhibitor inamounts of 3–7% (w/w).

Figure 21 Dependency of different concentrations of povidone and cellulose on the meandissolution times of tablets containing ibuprofen.
© 2005 by Taylor & Francis Group, LLC

454

Schroeder and Steffens

Figure 22 Dependency of different concentrations of HPMC and starch on the meandissolution times of tablets containing ibuprofen.

 Corn starch was gelatinized to a high degree even at low temperatures
resulting in good dispersion qualities for nitrogen at recipe I. Therefore,
starch can be used as a binder added as native powder to the dry blend.
 The process is mainly suitable for the granulation of hardly wettable substances at high concentrations and the granulation of poor or slowly soluble substances.
As an indicator for the excellent blending quality and the high shearing forcesbrought into the product an SEM picture of a granulate containing mefenamic acidis displayed (Fig. 23). The larger structures of the picture are mefenamic acid crystals. In standard granulation procedures the binder avoids contact with the active
resulting in insulated spots of binder on the surface of the active crystals. With thisprocess a forced contact between binder and active is given (small binder bridges in
the picture) leading to tablets of higher hardness. Due to the hydrophilization causedby the ‘‘binder coating’’ the disintegration and dissolution are very fast at high active
concentrations.

Table 3 Inﬂuence of Nitrogen Pressure on the Disintegration Times, the Mean Dissolution
Times of the Tablets, and the Contact Angle between Water and Granules
Ibuprofen
4% HPMC and 8% cellulose
Nitrogenpressure (bar)Disintegration
time (min)Mean dissolution
time (min)Contact angle ( )4% HPMC and 8% starch

0.0

1.5

3.0

0.0

1.5

3.0

33.0

47.9

61.6

17.9

45.2

52.2

20.7

34.4

46.6

25.6

27.4

31.6

73.4

80.6

86.2

75.6

81.1

84.9

© 2005 by Taylor & Francis Group, LLC

Continuous Granulation Technologies

455

Figure 23 SEM picture of granulate containing mefenamic acid.

5.3.2. Melt Granulation
Melt granulation processes are the standard applications for extrusion processes in
the pharmaceutical industry. But as this is not a standard machine for manufacturing pharmaceutics the behavior of the machine during processing and the behaviorof the products are hardly comparable to granules manufactured with a single- or
twin-screw extruder. The main difference is originated in the working principle.
While screw extruders mainly push and shift the material inside the extruder andblending can be carried out with specially constructed blending elements the planetary extruder rolls and blends the material on the whole extrusion length. Therefore,
planetary extruders need more lubrication to forward the material but enable excellent blended mixtures. Usually, the material pressures inside are lower than in screw
extruders and the mass temperatures are more homogenous. As a result from these
considerations formulations transferred from a twin-screw extruder to a planetary
extruder have to be slightly adapted.
Exemplarily, Figure 18 shows the process parameters of a pharmaceutical melt
extrusion process developed on a corotating twin-screw extruder.

5.4. Differences Compared to Classical Granulation Processes
The main advantages compared to classical granulation methods as high-shear granulation or ﬂuid bed granulation arise from the continuous way of manufacturing incontrast to the batch-wise orientation of the classical ones. Usually, the output of acontinuously working machine is expressed in mass per time allowing adjusting of
the batch size by changing the process time or, to be more precise, the production
time of the process (Fig. 18). Therefore, in a certain range the batch size is independent of the machine size, which makes scale-up for processes developed on a continuous machine much easier. Even during production the batch size can be chosen
freely depending on the need for that particular product.
The product quality can be ensured due to the fact that at the same time only asmall amount of raw material stays inside the machine for being processed. Furthermore, it is obvious that the actual energy intake is lower than in a batch oriented© 2005 by Taylor & Francis Group, LLC

456

Schroeder and Steffens

granulation process for the equivalent batch size. Resulting from the constant product ﬂow, inhomogeneities in the means of blending or binder distribution can bedetected and avoided by the instrumentation of the granulation unit and detected
at the end of the process by a nondestructive inline measurement tool like NIR spectroscopy for instance. Therefore, it is not necessary to rely on a small amount ofsamples for release; moreover, the whole batch can be analyzed.
For a stable process after reaching the production cycle there is no alternationin any of the process parameters in a certain range as all parts of the machine are
running at the same time. A separation in several production steps like in known
granulation machines is not given. This makes it very easy to detect deviations
during production.

ACKNOWLEDGMENTS
The authors thank Dr. Daniel Rytz and Dr. Bernhard Luy of Glatt, Klaus Schörnbörner of Heinen, Reiner Lemperle of Lödige and Harald Stahl of Niro/AeromaticFielder Division for their support in the preparation of this chapter.

REFERENCES
1. Dittgen M, Kala H, Moldenauer H, Zessin G, Schneider J. Zur pharmazeutischen Technologie der Granulierung. Pharmazie 1980; 35(4):237–S249.
2. Kristensen H. Particle Agglomeration. Advances in Pharmaceutical Sciences. London:
Academic Press, 1990:221–272.
3. Paul S. Pharmazeutische Eignung von Verfahren zur kontinuierlichen Granulation. Dissertation, Erlangen-Nürnberg, 1996.
4. Product Information, Aeromatic-Fielder.
5. Product Information, Glatt GmbH.
6. Product Information, Gebr. Lödige GmbH.
7. Püschner H. Wärme durch Mikrowellen. Eindhoven, The Netherlands: Philips Tech.
Bibl., 1964.
8. Lüchtefeld S. Mischer lässt Planeten kreisen. Chemie Technik 1998; 27(6):66–68.
9. Parikh D, ed. Handbook of Pharmaceutical Granulation Technology. 1st. ed. Vol. 81.
New York: Marcel Dekker, 1997.
10. Schütte A. Untersuchungen zur Feuchtgranulierung hydrophober Arzneistoffe am Beispiel der Mefenaminsäure. Dissertation, Bonn, 2001.
11. Stahl H. Trocknung pharmazeutischer Granulate in Eintopfsystemen. Pharm Ind 1999;
61(7):656–661.
12. Schmidt PC, Christin I. Wirk- und Hilfsstoffe für Rezeptur, Defektur und Großherstellung.
1st ed. Stuttgart: Wiss. Verl. Ges., 1999.
13. Davies O. The Design and Analysis of Industrial Experiments. 2nd ed. London: ICI,
1978:Longman.
14. Rauwendaal C. Understanding Extrusion. Munich: Carl Hanser Verlag, 1998.
15. Stahl PH. Feuchtigkeit und Trocknen in der pharmazeutischen Technologie. Darmstadt:
Steinkopff, 1980.
16. Dietrich R, Brausse R. Erste Erfahrungen und Validierungsversuche an einem neu
entwickelten GMP—gerechten und instrumentierten Pharma-Extruder. Pharm Ind 50
1988; 50:1179–1186.
17. Fikentscher H, Herrle K. Polyvinylpyrrolidone. Mod Plast 1945; 23(3):157–
161,212,214,216,218.
© 2005 by Taylor & Francis Group, LLC

Continuous Granulation Technologies

457

18. Goodhart FW, Draper JR, Niger FC. Design and use of a laboratory extruder for pharmaceutical granulations. J Pharm Sci 1973; 62:133–136.
19. Keleb EI, Vermeire A, Vervaet C, Remon JP. Cold extrusion as a continuous single-stepgranulation and tabletting process. Eur J Pharm Biopharm 2001; 52S:359–368.
20. Kibbe AH, ed. In: Handbook of Pharmaceutical Excipients. 3rd ed. London: Pharmaceutical Press, 2000.
21. Kleinebudde P, Lindner H. Experiments with an instrumented twin-screw extruder using
a single-step granulation/extrusion process. Int J Pharm 1993; 94S:49–58.
22. Lindner H, Kleinebudde P. Use of powdered cellulose for the production of pellets byextrusion spheronization. J Pharm Pharmcol 1994; 46:2–7.
23. Schefﬂer E. Statistische Versuchsplanung und auswertung, Eine Einführung für Praktiker. 3rd ed. Stuttgart: Dt. Verl. Für Grundstofﬁndustrie, 1997.
24. Sucker H. Methoden zum Planen und Auswerten von Versuchen: I. Factorial Design,eine Einführung, Informationsdienst der APV. 1971; 17:52–68.

© 2005 by Taylor & Francis Group, LLC

16
Scale-Up Considerations in Granulation
Y. He, L. X. Liu, and J. D. Litster
Particle and Systems Design Centre, Division of Chemical Engineering,
School of Engineering, The University of Queensland,
Queensland, Australia

1. INTRODUCTION
Scale-up of any engineering process is a great technical and economic challenge.
Scale-up of granulation processes, in particular, is difﬁcult and often problematicdue to the inherently heterogenous nature of the materials used. However, recent
improved understanding of the rate processes that control granulation improves
our ability to do rational scale-up.
There are two situations where process scale-up is needed: (1) commercialization of newly developed processes and products and (2) expansion of production
capacities in response to increased market demand.
For pharmaceutical applications, the challenge is almost always associatedwith new product development. Scale-up in the pharmaceutical industry is uniquein that experiments at laboratory and pilot scale are also required to produce
product of the desired speciﬁcation for different stages of clinical trials. This gives
additional constraints and challenges to engineers and technologists during
scale-up.
A change in scale invariably impacts on process conditions and, consequently,
on the product quality. For pharmaceutical industries, the Food and Drug Administration (FDA) ranks the impacts on the drug product arising from changes ofprocess conditions including production scales into three levels as shown in Table 1(1). Level 1 is reserved for changes that are unlikely to have any detectable impact on
the formulation quality and performance (2). For all practical purposes, scale-up
should aim to achieve an impact equivalent to or less than Level 1.
In this chapter, we will ﬁrst consider general scale-up approaches from achemical engineering perspective. We will then look speciﬁcally at understanding
pharmaceutical granulation scale-up through considering granulation as a combination of rate processes. Each rate process is affected by changes in process during
scaling, as well as by formulation decisions. Finally, we will present suggestions for
scaling of ﬂuid-bed and high-shear mixer granulation that follow from thisapproach.
459© 2005 by Taylor & Francis Group, LLC

460

He et al.

Table 1 Scale-Up and Postapproval Changes Level Component or Composition Change
Levels% Excipient (w/w of total dosage unit)
Excipient

Level 1

Level 2

Level 3

FillerDisintegrantStarchOther
BinderLubricantCa or Mg
Stearate
Other
Glidant
Talc
Other
Film coat
Total drug recipient change (%)

5

10

> 10

3
0.5
0.5

6
1
1

>6
>1
>1

0.25

0.5

> 0.5

1

2

>2

1
0.1
1
5

2
0.2
2
10

>2
> 0.2
>2
N/a

Source: Adapted from Ref. 2.

2. GENERAL CONSIDERATIONS IN PROCESS SCALE-UP:
DIMENSIONAL ANALYSIS AND THE PRINCIPLE OF SIMILARITY
It is important to recognize that designing a commercial scale operation via several
stages of scale-up is, in one sense, an admission of failure. If we have a strong understanding of our processes, then full-scale design can be performed using appropriate
mathematical models, given feed formulation properties and clear required productspeciﬁcations. Mature chemical engineering processes, such as distillation, aredesigned this way.
However, most solids processing technology do not have this level of maturity
yet. In this case, scale-up studies reduce uncertainties in the design and operation of
the scaled unit most economically. On this basis, the starting point in scale-up must
really be the commercial unit. In theory, once sufﬁcient information for the commercial unit is known, scale-up can be done by applying the similarity principles fromdata collected on a smaller unit. The similarity principle states (3): Two processes
can be considered similar if they take place in similar geometric space and all dimensionless groups required to describe the processes have the same numerical values.
To establish the necessary dimensionless groups, a systematic dimensional analysis needs to be carried out where Buckingham P theorem is used to reduce the number of dimensionless groups (4). Assuming that a process can be described by kvariables, we can express one variable as a function of the other k  1 variables, i.e.,x1 ¼ f ðx2 ; x3 ; K; xk1 Þ

ð2:1Þ

To conform to the dimensional homogeneity, the dimensions of the variable on
the left-hand side of the equation must be equal to those on the right-hand side. With
some simple mathematical rearrangements, Eq. 2.1 can be transformed into an© 2005 by Taylor & Francis Group, LLC

Scale-Up Considerations in Granulation

461

equation of dimensionless groups (P terms), i.e.,
P1 ¼ fðP2 ;P3 ; K; Pkr Þ

ð2:2Þ

Eq. 2.2 is a relationship among k  r independent dimensionless products,
where r is the minimum number of reference dimensions required to describe thevariables. While the Buckingham P theorem itself is straightforward, developmentof a dimensionless expression for a process or a phenomenon requires a systematic
dimensional analysis [Ref. 4 for more details]. For most engineering problems, variables can be divided into three groups: (1) geometric variables, (2) material property
variables, and (3) process variables. The reference dimensions are normally the basic
dimensions such as mass (M), length (L), and time (T).
It is important to note that a systematic dimensional analysis can only beapplied to processes where a clear understanding of the processes is established.
Omission of any important variables of the process will lead to an erroneous
outcome of the dimensional analysis, inevitably causing major problems in scale-up.
Zlokarnik et al. (3) divided the application of dimensional analysis to ﬁve generalcases with different levels of understanding in each case:
1. The science of the basic phenomenon is unknown—dimensional analysis
cannot be applied;
2. Enough is known about the science of the basic phenomenon to compile
a tentative draft list—the resulting P set is unreliable;
3. All the relevant variables for the description of the problems are known—
application of dimensional analysis is straight forward;
4. The problem can be described by a mathematical equation—mathematical
functions are better than P relationships, which may help reducing thenumber of dimensionless groups.
5. A mathematical solution of the problem exists—application of dimensional
analysis is unnecessary.
Clearly, the more we understand a process or phenomenon, the better we canscale it up with conﬁdence.
Full application of the similarity principle requires all the relevant P groups tobe measured at the small scale and kept constant during scale-up. Unfortunately,
most industrial processes are very complex with many physical and chemical
phenomena occurring. This leads to a large set of dimensionless groups required
to fully characterize the process. This is particularly the case with processes involving
particulate materials such as granulation. Maintaining all the dimensionless groups
constant on the two scales is very difﬁcult, if not impossible, due to constraints on the
degrees of freedom in variables that can be changed on scale-up. In this case, scale-up
can only be done on the basis of ‘‘partial similarity.’’ That is, not all dimensionless
numbers can be maintained the same on the two scales.
To scale up on the basis of partial similarity, experiments are carried out on a
succession of equipment at different scales and results extrapolated to the ﬁnal scale.
That is, the scale-up ratio is kept low. With conﬂicting requirements on the dimensionless groups during scale-up, a common approach is to maintain one dimensionless group constant and check the effect of other dimensionless groups on thedependent variable by varying these dimensionless groups during experimentation.
Once determined, only the dominant dimensionless number will be kept constanton scale-up. This partial similarity approach is often applied to granulation.
© 2005 by Taylor & Francis Group, LLC

462

He et al.

3. ANALYSIS OF GRANULATION RATE PROCESSESAND IMPLICATIONS FOR SCALE-UP
Many of the required granule product attributes are directly related to the size, size
distribution, and density of the granule product. These granule properties develop asa result of three classes of rate process in the granulator (Fig. 1):
1. Wetting and nucleation
2. Growth and consolidation
3. Breakage and attrition.
Each of these processes is analyzed in depth in Litster and Ennis (5). In thissection, we will summarize each rate process in turn, particularly highlighting themain formulation properties and process variables. Wherever possible, we will deﬁnedimensionless groups that can be used in scale-up.
3.1. Wetting and Nucleation
The ﬁrst step in granulation is the addition of a liquid binder to the powder to form
nuclei granules. Within the granulator, the key region for wetting and nucleation is
the spray zone where liquid binder droplets contact the moving powder surface. The
nucleation process is considered to consist of four stages (Fig. 2):
1. Droplet formation
2. Droplet overlap and coalescence at the bed surface

Figure 1 A classiﬁcation of granulation rate processes. (From Ref. 5.)© 2005 by Taylor & Francis Group, LLC

Scale-Up Considerations in Granulation

463

Figure 2 Wetting and nuclei formation in the spray zone of a granulator.

3. Drop penetration into the bed by capillary action
4. Mechanical dispersion of large clumps within the powder bed (onlyapplicable to mixer granulators).
Poor wetting and nucleation lead to broad granule size distributions and poor
distribution of the liquid binder, which increases substantially the chances of poor
drug distribution. Despite the action of other rate processes, the broad size distributions and poor liquid distribution often persist throughout the granulation.
For ideal nucleation, the granulator should operate in the drop-controlled
regime. Here, each drop which hits the powder bed penetrates into the bed to forma single nucleus granule. There is (almost) no drop overlap at the bed surface andmechanical dispersion of large, wet powder clumps is unnecessary.
To predict the required conditions for drop-controlled nucleation we must
understand1. The thermodynamics and kinetics of drop penetration, largely controlled
by formulation properties
2. The ﬂux of drops onto the bed surface, largely controlled by process parameters.
The drop penetration time tp can be estimated using a model, which considers
the rate at which liquid ﬂows into the pores in the powder surface under capillaryaction (6):2=3Vm
tp ¼ 1:35 2 0eeff Reff gLV cosy

ð3:1Þ

where V0 is the drop volume, m is the liquid viscosity, and gLV cosy is the adhesivetension between the liquid and the powder. The effective pore size Reff and porosity
eeff of the powder bed are given by
Reff ¼

fd32 eeff
3 ð1  eeff Þeeff ¼ etap ð1  e þ etap Þ© 2005 by Taylor & Francis Group, LLC

ð3:2Þ

ð3:3Þ

464

He et al.

where j is the particle sphericity, d32 is the speciﬁc surface mean particle size, e is theloose packed bed porosity, and etap is the tapped bed porosity.
For drop-controlled nucleation, the drop penetration time must be small compared to the bed circulation time tc before that section of powder passes again
through the spray zone, i.e., the dimensionless penetration time should be small:
tp
< 0:1
ð3:4Þ
tc
To avoid drop overlap on the bed surface and caking of the powder, the dimensionless spray ﬂux c must also be kept small. ca is the ratio of the rate of productionof drop projected area by the nozzle to the rate at which powder surface area passed
through the spray zone and is deﬁned as
tp ¼

3V
ð3:5Þ
2Add
Figure 3 shows how the nuclei granule size distribution broadens as the sprayﬂux increases. For drop-controlled nucleation, the dimensionless spray ﬂux should
be kept < 0.2. For ca > 0.7 the surface of the powder bed in the spray zone is effectively caked.
We can represent the nucleation behavior in a regime map (Fig. 4). Dropcontrolled nucleation is achieved only when both ca and tp are low. Figure 5 shows
an example of full granulation data from a 25 L ﬁelder mixer granulator on this typeof regime map. The granule size distribution is much narrower when nucleation is
kept in the drop-controlled regime (lower left-hand corner). This illustrates that poor
nucleation usually results in broad ﬁnal granule size distributions despite the impactof other processes occurring in the granulator.
ca ¼

3.2. Growth and Consolidation
Granule growth is very complex. The key question in establishing growth behavior
is: Will two granules which collide in a granulator stick together (coalesce) or

Figure 3 Effect of powder velocity on nuclei size distribution for lactose with water at 310
kPa. (From Ref. 6.)© 2005 by Taylor & Francis Group, LLC

Scale-Up Considerations in Granulation

465

Figure 4 Nucleation regime map. For ideal nucleation in the drop-controlled regime, it musthave (1) low ca and (2) low tp. In the mechanical dispersion regime, one or both of these
conditions are not met, and good binder dispersion requires good mechanical mixing.

Figure 5 Nucleation regime map in 25 L Fielder mixer at 15% liquid content. Merck lactosewith water and HPC as liquid binders. (From Ref. 6.)© 2005 by Taylor & Francis Group, LLC

466

He et al.

rebound? To answer this question it is useful to look at two extreme cases, which
cover most applications:Deformable porous granules: These granules are typically formed by a nucleation process described earlier with the drop size of the same order, or
larger, than the powder size. Most of the liquid in the granule is contained in the pores between particles in the granule and held there bycapillary action. For successful coalescence, this liquid must be madeavailable at the contact point between colliding granules. This model isoften suitable for drum mixer granulation.
Near-elastic granules: Here, the wetted granule is considered as a nearly elastic
sphere with a liquid layer on the surface. This is a good model for cases
where the drop size is much smaller than the granule size and the granulator has simultaneous drying. This model is often suitable for ﬂuid-bed
granulation.
The different growth modes for deformable porous granules can be represented
on a regime map (Fig. 6). For growth to occur by coalescence, the liquid content
needs to be large enough to provide 85–105% saturation of the pores in the granule.
Granules that are weak, i.e., form large contact areas on collision, fall into the steady
growth regime. When two granules collide, a large contact area is formed and liquid
is squeezed into the contact area, allowing successful coalescence. In this regime,
granules grow steadily and the growth rate is very sensitive to moisture content(Fig. 7A).
Strong granules do not deform much on collision and granules rebound, rather
than coalesce. However, as granules consolidate slowly, eventually liquid is squeezed
into the granule surface and this liquid layer causes successful coalescence. This is the

Figure 6 Granule growth regime map. (From Ref. 7.)© 2005 by Taylor & Francis Group, LLC

Scale-Up Considerations in Granulation

467

Figure 7 Coalescence growth modes for deformable granules.

induction growth regime (Fig. 7B). At lower moisture contents, nuclei granules formand consolidate. Some growth by layering may occur, but there is insufﬁcient liquidfor growth by coalescence. This is the nucleation regime. Very weak granules simply
fall apart and cannot sustain growth. This is the crumb regime.
There are two dimensionless groups that dictate the growth behavior, theStokes deformation number Stdef and the maximum pore saturation smax, which
are deﬁned as
Stdef ¼

rg U 2c
2Yð3:6Þ

Smax ¼

wrs ð1  emin Þ
r1 emin

ð3:7Þ

where rg, rs, and rl, are the granule, particle, and liquid densities, respectively; Uc isthe effective granule collision velocity; Y is the granule yield strength; w is the liquid
content (kg liquid/kg dry powder); and emin is the minimum granule porosity after
complete consolidation.
Understanding where your system sits on the growth regime map is important
for troubleshooting and scale-up. Granules that grow in the induction regime areeasy to scale with respect to granule size, provided that the induction time is notexceeded. However, granule density often changes with scale because consolidation
kinetics are important and these kinetics can change with scale. On the other hand, inthe steady growth region it is difﬁcult to control granule size, but granule density
quickly settles to a minimum value and varies little with process parameters.
To make effective use of the granulation regime map we need reasonable estimates of the effective collision velocity Uc (controlled by process conditions) anddynamic yield stress Y (a function of formulation properties). Table 2 gives estimatesof the average and maximum collision velocities for different process equipment. In© 2005 by Taylor & Francis Group, LLC

468

He et al.

Table 2 Estimates of Uc for Different Granulation Processes
Type of granulator

Average Uc

Maximum Uc

Fluidized beds
Tumbling granulators
Mixer granulators(6Ubdp)/db
odp
oidp, ocdp

(6Ubdp)/dbd2
oDdrumoiD, ocDc

Source: From Ref. 5.

high-shear mixers, the difference between the average and maximum collisionvelocities can be very large.
The dynamic yield stress of the granule matrix is a function of strain rate dueto the contribution of viscous dissipation to the granule strength. Therefore, it isdangerous to use static strength measurements to predict performance in the granulator. Iveson et al. (8) show how dynamic yield stress can be estimated from peak
ﬂow stress measurements in a high-speed load frame. They were able to correlate
data for different formulations and strain rates in a single line when plotted as thedimensionless peak ﬂow stress (Str) vs. the capillary number (Ca) (Fig. 8). This line
can be ﬁtted by a simple empirical equation of the form
Str ¼ k1 þ k2 Can

ð3:8Þ



where Str ¼ spkdp/g cos y is the dimensionless peak ﬂow stress, Ca ¼ m_edp/g cos y is
the ratio of viscous to capillary forces, spk is peak ﬂow stress, e_ is the bulk strain rate,
and y is the solid–liquid contact angle. k1 gives the static strength of the pellets. k2
determines the transition between strain-rate independent and strain-rate dependent
behavior. n is an exponent which gives the power law dependency of the ﬂow stresson viscosity and strain rate. The best-ﬁt value of n was found to be 0.58  0.04 andthe transition between strain-rate independent and dependent ﬂow stress occurred at
Ca  104.

Figure 8 Dimensionless ﬂow stress vs. capillary number for widely sized 35 mm glass ballotiniwith six different binders.
© 2005 by Taylor & Francis Group, LLC

Scale-Up Considerations in Granulation

469

The rate of consolidation of granules can also be correlated with Stdef in theform
kc ¼ bc expða  Stdef Þð3:9Þ

where bc and a are constant, kc is the consolidation rate constant for a ﬁrst-orderconsolidation equation of the forme  emin¼ expðkc tÞ
e0  eminð3:10Þ

For near-elastic granules the conceptual model originally developed by Enniset al. (9) considers the collision between two near-elastic granules each coated witha layer of liquid (Fig. 9). In this case the key dimensionless group is the viscous
Stokes number Stv
Stv ¼

4rg Uc dp
9m

ð3:11Þ

Stv is the ratio of the kinetic energy of the collision to the viscous dissipation in
the liquid layer. Successful coalescence will occur if Stv exceeds some critical valueSt and we can deﬁne three growth regimes as follows:
Noninertial growth (Stv,max < St): The viscous Stokes number for all collisions
in the granulator is less than the critical Stokes number. All collisions
lead to sticking and growth by coalescence. In this regime, changes toprocess parameters will have little or no effect on the probability of coalescence.
Inertial growth ((Stv,av  St): Some collisions cause coalescence while theothers lead to rebound. There will be steady granule growth by coalescence. The extent and the rate of growth will be sensitive to process parameters which will determine the proportion of collisions that lead tocoalescence. Varying process parameters and formulation properties
can push the system into either the noninertial or the coating regimes.

Figure 9 Two near-elastic granules colliding—the basis for the coalescence/rebound criteria.
(From Ref. 9.)© 2005 by Taylor & Francis Group, LLC

470

He et al.

Figure 10 Growth of glass ballotini granules in a ﬂuidized bed with binders of different
viscosity. (From Ref. 9.)

Coating regime (Stv,min > St): The kinetic energy in most or all collisions
exceeds viscous dissipation in the liquid layer. There is no coalescence.
Granule growth will only occur by the successive layering of new material
in the liquid phase (melt, solution, or slurry) onto the granule.
Figure 10 shows an example of granule growth in a ﬂuidized bed where thegrowth regime changes as the granules grow. Glass ballotini is grown with two liquidbinders of different viscosity. Initially, both systems grow steadily at the same rate(noninertial regime). When the granule size reaches 800 mm, the PVP bound granule growth begins to slow down indicating a transition to the inertial growth regime(only some collisions are successful). Finally, the PVP granules level off at a maximum size of 900 mm showing transition to the coating regime, where no granulecollisions are successful. In contrast, the more viscous CMC-M granules grow steadily throughout the 8 hr experiment, i.e., they remain in the noninertial regime forthe whole experiment.

3.3. Breakage and Attrition
Breakage and attrition really cover two separate phenomena:
1. Breakage of wet granules in the granulator
2. Attrition or fracture of dried granules in the granulator, drier, or in subsequent handling.
Breakage of wet granules will inﬂuence and may control the ﬁnal granule size
distribution. It is only an important phenomenon for high-shear granulators. Wet
granule breakage is much less studied than nucleation and growth. There is very little© 2005 by Taylor & Francis Group, LLC

Scale-Up Considerations in Granulation

471

quantitative theory or modeling available to predict conditions for breakage, or theeffect of formulation properties on wet granule breakage.
Tardos et al. (10) considered that a granule breaks if the applied kinetic energy
during an impact exceeds the energy required for breakage. This analysis leads to a
Stokes deformation number criteria for breakage:
Stdef > Stdef

ð3:12Þ

where Stdef is the critical value of Stokes number that must be exceeded for breakage
to occur. However, this model is probably an oversimpliﬁcation. Figure 8 shows
schematics of the failure mode of different formulations in dynamic yield strength
measurements. Failure behavior varies widely from semibrittle behavior at low capillary numbers to plastic failure at high capillary numbers. We expect a purely plastic
granule to smear rather than break when its yield stress is exceeded. At high impeller
speeds such materials will coat the granulator wall or form a paste. Semibrittle granules will break at high-impact velocity giving a maximum stable granule size or a weak
crumb. Nevertheless, Eq. 3.12 provides a good starting point for quantifying wet
granule breakage.
Dry granule attrition is important where drying and granulation occur simultaneously (e.g., in ﬂuidized beds) and in subsequent processing and handling of the
granular product. We can consider dry granule breakage as brittle or semibrittle
phenomena. The key granule properties that control the breakage are the granulefracture toughness Kc and the ﬂaw or crack size c in the granule. Kc is set by formulation properties, while c is closely related to granule porosity controlled by the
consolidation process in the granulator.
Dry granule breakage usually results in production of ﬁnes by wear, erosion, or
attrition brought about by diffuse microcracking. Within a ﬂuid bed there are a large
number of low-velocity collisions between particles as they shear past each other.
This process is analogous to abrasive wear. For abrasive wear of agglomerates,
the volumetric wear rate V is given by (11)
1=2

V¼

di

3=4

A1=4 Kc H 1=2

P5=4 lð3:13Þ

where di is indentor diameter, P is applied load, H is the hardness of the particles, l iswear displacement of the indentor, and A is the apparent area of contact of theindentor with the surface. The number and relative velocity of the collisions dependon the number of bubbles in the bed and hence the excess gas velocity (u  umf). The
applied pressure in a ﬂuid bed depends on bed depth. Thus, the attrition rate Bw ina ﬂuidized bed granulator is
1=2

Bw ¼

d0
3=4

Kc H 1=2

L5=4 ðu  umf Þð3:14Þ

where d0 is the distributor hole oriﬁce size and L is the ﬂuidized bed height. Figure 11
shows the attrition rates of several formulations in a ﬂuidized bed with a direct
correlation between attrition rate and the material properties grouping in Eq. 3.13
and (3.14).
Note that Eq. 3.13 and (3.14) only hold for breakage via a wear mechanism.
For attrition during impact or compaction, there are different dependencies of theattrition rate on the materials properties [Ref. 5 for more details].
© 2005 by Taylor & Francis Group, LLC

472

He et al.

Figure 11 Erosion rates of agglomerate materials during attrition of granules in a ﬂuidized
bed. (From Ref. 12.)3.4. Implications for Scale-Up
Table 3 summarizes the key controlling dimensionless groups for the rate processes
described earlier and the main process parameters and formulation properties that
impact on these groups.
In addition to these groups, there are dimensionless groups to describe: (1) thegeometry of the equipment and (2) the ﬂow of the powder and granules in the granulator. Both these classes of controlling groups are very equipment dependent.
For scale-up using full dimensional similarity, all these dimensionless groups
need to be held constant. This is normally impossible due to the small number ofTable 3 Summary of Controlling Groups for Granulation Rate Processes
Key formulation
properties

Rate process

Controlling groups

Wetting andnucleation

Dimensionless spray tp, m, g cos y, dp,e, etap
ﬂux c,
dimensionlesspenetration time tp

Growth andconsolidation

Stokes deformation
number Stdef,
viscous Stokes
number Stv, liquidsaturation S
Stokes deformation
number Stdef

Attrition andbreakage© 2005 by Taylor & Francis Group, LLC

Y, rg, m, g cos y,
dp, etap

Kc, H, Y, rg, m,
g cos y, dp, etap

Key processparameters
V&, A&(inﬂuenced by
nozzle design andposition, no. of
nozzles, and powder
ﬂow patterns)
Uc (inﬂuenced bypowder ﬂow
patterns; see
Table 2)
Uc, L, u  umf

Scale-Up Considerations in Granulation

473

degrees of freedom and the large number of constraints. In particular, for regulatory
reasons it is usually not possible to change formulation properties during scale-up
except during the very early stages of process development. This leaves only arelatively small number of process parameters as degrees of freedom.
Therefore, a partial similarity approach for scale-up is recommended. The
general steps are
1. Maintain similar geometry throughout the scale-up process. For most of
the pharmaceutical granulation equipment, this can be achieved fromeither 10 or 25 L nominal batch size to full scale. Be wary, however, insome cases key geometric parameters do vary with scale on a particular
design, e.g., relative chopper size, relative ﬁll height. Manufacturers should
be lobbied hard to provide geometrically similar designs at all scales.
2. Set key dimensionless groups to maintain similar powder ﬂow during scaleup. In particular, avoid changes of ﬂow regime during scale-up that makemaintaining granule attributes during scale-up impossible.
3. Use your experience and an understanding of your process to decide which
product attributes are the most important, and which granulation rate
process is most dominant in controlling these attributes. This is difﬁcult
to do a priori, but with good characterization of your formulation and process, the regime map approaches described earlier are very useful.
4. Use your remaining degrees of freedom in the choice of process parametervalues to keep the most important one or two rate process dimensionlessgroups constant.
This approach is most easily demonstrated on a particular type of equipment(Section 5 for ﬂuidized beds and Section 6 for high-shear mixers).

4. SCALE-DOWN, FORMULATION CHARACTERIZATION, AND
FORMULATION DESIGN IN PHARMACEUTICAL GRANULATIONIn the development of a new pharmaceutical product, important decisions about the
manufacturing process are made with a few grams or tens of grams of formulation.
To provide, the drug product for clinical trials and the ﬁnal design at large scale,granulations are often conducted at several laboratory-and pilot scales as well. Typical nominal batch sizes are 1, 10, 25, and 65 L scaling to commercial operation at 300
or 600 L.
Small-scale granulations up to 1 L are often done by hand, and certainly performed in equipment that is very different from the equipment that will be used forscales from 10 L and larger. At this level, the general scale-up approach described in
Section 3.4 does not hold. How do we scale down to make the best use of data from
granulation of these small amounts?
The key is to consider granulation as a particle design process (Fig. 12). During
scaling up from 10 L, formulation properties cannot be varied. Only processparameters can be used to keep key granule attributes in the target range. Therefore,
very small-scale-experiments should target major formulation design decisions
and attempts to mimic completely different geometries at larger scale should be
avoided.
Table 3 summarizes key formulation properties that should be measured. Mostof these require relatively small amounts of material and can be measured at this© 2005 by Taylor & Francis Group, LLC

474

He et al.

Figure 12 Granulation as an example of particle design. Both formulation properties andprocess parameters inﬂuence granule attributes.

level. By using these data to help estimate key controlling groups for the granulation
rate processes in the larger-scale equipment, appropriate changes to the formulation
can be made. This avoids major headaches at a later stage. Good communication
between the technologists who design the formulations and the process engineers
who scale the process and transfer the product to manufacturing is an essential partof this paradigm.
Some of the questions that can be addressed at this stage of formulation development and scale-up include:
1. Wetting and nucleation
Contact angle: Are the active and all the excipients easily wetted by theliquid binder?
Drop penetration time: Is the liquid phase too viscous, or the particle
size too small to achieve fast drop penetration?

2. Growth and consolidationWhat is the dynamic yield stress of the formulation?
How much liquid binder is required for granule growth?
What is the likely growth regime?
What range of granule density is likely?

3. Attrition and breakageWill extensive granule breakage occur in the granulator?
What are dry granule strength (fracture toughness) and porosity?
Are attrition and dust formation during handling likely?

4. Downstream processing issues
Does the formulation compress well for tableting?
Can the desired dissolution proﬁles be met?

Details of how to measure key formulation properties are described in moredetail in Litster and Ennis (5).
© 2005 by Taylor & Francis Group, LLC

Scale-Up Considerations in Granulation

475

5. SCALE-UP OF FLUIDIZED BED GRANULATORS
There are many different variations of ﬂuidized bed granulators including bubbling
ﬂuidized bed, draft tube ﬂuidized beds, and spouted beds (5). However, in this section, we limit ourselves only to the scale-up of the most commonly used ﬂuidized bed
granulator, i.e., bubbling ﬂuidized bed granulator. In particular, as most ﬂuidized
bed granulators used in the pharmaceutical industry are operated in batch mode,
we will concentrate on the scale-up of batch bubbling ﬂuidized bed granulators.
5.1. Bed Hydrodynamics and Scale-Up
Particle growth in a ﬂuidized bed is closely related to the particle mixing and the ﬂow
pattern in the bed. This dictates that the hydrodynamics of the scaled bed should be
the same as the small unit, i.e., hydrodynamic similarity. Basic ﬂuidized bed hydrodynamics are described in Chapter 9.
In bubbling ﬂuidized beds, bed expansion, solids mixing, particle entrainment,
granule growth, and attrition are intimately related to the motion of bubbles in thebed (Fig. 13). The volume ﬂow rate of bubbles in the bed Qb, the bubble size db, andthe bubble rise velocity ub are the key parameters that characterize the bubbly ﬂow.
There are numerous correlations relating these bubble parameters to process conditions [see, for example, Kunii and Levenspiel (13) and Sanderson and Rhodes (14)].
In general, Qb is a strong function of the excess gas velocity u  umf. Growing granules are usually Geldart type B powders, or perhaps type A powders at the start ofthe batch. For group B powders, db increases with bed height and is a function of

Figure 13 Effect of bubbles on (A) solids mixing and (B) solids entrainment. (From Ref. 13.)© 2005 by Taylor & Francis Group, LLC

476

He et al.

excess gas velocity. The bubble-rise velocity is directly related to db. For the simplest
models for group B powders we can writeQb ¼ ðu  umf ÞpD2F
pﬃﬃﬃﬃﬃﬃﬃ
ub ¼ 0:71 gdb

ð5:2Þ

db / ðu  umf Þ0:4 L0:8

ð5:3Þ

ð5:1Þ

Thus, the excess gas velocity u  umf and the bed height L are the key processparameters that control bubbling behavior in the bed.
Several rules exist for scaling up a bubbling ﬂuidized bed under the conditionof hydrodynamic similarity. Fitzgerald and Crane (15) proposed that the following
dimensionless numbers be kept constant during scale-up:Particle Reynolds number based on gas density (dpurG)/m
Spolid particle to gas density ratio rs/rG
Particle Froude number u/(gdp)0.5
Geometric similarity of distributor, bed, and particle L/dp

where dp is the particle diameter, u is the ﬂuidization velocity (superﬁcial gas velocity), m is the viscosity of ﬂuidizing gas, rG is the density of ﬂuidizing gas, g is thegravitational acceleration, and L is the ﬂuidized bed height.
In this approach, experiments on the smaller scale are performed with model
materials, i.e., model gas (different from the larger-scale one) and model solid particles (different particle density, size, and size distribution). For readers interested infollowing Fitzgerald’s scale-up rules, a detailed calculation procedure can be foundin Kunii and Levenspiel’s book (13), illustrated with an example.
In a series of publications, Glicksman et al. (16–18) divided the scale-up into
two regimes, namely, inertia-dominated and viscous-dominated ﬂow regimes. In
viscous-dominated ﬂow regime, where particle Reynolds number based on ﬂuid
density is 4, i.e., when, the (dpurG/m  4, dimensionless numbers that need to be
kept constant areuðgdp Þ

0:5;

dp urs L DF
; ;; f; particle size distribution; bed geometry
m dp dpð5:4Þ

where DF is the ﬂuidized bed diameter.
In contrast, in inertia-dominated ﬂow regime, (dpurG)/m 400, scale-up of theprocess demands that the following dimensionless numbers are kept constant:ur dp urs L DF
; ;; G;
; f; particle size distribution; bed geometry
m dp dpðgdp Þ0:5 rs

ð5:5Þ

In the intermediate region, where 4  (dpurG)/m  400, both the viscous and theinertial forces are important to the ﬂuid dynamics, and all the dimensionless numbers
for the two regions mentioned earlier will need to be kept constant during scale-up, i.e.,rs rG dp3 g
m2

;

u
0:5

ðgdp Þ

;rG L DF; ;; f; particle size distribution; bed geometry
rs dp dp
ð5:6Þ

© 2005 by Taylor & Francis Group, LLC

Scale-Up Considerations in Granulation

477

Experimenting with only ambient air and particles made of the same material
but different sizes, Horio et al. (19,20) developed what has been lately deﬁned as thesimpliﬁed scaling law. They demonstrated that, with similar bed geometry (ratio of
bed height to diameter), using particles of different mean sizes but the same distribution characteristics, and operating the bed in proportional superﬁcial gas velocities
would ensure that the hydrodynamic conditions of the two beds remain similar.
Expressed in mathematical terms
pﬃﬃﬃﬃ
u2  umf;2 ¼ mðu1  umf;1 Þpﬃﬃﬃﬃ
umf;2 ¼ mumf;1
ð5:7Þ
L2
m¼
L1
bed geometry
where 1 and 2 refer to the small-scale and large-scale beds, respectively.
Experimental results from Roy and Davidson (21) suggest that when (dpurG)/m < 30, the criteria of Horio et al. (19,20) are sufﬁcient to give similarity in behavior.
However, when (dpurG)/m > 30, the more restrictive approach of Fitzgerald andCrane has to be used.
Unfortunately, few of the previously mentioned scaling rules for bubbling
ﬂuidized beds have been strictly followed for the scaling up of ﬂuidized bed granulators. This is largely because the scaling rules require model materials to be
used at the smaller scale, whereas in pharmaceutical granulation, the formulationis unchanged during scale-up. However, the simpliﬁed rules presented by Horio
combined with our understanding of granulation rate processes do provide someguide.
5.2. Granulation Rate Processes in Fluidized Beds
Figure 14 shows the rate processes occurring during ﬂuidized granulation. Wetting,nucleation, and layered growth occur in the spray zone of the ﬂuidized bed. Most
consolidation and coalescence also occur in or near the spray zone because ﬂuidized
bed granulators are also driers. The drying process ‘‘freezes’’ the granule structure
and prevents further growth. Thus, good design of the spray zone is very importantand liquid ﬂow rate is a critical process parameter. Beds should be designed to keep
dimensionless spray ﬂux low (drop-controlled regime). If this is not done, the formation of large clumps leads to rapid wet quenching and deﬂuidization with likely
loss of the batch. Figure 15 shows how the product granule size distribution isclosely related to the design of the spray zone. The x-axis variable (spray surface area
per mass in granulator) is closely related to our deﬁnition of dimensionless sprayﬂux.
Due to the simultaneous drying, our consolidation and growth models for nearelastic granules is usually appropriate and the viscous Stokes number is a key controlling group [Eq. (3.11)]. This model predicts that in batch granulation, granules willgrow toward a maximum size corresponding to the critical Stokes number and transition to the coating regimes (e.g., Fig. 10). The average and maximum granule collisionvelocities are set by the ﬂow of bubbles in the ﬂuid bed and are a function of bubble
velocity and size (Table 3).
Fluidized beds produce porous granules because the consolidation time islimited to granule drying time, which is of the order of seconds, rather than minutes.
© 2005 by Taylor & Francis Group, LLC

478

He et al.

Figure 14 Important granulation processes in the ﬂuidized bed. (From Ref. 5.)

Thus, process changes that reduce drying time (higher bed temperature, lower liquid
ﬂow rate, and smaller drop size) will decrease granule density (increase granule porosity). Increasing the liquid binder viscosity decreases granule voidage by increasing
the resistance of the granule to deformation.
Dry granule attrition in the ﬂuid bed is an important source of ﬁnes. Eq. 3.14
quantiﬁes the attrition rate in terms of granule properties and process conditions(Fig. 11). Increasing ﬂuid bed height increases both consolidation and attrition for
two reasons: (1) it increases the effective ‘‘ﬂuid’’ pressure on granules in the bed
and (2) it increases the average bubble size in the bed, leading to more vigorous
mixing and higher-velocity granule collisions.

Figure 15 Geometric standard deviation of granule size in an agitated ﬂuid-bed granulator
as a function of gas ﬂuidization velocity and binder dispersion measured using spray surface
area to mass in mixer. (From Ref. 10.)© 2005 by Taylor & Francis Group, LLC

Scale-Up Considerations in Granulation

479

5.3. Suggested Scaling Rules for Fluid Bed Granulators
Given this understanding of ﬂuidized bed hydrodynamics and granulation rate process, we suggest the following guidelines for scaling ﬂuidized bed granulators:
1. Maintain the ﬂuidized bed height constant. Granule density and attrition
rate increase with the operating bed heightL2 ¼ L1
ð5:8Þ
2. If L is kept constant, then batch size scales with the bed cross-sectionalarea:
M2 D2F;2¼
M1 D2F;1

ð5:9Þ

3. Maintain superﬁcial gas velocity constant to keep excess gas velocity, andtherefore bubbling and mixing conditions similar:
Q2 u2 D2F;2¼ ¼
Q1 u1 D2F;1

ð5:10Þ

Note that the scaling rules deﬁned by Eqs. 5.8–5.10 are consistent with
Horio’s simpliﬁed scaling rules (Eq. 5.7).
4. Keep dimensionless spray ﬂux constant on scale-up. This is most easily
achieved by increasing the area of bed surface under spray (usually byincreasing the number of nozzles). By doing this, the liquid ﬂow rate canbe increased in proportion to batch size without changing critical sprayzone conditions. Thus, batch times at small and large scale should be
similar:V2& ¼ V1&

ð5:11Þ

Aspray;2 D2F;2¼
Aspray;1 D2F;1

ð5:12Þ

5. Keep viscous Stokes number constant. By adhering to the scaling rules
described earlier, Stv should automatically be similar at small and large
scale leading to similar consolidation and growth behavior.
There are also some cautionary notes relating to the minimum scale for thelaboratory scale studies. Slug ﬂow, a phenomenon where single gas bubbles as large
as the bed diameter form in regular patterns in the bed, signiﬁcantly reduces solid
mixing. It occurs in tall and narrow beds. Stewart (22) proposed a criterion forthe onset of sluggingu  umfpﬃﬃﬃﬃﬃﬃﬃﬃﬃ ¼ 0:2
ð5:13Þ
0:35 gDF
To ensure that the bed is operating in bubbling mode without risking slugging,
the ratio in Eq. 5.13 must be kept below 0.2. In addition, both the bed height to bed
diameter and the particle diameter to bed diameter ratios should be kept low. For
pilot ﬂuidized bed, the diameter should be > 0.3 m.
To avoid the gas entry effect from the distributor (gas jet), there is also arequirement on minimum ﬂuidized bed height. The jet length depends on the gas
velocity and the size of the opening on the distributor. For the same opening size,© 2005 by Taylor & Francis Group, LLC

480

He et al.

jet length increases with gas velocity through the hole; for a given gas velocity throughthe hole, small holes give shorter jets but are accompanied by a larger pressure drop
across the distributor. Even at a superﬁcial gas velocity as low as 0.2 m/sec with ahole size of 9.5 mm diameter, jet length as long as 0.6 m has been reported (23).
The amount of ﬂuidization gas required to maintain constant ﬂuidization velocity changes linearly with the cross-section area of the bed. However, for large
ﬂuidized beds, one of the major concerns is the even distribution of the ﬂuidization
gas across the whole area of the bed. In addition to the use of a plenum chamber andan even distribution of ﬂow channels across the distributor, the distributor should bedesigned in such a way that the pressure drop across it is at least 20% of the total.
If these scaling rules are applied, there is a good chance to keep granule properties within the desired range on scaling. If ﬁne tuning is needed at the large scale,minor adjustments to the liquid spray rate can be used to adjust granule properties,
as all the granulation rate processes in ﬂuidized beds are very sensitive to thisparameter.
6. SCALE-UP OF HIGH-SHEAR MIXER GRANULATORS
Effective scale-up of mixer granulators is more difﬁcult than in ﬂuidized beds. There
are several reasons for this: The geometric and mechanical design of mixer granulators varies enormously, as do the powder ﬂow patterns in the mixer. There is no such thing
as a generic high-shear mixer and caution is needed when transferring scaling rules from one design to another.
 Even with the same series from the same manufacturer, geometric similarity
is not always maintained between different scales, e.g., impeller size in
relation to bowl size.
 Powder ﬂow in high-shear mixers is not ﬂuidized and powder ﬂow patterns
are much harder to predict than in a ﬂuidized bed.
 All three rate processes, i.e., wetting and nucleation, growth and consolidation, and breakage and attrition, are taking place simultaneously in themixer granulator of all scales. However, the relative dominance of eachof the rate processes can vary signiﬁcantly on different scales of the sameseries, let alone in granulators of different series.
In this section, we will focus mainly on vertical shaft mixer, e.g., Fielder,
Diosna designs. Some of the suggested approaches may be used with caution forother mixer designs.
6.1. Geometric Scaling Issue
For a simple vertical mixer design, the key dimensions are the impeller diameter D,
which is usually equal to the bowl diameter, the chopper diameter Dc, and the ﬁllheight Hm. The dimensionless groups that need to be held constant for geometricsimilarity are
Dc Hm
;
D D
In addition, the shape and positioning of the impeller and chopper should be
the same on scale-up. Unfortunately, manufacturers do not always adhere to these© 2005 by Taylor & Francis Group, LLC

Scale-Up Considerations in Granulation

481

rules. It is common for the absolute size of the chopper to be invariant, meaning its
relative inﬂuence is much larger in the small-scale granulator.
Relative ﬁll height is also often varied with scale. This often reﬂects the smallsize batches required for early-stage clinical trials and the desire to maximize production rate (by maximizing batch size) at full scale. Varying relative ﬁll height is very
dangerous, as it can have a major impact on powder ﬂow patterns.
6.2. Powder Flow Patterns and Scaling Issues
There are two ﬂow regimes observed in a vertical shaft mixer granulator, namely,
bumping and roping regimes (24). At low impeller speeds in the bumping regime,
the powder is displaced only vertically as the blade passes underneath leading to aslow, bumpy powder motion in the tangential direction. There is almost no vertical
turnover of the powder bed, as shown in Figure 16A.
At a higher impeller speed in the roping regime, material from the bottom of
the bed is forced up the vessel wall and tumbles down at an angle of the bed surface
toward the center of the bowl. There is both good rotation of the bed and goodvertical turnover (Fig. 16B).
The transition from bumping to roping is due to a change in the balance
between centrifugal force and gravity. The centrifugal force, which is caused by
the rotational movement of the powder from the spinning of the blades, pushes
the powder outward toward the wall of the bowl, while gravity keeps the powdertumbling back toward the center of the bowl from the buildup at the wall region.
This balance between rotational inertia and gravity is given by the Froude number:
Fr ¼

DN 2
g

ð6:1Þ

where N is the impeller speed and g is the gravitational acceleration.
When the Froude number exceeds a critical value, transition from bumping toroping takes place:Fr > Frc
ð6:2Þ
Frc will be a function of relative ﬁll height (Hm/D), impeller design (size and geometry),and powder ﬂow properties.
Roping ﬂow is more difﬁcult to achieve as relative ﬁll height increases because
the centrifugal force is only imparted to powder in the impeller region. This region
becomes a smaller fraction of the total powder mass as ﬁll height increases. Schaefer(25) also showed that impeller design had a signiﬁcant effect on both Frc and bed
turnover rate.

Figure 16 Powder ﬂow regimes in Fielder mixer granulators: (A) bumping and (B) roping.
© 2005 by Taylor & Francis Group, LLC

482

He et al.

Cohesive powders transfer to roping at lower values of Fr because momentum
from the spinning impeller is more effectively transferred into the powder mass. Notethat powder ﬂow properties generally change with the addition of the liquid binderand, therefore, ﬂow patterns will probably change signiﬁcantly during a batch
granulation.
Figure 17 shows dry lactose powder surface velocity data in a 25 L ﬁelder granulator (24). In the bumping ﬂow regime, the powder surface velocity increases in proportion to the impeller speed. In the roping regime, the surface velocity stabilizes andis less sensitive to impeller speed. In all cases, the surface velocity of the powder isonly of order of 10% of the impeller tip speed. Knight et al. (26) showed that dimensionless torque T is a direct function of Froude number and effective blade height
heff:


2heff aT ¼ T0 þ kFr0:5
where k ¼ b
ð6:3Þ
DThus, to maintain a similar powder ﬂow pattern during scale-up, the Froudenumber should be kept constant, i.e.,
rﬃﬃﬃﬃﬃﬃ
N2
D1
¼
ð6:4Þ
N1
D2
In addition, the dimensionless bed height should also be kept constant, i.e., thesame fraction of the bowl is ﬁlled at all scales:
Hm;2 D2¼
Hm;1 D1

ð6:5Þ

Historically, mixer granulators have been more commonly scaled up using
constant tip speed or constant relative swept volume (25,27). Maintaining constantFigure 17 Powder surface velocities as a function of impeller tip speed. (From Ref. 24.)
© 2005 by Taylor & Francis Group, LLC

Scale-Up Considerations in Granulation

483

impeller tip speeds leads to the scaling rule:
N2 D1
¼
ð6:6Þ
N1 D2
This scale-up rule leads to Fr decreasing, as scale increases. Combined with thecommon practice of overﬁlling full-scale granulators, this approach to scaling canoften lead to a change in operating regime from roping to bumping on scale-up.
The constant swept volume approach to scale-up was introduced partly to
account for variations in geometry on scale-up. The relative swept volume is deﬁned as
VR& ¼

&
Vimp

Vmixerð6:7Þ

&is the rate of swept volume of impeller, andwhere VR& is the relative swept volume, Vimp
Vmixer is the mixer volume.
On scale-up,&&
VR;1¼ VR;2

ð6:8Þ

This approach is useful for comparing granulators where geometry changes
with scale. For geometrically similar granulators, Eq. 6.8 is equivalent to scale-up
with constant tip speed (Eq. 6.6).
6.3. Granulation Rate Processes and Related Scaling Issues
In high-shear mixer granulation, all three classes of rate process can have a signiﬁcant effect on the granule size distribution. Section 3.1 describes conditions for good
nucleation in the drop-controlled regime and uses examples from mixer granulation.
For good nucleation, the granulator should be operated in the roping regime forgood bed turnover and the dimensionless spray ﬂux ca should be kept low. Thisimplies careful choice of the liquid ﬂow rate, nozzle design, and positioning in the
granulator.
To maintain similar nucleation behavior and equivalent liquid distribution, thedimensionless spray ﬂux ca should be kept constant on scale-up. If drop size fromthe full-scale nozzle is similar to the small scale, this implies
V2& V1&
V & A&¼ & ) 2& ¼ 2&
&
A2
A1
V1
A1

ð6:9Þ

A common scale-up approach is to keep the same total spray time and still use
a single nozzle at large scale. Thus, V& is proportional to D3. Despite the fact that thepowder area ﬂux will increase slightly with scale, this approach generally leads to a
substantial increase in dimensionless spray ﬂux. To keep dimensionless spray ﬂux
constant, multiple spray nozzles or longer spray times should be used at a large scale.
It should be noted that consolidation, growth, and breakage processes arecontrolled by Stdef. This can lead to quite complicated growth behavior in mixer
granulators. Figure 18 illustrates some of this complex behavior (27). Both decreasing liquid viscosity and increasing impeller speed increase the rate of granule growth
but decrease the ﬁnal equilibrium granule size. Both these effects increase Stdef. In
the early stage of granulation, this increases the probability of successful coalescence.
However, as the granules grow, the critical value of Stokes number for breakage may
be exceeded—at least near the impeller blade leading to a balance of breakage andgrowth and an equilibrium granule size. This example also highlights that most© 2005 by Taylor & Francis Group, LLC

484

He et al.

Figure 18 Variations in granule growth rate and extent of growth in a mixer granulator withchanges to (A) binder viscosity and (B) impeller speed. (From Ref. 27.)high-shear mixers have a very wide range of collision velocities in different parts ofthe bed. Granule coalescence will occur in regions of low collision velocity, while
breakage and consolidation are more likely near the impeller. To properly quantify
and predict this behavior, we need more sophisticated models that divide the granulator into at least two regions and incorporate better understanding of powder ﬂow
than we currently have.
Nevertheless, we can make some intelligent comments with regard to scale-up.
In a mixer granulator, the maximum collision velocity for a granule will be of theorder of the impeller tip speed. To maintain constant Stdef, the impeller tip speed
should be kept constant, i.e., Eq. 6.6. If a constant Fr rule is used (Eq. 6.4),
2
Stdef;2 Uc;2N 2 D2 D2¼ 2 ¼ 22 22 ¼
Stdef;1 Uc;1 N1 D1 D1

ð6:10Þ

Thus, Stdef increases with scale. This will lead to an increase in the maximum
achievable granule density and a decrease in the maximum achievable particle size.
The actual granule density and size may also depend on the kinetics of consolidationand growth and are difﬁcult to predict without more sophisticated quantitative modeling. As such, the variation in Stdef with scale potentially leads to changes in granule
attributes that are difﬁcult to predict.
The liquid saturation s (Eq. 3.7) should be kept constant on scaling. Thisimplies a similar liquid content on a kilogram per kilogram dry powder basis
provided the granule density does not change with scale. For operation in the steady
growth regime, this is a reasonable assumption. However, for operation in the induction growth regime the change in density with scale is harder to predict.
6.4. Recommended Scaling Rules and a Case Study Example
The complexity of powder ﬂow and granulation rate processes makes it impossible torecommend a single deﬁnitive set of scaling rules. It is important to know which
granule attribute is of most importance during scaling and the main granulation rate
process that controls this attribute.
© 2005 by Taylor & Francis Group, LLC

Scale-Up Considerations in Granulation

485

Overall, we recommend the following approach:
1. Keep granulators geometrically similar during scale-up where manufacturer’s designs permit. In particular, keep dimensionless ﬁll height constantduring scale-up (Eq. 6.5).
2. To ensure similar powder mixing, keep Froude number constant during
scale-up by adjusting the impeller speed according to (Eq. 6.4). At the very
least, make sure Fr > Frc at all scales.
3. To achieve good binder distribution, ca should be kept constant on scaleup. This is likely to mean multiple spray nozzles at the large scale to give
sufﬁcient spray zone area (Eq. 6.9).
4. To keep Stdef constant for consolidation, breakage, and growth, constant
impeller tip speed should be maintained. This is in conﬂict with scaling rule
2 mentioned earlier. Scale-up with constant tip speed is possible, provided
that at large scale Fr > Frc.
5. Spray time during the batch and total batch time scaling rules require asound understanding of how the kinetics of growth and consolidation varywith scale. We do not know these rules yet, and they are likely to be different
for operation at different growth regimes. As a starting point, keeping batchtimes constant during scaling is probably reasonable provided this does not
conﬂict with other scaling rules (especially rule 3 mentioned previously).
Conﬂicting scale-up goals lead us to consider more sophisticated operating strategies at a large scale including programming impeller speed to change during thebatch operation. For example, begin the granulation with high impeller speed (constant Fr) to induce good dry powder turn over. This helps ensure good wetting andnucleation at the beginning of the batch when it is most important. Later, reducethe impeller speed to give a similar tip speed to smaller-scale operation to control
granule density or size. As the powder mass is now wet, it will be more cohesive andoperation above the critical Froude number for rolling ﬂow will be easier to maintain.
and Ennis (5) give a case study for scale-up of a lactose granulation that is useful for
illustrating these scaling rules and conﬂicts. It is represented in the next section.
6.4.1. Scale-Up of a Lactose Granulation from 25 to 300 L
A lactose-based granulation in a 25 L granulator has given granules with acceptableproperties. The operating conditions for the 25 L granulator are summarized asfollows:
Parameter
Nominal volume (L)Powder charge (kg)
Impeller speed (rpm)Spray time (min)Drop size (mm)eminWV& (m3/sec)
Spray width W (m)Powder surface velocity (m/sec)ca© 2005 by Taylor & Francis Group, LLC

Value
25
5
330
8
100
0.3
0.15
1.6  106
0.13
0.85
0.22

486

He et al.

The dimensionless spray ﬂux ca was calculated by
ca ¼

3V2&
2A&
2 dd

ð6:11Þ

This granulation is to be scaled to 300 L using the following rules and heuristics:
 Keep Fr constant Keep spray time constant Spray from a single nozzle at large scale.
How do ca and Stdef change on scale-up? What are the implications from granulation rate processes at full scale?
Scaling to 300 L granulation:
Assuming geometric similarity,
D2 =D1 ¼ 121=3
Keeping Fr constant,
N2 ¼ ðD1 =D2 Þ0:5 N1 ¼ 218 rpm
Assuming spray width scales with impeller diameter,
W2 ¼ ðD2 =D1 ÞW1 ¼ 0:3 m
powder surface velocity scales with tip speed,v2 ¼ ðD2 N2 =D1 N1 Þv1 ¼ 1:28 m=sec
Keeping spray time constant with one nozzle,
V2& ¼ 12V1&
Thus, the dimensionless spray ﬂux at 300 L isca;2 ¼

3V2&
3ð12V1& Þ¼¼ 3:41ca;1 ¼ 0:75
2W2 v2 d 2ð121=3 W1 Þ121=6 v1 d

There has been a substantial increase in ca on scale-up taking the granulationfrom nearly drop controlled into the mechanical dispersion regime. This could resultin a much broader granule size distribution at a large scale. A similar spray ﬂux
could be achieved by using an array of four nozzles spaced at 90 intervals aroundthe granulator (all positioned so the spray fan is at right angles to the direction of
powder ﬂow).
We cannot calculate the value of Stdef because the dynamic yield stress Y forthe lactose/binder system is not given. However, if we neglect changes in Y due tothe larger strain rate, then Stdef will increase as
Stdef;2 ¼

2Uc;2ðD2 N2 Þ2Uc;2

ðD1 N1 Þ2

Stdef;1 ¼
1

Stdef;1 ¼ 2:3Stdef;1

There is a signiﬁcant increase in Stdef with scale-up that could impact on
the granule density and maximum size. It is not possible to scale with constant© 2005 by Taylor & Francis Group, LLC

Scale-Up Considerations in Granulation

487

Stdef while simultaneously maintaining constant Fr. Scale-up summary data are
given in the following table:
Parameter
Nominal volume (L)Powder charge (kg)
Impeller speed (rpm)Spray time (min)Drop size (mm)eminWV& (m3/sec)
Spray width W (m)Powder surface velocity (m/sec)ca
Stdef/Stdef, 25 L

25 L

300 L

25
5
330
8
100
0.3
0.15
1.6  106
0.13
0.85
0.22
1

300
60
218
8
100
0.3
0.15
19.2  106
0.3
1.28
0.75
2.3

7. CONCLUDING REMARKS
Scaling of granulators using the traditional chemical engineering dimensional analysis approach of complete similarity is not possible due to the complexity of theprocess and the constraints on formulation changes during scaling pharmaceuticalprocesses. Nevertheless, scale-up using partial similarity that strives to keep somekey dimensionless groups invariant is possible. It is very important to understandthe powder ﬂow phenomena in the granulator of choice and to maintain the same
ﬂow regime during scaling (bubbling vs. slugging, bumping vs. roping).
The second important requirement is to maintain constant key dimensionlessgroups that control the important granulation rate process of most interest during
scale. This is somewhat easier to do in ﬂuidized beds than in high-shear mixers.
Very small-scale tests, which have no geometric similarity to pilot-and fullscale tests should be used to focus on formulation design and measurement of key
formulation properties that inﬂuence the granulation rate processes.
Insightful understanding of the granulation processes is essential for the identiﬁcation of key variables and parameters for the dimensional analysis and scale-up considerations. While development of deﬁnitive mathematical models for the granulation
processes is incomplete, the scaling approaches recommended in this chapter help
reduce uncertainty during new product development and transfer to industrial sites.
NOMENCLATURE
A&
dd
di
dp
db
Ddrum
D
Dc
DF

area ﬂux of powder through the spray zone
liquid drop size (diameter)
indentor diameterparticle or granule size
bubble size
drum granulator diameter
impeller diameter of mixer granulators
chopper diameter of mixer granulators
Fluidized bed diameter© 2005 by Taylor & Francis Group, LLC

488

Fr
g
H
Hm
L
Kc
M1, M2
m
N
Stdef
Smax
tp
u
u1
u2
umf,1
umf,2
ub
Uc
VR&
&
Vimp
Vmixer
V&
w
W
Y
m
rg
rG
rs
rl
y
gLV
d
o
oi
oc
ca
emin
etap

He et al.

Froude number
gravitational acceleration
hardness of granules
ﬁll height of mixer granulators
characteristic length of a ﬂuidized bed
fracture toughness of granules
mass of particles in the ﬂuidized bed
scaling ratio
impeller speed
Stokes deformation number
granule pore saturation
drop penetration timesuperﬁcial ﬂuidization velocity
ﬂuidization velocity on the smaller bed
ﬂuidization velocity on the larger bed
minimum ﬂuidization velocity on the smaller bed
minimum ﬂuidization velocity on the scaled bed
bubble rise velocity
particle collision velocity
relative swept volumerate of swept volume of impeller
mixer volume
volumetric spray rateliquid to solid mass ratio
spray zone width
dynamic yield stress of granules
viscosity of binder
granule density
density of ﬂuidizing gas
particle density
binder liquid density
solid liquid contact angle
liquid surface tension
dimensionless bubble space, deﬁned as the ratioof bubble space over bubble radius
drum peripheral speed
impeller peripheral speed
chopper peripheral speed
dimensionless spray ﬂux
minimum porosity of granulegranule bed tap density

REFERENCES
1. Hileman GA. Regulatory issues in granulation processes. Parikh DM, ed. Handbook of
Pharmaceutical Granulation Technology. New York: Marcel Dekker, Inc., 1997.
2. Skelly JP, et al. Scaleup of immediate release oral solid dosage forms. Pharm Res 1993;
10:2–29.
3. Zlokarnik M. Dimensional Analysis and Scale-up in Chemical Engineering. Berlin:
Springer-Verlag, 1991.
4. Munson BR, Young DF, Okiishi TH. Fundamentals of Fluid Mechanics. 2nd ed. New
York: John Wiley & Sons, Inc., 1994.
© 2005 by Taylor & Francis Group, LLC

Scale-Up Considerations in Granulation

489

5. Litster JD, Ennis B. The Science and Engineering of Granulation Processes. Dordrecht:
Kluwer Academic Publishers, 2004.
6. Hapgood KP, Litster JD, Smith R. AIChE J 2003; 49(2):350–361.
7. Iveson SM, Wauters PAL, Forrest S, Litster JD, Meesters GMH, Scarlett B. Powder
Technol 2001; 117(1,2):83–97.
8. Iveson SM, Beathe JA, Page NW. Powder Technol 2002; 127:149–161.
9. Ennis BJ, Tardos GI, Pfeffer R. Powder Technol 1991; 65:257.
10. Tardos GI, Irfran-Khan M, Mort PR. Powder Technol 1997; 95:245.
11. Evans AG, Wilshaw TR. Acta Metall 1976; 24:939.
12. Ennis BJ, Sunshine G. Tribol Int 1993; 26:319.
13. Kunii D, Levenspiel O. Fluidization Engineering. 2nd ed. Boston: ButterworthHeinemann, 1991.
14. Sanderson J, Rhodes M. Hydrodynamic similarity of solids motion and mixing inbubbling ﬂuidized beds. AIChE J 2003; 49:2317–2327.
15. Fitzgerald TJ, Crane SD. Cold ﬂuidized bed modelling. Proceedings of the International
Conference of Fluidized Bed Combustion. Vol. III. Technical Sessions, 1985:85–92.
16. Glicksman LR. Scaling relationships for ﬂuidized beds. Chem Eng Sci 1984; 39:1373–1379.
17. Glicksman LR. Scaling relationships for ﬂuidized beds. Chem Eng Sci 1987; 43:1419–1421.
18. Glicksman LR, Hyre M, Woloshun M. Simpliﬁed scaling relationships for ﬂuidized beds.
Powder Technol 1993; 77:177–199.
19. Horio M, Nonaka A, Sawa Y, Muchi I. A new similarity rule for ﬂuidized-bed scale-up.
AIChE J 1986; 32:1466–1482.
20. Horio M, Takada M, Ishida M, Tanaka N. The similarity rule of ﬂuidization and its
application to solid mixing and circulation control. Proceedings of Fluidization V.
New York: Engineering Foundation, 1986:151–156.
21. Roy R, Davidson JF. Similarity between gas-ﬂuidized beds at elevated temperature andpressure. Proceedings of Fluidization V. New York: Engineering Foundation, 1986:
293–299.
22. Steward PSB, Davidson JF. Powder Technol 1967; 6:61–80.
23. Werther J. Inﬂuence of the distributor design on bubble charcteristics in large diametergas ﬂuidized beds. Davidson JF, Keairns DL, eds. Fluidization. New York: Cambridge
University Press, 1978.
24. Litster JD, Hapgood KP, Kamineni SK, Hsu T, Sims A, Roberts M, Michaels J. Powder
Technol 2002; 124:272–280.
25. Schaefer T. Ph.D. thesis, The Royal Danish School of Phamacy, 1977.
26. Knight PC, Seville JPK, Wellm AB, Instone T. Chem Eng Sci 2001; 56:4457–4471.
27. Kristensen HG, Schaefer T. Drug Dev Ind Pharm 1987; 13:803.

© 2005 by Taylor & Francis Group, LLC

17
Sizing of Granulation
Gurvinder Singh Rekhi and Richard Sidwell
Elan Drug Delivery Inc., Gainesville, Georgia, U.S.A.

1. INTRODUCTION
Tablets are the most frequently administered solid oral dosage forms in contemporary
practice. Tablets consist of a mixture of powders or granules that are compacted in
the die of a tablet press. Even though the popularity of directly compressible materials
has increased, many powders are granulated to overcome the difﬁculties in obtaining
an acceptable tablet dosage form and meeting the product speciﬁcations. The mostchallenging task in a tableting process is to achieve a constant volume of homogenous
mixture to ﬂow into the tablet die cavity. Unfortunately, most powder materials do
not have inherent ﬂow properties. This, in turn, places demands on changing the physical characteristics of the powder or improving the design of the tablet press (1).
Therefore, granulation becomes an integral part of a pharmaceutical process that
attempts to improve powder ﬂow characteristics.
The granule properties play a pivotal role in the ﬁnal performance of a tablet;for example, granule size can affect the ﬂowability and, hence, the average tablet
weight and weight variation, and drying rate kinetics of wet granulations. The effectof granule size and size distribution on ﬁnal blend properties and tablet characteristics is dependent on formulation ingredients and their concentration, as well as thetype of granulating equipment and processing conditions employed. Therefore, granulation and sizing of granulation become critical unit operations in the manufactureof oral dosage forms (2,3). To some extent, the same requirements are necessary forcapsule manufacture, especially when the drug is bulky or has poor ﬂow properties,
or in the newer high-speed capsule-ﬁlling machines, where limited compaction occurs.
Few materials used in the manufacture of pharmaceutical dosage forms exist in
the optimum size, and most materials must be reduced in size at some stage during
production. The advantages of sizing of granules in tablet formulation development
are as follows:
1. Mixing and blending of pharmaceutical ingredients are easier and more uniform if the ingredients are of approximately the same size and distribution.
2. Improving color or active ingredient dispersion. Milling may reduce thetendency for mottling, and hence improve the uniformity of color frombatch to batch.
491© 2005 by Taylor & Francis Group, LLC

492

Rekhi and Sidwell

3. Wet milling produces uniformly sized wet granules, which promotes
uniform and efﬁcient drying.
4. Improving uniformity of dosage units by virtue of uniformity of particle
size distribution and reduction in the segregation of the mix.
5. Enhancing ﬂow properties reduces the weight variation and improvescontent uniformity.
6. Increasing surface area due to particle size reduction may enhance thedissolution rate and thereby, the drug’s bioavailability.
7. Reduction of dust, thereby reducing workers’ exposure.
Size reduction alone is not the panacea for all tableting problems. There aresome disadvantages to size reduction that may affect the ﬁnal characteristics of adosage form, such as degradation of the drug or a change in the polymorphic form
as a result of the excessive heat generated, or increase in surface energies leading toagglomeration, and so on. Hence, in optimizing the manufacture of pharmaceutical
dosage forms, it is important not only to characterize the formulation ingredients,
but also to study their effect on the manufacturing process (i.e., whether a granulation should be milled and to what extent based on the ﬁnal product speciﬁcations).
The objective of this discussion is to focus on sizing of granulation after drying
in a wet granulation process. However, a process of wet milling for obtaining uniformly sized granules for uniform drying will also be addressed. A full discussionof the theories of comminution or equipment description is beyond the scope of thischapter. However, the text of this chapter will address the various types of equipment used in the size reduction process, their merits and demerits and the variables
affecting the size reduction process, scale-up factors, and relevant case studies to beconsidered in the development and optimization of tablet and capsule manufacture.
2. THEORY OF COMMINUTION OR SIZE REDUCTION
Comminution, or size reduction, is the mechanical process of reducing the size ofparticles or aggregates. There is, as yet, only a basic understanding of the mechanismand quantitative aspects of milling (4,5). Reduction of particle size through fracture
requires application of mechanical stress to the material to be crushed or ground.
Materials respond to this stress by yielding, with consequent generation of strain.
In the case of a brittle substance, complete rebound occurs on release of appliedstress at stresses up to the yield point, at which fracture would occur. In contrast,
plastic material would neither rebound nor fracture. The vast majority of pharmaceutical solids lie somewhere between these extremes and thus possess both elastic
and viscous properties.
The energy expended by comminution ultimately appears as surface energy
associated with newly created particle surfaces, internal free energy associated withlattice changes, and heat. For any particle, there is a minimum energy required which
will fracture it; however, conditions are so haphazard that many particles receive
impacts that are insufﬁcient for fracture, and are eventually fractured by excessively
forceful impact. As a result, most efﬁcient mills use <1–2% of the energy input tofracture particles and to create new surfaces. The rest of the energy is dissipatedin the form of heat from the plastic deformation of the particles that are not fractured, by friction, and in imparting kinetic energy to the particles. The greater therate at which the force is applied, the less effectively the energy is utilized, and thehigher is the proportion of ﬁne material produced.
© 2005 by Taylor & Francis Group, LLC

Sizing of Granulation

493

A ﬂaw in a particle is any structural weakness that may develop into a crack
under strain. The Grifﬁth theory (4) of cracks and ﬂaws assumes that all solids contain ﬂaws and microscopic cracks, which increase as the applied force increases,
according to the crack length and focus of the stress at the crack apex.
A granule is an aggregation of particles that are held together by bonds of ﬁnite
strength, and the ultimate strength of a wet granule depends on the surface tension of
the granulating liquid and capillary forces. After drying, granules develop stronger
bonds owing to fusion and recrystallization of particles, and curing of adhesives orbinding agent. The ﬁnal strength of a granule depends on the base material, the type
and the amount of granulating agent used, and the granulating equipment employed.
A granule or particle may be subjected to one or more of the following four
forces during milling:
1.
2.
3.
4.

Shear (cutting forces)
Compression (crushing force)
Impaction (the direct, high-velocity collision force)
Tension (the force that works to elongate or pull a particle apart)

The mechanism by which sizing of dried granules occurs is similar to that of
crystalline materials. Cleavage occurs at the weakest point or points in the granuleand it could be at (2):
1. the binder–particle interface
2. the bridge of binder between the individual ingredient particles being
granulated
3. ﬂaws in the individual ingredient particles within the granules, or
4. a combination of any of these.
Granules held together with lower binding strength agents such as povidone
will require less severe grinding conditions because the fractures take place primarily
at the binder bridge or the binder–particle interface.
Although the milling process can be described mathematically (6–8), its theory
has not been developed to the point at which the actual performance of a mill can bepredicted quantitatively. Three fundamental laws (Kick’s Law, Rittinger’s Law, andBond’s Law) have been proposed to relate size reduction to a single variable, theenergy input to the mill. None of the energy laws apply well in practice (9). Generally, laboratory testing is required to evaluate the performance of a particular pieceof equipment; however, a work index and grindability index have been used to evaluate the mill performance (5). The efﬁciency of milling process is inﬂuenced by thenature of the force, as well as by its magnitude. The rate of application of force
affects comminution because there is a lag time between the attainment of maximum
force and fracture. Often, materials respond as a brittle material to fast impact, andas a plastic material to a slow force.

3. PROPERTIES OF FEED MATERIALS AFFECTINGTHE SIZING PROCESSThe milling or sizing process is affected by a variety of factors and has a direct effecton the quality of the ﬁnal product. The properties of feed material and the ﬁnishedproduct speciﬁcations determine the choice of equipment to be used for the processof comminution. The properties of feed material include melting point, brittleness,© 2005 by Taylor & Francis Group, LLC

494

Rekhi and Sidwell

hardness, and moisture content. The desired particle size, shape, and size distribution
must also be considered in the selection of milling equipment.
Materials can be classiﬁed as hard, intermediate, soft, or ﬁbrous materials (e.g.,
glycyrrhiza and rauwolﬁa) based on Moh’s Scale. Fibrous materials require cutting
or chopping action and usually cannot be reduced in size effectively by pressure or
impact techniques. Before selecting and optimizing a size reduction process one
needs to know the properties of the material and the characteristics of a mill. The
important material properties (5,10) are as follows:
1. Toughness: The material’s resistance to the propagation of cracks. Reduction of the particle size of tough material is difﬁcult, but can sometimes
be made easier by cooling the material, thereby diminishing its tendency
to exhibit plastic ﬂow, and making it more brittle.
2. Brittleness: The opposite of toughness. Size reduction poses no problems
except if the amount of ﬁnes is to be controlled.
3. Abrasiveness: This is an important factor because abrasive materials canwear mill parts and screens; hence, metal contamination may be a problem.
4. Cohesive/adhesiveness: Particles sticking together or to machine surfaces
are often dependent on moisture content and particle size. Problems withmoisture content can be mitigated by drying the material or avoided byusing a wet size reduction process.
5. Melting point: This is critical because considerable heat is generated insize reduction. High temperatures generated can cause melting of thedrug, blinding of screen, or can degrade heat-sensitive materials.
6. Agglomeration tendency: This tendency can be counteracted by drying thematerial, either before or during the size reduction operation. In somecases, mixing with other ingredients during milling might be helpful. Generally, materials having a strong tendency to agglomerate are wetted
prior to milling.
7. Moisture content: A moisture content above 5% can often lead to agglomeration or even liquefaction of the milled material. Hydrates will often
release their water of hydration under high temperatures and may requirecooling or low-speed milling.
8. Flammability and explosiveness: A measure of how readily a material will
ignite or explode. Explosive materials must be processed in an inert-gas
atmosphere.
9. Toxicity: This has little inﬂuence on the selection of the mill itself; however, it must be considered in determining operator safety, containment,
and setup for this type of material.
10. Reactivity: The possibility of materials chemically reacting with the materials of construction of the mill (including liners and gaskets) and cleaning solutions must be considered.
4. CRITERIA FOR SELECTION OF A MILL
The selection of equipment is determined by the characteristics of the material, theinitial particle size, and the degree of the desired size of the milled product, thatis, coarse, medium, or ﬁne.
The criteria for selection of a mill include the following (4):© 2005 by Taylor & Francis Group, LLC

Sizing of Granulation

495

1. Properties of feed material: Size, shape, moisture content, physical andchemical properties, temperature sensitivity, grindability, and material
compatibility
2. Product speciﬁcations: Size, particle size distribution, shape
3. Versatility of operation: Wet and dry milling, rapid change of speed andscreen, safety features
4. Scale-up: Capacity of the mill and production rate requirements
5. Repeatability: Ability to meter material to the mill to insure consistentprocess
6. Dust control: Loss of costly drugs, health hazards, contamination
7. Sanitation: Ease of cleaning (clean in place, CIP) and sterilization (sterilization in place, SIP)
8. Auxiliary equipment: Cooling system, dust collectors, forced feeding,stage reduction
9. Batch or continuous operation
10. Economic factors: Equipment cost, power consumption, space occupied,labor cost
After consideration of the foregoing factors for a speciﬁc milling problem, it issuggested that a variety of mills should be evaluated for optimum product results
such as shape of granules and/or scalability from laboratory to production. In addition to the standard adjustments of the milling process (e.g., screen, speed, rotor
design, feed rate), other techniques of milling may be considered for special materials.
Hygroscopic materials can be milled in a closed system supplied with dehumidiﬁed
air. As the bulk of the energy used in milling is converted into heat, heat-sensitive
materials, or hard materials that build up in the milling chamber may melt, decompose, or explode. A two- or multistep milling process can be used for harder and difﬁcult-to-grind materials. Materials can be milled using a coarser screen, and thematerial can then be recycled by screening the discharge and returning the oversizedmaterial for a second milling (closed circuit mill). Alternatively, one may chill the air
or gas (carbon dioxide or nitrogen) that transports the product, cool the product prior
to processing, or cool the comminuting chamber through which the product passes. A
chiller is necessary for all of these options and will add to the cost of processing (11). If
this not sufﬁcient to embrittle the material, it may be fed to the mill simultaneouslywith dry ice.

5. CLASSIFICATION OF MILLSThe majority of size reduction equipment may be classiﬁed according to the way inwhich forces are applied; namely, impact, shear, attrition, and shear-compression(Table 1). A given mill may operate successfully in more than one class: a hammer
mill may be used to prepare a 16-mesh granulation and to mill a crystalline material
to a 120-mesh powder. The mills used for size reduction of the granules can bedivided into two primary categories based on the energy input into the process. Even
though there are several high-energy mills available for size reduction, only a few areused in the pharmaceutical industry for the wet or dry sizing process. Milling is anextremely inefﬁcient unit operation with only 1–2% of the applied energy being
utilized in the actual size reduction. Milling efﬁciency is dependent on the characteristics of the material used and the type of mill employed.
© 2005 by Taylor & Francis Group, LLC

496

Table 1 General Characteristics of Various Types of Mills
Mechanism ofactionExampleProduct size

Type of material

Not used for

ImpactHammer millModerate to ﬁne

Brittle and dry material

Fibrous, sticky, low-melting
substances

Shear

Extruder and hand
screenCoarseDeagglomeration, wetgranulation

Dry material, hard, abrasive
materials

Attrition

Oscillating granulator

Coarse to moderate

Dried granulation

Wet granulation, abrasive
materials

Shear-compression

Conical screening millModerate to coarse

Wet, dry granulation

Abrasive materials

Rekhi and Sidwell© 2005 by Taylor & Francis Group, LLC

Sizing of Granulation

497

5.1. Low-Energy Mills
5.1.1. Hand Screen Size reduction occurs primarily by shear.
 They are made of brass or stainless steel and consist of a woven wire cloth
stretched in a circular or rectangular frame.
 They are available in sizes ranging from 4 to 325 mesh; however, for granulation, primarily mesh sizes from 4 to 20 are used.
 They are most widely used for sieve analysis or for size reduction of wet anddry granules in the early stages of formulation development.
5.1.2. Oscillating/Rotary Granulator
 They consist of an oscillating bar contacting a woven wire screen, and thematerial is forced through the screen by the oscillating-rotary motion of thebar (Figs. 1A and B).
 Size reduction is primarily by shear with some attrition
 Speed, rotary or oscillatory motion, and screen size are important variables
to be considered during the sizing process.
 They are used primarily for size reduction of wet and dry granulations and,to some extent, for milling tablets and compacts that must be reprocessed.
 The narrow size distribution and minimum amount of ﬁnes are advantages
during the size reduction of dry granulation (2).
 Heat-sensitive and waxy materials can be milled owing to the low heatgenerated during the sizing process.
 Low throughput rates and possible metal contamination from wearing
down or broken screen are some of its limitations.
5.1.3. Extruder
 It is primarily used for continuous wet granulation.

Figure 1 Oscillating granulator: (A) Frewitt MF line and (B) rotor, screen, and tensioning
spindles.
© 2005 by Taylor & Francis Group, LLC

498

Rekhi and Sidwell Wet material is forced through a screen and the extruded material is dried in a
tray or ﬂuid bed dryer or can be spheronized to produce granules with a highdegree of sphericity and then dried for controlled-release applications.
 Less dust generation and more uniform granules are some of the advantages.
 More information on extrusion may be found in Chapter 11.

5.2. High-Energy Mills
5.2.1. Hammer MillThe hammer mill is one of the most versatile and widely used mills in the pharmaceutical industry. The principle of size reduction in the hammer mill is one ofhigh-velocity impact between the rapidly moving hammers mounted on a rotor
and the powder particles (Figs. 2A and B). These mills can produce a wide rangeof particle sizes, even down to micrometer size. The particle shape, however, isgenerally sharper and more irregular than that produced by compression methods(5). The force imparted by the hammers and the screen opening size and shape control the degree of particle size reduction.
 They can be used for size reduction of wet or dry granulations and millingof raw materials.
 There is a wide range of interchangeable feed throats and variable feedscrew systems available to optimize the feed rate (12).
 Hammers can rotate horizontally or vertically, based on the rotor conﬁguration, and at variable speeds.
 Hammers can be ﬁxed or free-swinging.
 Hammers with blunt or impact edges are preferred for pulverizing and knife
or sharp edges are preferred for chopping or sizing of granules (12).
 Screen openings generally vary from 0.3 to 38 mm, with round or square
perforations, diagonal or straight slots, or with a rasping surface.
 Feed rate and dryness of the granules are important variables relative to thematerial.
 Type of hammers, rotor speed, screen type, thickness, and opening size areimportant variables relative to the machine.

Figure 2 Hammer mill: (A) Fitzmill model L1A and (B) principle of operation.
© 2005 by Taylor & Francis Group, LLC

Sizing of Granulation499

 Ease of setup, clean-up, minimum scale-up problems, and ability to handle
a wide variety of size and type of feedstock are some advantages.
 Heat buildup, screen wear, and potential clogging of screens are some of thelimitations.
 Integrated designs are available for dust containment.
 Examples include the Granumill and Fitzmill.
5.2.2. Conical Screening Mill
 It is effective for dry (deagglomeration–delumping) and wet milling of soft
to medium hard materials.
 The comminution chamber consists of an impeller rotating at variable
speed, imparting a compression or shear force inside a conical screen.
 The impeller imparts a vortex ﬂow pattern to the feed material, and the centrifugal acceleration forces the particles to the screen surface and up thecone (360 ) in a spiraling path (13) (Figs. 3A and B).
 The space between the impeller and the screen can be adjusted.
 The size and shape of the screen holes, screen thickness, impeller conﬁguration, and mill speed are important variables.
 It is used for difﬁcult-to-mill, heat-sensitive material and hard granules.
 Low heat and lower amounts of ﬁnes are produced compared with the hammer mill; hence, it produces a narrower particle size distribution.
 The impeller does not touch the screen; hence, chances of screen breakage
and metal contamination are greatly reduced compared with an oscillating
granulator.
 The dual action of conical screening mills (size reduction and mixing)
makes this equipment more desirable than the use of traditional oscillators(14,15).
 Integrated designs are available that are attached to a high-shear granulator
discharge, which provides a deagglomerated, lump-free product for thedryer (Fig. 4).
 Examples include the Comil, Glatt sieve GS or GSF, and FitzSiv.
5.2.3. Centrifugal-Impact Mills
Centrifugal-impact mills and sieves are useful to minimize the production of ﬁne particles, because their design combines sieving and milling into a single operation.
Unlike the conical screening mills, these consist of a nonrotating bar or stator which
is ﬁxed within a rotating sieve basket. This action produces a very low product agitation and impact; hence, no heat is generated. The particles that are smaller than theholes of the sieve can pass through the mill without comminution; however, the larger particles are directed by centrifugal force to impact the stator. Older designs are
not preferred because the likelihood of sieve-to-stator contact can result in metal
particulates in the product. Newer designs eliminate metal-to-metal contact. The
Frewitt SG line (Figure 5) is an example of this type.

6. WET MILLING
The discussion so far has been focused on dry milling. These mills can also be used
for wet milling or coarse milling. There are several reasons for wet milling, including
the following (16):© 2005 by Taylor & Francis Group, LLC

500

Rekhi and Sidwell

Figure 3 Conical-screening mill: (A) Glatt model GSF 180 and (B) principle of operation.

1.
2.
3.
4.
5.

To increase surface area for more efﬁcient drying
To improve size uniformity
To improve granule formation
To prevent large particles that will shatter to ‘‘ﬁnes’’ on dry milling
For further mixing or blending because ingredients are approximately of
the same size

As discussed for low-shear mills, extruders can be used as a continuous wet granulation method. Wet milling is necessary with low-shear mixers, such as planetary, ribbon, or sigma mixers, but with high-shear mixers, the combination of high impeller
speed and built-in choppers produces a product ready for drying. Also, integrated
designs are available such that the wet milling step in no longer a separate operation.
© 2005 by Taylor & Francis Group, LLC

Sizing of Granulation

501

Figure 4 An integrated pharmaceutical manufacturing facility (high-shear granulator–
conical screening mill–ﬂuid bed drier).

Figure 5 Centrifugal-impact mill: Frewitt SG Line.
© 2005 by Taylor & Francis Group, LLC

502

Rekhi and Sidwell

Finally, there are continuous granulators available (M6 NICA granulator) for
product applications that do not require extensive kneading treatment, and can beused for both batch and continuous operation. The wetted product is discharged
in continuous stream through an adjustable opening in the turbine cover. A homogenous mix is produced in a few minutes and further milling may not be necessary.

7. VARIABLES AFFECTING THE SIZING PROCESS
7.1. Process Variables
As discussed in the introduction, the granule properties can dictate the properties of
the ﬁnal tablet. Some of the problems faced during the tableting process are ﬂow of
granules, maintaining uniform density in the granule bed, and the particle size
distribution. Each of the stages of the granulation can be critical and can affecttableting. In addition to the wet granulation process, the sizing process can be critical
for the particle size distribution that, along with the amount of ﬁnes, dictates theﬂow properties. These, in turn, inﬂuence the packing and density of the granules.
Reproducibility of batches depends not only on the properties of the unmilled dry
granules, but also on the mill and milling parameters. Finally, the dry-milling stage
is important because of the excessive heat generated that might affect the stability of
the ﬁnal product.
The characteristics of the granules after size reduction depend mainly on thetype of mill, impeller type and speed, screen size, and thickness.
7.2. Type of Mill
The type of mill chosen can affect the shape of the granules and throughput. The
shape of the milled granules can affect the ﬂow properties. An impact mill produces
sharp, irregular particles that may not ﬂow readily, whereas an attrition mill produces free-ﬂowing spheroidal particles. An oscillating granulator uses shear andattrition as the main mechanisms for size reduction. The granules produced are more
spheroidal, because size reduction takes place by surface erosion. If the same material is subjected to impact by hammers in a hammer mill, the granules will shatterand cause irregularly shaped granules. If a conical screening mill is used for the samematerial for size reduction, it imparts some shear and some compression between therotating impeller and the screen.
7.2.1. Hammer Mill
There are a number of variables in a hammer mill that can inﬂuence comminution(12,17–19). The following section discusses ﬁve operating variables in detail:1. Rotor shaft conﬁguration: The hammers may be mounted on a vertical or
horizontal shaft (Figs. 6A and B). The vertical shaft mills (Stokes-Tornadomill) have feed inlets at the top and material is fed perpendicular to theswing of the hammers. In the case of horizontal shaft mills (Fitzpatrick–Fitzmill), the material is fed tangentially to the hammer swing. Rotor conﬁguration can inﬂuence the particle size distribution of granules. In the vertical conﬁguration, the screen is placed 360 around the hammers and thisprovides more screen open area and less time for the granules to stay in the
milling chamber when compared with the horizontal shaft mills.
© 2005 by Taylor & Francis Group, LLC

Sizing of Granulation

503

Figure 6 Different types of hammer mills: (A) vertical shaft (B) horizontal shaft.

2. Material feed rate: The feed rate controls the amount of the feed material
that enters the comminutor and prevents overfeeding (slugging) or underfeeding (starving) in the milling chamber. Although both affect the particle
size distribution, overfeeding is relatively more detrimental. If the rate offeed is relatively slow, the product is discharged readily, and the amountof undersize material, or ﬁnes, is minimized. On the other hand, overfedmaterial stays in the milling chamber for a longer time, because its
discharge is impeded by the mass of material. This leads to a greater reduction of particle size, overloads the motor, and the capacity of the mill is
reduced. The rule of thumb is to keep the feed rate equal to the rate ofdischarge. The feed rate can be controlled using variable-feed screws,
vibratory feeders, or dischargers controlled by gravity. In addition to controlling the ﬂow, the feed throat must allow the material to enter at aproper angle. There are more than 50 feed throat designs available that
one needs to consider for optimizing the milling process. Most mills usedin the pharmaceutical operations are designed so that the force of gravity
is sufﬁcient to give free discharge, generally from the bottom of the mill.
3. Blade type: Comminution is effected by the impact of the material with thefast moving blades and attrition with the screen. Generally, the blades of ahammer mill have a blunt or ﬂat edge on one side and a sharp or knife-edgeon the other side. The desired particle size range determines which blades
to use. Many models of hammer mills have a rotor that may be turned
180 , so that the blunt edges can be used for ﬁne grinding or the knife-edge
can be used for cutting or granulating. The blunt edge offers the surface
and the impact during milling, generating smaller granules. The knife-edge,
because the sharper edge causes cutting of the granules, thereby generates
larger granules. Individual blades—blunt, sharp, or reversible—are
installed either ﬁxed or swinging (Fig. 7A–C). Fixed blades plough throughthe material being ground, while swinging blades lie back and depend on
the centrifugal force for movement. Fixed blades are preferred over swinging blades because they are easier to clean, and work better than swinging
blades at low rotor speeds, when grinding ﬁbrous material or if carefully© 2005 by Taylor & Francis Group, LLC

504

Rekhi and Sidwell

Figure 7 Different types of hammer mill rotors (Fitzmill): (A) cast rotor, (B) bar rotor and(C) swing-blade rotor.

controlled grinding is needed. The material to be ground determines the
conﬁguration of the blades on the motor shaft, as well as the blade density.
The shape of the blades (straight, stepped, sickle, or other) is largely a matter of designer preference; little empirical evidence exists to establish thesuperiority of one shape over another. The size of the grinding chamber
generally determines the number of blades (e.g., a 6 in. grinding chamber
will have 16 blades).
4. Rotor speed: The size of the product is markedly affected by the speed of thehammers. As a general rule, and with all other variables remaining constant,the faster the rotor’s speed, the ﬁner the grind. Usually, three speed settings
are available: slow (1000 rpm), medium (2500 rpm), and fast (4000 rpm).
Changes in rotor speed are accomplished by variable-speed drive, or bymanually changing the hammer drive and motor pulley ratio. Rotor speedsof 2500–4000 rpm are typically used with blunt edges in ﬁne grinding applications, whereas speeds of 1000–2500 rpm are typically used with knifeedges for coarse grinding. Particle size distributions are wider at low speed
than at medium and high speeds (12). Below the critical rotor speed, the© 2005 by Taylor & Francis Group, LLC

Sizing of Granulation

505

material experiences attrition, rather than impact action, which causes
more spheroidal granules and may result in overheating of the material.
5. Screen size and type: The screen is usually an integral part of the hammer
mill and does not act as a sieve. The particle size of the product depends
on the openings in the screen, the thickness of the screen, and the speedof the hammer. The particle size of the output granules will be much smaller
than the size of the screen used, because particles exit at an angle, with highvelocity.
Screens can be perforated, woven wire type, or with a slot conﬁguration. The
screen openings may range in size and open area based on screen conﬁguration.
Because of the large forces that the screens are subjected to, the perforated screensare preferred over the woven-type screens. However, if the raw material fuses fromthe heat generated, or if the material is difﬁcult to mill, woven-type screens are
preferred for their increased open area. The herringbone design and cross-slot are
preferred for grinding amorphous and crystalline materials (Fig. 8).
7.2.2. Conical Screening Mill
Similarly, for conical screening mills, the operating variables affecting particle size
distribution are type of impeller, impeller speed, and screen size and type:
1. Material feed rate: In contrast to hammer mills, conical screening mills perform with greater efﬁciency when the comminution chamber is kept relatively full. Underfeeding results in low efﬁciency and reduced throughput.
2. Impeller: There are several types of impellers available (13); however, thefour main types used frequently are as follows (Fig. 9A).
Knife-edge: Its principle mode of operation is shear, and hence, it is used forcompression-sensitive, heat-sensitive materials.
Round-edge: Its principle mode of operation is compression, and it provides
high throughput and low retention. It is mainly used for wet or dry deagglomeration–delumping.

Figure 8 Different types of hammer mill screens.
© 2005 by Taylor & Francis Group, LLC

506

Rekhi and Sidwell

Figure 9 Conical screening mill (Comil): (A) impellers and (B) screens.

Round-edge with teeth: It is the same as the round-edge impeller except thatit has teeth on one side, providing aggressive, high throughput. It reducesﬁnes in milling compacted materials by prebreaking with teeth and reducing retention time. It is often used for tablet rework.
Knife-edge low-intensity impeller: It is used where a shear or cut is required;it gives a scissor-like action, for ﬁbrous materials or capsule rework.
3. Speed: The speed of the impeller can affect the particle size of the product.
Conical screening mills available have variable- or ﬁxed-speed drives, however, the number of revolutions per minute vary depending on the size ofthe impeller. It is suggested that one keep the tip speed of the impeller
the same on scale-up to achieve the same particle size distribution.
4. Screen size and type: Screens are available in various sizes (Fig. 9B), basedon thickness, open area, and hole conﬁguration such as round, square,slotted, and grater-type openings. Only perforated screens are available.

Various researchers have performed extensive studies of the effects of the foregoing variables on granulation and milling processes (20–22). Motzi et al. (21), basedon their observations of signiﬁcant interaction effects, concluded that effects of mill
speed, screen size, and impeller shape on particle size distribution cannot be evaluated individually, but must be evaluated at a level that is a combination of all three.
7.2.3. Hybrid Designs
Hybrid designs, such as the Granumill (Fig. 10A and B), are now available which
utilize a one-piece cantilever rotor with heavy blades mounted parallel to the center© 2005 by Taylor & Francis Group, LLC

Sizing of Granulation

507

Figure 10 Hybrid design: (A) Granumill and (B) detail of Granumill rotor and screen.

shaft. Incorporating a variable-speed drive, these mills operate as screening mills
when run at low speed, and as impact mills when run at high speed.
7.3. Other Variables
There are other variables that can affect the sizing process, such as feed material properties, granulation process, and drying process. The properties of materials have been
discussed in Section 3. The type of granulation [i.e., dry (roller compaction), planetary, high-shear, or ﬂuid-bed] can determine the strength of the granules and, hence,the sizing process. Furthermore, the drying process, whether tray or ﬂuid-bed, canalso be important. Tray-dried granules are usually case hardened and difﬁcult to mill,
whereas the ﬂuid-bed process yields more porous and friable granules. Similarly,
granules produced by high-shear granulators are harder and are therefore more difﬁcult to mill than those manufactured using low-shear or ﬂuid-bed processes.

8. SCALE-UP
8.1. Hammer Mill
Table 2 shows the various sizes of Fitzmills available (12). In addition to having thesame screen size and type used on the lower scale, keeping the rotor tip speed constant is one of the most important considerations in scale-up of a milling process.
Vertical and horizontal rotor conﬁgurations may affect throughput and also particle
size distribution.
8.2. Conical Screening Mill
Table 3 shows the scale-up parameters for various Comils (13). In addition to having
the same impeller type, screen size, and screen type used on the lower scale, the tip© 2005 by Taylor & Francis Group, LLC

508

Table 2 Scale-up Parameters for Fitzmill
ChamberModel
Homoloid
M5A
D6A
DAS06

Rotor

CapacityafactorNominalwidth

Screen area(in.2)

Diameter ofchamber

0.4
0.7
1.0
1.0

2.5
4.5
6.0
6.0

43.0
76.0
109.0
109.0

6.625
8.0
10.5
10.5

Rotor
conﬁguration
Horizontal
Horizontal
Horizontal
Horizontal

No. ofbladesTip speedfactorb

Maximumrpm

Maximumhorsepower

12
16
16
16

1.73
2.09
2.75
2.75

7200
4600
4600
4600

10.0
3.0
5.0
15.0

a

Throughput relative to Model D6 at the same tip speed.
Tip speed ¼ factor  operating speed.
Source: From Ref. 12.
b

Table 3 Scale-up Parameters for Comil

Model

Impellerdiameter
(in.)

A

B

C

1
5
10
20
40

4.375
7.625
11.12523.25029.469

5
8
12
24
30

1.5
2.5
4
16
16

3
5
7
7
12

Impeller speed scale-up comparison (rpm)
1200
700
450
225
180
1400

a
A, screen upper diameter; B, screen lower diameter; C, screen height.
Source: From Ref. 13.

© 2005 by Taylor & Francis Group, LLC

2400
1400
900
450
360
2800

3600
2100
1350
675
540
4200

4800
2800
1800
900
—
5600

6000
3500
2250
—
—
7000

7200
4200
2700
—
—
8400

—
5600
3600
—
—
11,200Motorhorsepower

Infeed opening (in.)

1 or 25
10 or 15
20
30

3 Round
6 Round
8 Round
11  22 Rectangular
12  24 Rectangular

Rekhi and Sidwell

197
194
196
198
199
Tip speed(ft/min)

Screen size (in.)a

CapacityfactorSizing of Granulation509

speed of the impeller is one of the key variables in scale-up; thus, it should be kept
constant.
9. CASE STUDIES
9.1. Comparison of Fitzmill vs. Comil
It is often difﬁcult to predict the results from similar pieces of equipment having thesame operating principle at two different scales, let alone using two pieces of equipment having different operating principles. Many times in the development of a pharmaceutical dosage form the equipment used during formulation development andthat used in production are quite different. Apelian et al. (22) studied the effect of particle size distribution on chlorpheniramine maleate granules using a Fitzmill and
Comil. For the Fitzmill, various screens sizes (1, 2, 3, and so on) at medium speed
were evaluated, and for the Comil, impellers (1601 and 1607) at two speeds (1680
and 3420 rpm) using various screen sizes (039, 045, 055, and 055G) were studied. They
reported that milling the granulation using a Fitzmill with a screen size of 2, at medium speed, gave a particle size distribution similar to the granulation milled using a
Comil (1601 impeller, 055 screen at 1680 rpm) (Fig. 11). The results of this study suggest that in making a major change in the milling process, one needs to optimize thecritical processing variables in order to achieve a similar particle size distribution.
9.2. Comparison of Hand Screen vs. Comil
The effect of changing the dry milling from a hand screen operation to a conicalscreening mill is shown in Figure 12. Naproxen granulations (0.5 and 4 kg) were

Figure 11 Particle size distribution of chlorpheniramine maleate granulations milled using
FitzMill and Comil.
© 2005 by Taylor & Francis Group, LLC

510

Rekhi and Sidwell

Figure 12 Particle size distribution of naproxen granulations milled using hand screen and
Comil.

manufactured in a ﬂuid-bed granulator using PVP K-90 as a binder (23). The particle
size distribution of granules (0.5 kg), passed manually through an 18-mesh screen,
was much coarser than that of the granules (4 kg) that were milled using a Comil(Model 197S). A ﬂat-faced impeller (1607) at an impeller speed of 2500 rpm with aspacer setting of 0.25 in. and screen number 2A055 (14-mesh) were used for the
milling operation. Even though the granulations were prepared by the same procedure, the milling conditions drastically affected the particle size distribution. As ageneral rule, during a switch over from a low-energy milling operation to a highenergy milling operation the screen size should be coarser in the high-energy mill.
The particle velocity is higher and therefore the size of the granule exiting out of
the screen is much smaller than the screen opening. As seen from Figure 12, when
the screen size was increased to 14-mesh for the conical-screening mill, the amountof ﬁnes generated was higher. Hence, during scale-up, optimization of milling conditions may be necessary to achieve the same particle size distribution.

10. LIST OF EQUIPMENT SUPPLIERS
1. The Fitzpatrick Company, 832 Industrial Drive, Elmhurst, IL 60126, USA;www.ﬁtzmill.com
2. Fluid Air, Inc., 2550 White Oak Circle, Aurora, IL 60504, USA;
www.ﬂuidairinc.com
3. Frewitt Ltd., P.O. Box 61, CH-1706 Fribourg, Switzerland;
www.frewitt.com
4. Glatt Air Techniques Inc., 20 Spear Road, Ramsey, NJ 07446, USA;www.glattair.com© 2005 by Taylor & Francis Group, LLC

Sizing of Granulation

511

5. Niro, Inc., 9165 Rumsey Road, Columbia, MD 21045, USA;www.niro.com
6. Quadro Inc., 55 Bleeker Street, Millburn, NJ 07041, USA;
www.quadro.com
7. Vector Corporation, 675 44th Street, Marion, IO 52302, USA;www.vectorcorporation.com
ACKNOWLEDGMENTS
The authors would like to thank Dr. Murali K. Vuppala of Praecis Pharmaceuticals
Inc. for coauthorship of the ﬁrst edition of this chapter, Mr. Scott Wennestrum fromThe Fitzpatrick Company, Mr. John Bender from Fluid Air, Inc., Mr. David Adams
and Mr. Patrick Arthur from Quadro, Inc., and Mr. Jeff Montross from Glatt Air
Techniques, Inc. for providing the photographs shown in this chapter.

REFERENCES
1. Prescott JK, Hossfeld RJ. Maintaining product uniformity and uninterrupted ﬂow to
direct-compression tableting presses. Pharm Tech 1994; 18:98–114.
2. Lantz RJ Jr. Size reduction. In: Lieberman HA, Lachman L, Schwartz JB, eds. Pharmaceutical Dosage Forms: Tablets. Vol. 2. New York: Marcel Dekker, Inc., 1990:107–157.
3. Fonner DE, Anderson NR, Banker GS. Granulation and tablet characteristics.
Lieberman HA, Lachman L, eds. Pharmaceutical Dosage Forms: Tablets. Vol. 2. New
York: Marcel Dekker, Inc., 1981:201.
4. Parrot EL. Milling. Lachman L, Lieberman HA, Kanig JL, eds. The Theory and Practiceof Industrial Pharmacy. Philadelphia: Lea & Febiger, 1986:21–46.
5. O’Conner RE, Rippie ED, Schwartz JB. Powders. Gennaro AR, ed. Remington’s Pharmaceutical Sciences. Easton, PA: Mack Publishing Company, 1990:1615–1617.
6. Carstensen JT, Puisieux F, Mehta A, Zoglio MA. Milling kinetics of granules. Int
J Pharm 1978; 1:65–70.
7. Steiner G, Patel M, Carstensen JT. Effect of milling on granulation particle—size distribution. J Pharm Sci 1974; 63:1395–1398.
8. Motzi JJ, Anderson NR. The quantitative evaluation of a granulation milling process.
III. Prediction of output particle size. Drug Dev Ind Pharm 1984; 10:915–928.
9. Snow RH, Kaye BH, Capes CE, Sresty GC. Size reduction and size enlargement.
Perry RH, Green D, eds. Perry’s Chemical Engineers’ Handbook. New York:
McGraw-Hill Inc., 1984:8-9–8-20.
10. Prior MH, Prem H, Rhodes MJ. Size reduction. Rhodes MJ, ed. Principles of Powder
Technology. New York: John Wiley & Sons, 1990:237–240.
11. Kukla RJ. Strategies for processing heat-sensitive materials. Powder Bulk Eng 1988;
2:35–43.
12. FitzMill Technical Bulletin. The Fitzpatrick Company, Elmhurst, IL.
13. Quadro Inc., CoMil Product Literature, Millburn, NJ .
14. Poska RP, Hill TR, van Schaik JW. The use of statistical indices to gauge the mixing efﬁciency of a conical screening mill. Pharm Res 1993; 10:1248–1251.
15. Fourman GL, Cunningham DL, Gerteisen RL, Glasscock JF, Poska RP. Improved color
uniformity in tablets made by the direct compression method: a case study. Pharm Tech
1990; 14:34–44.
16. Schwartz JB. Theory of granulation. Kadam KL, ed. Granulation Technology for Bioproducts. Boca Raton, FL: CRC Press, 1990:17.
17. Johnson C. Comminution variables and options. Powder Bulk Eng 1989; 3:40–44.
© 2005 by Taylor & Francis Group, LLC

512

Rekhi and Sidwell

18. Owens JM. How to correct common hammermill problems. Powder Bulk Eng 1991;
5:38–43.
19. Hajratwala BR. Particle size reduction by a hammer mill I: effect of output screen size,
feed particle size, mill speed. J Pharm Sci 1982; 71:188–190.
20. Byers JE, Peck GE. The effect of mill variables on a granulation milling process. Drug
Dev Ind Pharm 1990; 16:1761–1779.
21. Motzi JJ, Anderson NR. The quantitative evaluation of a granulation milling process. II.
Effect of output, screen size, mill speed and impeller shape. Drug Dev Ind Pharm 1984;
10:713–728.
22. Apelian V, Yelvigi M, Zhang GH, et al. Comparison of quadromill and ﬁtzmill used inmilling process of granulation. Pharm Res 1994; 11:S-142.
23. UMAB/FDA Collaborative Agreement RFP # 223–91–3401.

© 2005 by Taylor & Francis Group, LLC

18
Granulation Characterization
Raj Birudaraj
Roche Palo Alto, Palo Alto, California, U.S.A.

Sanjay Goskonda
Durect Corp., Cupertino, California, U.S.A.

Poonam G. Pande
Synthon Pharmaceuticals Inc., Research Triangle Park, North Carolina, U.S.A.

1. INTRODUCTION
Granulation is a process selected by formulation scientists to prevent segregation of
formulation components in a powder mix, improve blend ﬂow, bulk volume of
granulation, content uniformity, compressibility, and other properties. Granulation
minimizes the technical risks associated from batch to batch variability in raw materials that could impact the manufacturing process and performance. Various granulation techniques such as high- and low-shear granulation, roller compaction, spraydrying, ﬂuid-bed granulation, extrusion speronization, and melt granulation are usedin solid dosage form development. The choice of granulation technique depends on
various factors such as chemical and physical stability of the ﬁnal dosage form,
intended biopharmaceutical performance, and is occasionally limited due to available equipment. Dosage form performance is assessed through a characterization
program in which drug dissolution, bioavailability, chemical stability, or manufacturing ruggedness is taken into account. The scientist can rely on many different tools
for granulation characterization. These tools can probe the physical and chemical
attributes of the material. In this chapter many characterization techniques thatare applied to granulation will be reviewed. Most of the techniques used for granulation characterization are conducted during the research and development stage of
product development. A signiﬁcant portion of this chapter was adapted from theprevious edition of Handbook of Pharmaceutical Granulation Technology (1).

2. PHYSICAL AND CHEMICAL CHARACTERIZATION OF GRANULES
Physical property characterization of pharmaceutical granulations has been extensively reported in literature. Chemical properties are equally important due to theirimpact on speciﬁcations of a dosage form such as content uniformity, chemical
513© 2005 by Taylor & Francis Group, LLC

514

Birudaraj et al.

purity, and in vitro performance. The interaction between physical characteristics ofa formulation and chemical-based performance should not be understated. In vivo
performance such as bioequivalence is the ultimate performance test because it is this‘‘characterization’’ that determines whether a pivotal bioequivalency batch passes or
fails. The effect of granule size on the dissolution performance, for example, could
ultimately affect the outcome of such a bioequivalence study. The complexity of thiskind of relation underscores how something seemingly simple, such as particle size
and its dependence on granulation process parameters, can inﬂuence dissolution
and ultimately in vivo performance.
Physical characterization can be performed at molecular, particulate, or bulk
(macroscopic) levels. From the terminology cited by Brittain et al. (2), molecularproperties are associated with individual molecules, particulate properties are considered as properties that pertain to individual solid particles, and bulk properties
are those that are associated with an assembly of particulate species. Most reports
in pharmaceutical literature cover characterization of bulk properties.

2.1. Particle Morphology
Particle morphology can be assessed using optical microscopy. Samples of granulation can be evaluated directly under a microscope or sorted using a device proposedby Ridgeway and Rupp (3) in which the granulation is fed onto a triangular metal
deck and vibrated. Particles of different shapes segregate on this deck and arecollected for analysis by microscopy.
Another technique to study particle morphology is scanning electron microscopy. Yoshinari et al. (4) studied morphological changes in granule shape withthe addition of different amounts of granulating ﬂuid (Fig. 1).

Figure 1 Scanning electron micrographs of mannitol granules obtained after treating
d-crystal with various ratio of water: (A) 5% w/w, (B) 10% w/w, (C) 15% w/w, and(D) 25% w/w. (From Ref. 4.)© 2005 by Taylor & Francis Group, LLC

Granulation Characterization

515

Particle shape can be quantiﬁed by different methods. One popular method isthrough the use of Heywood coefﬁcients (5). The Heywood shape coefﬁcient is deﬁned
as the ratio of the surface shape coefﬁcient (p for a sphere) to the volume shape coefﬁcient (p/6 for a sphere); hence, the shape coefﬁcient for a sphere would be 6.0. Applying this to a cube and using its projected area in its most stable position, the shape
coefﬁcient is 6.8. Cutting the cube in half in one dimension increases the shape factor
to 9.0, whereas it increases to 26.6 if that cube was sliced one-tenth in one dimension.
Further details of these types of calculations are provided by Rupp (5).
The effect of particle shape on bulk powder properties has been illustrated by
Rupp (5). The effect of particle size and shape on the bulk density and ﬂow rate isillustrated in Figures 2 and 3. As illustrated in these examples, packing of powderin the bulk becomes more efﬁcient as the shape factor or loss in sphericity increases.
The ﬂow rate becomes worse with loss in sphericity.
2.2. Particle Size Distribution
Particle size distribution can be measured by sieve analysis, laser light scattering, or
optical microscopy (2). Light-scattering techniques are generally not applied togranulations due to the large size distribution of granules. Dry-sieve analysis andFigure 2 Bulk density as a function of shape factor: triangles, 302 mm; squares, 461 mm; andcircles, 805 mm. (From Ref. 3.)© 2005 by Taylor & Francis Group, LLC

516

Birudaraj et al.

Figure 3 Effect of particle shape on ﬂow rate for an oriﬁce diameter of 6.34 mm: triangles,
302 mm; squares, 461 mm; and circles, 805 mm. (From Ref. 3.)

microscopy are generally the most popular methods for determining size distribution of granules. Microscopy provides a more exact measurement of size, although
it is the most labor-intensive method. Computer-aided image analysis techniques
have been employed to simplify the method, but some problems, such as threedimensional surface effects could be misinterpreted by the computer, resulting inerrors in the calculated distribution.
Dry-sieve analysis is the easiest and the most convenient method for measuring
granule size. The granulation is placed on top of a stack of ﬁve to six sieves whichhave successively smaller-sized openings from top to bottom. The stack is vibrated,
and the particles collect on top of the sieves. The data are usually represented interms of percentage retained on the sieve, or percentage that is undersize or oversize
vs. screen-opening size (Fig. 4) (6).
Two factors—particle size distribution and shape—can bias a distribution
obtained by sieve analysis. According to Shergold (7), variations in particle size
distribution can be obtained due to the loading of the stack, which in turn, is affectedby the particle size distribution and shape of the powder being analyzed. In a more
extensive evaluation, Fonner and co-workers (8) studied the effect of loading, shaker
speed, and time on the data obtained for particle size distribution of model granulations. Particle breakage occurred at increasing shaker speeds and times. According to© 2005 by Taylor & Francis Group, LLC

Granulation Characterization

517

Figure 4 Sieve analysis of lactose granules formed by massing and force screening showing
effect of binder ﬂuid level: circles, 15.3% v/v; squares, 18.4% v/v; upward triangles, 23% v/v;
and downward triangles, 30.6% v/v. (From Ref. 6.)

the authors, particle attrition causes the loading of material to inﬂuence the time toreach equilibrium. In this article, time to reach equilibrium is deﬁned as the time atwhich the material passes through the sieve. The authors ﬁnally concluded that anonbiased analysis of particle size distribution should include an analysis of equilibrium times for each sieve.
An example for use of sieve analysis was offered by Stevens (9), who addressed
the effect of granule size distribution on the weight variation of tablets by constructing ‘‘isovariational curves.’’ The intent of this evaluation was to deﬁne a geometricmean diameter and distribution that would result in an acceptable tablet weightvariation. The geometric standard deviation was inverted and named the ‘‘R-value.’’
Granulations with various mean diameters and distributions were prepared by sieving, recombining, and running on a rotary tablet press. The coefﬁcient of variation(CV) for tablet weight was recorded for each run. R-values and CV for each geometric mean diameter were obtained from CV–R plots and then placed on a contour
plot containing geometric mean diameter (abscissa), R-value (ordinate), and CV(isovariational contour lines). Although the author claimed this must be done ona case-by-case (and press-by-press) basis, these curves can be used to select the
optimal mean granule size and distribution to minimize tablet weight variation.
© 2005 by Taylor & Francis Group, LLC

518

Birudaraj et al.

2.3. Powder X-Ray Diffraction
A detailed description of powder x-ray diffraction is provided by Brittain et al. (2)and the references cited therein. This technique is mostly used to determine the crystalline form of a solid. Understanding the effect of granulation on the form of bulk
drug has gained increasing attention in the past few years (10). X-ray techniques provide the formulator with a ﬁrst line of analysis in the determination of polymorphchanges as a result of processing. In a joint American Association of Pharmaceutical
Science–Federal Drug Administration (AAPS–FDA) report, an experimental rationale ‘‘where both the applicant (industry) and the FDA are in better position toassess the possible effects of any variations in the solid-state properties of the drug
substance’’ was provided. Both x-ray and solid-state nuclear magnetic resonancewere recommended techniques for assessing the crystalline form of drug substancein a drug product (8).
Yoshinari et al. (4) used x-ray techniques to report polymorphic transition ofmannitol during wet granulation. These authors stated that after vacuum drying
the wet granulated d-crystal of mannitol, a polymorphic change occurred to b-crystal
polymorph (Fig. 5). Concomitant morphological changes were noted in the scanningelectron micrographs (Fig. 6) which showed that d-granules consisted of small
primary particles of the b-form of mannitol.
Modulated temperature x-ray powder diffraction (XRPD) is being used
increasingly in the pharmaceutical industry both at preformulation and at formulation stages. Airaksinen et al. (11) studied polymorphic transitions during drying
using two methods: a multichamber microscale ﬂuid-bed dryer or a variable temperature powder x-ray diffractometer. Relative amounts of different polymorphic

Figure 5 Powder X-ray patterns of mannitol: (A) d-crystal of mannitol after granulationand vacuum drying, (B) d-crystal of mannitol before granulation, and (C) b-crystal. (FromRef. 4.)© 2005 by Taylor & Francis Group, LLC

Granulation Characterization

519

Figure 6 Scanning electron micrographs of d-crystal of mannitol: (A) before and (B) after
granulation. (From Ref. 4.)

forms of theophylline remaining in the dried granules were determined by XRPD.
The authors concluded that metastable anhydrous theophylline predominated when
the granules were dried at 40–50 C. Temperature >50 C produced mostly anhydrous theophylline, more than 20% of the metastable form remained even at 90 C(Fig. 7).
Morris and co-workers (12) reported polymorphic changes when hydroxymethylglutarate coenzyme A reductase inhibitor was wet-granulated with water.
The starting material was in the anhydrous form, which then converted to an
amorphous form during the wet-granulation process. The loss in crystallinity
was experimentally determined using powder x-ray diffraction. Exposure of this© 2005 by Taylor & Francis Group, LLC

520

Birudaraj et al.

Figure 7 (A) XRPD patterns of theophylline granules dried using a multichamber microscale ﬂuid-bed dryer (MMFD) at temperatures ranging from 30 C to 90 C using dry inlet
air (under 0.5 g/m3). (B) XRPD patterns of theophylline granules dried using MMFD at temperatures ranging from 30 C to 90 C using ambient inlet air (7.6 g/m3). Note the characteristic peaks of theophylline anhydrate metastable form (). XRPD patterns of theophylline
monohydrate and theophylline anhydrate at room temperature are shown below as controls.
(From Ref. 11.)

granulation to an environment of >33% relative humidity, caused a form conversion
to its crystalline hydrate. This series of experiments demonstrated the usefulness ofa sophisticated technique, such as XRPD, in the assessment of the physical stabilityof bulk drug during granulation.
© 2005 by Taylor & Francis Group, LLC

Granulation Characterization

521

2.4. Thermal Analysis
Standard thermal methods of analysis include differential scanning calorimetry(DSC), differential thermal analysis, and thermogravimetric analysis. A common
application of thermal analysis in characterization of granulations is based on thermogravimetry and is known as loss on drying (LOD). In a LOD analysis, a sample of
the granulation is heated at a temperature near the boiling point of water or solvent.
The weight loss, recorded directly on an analytical balance, is due to the evaporationof water or solvent and is considered the residual moisture content of a granulation(13). This technique is extensively used to establish both granulation and drying
parameters for wet-granulation unit operations (14–16).
DSC was used in the evaluation of a phase change of chlorpromazine hydrochloride after wet granulation (17). The starting drug substance (form II) converted
to a hemihydrate (form I-H) after it was wet-granulated with water–ethanol binder
ﬂuid. Form I-H converted to a partially dehydrated form (I-H0 ) after drying. An investigation of this form led the authors to another anhydrous polymorph (form I). Extensive characterization by DSC showed the transition from hemihydrate (form I-H) toanhydrous form (form I) at 40–50 C, followed by a conversion from form I to form II
at 135 C, and ﬁnally, melting at 185–189 C (17). By solution calorimetry, form I wasfound to be the most stable based on their heat of solution (DH) values. Although thedissolution proﬁles of both anhydrous forms were equivalent, the two forms had
different tableting characteristics. The more stable form I did not exhibit the severe
capping problems originally observed for form II. Granulations made with ibuprofen
and b-cyclodextrin were evaluated using DSC. Lower DH values for oven-driedgranulations indicated better complexation and faster dissolution than air-driedgranulations (18).
DSC is a valuable tool in characterizing granulations made by hot melt
extrusion for determining glass transition temperatures and crystalline or amorphousnature of the formulation. Perissutti et al. (19) used this technique to characterizecarbamazepine and polyethylene glycol 4000 granules obtained after hot melt
granulation.

2.5. Near-Infrared Spectroscopy
Near-infrared (NIR) spectroscopy is a fast, nondestructive method and requires nosample preparation (20) In the NIR region, absorption bands are mainly caused byovertones and combination vibrations of CH, NH, and OH groups. Intact and rapid
NIR spectroscopy offers advantageous possibilities of in-line measurements during
granulation processes to measure moisture content and detect any physicochemicalchanges (21,22). Rasanen et al. (20) studied the polymorphic conversion of theophylline during wet granulation using NIR. The authors found that at a low level of
granulation liquid (0.3 mol of water per mole of anhydrous theophylline), water
absorption maxima in the NIR region occurred ﬁrst at around 1475 and 1970 nm.
These absorption maxima were identical to those of theophylline monohydrate. At
higher levels of granulation liquid (1.3  2.7 mol of water per mole of anhydrous
theophylline), increasing absorption maxima occurred at 1410 and 1905 nm due to
OH vibrations of free water molecules (Fig. 8).
© 2005 by Taylor & Francis Group, LLC

522

Birudaraj et al.

Figure 8 Second derivative of absorbance of anhydrous theophylline, theophylline monohydrate, and theophylline granules at 1380–1520 nm: (A) anhydrous theophylline transformation
into theophylline monohydrate at around 1475 nm; and (B) effect of free water molecules ataround 1410 nm (number indicating mole(s) of water per mole of anhydrous theophylline).
(From Ref. 20.)

2.6. Electrostatic Charge
Static charge is generated when two bodies come into intimate contact and then are
separated. The surface of one of the contacting bodies attracts electrons from theother surface, thereby resulting in a negative charge. Forces of attraction and repulsion can cause signiﬁcant problems in powder handling. Gold and Palermo (23)described a technique that measures the static charge of a powder as it passes outof a hopper. The surface separation between particles occurs frequently in thisdynamic environment. In the system proposed by these authors, powder was allowed
to ﬂow out of a hopper onto a glass receptacle. Directly beneath this receptacle wasa copper disk that was attached to another copper disk beneath an ionostat. The© 2005 by Taylor & Francis Group, LLC

Granulation Characterization

523

ionostat recorded voltage transmitted by the ﬁrst disk. It was found that acetaminophen, when granulated with either starch paste or syrup, exhibited a much lower static charge than ungranulated powder. This reduction in static charge correlated withimproved ﬂow out of the hopper.

2.7. Surface Area
Granulation properties are mainly dependent on the size and surface area of particles
and granules (24,25) The surface area of a granule or particle can also affect the dissolution rate of a solid. Gas adsorption is the most common method to determine
surface area, although liquid penetration methods have also been proposed (26).
In one of the methods developed by Brunauer, Emmet, and Teller, called the BET
method (27), an inert gas is adsorbed onto the surface of a solid at low temperatureand then desorbed at room temperature (1). Either nitrogen or krypton is used as theadsorbate, and helium is usually used as a carrier gas for the adsorbate. Various concentrations of adsorbate in carrier gas are used in this analysis to determine thevolume of gas that is adsorbed in a monolayer on to the solid. Eq. 2.1 is used todetermine this valueP1ðC  1ÞP
¼
þV ðP0  PÞ Vm C
Vm CP0ð2:1Þ

where V ¼ volume of gas adsorbed at pressure P, P ¼ partial pressure of adsorbate,
C ¼ a constant relating the heats of adsorption and condensation of the adsorbate,
P0 ¼ saturation pressure of adsorbate at experimental temperature, and Vm ¼
volume of gas adsorbed in monolayer of solid.
A plot of P/V (P0 – P) vs. P/P0 yields a straight line. Vm is calculated fromboth the slope and the intercept of this line (27). The speciﬁc surface area (SSA),
in units of square meters per gram is calculated using Eq. 2.2
SSA ¼

ðVm N0 Acs Þ
M

ð2:2Þ

where N0 ¼ Avogadro’s number, Acs ¼ cross-sectional area of adsorbate, and M ¼
mass of solid sample.
Another method that has been proposed for measuring the surface area of
powders is known as air permeability (28). A column packed with powder is subjected to a stream of air. The system is sealed off and the pressure drop is measured
across the bed. To take into account the ‘‘slip’’ of gas along walls of pores a modiﬁcation of the governing equation is employed (28) This correction minimizes theapparent dependence of SSA on air pressure. Although this method has not been
extensively used on granulations or powders in the pharmaceutical sciences, it has
been applied to compressed tablets (29).

2.8. Granule Porosity
Mercury intrusion methods are routinely applied in the determination of pore sizeand distribution to both granulations and tablet compacts (30). In this method,excess pressure is applied to a nonwetting liquid, such as mercury, for the smallest© 2005 by Taylor & Francis Group, LLC

524

Birudaraj et al.

pores to be ﬁlled. A relation between the applied pressure and pore radius, known as
the Washburn equation Eq. 2.3 is then used to calculate pore size opening
 
2g
DP ¼ 
cosy
r

ð2:3Þ

where DP ¼ pressure difference across interface, g ¼ surface tension of the penetrating liquid, y ¼ contact angle of the penetrating liquid, and r ¼ pore radius.
In this analysis (2), the sample is introduced into the chamber, degassed, andthen completely covered with mercury. Pressure is incrementally applied, and thevolume of mercury that penetrates into the pores is recorded. A plot of cumulative
volume intruded vs. pressure is obtained and converted to cumulative volume vs.
pore radius. The pore size distribution is obtained by differentiating the latter curve.
Wikberg and Alderborn (31) have suggested that increase in intragranular porosity, increases the propensity of the granules to fragment leading to formation ofstronger tablets. For granulations, which are less prone to fragmentation, Johansson
et al. (32) showed that increased intragranular porosity increased the degree of
deformation, resulting in formation of a closer intragranular pore structure during
compression and stronger tablets.
Ganderton and Hunter (6) used mercury intrusion to compare the intragranular porosity of granulations manufactured by different processes. Calcium phosphate
was granulated with 10% dextrose–water binder and the comparison was madebetween a pan granulator and a Z-blade mixer. A plot of intragranular porosity
vs. binder level (denoted as moisture content) is shown in Figure 9. A signiﬁcantdecrease in intragranular porosity was observed when massed in a Z-blade mixer
and then screened. An opposite trend was noted for lactose granulated with water
as a binder. The results of this study suggest that the physicochemical propertiesof the powder being granulated can have a signiﬁcant inﬂuence on the sensitivityof granule properties to granulation process.
Farber et al. (33) studied the porosity and morphology of granules by two different techniques, x-ray computed tomography (XRCT) and mercury porosimetry(Fig. 10). These authors concluded that XRCT is less accurate in the determinationof total porosity when compared to mercury porosimetry. However, XRCT provided detailed morphological information such as pore shape, spatial distribution,and connectivity (Fig. 11).
2.9. Granule Strength
The strength of granules is a property that can be measured in the development of aformulation. In a classic treatment of the topic, Rumpf (34) has described numerous
mechanisms that contribute to granule and agglomerate strength: (a) solid bridges
between particles, (b) interfacial forces and capillary pressure in moveable liquidsurfaces, (c) adhesional and cohesional forces in bonding, (d) attraction between solid
particles, and (e) particle shape-inﬂuenced mechanical interlocking. Rumpf (34)considered the tensile strength of the particle bond to be the most important factor
in the determination of agglomerate strength. He proposed a direct test of the tensile
strength of agglomerates; although the size of the granules that were tested was2.5 cm (1 in.) in diameter.
Several methods have been proposed in the pharmaceutical literature for themeasurement of the strength of granules. One way of measuring granule strength is© 2005 by Taylor & Francis Group, LLC

Granulation Characterization

525

Figure 9 The effect of moisture content on the porosity of –12þ16 mesh calcium phosphate
granules processed for 10 min: circles, pan granulated; squares, massed and screened. (FromRef. 6.)by directly crushing them, a test proposed by Harwood and Pilpel (35) and subsequently modiﬁed by both Ganderton and Hunter (6) and Gold et al. (36). The
force required to crush the granule is recorded when a platen is moved at a constantstrain rate. Deﬂections in the load proﬁle are interpreted as break points and thestrength is recorded in units of mass or force (36). A direct measurement of tensile
strength is difﬁcult owing to the lack of understanding of the surface area on which
the applied load acts.
Mehta and co-workers (37) have criticized this method because of the inherent
variability of the properties of granules as well as for the difﬁculty in measuring thestrength of granules smaller than 40 mesh. Many samples must be measured andresults averaged to make the granule-crushing measurement meaningful. In their
method, ball milling is used to estimate granule strength by following granule attrition (37). Attrition is monitored using dry sieve analysis. Their method correlated
very well with the Harwood-Pilpel method with a much better coefﬁcient of variation
for their technique (1–5% for the ballmilling method and 50–80% for the directcrushing method) (37)
Another attrition method used in determining granule strength is determination of the friability of granulations (38,39). In this measurement, a friabilator ischarged with the granulation to be tested and then rotated a set number of times.
The percentage loss of mass for a particular size is usually the value that isrepresented in a granule friability analysis (30,39). This method is useful to identify© 2005 by Taylor & Francis Group, LLC

526

Birudaraj et al.

Figure 10 The granule growth of the one of the batch. Each dot (.) shows the data point forthe particle mean size measured from the surface image information. Each numbered dot
corresponds to the numbered surface images. Additionally, three end-point data points andimages are shown together with three replicate data points from end-point sieve analysis (.).
The spraying and drying phases of the process are separated with a dashed line. (FromRef. 33.)

properly the differences as a function of granule size within a granulation (39). An
example is given for a sulfadiazine granulation in Figure 12.
2.10. Granule Flowability and Density
Flow behavior of granules is affected by multiple variables such as physical properties of the granulation and the equipment design used for handling during a given
process. Prescott and Barnum (40) show the value of selecting ﬂow property measurements that are meaningful to actual processing. Rump and Herrmann (41)and Podczeck (42) provide more information on underlying particle properties that
contribute to powder ﬂow.
Speciﬁc volume is one of the properties of a powder that is believed to affectpowder ﬂowability. Speciﬁc volume is determined by pouring a known mass of blend
into a graduated cylinder. The volume is read off the cylinder and the speciﬁc volume
is calculated by dividing the volume by the mass of the blend (43). Bulk density is
calculated by dividing the mass by volume. The compressibility of a blend can also
be determined at this time. The granulated cylinder is vibrated on a shaker for a time
period. This vibration reduces the volume that the blend occupies in the graduatedcylinder. The percentage compressibility (6) is calculated as in Eq. 2.4% Compressibility ¼

100  ðP  AÞ
P

ð2:4Þ

where P ¼ packed density (after vibration) and A ¼ bulk density (untapped).
© 2005 by Taylor & Francis Group, LLC

Granulation Characterization

527

Figure 11 Tomographic images and pore size distributions of granules produced under highshear in the Fukae mixer. (A) X-ray shadow image; (B) typical reconstructed cross-sectional
image; (C) high-magniﬁcation image of area in the box in 9b; (D) pore size distribution calculated from tomographic image; and (E) pore size distribution as measured by mercury porosimetry. (From Ref. 33.)

The percentage compressibility is commonly known as Carr’s index (44). This
index is interpreted in the following way: the higher the compressibility, the poorer
the ﬂowability. An example of how this is used in the evaluation of a granulation
process was reported by Ertel et al. (45). In this report, the authors evaluated effectsof the scale of preparation of a sucrose–lactose–starch granulation using Lodige
granulators at the 4 and 30 kg scale. The compressibility of the granulations wasdependent on the kneading time as well as the scale of preparation.
Powder ﬂowability can be directly measured using the ‘‘ﬂow through an oriﬁce’’ technique (12,46). This test is close to an actual ‘‘use test,’’ because a hopper
is charged with the blend and the ﬂow rate during discharge is measured. A variationof this test is achieved by determining the relation between the ﬂow rate of a blend
and the diameter of the oriﬁce. Harwood and Pilpel (35) describe various methods of© 2005 by Taylor & Francis Group, LLC

528

Birudaraj et al.

Figure 12 Friability of sulfadiazine granulations. (From Ref. 39.)

data analysis for this technique in detail. These methods include empirical equations,dimensional analysis, and energy considerations.
A more fundamental evaluation of powder ﬂowability can be obtained byassessing interparticulate friction. The angle of repose is a parameter that is dependent on interparticulate friction and cohesion (47–49). The static angle of repose is
obtained by ﬁlling an open-ended cylinder with the blend and then slowly raising
the cylinder, allowing the powder to ﬂow out. The angle of the heap that is formed
is called as the static angle of repose (46). In general, the higher the angle of repose
the poorer the ﬂowability of the blend. A dynamic, or kinetic, angle of repose can beobtained by charging a hollow drum with blend and rotating it. The angle of repose
can be calculated by recording how high the blend travels up the wall of the drum
(46,50). This angle of repose will be 1–5 lower than the static angle (46). However,there are some problems with this technique. Danish and Parrott (47) found that theangle of repose of blends did not correlate with the ﬂow through an oriﬁce data, aresult that is in agreement with other authors (36).
A better method for determining the cohesive and frictional effects of particles
is by using a shear cell (48,51,52). There are various cell conﬁgurations, the mostpopular proposed by Jenike (51). In the Jenike cell (Fig. 13), a powder is loaded
and then compressed by twisting the lid of the cell. The number of twists required
to load the powder to the point at which the resistance to shear (measured as stressapplied to ring around the bed) is constant. This phase of the test is known as ‘‘shear
consolidation.’’ The load is reduced and the resistance to shear is then recorded. A‘‘yield locus’’ of this shear stress vs. the reduced load is obtained and used to calculate various ﬂow-related parameters (47,48,51). Numerous parameters can be© 2005 by Taylor & Francis Group, LLC

Granulation Characterization

529

Figure 13 Schematic of Jenike shear cell. (From Ref. 48.)

derived from the yield locus: ﬂow factor, shear index, cohesion, tensile strength,
effective angle of internal friction, and unconﬁned yield stress (48). All of these parameters can be used in the characterization of powder ﬂowability.
Other shear cells have been used to characterize the ﬂowability of blends. Carrand Walker describe an annular shear cell that measures the resistance to the angularmovement of the shoe that is placed on top of the powder (53). The advantage to thistype of design is that unlimited travel of the shoe provides the opportunity tomeasure successive initial consolidation loads without reloading the powder (53)Hiestand (52) and later on, Amidon and Houghton (54), describe a plate-type shear
cell that is similar to the Jenike shear cell, with the exception that the powder bed is
unconstrained at the edge of the bed.
Sinko and co-workers (55) have demonstrated the usefulness of the plate-type
shear cell in directly measuring the improvement in ﬂowability that is afforded
by wet granulation. In this study, the measurement of ﬂowability estimated by theeffective angle of internal friction, a parameter that estimates the powder’s resistanceto shear stress as a function of applied load, was used to track the potential
improvement in ﬂowability achieved through dry- and wet-granulation. A comparison of the effective angle of internal friction for a direct compression, wetgranulated, and dry-granulated formulation of near equivalent composition isprovided in Figure 14. Wet-granulation resulted in a greater improvement in theﬂowability of the formulation than a similarly sized dry granulation.
2.11. Moisture Control in Granulations
Control of moisture content in granulations is very important and it could affectthe physical and chemical performance of ﬁnal dosage forms. Moisture could affectﬂow of granules, tablet compression, tablet disintegration, crystal habit, capsule© 2005 by Taylor & Francis Group, LLC

530

Birudaraj et al.

Figure 14 The effect of process on the ﬂowability of lactose based granulations: DC, directcompression, RC, roller compaction; Wet, wet granulated. (From Ref. 55.)

brittleness, chemical stability, and many other properties. Moisture content is generally measured using moisture analyzer during product development; a thin layer ofsample is heated at a set temperature until it reaches a constant weight and theresults are expressed as LOD. Chowhan (56) showed that tablets made using low
moisture content granulations when exposed to higher humidity increased in hardness and disintegration. Badawy et al. (57) showed in a processing study the moisture
content had the largest effect on compressibility of the granulation compared toseven other process parameters. Within the tested levels increasing moisture content
increased the granulation compressibility. It should be noted that due to the great
diversity of granulation formulation, one has to characterize each of their formulation and process to evaluate the moisture effect on physical and chemical properties.
Some polymorphic transitions in granulations are moisture mediated.
Wostheinrich and Schmidt (58) showed that thiamine hydrochloride granulations
were caking on storage and the tablets were increasing in hardness due to conversionof form I crystal to hydrate forms due to exposure to humidity at room temperature.
Williams et al. (59) indicated that the active ingredient which is highly crystallinehydrochloride form was dissociated in minute quantities (1% of tablet weight) into
amorphous free form due exposure to moisture and altering tablet properties. Minimizing moisture exposure during process and storage was recommended.
It is ideal to develop equilibrium moisture isotherms for granulations to understand the moisture content at different humidities. To develop moisture isotherms
granulations are exposed to different relative humidities at a set temperature andthe equilibrium moisture content is determined. This information could be used todevelop speciﬁcations for the moisture content of the granulation and would help
device ideal processing and packaging conditions. One application of moisture© 2005 by Taylor & Francis Group, LLC

Granulation Characterization531

isotherms data could be applied to the formulation development of capsules. Capsules show brittleness at low relative humidity and a tendency to cross-link at highhumidity and high temperature. Asorption–desorption moisture transfer model
was developed by Zograﬁ et al. (60) to predict moisture transfer between excipients,
and this model was used later to control brittleness of capsules successfully by Kotny
et al. (61) and Chang et al. (62).

3. CONCLUSION
The diverse nature of formulations and processes are used to manufacture granulations calls for various tools that are needed to help characterize granule properties.
The tools mentioned in this chapter could be used as a guide for the formulationprocess scientist during research and development stages. There are also several
other sophisticated tools (like Raman imaging) still being evaluated for speciﬁccharacterization of the granulation like uniformity of drug distribution.

REFERENCES
1. Sinko C. Granulation characterization: methods and signiﬁcance. Parikh DM, ed. Handbook of Pharmaceutical Granulation Technology. New York: Marcel Dekker, 1997.
2. Brittain HG, Bogdanowich SJ, Bugay DE, DeVincentis J, Lewen G, Newman AW.
Physical characterization of pharmaceutical solids. Pharm Res 1991; 8:963.
3. Ridgeway K, Rupp R. J Pharm Pharmacol 1969; 21:30S.
4. Yoshinari T, Forbes RT, York P, Kawashima Y. The improved compaction properties ofmannitol after a moisture-induced polymorphic transition. Int J Pharm 2003; 258:121.
5. Rupp R. Flow and other properties of granulates. Bol Chim Farm 1977; 116:251.
6. Ganderton D, Hunter BM. A comparison of granules prepared by pan granulation andby massing and screening. J Pharm Pharmacol 1971; 23:1S.
7. Shergold FA. The effect of sieve loading on the results of sieve analysis of natural sands.
J Soc Chem Ind 1946; 65:245.
8. Fonner DF, Banker GS, Swarbrick J. Micromeritics of granular pharmaceutical solids II:
factors involved in the sieving of pharmaceutical granules. J Pharm Sci 1966; 55:576.
9. Stevens PTA. The relationship between particle size distribution of granules and weightvariation of tablets. Acta Pharm Technol 1980; 26:304.
10. Byrn S, Pfeiffer R, Ganey M, Hoiberg C, Poochikian G. Pharmaceutical solids: a strategic approach to regulatory considerations. Pharm Res 1995; 12:945.
11. Airaksinen S, Karjalainen M, Räsänen E, Rantanen J, Yliruusi J. Comparison of theeffects of two drying methods on polymorphism of theophylline. Int J Pharm 2004;
276:129.
12. Morris KR, Newman AW, Bugay DE, Randive SA, Singh AK, Szyper M, Varia SA,
Brittain HG, Serajuddin ATM. Characterization of humidity-dependent changes in crystal properties of a new HMG-CoA reductase inhibitor in support of its dosage form
development. Int J Pharm 1994; 108:195.
13. Carstensen JT. Pharmaceutical Principles of Solid Dosage Forms. Lancaster, PA: Technomic Publishing, 1993.
14. Hellén L, Yliruusi J, Merkku P, Kristofferson E. Process variables of instant granulator
and spheroniser: I. Physical properties of granules, extrudate, and pellets. Int J Pharm
1993; 96:197.
15. Lipps DM, Sakr AM. Characterization of wet granulation process parameters using
response surface methodology. I. Top-spray ﬂuidization. J Pharm Sci 1994; 83:937.
© 2005 by Taylor & Francis Group, LLC

532

Birudaraj et al.

16. Schaefer T, Wørts O. Control of ﬂuidized bed granulation. III. Effects of inlet air distribution. Control of moisture content of granules in the drying phase. Arch Pharm ChemSci Ed 1978; 6:1.
17. Wong MWY, Mitchell AG. Physiochemical characterization of a phase change produced
during the wet granulation of chlorpromazine hydrochloride and its effects on tableting.
Int J Pharm 1992; 88:261.
18. Ghorab MK, Adeyeye MC. Enhancement of ibuprofen dissolution via wet granulation
with beta-cyclodextrin. Pharm Dev Technol 2001; 6:305.
19. Perissutti B, Rubessa F, Moneghini M, Voinovich D. Formulation design of carbamazepine fast-release tablets prepared by melt granulation technique. Int J Pharm 2003;
256:53.
20. Räsänen E, Rantanen J, Jørgensen A, Karjalainen M, Paakkari T, Ylirussi J. Novel identiﬁcation of pseudopolymorphic changes of Theophylline during wet granulation usingnear infrared spectroscopy. J Pharm Sci 2001; 90:389.
21. Aldridge PK, Evans CL, Ward HW II, Colgan ST, Boyer N, Gemperline PJ. Near-IR
detection of polymorphism and process-related substances. Anal Chem 1996; 68:997.
22. Buckton G, Yonemochi E, Hammond J, Moffat A. The use of near infra-red spectroscopy to detect changes in the form of amorphous and crystalline lactose. Int J Pharm
1998; 168:231.
23. Gold G, Palermo BT. Hopper ﬂow electrostatics of tableting material I. Instrumentation
and acetaminophen formulations. J Pharm Sci 1965; 54:310.
24. Chalmers AA, Elworthy PH. Oxtetracycline tablet formulations: effect of variations inbinder concentration and volume on granule and tablet properties. J Pharm Pharmacol
1976; 28:228.
25. Harwood CF, Pilpel N. Granulation of griseofulvin. J Pharm Sci 1968; 57:478.
26. Carmen PC. The determination of the speciﬁc surface of powders. I. J Soc Chem Ind
1938; 57:225.
27. Brunaeuer S, Emmett PH, Teller E. Adsorption of gases in multimolecular layers. J Am
Chem Soc 1938; 60:309.
28. Rigden PJ. The speciﬁc surface of powders. A modiﬁcation of the theory of the airpermeability method. J Soc Chem Ind 1947; 66:130.
29. Alderborn G, Duberg M, Nystrom C. Studies on direct compression of tablets X.
Measurement of tablet surface area by permeametry. Powder Technol 1985; 41:49.
30. Hayes JM, Rossi-Doria P. Principles and Applications of Pore Structural Characterization. Bristol, UK: JW Arrowsmith, 1985.
31. Wikberg M, Alderborn G. Compression characteristics of granulated materials. IV. The
effect of granule porosity on the fragmentation propensity and compactibility of somegranulations. Int J Pharm 1991; 69:239.
32. Johansson B, Wikberg M, Ek R, Alderborn G. Compression behaviour and compactibility of microcrystalline cellulose pellets in relationship to their pore structure and mechanical properties. Int J Pharm 1995; 117:57.
33. Farber L, Tardos G, Michaels JN. Use of X-ray tomography to study the porosity andmorphology of granules. Powder Technol 2003; 132:57.
34. Rumpf H. The strength of granules and agglomerates. Knepper WA, ed. Agglomeration.
New York: Wiley Interscience, 1962; 379.
35. Harwood CF, Pilpel N. Granulation of griseofulvin. J Pharm Sci 1968; 57:478.
36. Gold G, Duvall RN, Palermo BT, Slater JG. Powder ﬂow studies II: effect of glidants on
ﬂow rate and angle of repose. J Pharm Sci 1996; 55:1291.
37. Mehta A, Zoglio MA, Carstensen JT. Ball milling as measure of crushing strength of
granules. J Pharm Sci 1978; 67:905.
38. Hill PM. Starch paste granulations: binder dilution effects on granulations and tablets.
J Pharm Sci 1976; 65:313.
39. Marks AM, Sciarra JJ. Effect of size on other physical properties of granules and theircorresponding tablets. J Pharm Sci 1968; 57:497.
© 2005 by Taylor & Francis Group, LLC

Granulation Characterization

533

40. Prescott JK, Barnum RA. On powder ﬂowability. Pharm Technol Oct 2000; 60–84.
41. Rumpf H, Herrmann W. Properties, bonding mechanisms, and strength of agglomerates.
Process Prep 1970; 11:117.
42. Podczech F. Particle-particle adhesion. Pharmaceutical Powder Handling. London:
Imperial College Press, 1998:256.
43. Lachman L, Lieberman HA, Kanig JL, eds. Theory and Practice of Industrial Pharmacy.
Philadelphia, PA: Lea & Febiger, 1986.
44. Gordon RE, Rosanske TW, Fonner DE, Anderson NR, Banker GS. Granulation technology and tablet characterization. Lieberman HA, Lachman L, Schwartz JB, eds. Pharmaceutical Dosage Forms: Tablets. New York: Marcel Dekker, 1990.
45. Ertel KD, Zoglio MA, Rischel WA, Carstensen JT. Physical aspects of wet granulation
IV: effect of kneading time on dissolution rate and tablet properties. Drug Dev Ind
Pharm 1990; 16:963.
46. Pilpel N. The ﬂow of powders and granular solids. Br Chem Eng 1966; 11:699.
47. Danish FQ, Parrott EL. Flow rates of solid particulate pharmaceuticals. J Pharm Sci
1971; 60:548.
48. York P. Powder failure testing—pharmaceutical applications. Int J Pharm 1980; 6:89.
49. Train D. Some aspects of the property of angle of repose of powders. J Pharm Pharmacol
1958; 10:127T.
50. Carr RL. Evaluating the ﬂow properties of solids. Chem Eng 1965; 72:163.
51. Jenike AW. Gravity Flow of Solids, Bulletin 108. Salt Lake City, UT: Utah Engineering
Experimental Station, University of Utah, 1961.
52. Hiestand EN. The determination of some important physical properties of powders.
Pharm Ind 1972; 34:262.
53. Carr JF, Walker DM. An annular shear cell for granular materials. Powder Technol
1968/1969; 1:369.
54. Amidon GE, Houghton ME. Powder ﬂow testing in preformulation and formulation
development. Pharm Manuf 1985.
55. Sinko CM, Carlson GT, Beckwith BA. Mechanical property modiﬁcation of powder.
Proceedings of the First International Particle Technology Forum, Denver, CO,
1994; 121.
56. Chowhan ZT. Moisture, hardness, disintegration, and dissolution interrelationships incompressed tablets prepared by wet granulation process. Drug Dev Ind Pharm 1979;
5:41.
57. Badawy SI, Menning MM, Gorko MA, Gilbert DL. Effect of process parameters oncompressibility of granulation manufactured in a high-shear mixer. Int J Pharm 2000;
198:51.
58. Wostheinrich K, Schmidt PC. Polymorphic changes of thiamine hydrochloride during
granulation and tableting. Drug Dev Ind Pharm 2001; 27:481.
59. Williams AC, Cooper VB, Thomas L, Grifﬁth LJ, Petts CR, Booth SW. Evaluation of
drug physical form during granulation, tabletting, and storage. Int J Pharm 2004; 275:29.
60. Zograﬁ G, Grandolﬁ GP, Kotny MJ, Mendenhall DW. Prediction of moisture of moisture transfer in mixtures of solids: transfer via vapor phase. Int J Pharm 1988; 42:77.
61. Kontny MJ, Mulski CA. Gelatin capsule brittleness as a function of relative humidity atroom temperature. Int J Pharm 1989; 54:79.
62. Chang RK, Raghavan KS, Hussain MA. A study of gelatin capsule brittleness: moisturetransfer between the capsule shell and its content. J Pharm Sci 1988; 87:556.

© 2005 by Taylor & Francis Group, LLC

19
Bioavailability and Granule Properties
Sunil S. Jambhekar
South University School of Pharmacy, Savannah, Georgia, U.S.A.

1. INTRODUCTION
The most important property of a dosage form is its ability to deliver the active
ingredient to the ‘‘site of action’’ in an amount sufﬁcient to elicit the desired pharmacological response. This property of a dosage form has been variously referred to as
its physiological availability, biological availability, or bioavailability.
Bioavailability may be deﬁned more accurately as the rate and extent ofabsorption of a drug from its dosage form into the systemic circulation. Accordingly,
the absorption of a drug following intravenous administration is extremely rapid andcomplete. However, due to convenience and stability problems, drugs are often
administered orally in a tablet or capsule dosage form. Therefore, it is imperativethat their rate and extent of absorption in individual be known accurately. Furthermore, it is equally important that the factors that inﬂuence the rate and extent ofabsorption of drugs be also known and understood by formulators.
The subject of bioavailability began to receive growing attention as studies
showed that the therapeutic effectiveness of a drug from the dosage form depends,
to a large extent, on the physiological availability of their active ingredient(s), andis a function of the drug concentration in the patient’s blood or plasma. The importance of bioavailability in drug therapy, therefore, stems from the fact that the rateand extent of absorption of a drug from a dosage form can, in fact, affect the patient’s
response to a drug. In light of these facts, the determination of bioavailability has
become one of the ways to assess the in vivo performance of a dosage form following
its formulation development. It must, however, be remembered that bioavailability
studies, very often, are conducted in normal, fasted, and a small number of subjects
and, therefore, the results of these studies may not always reﬂect the true efﬁcacy
relationship in patients under treatment conditions.
For many years it was assumed that if a dosage form contained the labeledamount of a drug, its performance could be taken for granted. However, it is
now evident for some time that many factors acting individually or in concert
may produce the therapeutic failure.

535© 2005 by Taylor & Francis Group, LLC

536

Jambhekar

2. BIOAVAILABILITY PARAMETERS
In assessing the bioavailability of a drug from a dosage form, three parameters aremeasured following the administration of a drug through a dosage form and obtaining the drug blood concentration time proﬁle (Fig. 1):
1. Peak concentration (Cp) max
2. Peak time, tmax
3. The area under the concentration time curve, ðAUCÞ1
0
The parameters tmax and (Cp) max are the measure of the rate of absorption andthe ðAUCÞ1
0 is a measure of the extent of absorption.

2.1. Peak Time
This parameter represents the length of time required to attain the maximum concentration of drug in the systemic circulation. The parameter reﬂects the onset of action
and, hence, can be utilized as a measure of the rate of absorption. The faster the rateof absorption, the smaller the value for the peak time and the quicker the onset ofaction of the drug. The peak time is determined by using the following equation:
tmax ¼InðKa =KÞðKa  KÞ

ð2:1Þwhere Ka and K are the ﬁrst-order absorption and elimination rate constants, respectively.
Eq. 2.1 clearly indicates that larger the value of the absorption rate constant(Ka), the smaller is the value of peak time (tmax) and the quicker is likely to be theonset of action.

Figure 1 A graphical representation of plasma/serum drug concentration data following theadministration of a drug by an extravascular route.
© 2005 by Taylor & Francis Group, LLC

Bioavailability and Granule Properties

537

The elimination rate constant (K) is constant for a drug in normal healthy individuals and it changes when organs responsible for the elimination of the drug (i.e.,kidney and liver) exhibit abnormalities. The absorption rate constant (Ka), on theother hand, depends on the route of administration, the dosage form, and the formulation of a drug. And, for hydrophobic drugs or when the absorption is dissolution
rate limited, the faster dissolution is generally reﬂected in the higher value for theabsorption rate constant. Therefore, by changing the formulation of a drug or routeof administration, one can alter the peak time and, therefore, the rate of absorption
and time for the onset of action.

2.2. Peak Plasma Concentration (Cp) max
This parameter represents the highest drug concentration in the systemic circulationor the plasma concentration that corresponds to the peak time. Furthermore, thisparameter is often associated with the intensity of the pharmacologic response of
the drug. Therefore, the peak plasma concentration (Fig. 1) of a drug following
the administration of a dosage form should be above the minimum effective concentration and below the minimum toxic concentration. The peak plasma concentration
can depend on the absorption rate constant (Ka) and the fraction of the administereddose that eventually reaches the systemic circulation. The higher the absorption rate
constant and fraction that reaches the general circulation, the greater is the peakplasma concentration for the administered dose. The route of administration, thedosage form, and the formulation can therefore inﬂuence the peak plasma concentration. It is determined by using the following method:
Ka F ðXa Þ0 ktmaxðe eka tmax Þð2:2Þ
V ðKa  KÞ
where F is the fraction of the dose that eventually reaches the systemic circulation,(Xa)0 is the administered dose, V is the apparent volume of distribution of a drug,
and tmax is the peak time.
Since the term ðKa F ðXa Þ0 Þ=ðV ðKa  KÞÞ in Eq. 2.2 constitutes the intercept of
the plasma concentrations against the time proﬁle, Eq. 2.3 can be written asðCp Þmax ¼

ðCp Þmax ¼ Iðektmax  eka tmax Þð2:3Þ

where I is the intercept (mg/mL) of the plasma concentrations against time proﬁle.

2.3. Area under the Plasma Concentration Time Curve
This parameter represents the extent of absorption of a drug following the administration of a dosage form. The greater the fraction of the dose that reaches the generalcirculation the greater is the extent of the absorption and, hence, ðAUCÞ1
0 . The termðAUCÞ1,expressed
asmg/mL/hr,
for
a
drug
followingits
administration
by various
0
extravascular routes or various dosage forms that are administered extravascularly,
is determined by employing the following equation:

Ka F ðXa Þ0 1
1ðAUCÞ1¼
ð2:4Þ
0V ðKa  KÞ K Ka
All the terms of the Eq. 2.4 have been deﬁned previously. Eq. 2.4 can further be
reduced to© 2005 by Taylor & Francis Group, LLC

538

Jambhekar




1
1

ð2:5Þ
K Ka
the intercept in Eq. 2.5 being the intercept of the plasma concentration time proﬁle.
The extent of absorption can also be determined by using the following equation:ðAUCÞ10 ¼ Intercept

F ðXa Þ0
ð2:6ÞVK
where, the term VK is the systemic clearance of the administered drug. This parameter being independent of the route of administration, the formulation, and theextravascularly administered dosage form, it is ostensible that the extent of absorption [i.e., ðAUCÞ10 ] is controlled by the product of the fraction of the administereddose reaching the general circulation and the administered dose [i.e., F(Xa)0].
ðAUCÞ10 ¼

2.4. Factors Affecting the Bioavailability
There are a number of factors responsible for the variation in bioavailability.
Broadly speaking, these factors can be classiﬁed as patient related or dosage form
related. Patient related factors include age, disease state, abnormal genetic characteristics, and gastrointestinal physiology. The detailed discussion on these factors isbeyond the scope of the objectives of this chapter.
Dosage form related factors include formulation and manufacturing related
variables such as particle size, type, and quantity of excipient used, method of manufacturing, compression pressure, derived properties of the powder, and many otherfactors.
The fact that the bioavailability of a drug may be signiﬁcantly affected by its
physical state of the drug and the dosage forms via which it is administered has beenunequivocally demonstrated. And, because drugs are administered through dosage
forms, these dosage forms should have adequate stability, consistent bioavailability,
and uniform composition.
Following the administration of a drug through a solid dosage form, asequence of steps are required before the drug reaches the systemic circulation. As
shown in Figure 2, an orally administered solid dosage form undergoes disintegration and deaggregation, followed by the dissolution of the drug. The dissolved drug
molecules must penetrate the gastrointestinal membrane and picked up by the blood.
Each of the steps involved may limit how fast the drug molecules reach the generalcirculation and, therefore, site of action. The step that offers the maximum resistanceis referred to as the rate-limiting step. Which step will be rate limiting, on the other
hand, will depend on the physicochemical properties of the dosage form and the physiology of the gastrointestinal tract. The focus of the discussion here, however, will
be on the physicochemical properties of the dosage form.
As illustrated in Figure 2, solid dosage form must disintegrate or deaggregate
before much of the drug is available for absorption. Drug dissolution subsequently
occurs from the resulting granules. Therefore, the properties of granules are important in understanding how dissolution is inﬂuenced by these properties. Following
the ingestion of a solid dosage form, whether or not a drug is deaggregated, it will
not be absorbed until it has dissolved into the luminal ﬂuids of the gastrointestinal
tract. Because of the effects of disintegration and deaggregation on the dissolution,
the remaining discussion will focus on the factors inﬂuencing the dissolution of
the drug.
© 2005 by Taylor & Francis Group, LLC

Bioavailability and Granule Properties

539

Figure 2 Schematic representation of the process of the drug dissolution and its entry into
the general circulation.

2.5. Dissolution and Granule Properties
Amongst available dosage forms, compressed tablets are the most widely used dosage
form. Tablets are generally obtained by using either wet granulation or directcompression process. Wet granulation process consists of mixing a drug with otherpowdered material and wetting the mixture with an aqueous or hydroalcoholic solution of a suitable binder such as gelatin, starch, or polyvinylpyrrolidone. The damp
mass is passed through the screens of 8–12 mesh and dried to produce cohesive
granules. Each granule, in theory, is a blend of an active ingredient and excipients.
The granules ﬂow easily through the hopper into the tablet press and are easily
compressed.
Many derived properties of the powder greatly inﬂuence the granule properties,
which, in turn, inﬂuence the dissolution of an active ingredient from the dosage
form. These derived properties include powder density, porosity, speciﬁc surface,particle number, and powder ﬂow. These derived properties are, in essence, determined by the particle size and size distribution. Consequently, particle size and size
distribution play a vital role in inﬂuencing the bioavailability of drugs, particularly,
when dissolution is the rate-limiting step in the absorption process. The importantrole these properties play in inﬂuencing the bioavailability must, therefore, be recognized and taken into consideration during optimization of a dosage form formulation. For example, a smaller particle size is desirable, if the drug is hydrophobic,
to improve the drug dissolution due to increased speciﬁc surface; however, too smalla particle size may adversely affect the powder ﬂow and content uniformity of adosage form. Other derived powder properties like true and bulk density and particle
size will play an important role in the mixing of powder blends, prior to granulationand compression. Powder ﬂow is another derived property of importance. Flow of
the powder and granules can present difﬁculties in the manufacturing of a tablet© 2005 by Taylor & Francis Group, LLC

540

Jambhekar

dosage form, which, in turn, can affect the content uniformity of a drug and thebioavailability.
Many processes used in the tablet manufacturing greatly inﬂuence the dissolution rates of the active ingredient. The method of manufacture, the size, the moisture
content, age and the ﬂow property of the granules, the order of mixing of ingredientsduring the granulation, as well as the compression force employed in the tableting
process, all contribute to the dissolution characteristics of the ﬁnal product and,
therefore, may be the bioavailability of a drug from the ﬁnished product.
Several studies have demonstrated that the granulation process, in general,enhances the dissolution rate of poorly soluble drugs (1). The use of diluents and ﬁllers such as starch (2), anhydrous (3) and spray dried lactose (4,5), microcrystalline
cellulose (6), and compression force, particle size and lubricants (7) tends to enhance
the hydrophilicity of the active ingredients and improve their dissolution characteristics. In this regard, the wet granulation procedure was considered a superior
method compared to other methods. However, newer tableting machines and excipients, accompanied by careful formulation and proper mixing sequence, will permit
preparation of tablets with good dissolution characteristics and not dictated by
the method of preparation per se.
Marlow and Shangraw (8) reported that sodium salicylate tablets prepared bydirect compression with spray dried lactose uniformly exhibited more rapid andcomplete dissolution compared to those prepared by wet granulation. Furthermore,
it was reported that the presence of disintegrate in the dry compression was essential
for good dissolution. Finholt et al. (9) reported, in a separate comparative study, utilizing phenobarbital tablets that were manufactured by both wet and dry granulationthat both procedures yielded comparable dissolution rates provided a disintegrate
was incorporated and mixed with drug before dry granulation. However, the incorporation of disintegrate following the dry granulation of a drug resulted in slower
dissolution rates.
In the manufacturing of tablets by the conventional wet granulation method,
there are many independent factors that affect the property of granules and, therefore, the dissolution rate. Recent advances in granulation technology and theemployment of high-shear mixers and ﬂuid bed granulating equipment have helped
to identify several critical in-process variables. The systematic control of variables
such as the type and time of mixing of the granules, time and temperature of drying,
blending time with lubricant, age of the granules, moisture content of the granules at
the time of compression, and the tablet crushing strength are of importance to ensure
the consistency in the dissolution and, hence, bioavailability.
In early studies on the physics of tablet compression, Higuchi et al. (10) recognized the inﬂuence of compressional forces employed in the tableting process on theapparent density, porosity, hardness, disintegration time, and average particle size ofthe compressed tablets. Hardness is a measure of resistance of a dosage form to themechanical deforming. It is a function of high compression forces used in the manufacturing, and it may change with the aging of granules. Higuchi et al. (10) reported
a linear relationship between hardness and the logarithm of the compressional force,and the speciﬁc surface of the compressed tablets was found to undergo marked
changes during the compressional process. The high compression may increase thespeciﬁc surface and, hence, may enhance the dissolution. On the other hand, the highcompression may also inhibit the wettability of a tablet due to the formation of
a ﬁrmer and more effective sealing layer of the lubricant due to high pressure andtemperature that accompany a strong compressional force. Levy et al. (2) reported© 2005 by Taylor & Francis Group, LLC

Bioavailability and Granule Properties

541

that salicylic acid tablets, when prepared by double compression, showed an increasein the dissolution with an increase in the pre-compression pressure due to fracturingof drug particles at higher pressure. The higher compression may also produce
slower dissolution, at least in the initial period, due to an increased difﬁculty of ﬂuid
penetration into the compressed tablets. Luzzi et al. (11) and Jalsenjak (12) observed
the dissolution rate of sodium phenobarbital to be inversely proportional to thehardness from tablet and microcapsule, respectively.
Another important granule property that inﬂuences the dissolution of drug isthe moisture content of the granule at the time of compression. Chowhan et al.
(13–17) studied the effect of moisture content and crushing strength on ticlopidinehydrochloride tablet friability and dissolution. It was observed (16) that at the moisture content of 1–2%, the drug dissolution was inversely related to the tablet crushingstrength. However, at the moisture content level of 3–4%, there was no clear relationship between the dissolution and the crushing strength.
In later studies by Chowhan et al. (14,17), it was reported that the granules prepared by high-speed shear mixer were less porous than those prepared by planetary
mixer, and the porosity of the tablet may improve the dissolution of drug by facilitating solvent penetration provided the entrapment of air in the pores is minimized
or avoided.
In yet another important study, Levy et al. (2) studied the effect of the granulesize on the dissolution rate of salicylic acid tablets and found that the dissolution rateincreased with a decrease in the granule size; the increase in dissolution rate, however, was not proportional to the increase in the apparent surface area of the granules. Furthermore, it was also reported that the dissolution rate decreased
signiﬁcantly with the increase in the age of the granules.
The chemical components of the formulation have also been shown to prolong
disintegration time, which subsequently affect the drug dissolution and bioavailability. Inert ﬁllers have been found to potentiate the chemical degradation of active
ingredient causing alteration in the disintegration and dissolution time of compressedtablets to change with storage. Alam and Parrott (18) have shown that hydrochlothiazide tablets, granulated with acacia and stored at temperatures ranging fromroom temperature to 80 C increased in hardness with time. This was reﬂected inincreased disintegration and dissolution time. On the other hand, tablets granulatedwith starch and polyvinylpyrrolidone did not show any change in disintegration anddissolution time.

3. CONCLUSION
Drug availability following the oral dosing may be thought of as the result of thefollowing steps:
1. Getting the drug into solution.
2. Moving the drug molecules through the membrane of the gastrointestinal
tract.
3. Moving the drug away from the site of administration into the generalcirculation.
It is clear from the discussion that the bioavailability of drugs, particularly
poorly soluble drugs, mainly depends on the ability of the drug to dissolve at the siteof administration. The dissolution, in turn, especially from solid dosage forms such
© 2005 by Taylor & Francis Group, LLC

542

Jambhekar

as tablet and capsule, depends on the powder properties, granule properties, and theprocessing variables used in the manufacture of the dosage forms. The granule properties and other variables, which determine and inﬂuence the granule properties, willserve as major topics of discussion in subsequent chapters. Knowledge of these factors and their role in inﬂuencing the bioavailability of a drug will allow the formulators to develop an optimum drug dosage form by selecting the process andpreparation variables involved in a rational manner.

REFERENCES
1. Solvang S, Finholt P. Effect of tablet processing and formulation factors on dissolution
rates of active ingredient in human gastric juice. J Pharm Sci 1970; 59:49–52.
2. Levy G, Antkowiak J, Procknal J, White D. Effect of certain tablet formulation factors
on dissolution rate of the active ingredient II: granule size, starch concentration, andcompression pressure. J Pharm Sci 1963; 52:1047–1051.
3. Batuyios N. Anhydrous lactose in direct tablet compression. J Pharm Sci 1966; 55:
727–730.
4. Gunsel W, Lachman L. Comparative evaluation of tablet formulations prepared byconventionally processed and spray dried lactose. J Pharm Sci 1963; 52:178–182.
5. Duvall R, Koshy K, Dashiell R. Comparative evaluation of dextrose and spray driedlactose in direct compression systems. J Pharm Sci 1965; 54:1196–1200.
6. Reier G, Shangraw R. Microcrystalline cellulose in tableting. J Pharm Sci 1966; 55:
510–514.
7. Iranloye T, Parrott E. Compression force, particle size, and lubricants on dissolution
rates. J Pharm Sci 1978; 67:535–539.
8. Marlow E, Shangraw R. Dissolution of sodium salicylate from tablet matrices preparedby wet granulation and direct compression. J Pharm Sci 1967; 56:498–504.
9. Finholt P, Pedersen P, Solvang R, Wold K. Medd Norsk Farm Selsk 1966; 28:238.
10. Higuchi T, Rao A, Busse E, Swintosky J. The physics of tablet compression II: the inﬂuence of degree of compression on properties of tablets. Am Pharm Assoc Sci Ed 1953;
42:194–200.
11. Luzzi L, Zoglio M, Maulding H. Preparation and evaluation of the prolonged releaseproperties of nylon microcapsules. J Pharm Sci 1970; 59:338–341.
12. Jalsenjak I, Nicolaidou C, Nixon J. Dissolution from tablets prepared using ethylcellulose microspheres. J Pharm Pharmacol 1977; 29:169–172.
13. Chowhan ZT, Palagyi L. Hardness increase induced by partial moisture loss in compressed tablets and its effect on in vitro dissolution. J Pharm Sci 1978; 67:1385–1389.
14. Chowhan ZT. Moisture, hardness, disintegration and dissolution interrelationships incompressed tablets prepared by the wet granulation process. Drug Dev Ind Pharm
1979; 5(1):41–62.
15. Chowhan ZT. Role of binders in moisture-induced hardness increase in compressedtablets and its effect on in vitro disintegration and dissolution. J Pharm Sci 1980;
69:1–4.
16. Chowhan Z, Yang I, Amaro A, Chi L. Effect of moisture and crushing strength on tablet
friability and in vitro dissolution. J Pharm Sci 1982; 71:1371–1375.
17. Chowhan Z, Chatterjee B. A method for establishing in process variable controls for
optimizing tablet friability and in vitro dissolution. Int J Pharm Technol Prod Manuf
1984; 5(2):6–12.
18. Alam AS, Parrott EL. Effect of aging on some physical properties of hydrochlorothiazide
tablets. J Pharm Sci 1971; 60:263–266.

© 2005 by Taylor & Francis Group, LLC

Bioavailability and Granule Properties

543

RECOMMENDED READING
Abdou HM. Dissolution, Bioavailability and Bioequivalence. Easton, PA: Mack Publishing
Company, 1989.
Blanchard J, Sawchuk R, Brodie B, eds. Principles and Perspectives in Drug Bioavailability.
Basel, Switzerland: S. Krager AG, 1979.
Gibaldi M. Biopharmaceutics and Clinical Pharmacokinetics. 4th. Philadelphia, PA: Lea andFebiger, 1991.
Jambhekar S. Micromeritics and rheology. In: Ghosh and Jasti, eds. Theory and Practice ofContemporary Pharmaceutics. Boca Raton, FL: CRC Press. In press.
Leeson LJ, Carstensen J, eds. Dissolution Technology. Washington, DC: Academy of Pharmaceutical Sciences, 1974.
Stavchansky SA, McGinity JW. Bioavailability. In: Lieberman HA, Lachman L, Schwartz JB,
eds. Tablet Technology Pharmaceutical Dosage Forms: Tablets. Vol. 2. 2nd ed. New
York: Marcel Dekker, Inc., 1990.

© 2005 by Taylor & Francis Group, LLC

20
Process Analytical Technology
D. Christopher Watts and Ajaz S. Hussain
Office of Pharmaceutical Science, Center for Drug Evaluation and Research,
Food and Drug Administration, Bethesda, Maryland, U.S.A.

1. INTRODUCTION
Pharmaceutical granulation is a critical unit operation that is frequently utilized tomodulate attributes of powder mixtures to aid in further processing (e.g., compaction or encapsulation), as today few pharmaceutical products are granules. The granulation processes must be designed to impart a high degree of control on many
important physical attributes, such as granule size distribution, shape, content uniformity, moisture content and distribution, porosity, density, tensile strength, andsurface morphology. These physical attributes are often critical to process-abilityof granulations and for ﬁnal product quality and performance (e.g., content uniformity, dissolution, stability, and bioavailability). An optimally designed granulation
unit operation can be an excellent tool for minimizing variability and thereby reducing the risk of poor quality. Traditionally, granulation has been utilized to manage
lot–lot and supplier–supplier variability in the physical attributes of pharmacopiealmaterials—excipients and drug substances.
Over the last three decades signiﬁcant scientiﬁc and technological advances
have occurred in pharmaceutical granulation processes. During this period, thepractice of pharmaceutical granulation, especially wet granulation, has made significant progress in moving from an art to a more science and engineering foundation. If we use ‘‘granulation end point’’ in wet granulation as a gauge tomeasure this progress, the practice of granulation end point moved from an operator dependent evaluation (i.e., observing the behavior of a hand compacted mass)
to a time dependent end point and, in some cases, a more predictive end-point
criteria. The next few steps in this evolutionary process can be envisioned to berobust metrics of granule functionality, the ability to predict optimal granulation
processing conditions and end points from an understanding of the attributes ofraw materials and feed-forward control. Furthermore, a mechanistic understanding
the granulation process and the ability to predict the impact of granule properties
on product performance seems to be a worthy and achievable goal in the near
future.
The objectives of this chapter are to discuss the FDA’s Process Analytical
Technology (PAT) framework using selected literature examples on granulation
545© 2005 by Taylor & Francis Group, LLC

546

Watts and Hussain

operations. This discussion is primarily to illustrate certain aspects of the PAT
deﬁnition and tools. As outlined in the draft guidance, ‘‘Process Analytical Technology (PAT) is deﬁned as a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality andperformance attributes of raw and in-process materials and processes with the goalof ensuring ﬁnal product quality’’ (1). It should be noted that the primary motivationof PAT is to understand manufacturing processes through identiﬁcation of all relevant sources of variability and their impact on product quality, in order to designand develop monitoring and control strategies to minimize variability in the ﬁnal
product. Therefore, the term analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical, and risk analysis conducted in an
integrated manner. Simply, analytical is interpreted as ‘‘analytical thinking,’’ not
only chemical analysis.
The focus on process understanding comes from the basic tenet of building, nottesting, quality into products. This is a fundamental tenet championed by Deming,
Juran, and others (2,3). It is important to emphasize that considering any unit operation (granulation or otherwise) in isolation from the entire manufacturing process
would be incomplete in meeting the desired product quality attributes, as eachprocedure in the manufacturing process should be directed at meeting the needsof subsequent manufacturing operations and, ultimately, ﬁnal product quality.
For example, how do attributes of the raw materials and the blend (assuming thisunit operation precedes granulation), and the inherent variability in these attributes
impact an optimal granulation process and end point? This is a critical question to
be addressed as one designs a granulation process and its control strategy. Equallyimportant is the question: what are the critical attributes of the granules for theirsubsequent processing and ﬁnal product quality?

2. BACKGROUND
At the July 2001 meeting of the FDA’s Advisory Committee for Pharmaceutical
Science (ACPS), the Ofﬁce of Pharmaceutical Science proposal to facilitate application of modern pharmaceutical engineering principles and new technologies inpharmaceutical development and manufacturing received an enthusiastic endorsement by the ACPS (4). This proposal was further elaborated and discussed at
the November 2001 and April 2003 meetings of the Science Board to the FDA(5,6), and once again, received strong support. These meetings were the beginningof the FDA’s PAT Initiative and the broader CGMP’s for the 21st Century Initiative: A Risk-Based Approach (7,8). The PAT Initiative was further developed
through public discussions at the PAT—Subcommittee of ACPS and numerous
scientiﬁc conferences and workshops such as the American Association of Pharmaceutical Scientists (AAPS) Arden House, International Forum on Process Analytical Chemistry (IFPAC), International Society of Pharmaceutical Engineers (ISPE),and Parenteral Drug Association (PDA). These discussions led to the developmentof the ﬁnal FDA guidance ‘‘PAT—A Framework for Innovative Pharmaceutical
Manufacturing and Quality Assurance’’ (1). The following section from the ﬁnal
guidance provides an excellent summary of the issues FDA is trying to address
with its initiatives.
Conventional pharmaceutical manufacturing is generally accomplished usingbatch processing with laboratory testing conducted on collected samples to ensure© 2005 by Taylor & Francis Group, LLC

Process Analytical Technology

547

quality. This conventional approach has been successful in providing quality
pharmaceuticals to the public. However, today signiﬁcant opportunities exist for
improving the efﬁciency of pharmaceutical manufacturing and quality assurance
through the innovative application of novel product and process development, process controls, and modern process analytical chemistry tools. Unfortunately, thepharmaceutical industry generally has been hesitant to introduce new technologies
and innovative systems into the manufacturing sector for a number of reasons.
For example, one reason often cited is regulatory uncertainty, which may result fromthe perception that our existing regulatory system is rigid and unfavorable to theintroduction of new technologies. In addition, a number of scientiﬁc and technicalissues have been raised as possible reasons for this hesitancy. Nonetheless, industry’s
hesitancy to broadly implement new pharmaceutical manufacturing technologies isundesirable from a public health perspective. The health of our citizens and animals
in their care depends on the availability of safe, effective, and affordable medicines.
Efﬁcient pharmaceutical manufacturing is a critical part of an effective U.S. healthcare system.
In the future, pharmaceuticals will have an increasingly prominent role inhealth care. Pharmaceutical manufacturing will need to employ innovation, cutting edge scientiﬁc and engineering knowledge, along with the best principles ofquality management to respond to the challenges of new discoveries (e.g., novel
drugs and nanotechnology) and ways of doing business (e.g., individualized
therapy, genetically tailored treatment). Regulatory policies must also rise to thechallenge.
In August 2002, recognizing the need to free industry from its hesitant perspective, the FDA launched a new initiative entitled Pharmaceutical cGMPs for the 21stCentury: A Risk-Based Approach. This initiative has several important goals, which
ultimately will help improve the American public’s access to quality health careservices. The goals are intended to ensure that: The most up-to-date concepts of risk management and quality systems
approaches are incorporated into the manufacture of pharmaceuticals
while maintaining product quality.
 Manufacturers are encouraged to use the latest scientiﬁc advances in pharmaceutical manufacturing and technology.
 The Agency’s submission review and inspection programs operate in acoordinated and synergistic manner.
 Regulations and manufacturing standards are applied consistently by the
Agency and the manufacturer, respectively.
 Management of the Agency’s Risk-Based Approach encourages innovationin the pharmaceutical manufacturing sector.
 Agency resources are used effectively and efﬁciently to address the most signiﬁcant health risks.
Pharmaceutical manufacturing continues to evolve with increased emphasis on
science and engineering principles. Effective use of the most current pharmaceuticalscience and engineering principles and knowledge—throughout the life cycle of a
product—can improve the efﬁciencies of both the manufacturing and regulatory processes. This FDA initiative is designed to do just that by using an integrated systems
approach to regulating pharmaceutical product quality. The approach is based on
science and engineering principles for assessing and mitigating risks related to poor
© 2005 by Taylor & Francis Group, LLC

548

Watts and Hussain

product and process quality. In this regard, the desired future state of pharmaceutical manufacturing may be characterized as follows:
1. Product quality and performance are ensured through the design of effective and efﬁcient manufacturing processes.
2. Product and process speciﬁcations are based on a mechanistic understanding of how formulation and process factors affect product performance.
3. Continuous real-time quality assurance.
4. Relevant regulatory policies and procedures are tailored to accommodate
the most current level of scientiﬁc knowledge.
5. Risk-based regulatory approaches recognize:The level of scientiﬁc understanding of how formulation and manufacturing process factors affect product quality and performance.
The capability of process control strategies to prevent or mitigate therisk of producing a poor-quality product.

3. PAT AND PROCESS UNDERSTANDING
The PAT framework is intended to support innovation and efﬁciency in pharmaceutical development, manufacturing, and quality assurance. It utilizes process understanding as its foundation to facilitate innovation by industry and risk-based
regulatory decisions. For processes that are well understood, signiﬁcant reduction
in regulatory requirements for both CMC review and cGMP inspection may berealized. In the context of granulation one can describe three levels of process
understanding: (1) all critical sources of variability in quality and performance are
identiﬁed and explained; (2) material and process variability is managed by theprocess design; and (3) quality attributes of the granulation and the ﬁnal productcan be accurately and reliably predicted. Ultimately, the ability to accurately andreliably predict product quality attributes, for example via mathematical models,
may be considered to reﬂect a high degree of process understanding.
Obtaining an increased understanding of the granulation process requires amultidisciplinary approach, combining expertise and scientiﬁc principles fromseveral ﬁelds, including material science, pharmaceutics, engineering, and mathematics. The process knowledge should grow when organized knowledge management programs are instituted to collect appropriate information over the life cycleof a speciﬁc product and from information gathered from development and manufacturing experience of other products. The following expression is an initial attemptthat brings many of the key elements (i.e., design, predictability, and capability)that provide a basis for assessing process understanding (PU) in a summary form.
The triple integration function is utilized to symbolize the need for integration
across: (1) scientiﬁc disciplines, (2) across organizations, and (3) over time (lifecycle).
ZZZ
PU ¼
ðDesignÞ ðPredictabilityÞ ðCapabilityÞ
Successful implementation of the PAT framework will require cooperation andcollaboration across scientiﬁc disciplines and divisions within an organization suchas R&D, manufacturing, quality, and information/knowledge management. Such
© 2005 by Taylor & Francis Group, LLC

Process Analytical Technology549

cooperation and collaboration within the FDA organization is also necessary for
science and risk-based regulatory decisions; hence, the FDA established a teamapproach for review and inspection for PAT (the FDA PAT Team).

4. PAT TOOLS AND THEIR APPLICATION
There are a variety of tools available to facilitate increased understanding andprovide an integrated, systems approach to measuring, analyzing, optimizing,
controlling, and modeling of the granulation process. Many of these tools are wellestablished and utilized frequently in many industrial sectors, and are beginning toﬁnd wider utility in the pharmaceutical industry.

4.1. Multivariate Tools for Design, Data Acquisition, and Analysis
Pharmaceutical products are complex multifactorial systems; consequently, the‘‘one-factor-at-a-time’’ approach to experimentation is often insufﬁcient for identifying and addressing interactions between product and process variables. Whenattempting to identify the critical product and process variables with signiﬁcanteffects on ﬁnal product quality, a statistically sound experimental design is essential.
Having a sound experimental design not only increases the efﬁciency of experimentation, but also identiﬁes interactions of the variables, providing opportunities to
efﬁciently and accurately identify the ‘‘best’’ product and process parameters withvarious optimization techniques.
For example, pharmaceutical companies that utilize structured design ofexperiments are not only likely to develop robust product and processes, but are alsoable to clearly articulate why certain variables are critical and justify acceptable
ranges for these critical variables to ensure quality. This approach is often essential
to minimize manufacturing problems during routine production, especially forprocesses that have a ﬁxed time as end point. Although the frequently used ‘‘ﬁxed
granulation time’’ provides a means to demonstrate ‘‘process validation’’ in theconventional ‘‘three-batch’’ mode, it presupposes that the ﬁxed time is optimal for
addressing the raw material variability encountered in routine production. This
source of variability is often underestimated during product development and during
demonstration of ‘‘process validation’’ under very controlled conditions (e.g., use of
the same lot of raw materials, etc.). Manufacturing difﬁculties and out of speciﬁcation results, with no clear root cause, for ‘‘validated’’ processes increases production
cycle time, results in rejection or recalls, and erodes regulatory and public
conﬁdence.
Sahni et al. (9) have described a general framework for utilizing an appropriate
experimental design to identify critical process parameters and using multivariatetechniques for data analysis. Speciﬁcally, the authors investigated two material
streams and ﬁve different process variables. Using a full factorial design to probe
the effects of these variables and their interaction(s) would require 27, or 128,experiments. In order to take a more efﬁcient, yet structured approach, a fractional
factorial design (using 32 experiments) was employed to identify critical material andprocess attributes.
Because the system described above is multifactorial, a simple univariate
approach to data analysis would likely not elicit the critical factors. In that regard,© 2005 by Taylor & Francis Group, LLC

550

Watts and Hussain

principal component analysis (PCA) and partial least squares (PLS) regression,
typical multivariate analysis techniques, were used for analyzing data from the 32
experiments. Several sources are available for in-depth understanding of these techniques (10,11).
Brieﬂy, PCA models the data in terms of the signiﬁcant factors, or ‘‘principal
components,’’ which describe the systematic variability of the data. PCA also
describes the data in terms of ‘‘residuals’’ that represent the noise in the system.
PLS may be described as a method for constructing predictive models from data setswith many collinear factors. Both have received considerable attention in the analysis of multivariate data.
A group of investigators from the Netherlands employed similar multivariatetechniques for modeling the manufacture of tablets, using wet granulation for
optimization and in-process control (12). Again, material and process attributes were
investigated using a systematic approach to identify the critical process parameters/material attributes having a signiﬁcant effect on tablet quality. Once identiﬁed, theauthors developed a strategy for in-process control of the critical variables, such thattablet quality could be ensured and predicted via the developed models, throughout
the production process. Consequently, a test of the ﬁnal product/tablet would
conﬁrm the prediction of product quality, thereby validating both the processcontrol strategy and the model.
In order to adequately evaluate these complex systems, multivariate data
analysis techniques must be used. The examples previously discussed highlight only
a few approaches to multivariate data acquisition and analysis. There are many
approaches for using these tools to obtain an increased understanding of granulation, and to elicit critical process/material attributes, as well as their relationshipwith ﬁnal product quality attributes, for controlling the manufacturing process.
4.2. Process Analyzers
In terms of innovation, some of the most signiﬁcant advances have occurred in thearea of process analyzers, and there are numerous examples of the application ofthese tools to obtain a greater understanding of the granulation process. Certainly,
once critical process and material attributes have been identiﬁed, an appropriate tool
for the analysis of these attributes is crucial for timely analysis, as well as ultimately
controlling the granulation process.
Many studies have detailed the use of various devices for monitoring granulation process conditions, including drive shaft torque (13) and power consumption of
the motor (14) for high-shear granulation processes. Although other investigations
have demonstrated the relationship between these measurements and granule growth(15), they are indirect measures of in-process material quality. As such, any change inthe process or material (including raw material) would affect these measurements.
Consequently, a measurement of the process parameter would not accurately
represent the true value of the quality attribute of interest.
Spectroscopic sensors, most notably near infrared (NIR), have received
signiﬁcant attention in the analysis and control of the granulation process. Rantanen
et al. have published several examples on the use of NIR for in-line measurement ofmoisture and particle size during ﬂuid-bed granulation (16,17), as well as automationof the granulation process (18). Using sensors in this manner provides insight into
the process, allowing the direct measurement and nondestructive analysis of‘‘samples’’ in the product stream.
© 2005 by Taylor & Francis Group, LLC

Process Analytical Technology

551

These sensors have also been used to elicit physical information about the
granules, such as particle size, to understand (and subsequently control) the impactof other material attributes and process parameters on product quality. For example,
Watano et al. developed a system for monitoring granule growth via an imaging system, which employed, among other items, a CCD camera (19) and an image probe
inserted into a high-shear granulator. The system was used not only for monitoring
granule growth, but also for control of the high-shear granulation process.
4.3. Process Control Tools
Currently, the end point of most granulation processes are based on measurements oftime (i.e., add binder for t1 min, mass for t2 min, etc.) or process parameters (such as
power or torque as described earlier). However, a direct measure of the critical/
desired product quality attribute (particle size, density, moisture, etc.) would be ideal
for its control. Subsequent determination of granulation end point would therefore bebased on a direct measure of the desired quality attribute, rather than it being inferredfrom process parameters, and later conﬁrmed through laboratory measurements.
Materials entering the granulation process are widely known to vary, especiallyin their physical attributes. The granulation process should therefore manage thisvariability, and consequently mitigate its risk to product quality by an integrated
approach to process control. Additionally, it is important to note that the functionality of incoming material must be measured and understood. This information
should ideally be ‘‘fed forward’’ to adjust/control the following unit operations toensure optimal processing and end-point establishment, such that starting variability
is minimized and not transferred to the ﬁnal product. Limits are often necessary on
incoming materials to ensure their variability does not exceed the design space used
for developing a given control strategy, lending data from the sensors open toerroneous interpretation/analysis and thus introducing a failure risk to the control
strategy. However, such excursions from the design space, if and when they occur,
can provide an opportunity for its expansion, as well as expand the generalknowledge base of the process.
Many examples of controlling the granulation process can be found in theliterature. Following development of the on-line imaging system for monitoring granule growth, Watano et al. incorporated a fuzzy control system for granule growth (20).
Granule growth was measured via the imaging system and fed into the fuzzy control
system. Based on measurements of granule size, the fuzzy control system adjusts
various process parameters in order to obtain the desired particle size distribution.
Several other investigations have also focused on the use of NIR for moisture
analysis and control during granulation, including Frake et al. (21). In their study,
the investigators employed the use of an NIR sensor for real-time determinationof the moisture content and particle size distribution of a ﬂuid-bed granulation. This
control strategy permits any necessary modiﬁcations to process conditions, as well as
the identiﬁcation of a process end point, once the desired moisture content andparticle size are obtained.
Although a few examples of traditional ‘‘feed-back’’ control for granulation
processes were described, the concept of ‘‘feed-forward’’ control has been investigated as well. Paul Mort et al. discuss the aspects of feed-forward control associatedwith a continuous granulation process (22). Based on the amount of recycled ﬁnes
reintroduced into the system, and attributes of the incoming materials, the binder
solution is modiﬁed to obtain the desired granule density and particle size.
© 2005 by Taylor & Francis Group, LLC

552

Watts and Hussain

Appropriate strategies for process control provide an assurance, with every
product manufactured, that the desired product quality will be obtained. A test of
the ﬁnal product thereby ‘‘validates’’ that the process is indeed under control.
4.4. Continuous Improvement and Knowledge Management Tools
Continuous learning of the production process also allows for optimization of processparameters that may not have been fully explored during development. Additionally,
any changes to a given process, granulation or otherwise, could be considered lowrisk because of the level of process understanding achieved and demonstrated,
thereby reducing the regulatory burden to change control/management. Ultimately,
an inverse relationship exists between the level of process understanding and the riskof producing a poor-quality product. Thus, a focus on process understanding canfacilitate risk-based regulatory decisions and innovation (1).
Continuous learning through data collection and analysis over the life cycle ofa product is crucial. However, information gleaned from the production process of
one product should not be considered in isolation. Management and generalizationof knowledge from one product to another can allow for the development of expert
systems and a large knowledge base that can be used to facilitate future processdevelopment, scale-up, optimization, etc.
For example, expert systems such as neural networks can be employed tomodel various stages of the production process, including granulation. Investigators
in Finland have noted the advantages of such systems in modeling the ﬂuid-bed
granulation process (23). Results from this investigation demonstrated that the
networks were able to more accurately predict responses to the granulation process
than multilinear stepwise regression analysis.

5. CONCLUSION
Implementing the PAT framework and having a greater understanding of the
manufacturing process has obvious advantages to the pharmaceutical industry, theregulators, and the public health. The PAT Initiative provides a regulatory environment that encourages and facilitates pharmaceutical companies to innovate andemploy the tools necessary to achieve an in-depth understanding of the manufacturing
process. There are many examples in the literature that suggest that active control of
the granulation is not only possible, but may soon become the rule, rather than the
exception. This paper was written prior to the FDAs ﬁnal report on CGMPs for the
21st century. The readers are requested to review this report (http://www.fda.
gov/cder/gmp/gmp2004/GMP_ﬁnalreport2004.htm), in particular the FDA’s White
Paper entitled ‘‘Innovation and Continuous Improvement in Pharmaceutical
Manufacturing’’ available at http://www.fda.gov/cder/gmp/gmp2004/manufSciWP.pdf.
REFERENCES
1. Guidance for Industry: PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. September 2004. http//www.fda.gov/
cder/guidance/6419fnl.htm.
2. Aguayo R. Dr. Deming: the American who taught the Japanese about quality. Fireside
1991; September 15.
© 2005 by Taylor & Francis Group, LLC

Process Analytical Technology

553

3. Juran JM. Juran on quality by design: the new steps for planning quality into goods andservices. Free Press 1992; May 4, revised edition.
4. Advisory Committee for Pharmaceutical Science. Transcript of Meeting, July 2001.
http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3763t1.htm.
5. Science Board to the Food and Drug Administration. Transcript of Meeting, November
2001. http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3799t1.htm.
6. Science Board to the Food and Drug Administration. Transcript of Meeting, April 2003.
http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3944t1.DOC.
7. Food and Drug Administration. Unveils New Initiative to Enhance Pharmaceutical
Good Manufacturing Practices, August 21, 2002. http://www.fda.gov/bbs/topics/
NEWS/2002/NEW00829.html.
8. Food and Drug Administration. Announces New Progress toward ‘‘21st Century’’ Regulation of Pharmaceutical Manufacturing, September 3, 2003. http://www.fda.gov/
cder/gmp/index.htm.
9. Sahni NS, Isaksson T, Tormod Naes. The use of experimental design methodology andmultivariate analysis to determine critical control points in a process. Chemometrics
Intelligent Lab Syst 2001; 56:105–121.
10. Brereton RG. Multivariate Signal Processing in Chemometrics. Application of
Mathematics and Statistics to Laboratory Systems. Chichester, U.K.: Ellis Horwood,
1990:209–237.
11. Wold S, Albano C, Dunn WJ, Edlund U, Esbensen K, Geladi P, Hellberg S, Johansson E,
Lindsberg W, Sjostrom M. Multivariate Data Analysis in Chemistry. Chemometrics:
Mathematics and Statistics in Chemistry. Reidel DDordrecht, The Netherlands 1984:17–95.
12. Westerhuis JA, Coenegracht PMJ, Lerk CF. Multivariate modeling of the tablet
manufacturing process with wet granulation for tablet optimization and in-processcontrol. Int J Pharm 1997; 156:109–117.
13. Lindberg NO, Leander LL, Reenstierna B. Instrumentation of a Kenwood Major domestic type mixer for studies of granulation. Drug Dev Ind Pharm 1982; 8:775–782.
14. Leuenberger H. Scale-up of granulation processes with reference to power consumption
monitoring. Pharm Acta Helv 1983; 29:274–280.
15. Holm P, Schaefer T, Kristensen HG. Granulation in high-speed mixers. Part V: Power consumption and temperature changes during granulation. Powder Technol 1985; 43:213–223.
16. Rantanen J, Rasanen E, Tenhunen J, Kansakoski M, Mannermaa J, Yliruusi J. In-line
moisture measurement during granulation with a four-wavelength near infrared sensor:
an evaluation of particle size and binder effects. Eur J Pharm Biopharm 2000; 50:271–276.
17. Rantanen J, Jorgensen A, Rasanen E, Luukkonen P, Airaksinen S, Raiman J, Hanninen
K, Antikainen O, Yliruusi J. Process analysis of ﬂuidized bed granulation. AAPS
PharmSciTech 2001; 2(4):21.
18. Rantanen J, Kansakoski M, Suhonen J, Tenhunen J, Lehtonen S, Rajalahti T,
Mannermaa JP, Yliruusi J. Next generation ﬂuidized bed granulator automation. AAPS
PharmSciTech 2000; 1(2):10.
19. Watano S, Numa T, Koizumi I, Osaka Y. Feedback control in high shear granulation ofpharmaceutical powders. Eur J Pharm Biopharm 2001; 52:337–345.
20. Watano S, Numa T, Miyanami K, Osaka Y. A fuzzy control system of a high shear
granulation using image processing. Powder Technol 2001; 115:124–130.
21. Frake P, Greenhalgh D, Grierson SM, Hempenstall JM, Rudd DR. Process control andend-point determination of a ﬂuid bed granulation by application of near infrared
spectroscopy. Int J Pharm 1997; 151:75–80.
22. Mort PR, Capeci SW, Holder JW. Control of agglomerate attributes in a continuous
binder-agglomeration process. Powder Technol 2001; 117:173–176.
23. Murtoniemi E, Yliruusi J, Kinnunen P, Merkke P, Leiviska K. The advantages by the useof neural networks in modeling the ﬂuidized bed granulation process. Int J Pharm 1994;
108(2):155–164.

© 2005 by Taylor & Francis Group, LLC

21
Granulation Process Modeling
I. T. Cameron and F. Y. Wang
Particle and Systems Design Centre, School of Engineering,
The University of Queensland, Queensland, Australia

1. MODELING OF GRANULATION SYSTEMSIn this section, we introduce the background to granulation modeling by posing thequestion, ‘‘Why model?’’ and a further one, ‘‘How are models used in granulation
systems technology?’’ The following sections seek to answer these questions anddemonstrate the beneﬁts that can be derived from appropriate granulation processmodeling.
1.1. Motivation for Modeling
There are many motivations for modeling granulation systems that are common to
all process-related modeling. This is an area, that has grown enormously over the last
50 years. Michaels (32) has pointed out that despite the change of particle technology
from an underfunded and widely scattered research enterprise to a thriving globally
recognized engineering discipline over the past 25 years, design and analysis of industrial particulate processes remain rooted in empiricism. Without exception, granulation processes, like most solid-handling operations, continue to be one of the least
understood and hence inefﬁcient in the process industries. Thus, granulation
remained more of ‘‘an art than a science’’ until a decade ago, as stated by Litster(24). Granulation operations were performed by employing popular practice rather
than through systematic scientiﬁcally-based strategies. The ineffectiveness of thisapproach led researchers on a quest to represent the dynamic or steady-state characteristics of systems through a deeper understanding of the relevant phenomena of thephysico-chemical phenomena being studied. Likewise in granulation systems, there
has been a growing interest in the building of models and their deployment toaddress a range of applications.
1.1.1. Beneﬁts
The beneﬁts from the use of modeling include: An increased understanding of the governing mechanisms through endeavoring to represent them in the model description.
555© 2005 by Taylor & Francis Group, LLC

556

Cameron and Wang

 An increased understanding of the relative importance of mechanistic
contributions to the outputs of the process.
 Capturing of insight and knowledge in a mathematically usable form.
 Documentation of research ﬁndings in accessible form for various applications.
 Application of models for improved control performance and process diagnosis.
 Potential reuse of model components for a variety of applications fromdesign through to process diagnosis.
 As a vehicle for new, novel designs of processing equipment.
 As a means to direct further experimentation and process data generation.
1.1.2. Costs
There are several important and not insubstantial costs involved in process modelingincluding: Time to plan, develop, test, and deploy models.
 Personnel with the requisite discipline background to generate effectivemodels through insight and modeling skills.
 The effort in laboratory-scale or plant scale-trials to elucidate process
behavior and the cost of doing so.
 The cost of poor modeling practice in terms of inadequate documentation
through the modeling phases and loss of corporate memory.
1.2. Process Modeling Fundamentals
Process modeling is purpose driven in that a model is developed for a particular area.
These areas could include: Improved control performance through the use of process model-based
control algorithms.
 Optimal performance of granulation systems through model-based optimization of production parameters such as shortest batch time or optimal
product size distribution.
 Improved production scheduling using models to generate improved batchtimes estimates.
 Plant diagnosis for real-time plant operator guidance systems (OGS).
 Extraction of parameter estimates such as rate constants and granulation
kernel parameters.
 Improved design of equipment or development of new designs based on
better understanding and use of mechanistic phenomena.
The resultant model must be ‘‘ﬁt-for-purpose,’’ and this is achieved by having
clearly stated goals for the modeling that are used to help assess the appropriatenessof the model form and the model ﬁdelity required for the job. In particular, modelingrequires a methodology, especially one that is generic in nature.
1.2.1. A Systems Perspective
Models need to be built on a clear systems engineering understanding of the process.
A typical system schematic is seen in Figure 1. For the system (S), we need to clearlydeﬁne the inputs (u), and disturbances (d), to our system as well as the outputs (y)© 2005 by Taylor & Francis Group, LLC

Granulation Process Modeling

557

Figure 1 Schematic of a process system.

and the states of interest (x). The system S converts inputs and disturbances to
outputs and is expressed as:
y ¼ S½u; dð1:1Þ

A model M is a representation of the system that transforms inputs to predicted
outputs y(M) in the form:yðMÞ ¼ M½u; d

ð1:2Þ

How close y and y(M) are is a key question in model validation.
Approaching modeling from a systems perspective provides a clear frameworkfor developing models and identifying the key issues to be considered. Four principal
classes of variables play particular roles in the modeling. They are:Inputs:
Inputs u are the variables that are manipulated to ‘‘drive’’ the system or maintainits condition in the face of changes from disturbances. Typically, we consider suchaspects as binder addition rate or mixing intensity as inputs that we can manipulate.
Disturbances:
Disturbances d are variables over which we do not have clear control. They arise
from raw material properties that might change from batch to batch. They could
be environmental factors such as ambient temperature and humidity. They might be
ﬂuctuations in input voltage to motors or steam pressure that produce temperature
disturbances in heated systems. Principal disturbances in all relevant categories need
to be identiﬁed.
Outputs:
Outputs y are the variables of interest for the designer, operator, or manager.
They might be quality variables that are related to granule properties such as size
distribution, granule moisture, or granule hardness. Other outputs of interest could
be related to product temperature, ﬂowrates, and composition. The outputs arenecessarily measurable in some way, either directly on-line such as PSD or moisture,or via laboratory analysis such as composition.
States:States x of the system represent the internal variables that characterize the system behavior at any point in time.
Finally the system S is a major consideration in modeling because of thevarious ways the real system can be represented by the model M of that system.
Numerous forms of the model M are available. They can have a structure basedon capturing fundamental phenomena from physics and chemistry (‘‘white box’’© 2005 by Taylor & Francis Group, LLC

558

Cameron and Wangmodels) to internal structures based on purely empirical approaches known as‘‘black box’’ models. For black box models, the form is simply a convenient equationthat captures the relationships amongst inputs, disturbances, and outputs.
1.2.2. Modeling Methodology and Workﬂow
Modeling should not be a haphazard activity. It is essential that a consistent anddefensible methodology be adopted. One such methodology is given by Hangos &Cameron (2001) and is seen in Figure 2. Each of the seven key steps is a vital partof any modeling activity, emphasizing that modern process modeling is not justFigure 2 Modeling methodology and workﬂow.
© 2005 by Taylor & Francis Group, LLC

Granulation Process Modeling559

about generating a set of equations. It is a much more holistic activity. It is also iterative in nature as seen in Figure 2.
The key aspects can be summarized as: Goal-set deﬁnition: making clear the reason for the modeling and the goals
to be addressed in the modeling.
 Model conceptualization: clarifying the conserved quantities and the governing mechanisms to be included. Clearly setting out the assumptions underlying the model.
 Modeling data: generating or referencing physical property data or plantdata relevant to model building and model validation.
 Model building and analysis: putting the model together and then analyzing
the model for properties relevant to solution and dynamic properties.
 Model veriﬁcation: ensuring that the coded model in the simulation environment is correctly represented and bug-free.
 Model solution: solving the model numerically or analytically in some
limited circumstances. This can be a challenging task.
 Model calibration and validation: performing parameter estimation and thenvalidating the model against plant or laboratory data.
1.2.3. The Modeling Goal
The modeling goal plays a vital role in the development of the model. Here we
consider the most important general goals and describe brieﬂy what is achieved.
We make reference to the general process system illustrated in Figure 1.
Dynamic simulation problem
The model is developed to predict the system behavior in time. We wish to predict the outputs y, given the inputs u, the disturbance pattern d, the model structure
M with the model parameters p. This is the most common goal.
Design problem
We are interested in calculating certain parameters or design from the parameterset given all the other inputs, model form, disturbances, and a set of desired outputs.
Process control
Regulation and state-driving problems
We aim at designing or computing the inputs u for a prescribed response y ofthe system.
System identiﬁcation problem
We seek to determine the structure of the model M and its parameters p, using
input and output information.
State estimation problem
We attempt to estimate the internal states x of a particular model M.
Fault detection and diagnosis problem
We bring to light the faulty modes and/or system parameters which correspond to the measured input and output data.
These three key areas show the various goals that are often given for modelingof processing systems.

1.3. Approaches to Modeling
There are several approaches to modeling process systems. At one extreme, we havemechanistic modeling that seeks to incorporate fundamental physics and chemistry© 2005 by Taylor & Francis Group, LLC

560

Cameron and Wang

into the model. This is the so-called ‘‘white box’’ approach. At the other end of
the spectrum, we have the ﬁtting of an arbitrary function to the input–output data—
the empirical model. In between, we have the so-called ‘‘gray box’’ models that arenormally what is developed. Some relevant comments follow.
1.3.1. Empirical or Black Box Methods
These models are based on actual plant data, typically in the form of time series of
input and output data at ﬁxed time intervals. The model is built by selecting a model
structure M and then ﬁtting the model parameters to get the best ﬁt of the model tothe data. Model forms such as auto-regressive moving average (ARMA) or autoregressive moving average exogenous (ARMAX) are typically used.
In most cases, techniques are used to vary both the structure and the model
parameters to obtain the ‘‘best’’ or simplest model that gives the ‘‘best’’ ﬁt. Various
information criteria like Akaike’s or Bayesian measures can be used that essentially
get the simplest model for the best ﬁt. It is a form of parsimony in model building.
Many packages such as the MATLABTM Identiﬁcation Toolbox help in such modeling.
This approach can be very useful if no signiﬁcant insight is needed into themodel, but when a model is needed quickly to be used for a control application. The
structural form of the model and the parameter values normally have no physicalsigniﬁcance. The application range of such a model is limited to the range of data,and hence this can be a signiﬁcant limitation. Extrapolation is dangerous.
1.3.2. Mechanistic and Gray-Box Models
Mechanistic models incorporate the underlying understanding of physics and chemistry into the models. Typically, we can identify three major aspects in mechanistic
modeling that cover conservation and constitutive aspects:
 Application of thermodynamic conservation principles for mass, energy,
and momentum and,
 Application of population balances that track particle size distributions asvarious particulate phenomena take place.
 Development of appropriate constitutive relations that deﬁne intensive
properties, mass and heat transfer mechanisms, as well as particle growthand breakage mechanisms.
The development of mechanistic models is far more complex and time-consuming
than it is for empirical models and is only justiﬁed when time permits. The model is to
be used over a wide operating range and the relevant insight in establishing the constitutive relations is available.
Inevitably, even the best mechanistic models require some data ﬁtting, leading
to the concept of ‘‘gray box’’ models. This is the normal practice in industrial modeling of such systems. It means that adequate data must be available to carry out thevalidation studies. This task is particularly difﬁcult for the validation of dynamic
models.
2. KEY FACTORS IN GRANULATION MODELINGThe modeling of granulation system from a mechanistic perspective inevitably means
representing the conservation principles and the constitutive relations that reﬂect the© 2005 by Taylor & Francis Group, LLC

Granulation Process Modeling561

key factors in granulation. We brieﬂy consider these in turn but refer the reader tothe relevant chapters in this handbook for detailed descriptions of the phenomena.
2.1. Conservation Principles
The conservation of mass, energy, momentum, and particle number can be important aspects of granulation modeling.
Mass conservation is crucial and is the fundamental concept for any granulation system. Key factors here will be solids or slurry feed rates, any out ﬂows, and the
addition of binders and additives to the granulation device. Accompanying the massbalance over the device will be the energy balance, from which the intensive propertyof temperature can be estimated.
Of particular importance in granulation systems is the factor of particle populations. The particle size distribution within granulation devices is crucial, and there
are a number of mechanisms that simultaneously occur in the device depending on
the powder properties and operating regime. The challenge is in the description ofthese mechanisms that occur. The following section outlines those mechanisms that
require consideration. Section 3 deals in detail with the development of population
balance representations and their variants.
2.2. Principal Constitutive Mechanisms
There are three principal mechanisms that need to be considered.
2.2.1. Nucleation
Nucleation refers to the formation of initial aggregates that are typically a result of
the interaction between the binder spray droplets and the powder in the device. Thismechanism provides the initial stage for further growth through a number of
mechanisms. A number of nucleation models have been proposed in the literature.
2.2.2. Growth
Granule growth occurs through two key mechanisms that can be distinguished for
discussion purposes. The topic is discussed more fully in ‘‘One-Dimensional Population Balance Models’’.
2.2.2.1. Layering. Layering refers to the taking up of ﬁne particles onto thesurface of larger granules. It is often induced by rolling action and is a means of
granule growth that creates hard, compact granules. A practical layering model is
proposed in ‘‘Optimization and Open-Loop Optimal Control Equations’’ for solving
optimal control of granulation processes.
2.2.2.2. Agglomeration. Agglomeration or coalescence refers to the successful
collision of two particles that result in a composite particle. The success of collisions
can be a function of particle size, binder and powder properties, and operational
factors such as bed height, powder velocity, and shear for mixer granulators. See‘‘Coalescence Kernels’’ for more details.
2.2.3. Breakage
Breakage in high shear and drum granulation is a signiﬁcant issue, and is especiallymore important in high-shear devices. There are various forms of breakage fromcleavage of particles to particle surface attrition where granule is chipped by collision
with other particles, wall, or impeller. Complexity of breakage models extends from© 2005 by Taylor & Francis Group, LLC

562

Cameron and Wangbinary breakage models to full particle distributions represented by breakage andselection functions, or empirical models (38,45,54).
The following sections develop in detail some of the important aspects of granulation process modeling, through the use of population balances and alternative
approaches.

3. REPRESENTING GRANULATION PROCESSES THROUGHPOPULATION BALANCESThe particulate nature of solids is characterized by a number of properties, suchas size, shape, liquid and gas content, porosity, composition, and age. These aredenoted as internal coordinates, whereas Euclidian coordinates, such as rectangularcoordinates (x, y, z), cylindrical coordinates (r, f, z), and spherical coordinates (r, y, f)used to specify the locations of particles, are deﬁned as external coordinates.
The most important property for the characterization of particles is particle
size. Randolph and Larson (36) pointed out that: ‘‘As no two particles will be exactly
the same size, the material must be characterized by the distribution of sizes orparticle-size distribution (PSD).’’ If only size is of interest, a single-variable distribution function is sufﬁcient to characterize the particulate system. If additional properties are also important, multivariable distribution functions must be developed.
These distribution functions can be predicted through numerical simulations using
population balance equations (PBE).
Ramkrishna (35) provided a brief explanation on the population balance equation: ‘‘The population balance equation is an equation in the foregoing number
density and may be regarded as representing a number balance on particles of a particular state. The equation is often coupled with conservation equation for entities in
the particles’ environmental (or continuous) phase.’’In this chapter, both single-variable and multivariable population balances aredescribed. However, emphasis will be placed on the single-variable population
balance equations with size as the only internal coordinate.
3.1. General Population Balance Equations
A population balance for particles in some ﬁxed subregion of particle phase spacecan be conceptually represented as follows:

 
 

density function change
disperse indisperse out¼

in class; location & timethrough boundary
through boundary 
flow inflow outþthrough boundary
through boundary 
grow ingrow outþfrom lower classes
from current class 
birth due todeath due toþcoalescencecoalescence 
break  up in
breakup outþfrom upper classes
from current classð3:1Þ
© 2005 by Taylor & Francis Group, LLC

Granulation Process Modeling563

The superstructure of the general population balance equation can be represented asfollows:@_ f ðx; r; tÞ  Hx  X_ f ðx; r; tÞf ðx; r; tÞ ¼Hr  rmHr ½ Dr f ðx; r; tÞ  Hr  R@tþ Bc ðx; r; tÞ  Dc ðx; r; tÞ þ Bb ðx; r;tÞ  Db ðx; r; tÞð3:2Þ

where f is the multivariant number density as a function of properties and locations;r is the external coordinate vector (also known as spatial coordinate vector) for thedetermination of particle locations; x is the internal coordinate vector for the identiﬁcation of particle properties, such as size, moisture content, and age; Dr is the dispersion coefﬁcient; Ṙ is the velocity vector in the external coordinate system; Ẋ is therate vector in the internal coordinate system; Bc and Dc are birth and death rates forcoalescence, respectively; Bb and Db are birth and death rates for breakage, respectively. The ﬁrst and second terms in the right-hand side of Eq. 3.2 represent dispersion and convection particle transport, respectively, whereas the third quantiﬁes thegrowth of particles with respect to various properties, such as size and moisture. The
birth and death rates for coalescence are given by:
Z

Z

~Þ
1
@ð~
x; r
~; x0 ; r0 Þf ðx; r; tÞf ðx0 ; r0 ; tÞ
bð~
x; r
dVr0
d
@ðx;
rÞ
Ox
Or
Z
Z
Dc ðx; r; tÞ ¼ f ðx; r; tÞ
dVx0
bðx0 ; r0 ; x; rÞfðx0 ; r0 ; tÞ dVr0
Bc ðx; r; tÞ ¼

dVx0

Ox

ð3:3Þ

Or

where b is the coalescence kernel, Ox and Or are integration boundaries for internaland external coordinates, respectively, d represents the number of times identicalpairs have been considered in the interval of integration so that 1/d corrects forx;~rÞ
the redundancy, the term @ð~@ðx;rÞ stands for the coordinate transformation such that~ and ½x0 ; r0 , respectively, before colthe colliding pair with original coordinates ½~
x; rlision should be identiﬁed by the coordinates [x, r] after coalescence. Mathematically,~ðx; rjx0 r0 Þ~ ðx; rjx0 r0 Þ; r
this requires that the density with respect to coordinates ½xmust be transformed into one in terms of (x, r) by using the appropriate Jacobianof the transformation. Ramkrishna (35) showed that the determinant of the Jacobianof the transformation satisﬁes the following equation:


x1
 @~

 @x1

 .
 ..

 @~
 xn

~Þ  @x1
~; r
@ ðx
¼
@ ðx; rÞ  @~r1
 @x1

 @~r
 2
 @x1

 @~r
 3

@x1


..
.





© 2005 by Taylor & Francis Group, LLC

@~
x1
@xn
..
.
@~
xn
@xn
@~r1
@xn
@~r2
@xn
@~r3
@xn

@~
x1
@r1
..
.
@~
xn
@r1
@~r1
@r1
@~r2
@r1
@~r3
@r1

@~
x1
@r2
..
.
@~
xn
@r2
@~r1
@r2
@~r2
@r2
@~r3
@r2


@~
x1 

@r3 
.. 
. 
@~
xn 
@r3 
@~r1 
@r3 
@~r2 
@r3 
@~r3 

@r3

ð3:4Þ

564

Cameron and Wang

The birth and death rates for breakage are described as:ZZ0
Bb ðx; r; tÞ ¼
dVr
bðx0 ; r0 ; tÞPðx; rjx0 ; r0 ; tÞSðx0 ; r0 ; tÞf ðx0 ; r0 ; tÞ dVx0Or

Db ðx; r; tÞ ¼ Sðx; r; tÞf ðx; r; tÞ
0

ð3:5Þ

Ox

ð3:6Þ

0

where b(x , r , t) is the average number of particles formed from the breakage of a0single particle of state (x0 , r) at time t, P(x, r,jx0 , r , t) is the probability density
function for particle from the breakage of state (x0 , r0 ) at time t that have state (x, r),S(x, r, t) is the selection function, which represents the fraction of particles of state(x, r) breaking per unit time.
~ and r0 for theEquations 3.3 and 3.4 and involve three different locations: and r
colliding pair of particles and r for the agglomerated particle. Although this treatment
is general and mathematically rigorous, it could be unnecessarily complicated for engineering applications. A common practice is to assume that these three locations arevery close to each other during the particle collision and granule formation. That is:~  r0  rr
ð3:7ÞThis assumption requires that the phenomenon of fast particle jumps in the system is
not severe, which is achievable in most industrial granulation processes. If Eq. 3.7
holds, Eq. 3.3 and 3.4 can be simpliﬁed considerably to obtain:
Z
~Þ
1
@ ðx
~ ; x0 ; rÞf ðx~ ; r; tÞf ðx0 ; r; tÞdVx0bðxBc ðx; r; tÞ ¼
2 Ox
@ ð xÞ
Z
ð3:8Þ
Dc ðx; r; tÞ ¼ f ðx; r; tÞbðx0 ; x; rÞf ðx0 ; tÞ dVx0
Ox


 @~
x
 1
 @x1

~Þ  .
@ ðx¼ .
@ ð xÞ  .
 @~
 xn

@x1


..
.



@~
x1 

@xn 
.. 
. 
@~
xn 

@xn

Similarly, Eq. 3.5 becomes:Zbðx0 ; r; tÞPðxjx0 ; r; tÞSðx0 ; r; tÞf ðx0 ; r; tÞ dVx0
Bb ðx; r; tÞ ¼

ð3:9Þ

ð3:10ÞOx

In the following, breakage effects have been considered negligible and Eq. 3.7
is always assumed to be valid.
3.2. One-Dimensional (1-D) Population Balance Models
One-dimensional population balance models for both batch and continuous systems
are described in this section as special cases of the generalized population balance
model stated in ‘‘General Population Balance Equations.’’
3.2.1. Batch Systems
For a well-mixed batch system with only one internal coordinate v (particle size), is
Eq. 3.2 reduced to:© 2005 by Taylor & Francis Group, LLC

Granulation Process Modeling

565

@
@
nðv; tÞ ¼  ½Gnðv; tÞ
@t
@vZ
1 v
þ
bðv  v0 ; v0 Þnðv  v0 ; tÞnðv0 ; tÞ dv0  nðv; tÞ
2 0
Z 1

bðv; v0 Þnðv0 ; tÞ dv0

ð3:11Þ

0where n is the one-dimensional number density, G is the growth rate. For notational
clarity, we use f and n to denote the multidimensional and one-dimensional number
density functions, respectively. Both notations bear the same physical signiﬁcance.
Through a comparison of Eq. 3.11 with Eq. 3.2, 3.8, and 3.9, it is easy to observe
the following membership relationships:
v 2 x;

v 0 2 x0 ;~;
ð v  v0 Þ 2 x

G¼

dv _
2 X;
dt

~ Þ @ ðv  v0 Þ
@ ðx
¼
¼1
@ ðxÞ
@v

ð3:12Þ

Equation 3.11 is more frequently applied to industrial granulation processes than its
generalized format described in Eq. 3.2.
3.2.2. Continuous Systems
The population balance equation for continuous systems with one internal coordinate and one external coordinate is given by:
 @
@
@ _
nðv; z; tÞ ¼ 
Z nðv; z; tÞ  ½Gnðv; z; tÞ
@t
@zZ
@v
1 v
0 0
þ
bðv  v ; v Þnðv  v0 ; z; tÞnðv0 ; z; tÞ dv0
2 0
Z 1
 nðv; z; tÞbðv; v0 Þnðv0 ; z; tÞdv0ð3:13Þ

0where the special velocity is deﬁned as:
dz _2Rð3:14Þ
Z_ ¼
dt
Although continuous granulation processes are commonly encountered in the fertilizer and mineral processing industries, they are also performed in the pharmaceutical industry as batch processes employing either high-shear mixers or batch
ﬂuidized-bed granulators. Consequently, most modeling studies on pharmaceutical
granulation have focused on batch processes. However, it is important to obtain complete knowledge of both batch and continuous granulation processes for improved
design and operations.
3.2.3. Coalescence Kernels
It is easy to see that a coalescence kernel is affected by two major factors: (1) collision probability of the speciﬁed pair of particles, and (2) successful coalescence orrebounding after collision. The ﬁrst mainly depends on the particle sizes, granulator
conﬁgurations, particle ﬂow patterns, and operating conditions. The second has been
intensively studied by Liu et al. (25) who identiﬁed the following four most important aspects affecting the success of coalescence: elasticplastic properties, viscous
ﬂuid layer, head of collision, and energy balance. The authors have also observed that
there are two types of coalescence distinguished by particle deformations. That is,© 2005 by Taylor & Francis Group, LLC

566

Cameron and Wang

Table 1 Summary of the Proposed Coalescence Kernel in the Literature
KernelReferencesb ¼ b0(18)ab ¼ b0

ðuþvÞ
b
ðuvÞ

b ¼ b0ðu2=3 þv2=3 Þ
1=uþ1=v(19)(40)

b ¼ aðu þ vÞ

(14)

2

ðuvÞ
ðuþvÞ

k; t < tsb¼
aðu þ vÞ; t > ts

b¼a

(14)
(1)

k: constant, ts: switching timek; w < w
b¼
0; w > wðu þ vÞa
w¼
ðuvÞb

(2)

k, a, b: constantsw: critical granule volume
2b ¼ b0 ð1=u þ 1=vÞ1=2 u1=3 þ v1=3

1=3b ¼ b0 ubu;v ¼

(

1=3

þv



1=3

u

1=3

þv



b1 Types I & II without permanent deformationb2 Type II with permanent deformation
0 rebound(13)

Liu and Litster (2001)

Type I coalescence is not associated with any particle deformation during thecollision, whereas the Type II is accompanied by particle deformations. Liu andLitster (26) further proposed a new physically based coalescence kernel model basedon the criteria developed earlier [Liu et al., (25)]. From these fundamental studies, it
can be determined qualitatively that the coalescence kernels should depend on particle sizes, energy consumption, particle deformability, and most importantly, themoisture content (viscous ﬂuid layer). A historical summary of the proposed coalescence kernels is given in Table 1, which is an extension of the table originally presented
by Ennis and Litster (11) with the new coalescence kernel developed by Liu and Litster(26) and another kernel from aerosol dynamics [Friedlander, (13)].

3.3. Two-Dimensional (2-D) Population Balance Models
In this section, we study a perfect mixing, batch granulation system with two internal(property) coordinates: particle value v and liquid value vL. Because of the perfect© 2005 by Taylor & Francis Group, LLC

Granulation Process Modeling

567

mixing feature, there is no spatial coordinate in the model. However, the proposedmodeling strategy can be easily extended to continuous processes with both internaland external coordinates. The 2-D population balance equation for a batch granulation process is:


@
@ dv
@ dvL
f ðv; vL ; tÞ ¼ 
f ðv; vL ; tÞ f ðv; vL ; tÞ@t@v dt
@vL dt1
þ2

Z v Z minðvL ;vv0 Þ
00b v  v0 ; vL  v0L ; v0 ; v0L

ð3:15Þ

 f v  v0 ; vL  v0L ; t f v0 ; v0L ; t dv0L dv0
Z 1 Z vLf ðv; vL ; tÞb v; vL ; v0 ; v0L f v0 ; v0L ; t dv0L dv000

The relationship between the bivariant number density function f and single-variant
number density function n is determined as:
nðv; tÞ ¼

Z v

f ðv; vL ; tÞ dvL

ð3:16Þ

0

For the aggregation-only processes, the ﬁrst two terms on the right-hand side ofrepresenting convective particle transport and particle growth by layering are negligible. Equation 3.15 is reduced to:@1f ðv; vL ; tÞ ¼ þ@t2

Z v Z minðvL ;vv0 Þ
00b v  v0 ; vL  v0L ; v0 ; v0L

 f v  v0 ; vL  v0L ; t f v0 ; v0L ; t dv0L dv0
Z 1 Z vL f ðv; vL ; tÞb v; vL ; v0 ; v0L f v0 ; v0L ; t dv0L dv00ð3:17Þ

0Under certain mathematical assumptions, a two-dimensional population balance
equation can be reduced to two single-dimension population balance equations thatare described in the following section.

3.4. Reduced Order Models
3.4.1. Reduced Order Models Using the Concept of Lumped Regions in Series
When particle populations are spatial-dependent, such as that in a long rotating
drum granulator, the population balance model is described in Eq. 3.13 with spatial
variable z included in the model equation. In many industrial applications, the concept of lumped regions in series is used to reduce the model order. By using thismethod, a granulator is divided into a number of sections with an assumption that
perfect mixing can be achieved in each section. The basic idea is schematically
depicted in Figure 3.
In Figure 3, Q denotes the number ﬂow -rate, the subscripts F and P represent
the feed and product streams, respectively, and NR is the total number of regions© 2005 by Taylor & Francis Group, LLC

568

Cameron and Wang

Figure 3 Concept of lumped regions in series.

used to approximate the granulator. The reduced order model Eq. 3.13 for using themethod of lumped regions in series is given by:@@nðv; i  1; tÞnðv; i; tÞnðv; i; tÞ ¼  ½Gi nðv; i; tÞ þ Qði  1Þ
 QðiÞ
@t@v
nt ði  1; tÞnt ði; tÞZ v
1þbðv  v0 ; v0 Þnðv  v0 ; i; tÞnðv0 ; i; tÞ dv0
2 0
Z 1
 nðv; i; tÞbðv; v0 Þnðv0 ; i; tÞ dv0

ð3:18Þ

0

i ¼ 1; 2; . . . ; NR
where i represents the ith region, nt is the total number density, and Q(0) ¼ QF.
3.4.2. Model Order Reduction for Multi-Dimensional Population Balances
Biggs et al. (7) have developed the concept of binder size distribution (BSD) tocorrelate moisture content with particle size. Based on BSD, the mass of binder inthe size range (v, v þ dv) is quantiﬁed as dM ¼ M(v) dv and:Z v
Mðt; vÞ ¼ rL
vL f ðv; vL ; tÞ dvL
ð3:19Þ
0where rL is the binder density.
They showed that if the assumption that at a given size all granules have thesame liquid content, the 2-D population balance equation given by Eq. 3.17 canbe reduced to a set of two, one-dimensional equations described as follows:Z@
1 v
nðv; tÞ ¼
bðv  v0 ; v0 Þnðv  v0 ; tÞnðv0 ; tÞ dv0
@t
2 0
Z 1
ð3:20Þ
00 nðv; tÞbðv; v Þnðv ; tÞ dv
0@1
Mðv; tÞ ¼
@t
2

Z v

bðv  v0 ; v0 ÞM ðv  v0 ; tÞnðv0 ; tÞ dv0
Z 1
 Mðv; tÞbðv; v0 Þnðv0 ; tÞ dv
0

ð3:21Þ

0

In their experiments, pharmaceutical materials were granulated in a high-shear
mixer. Good agreements between experimental and simulation results were achieved© 2005 by Taylor & Francis Group, LLC

Granulation Process Modeling569

enabling the granulation rates to be deﬁned by two parameters: the critical binder
volume fraction and the aggregation rate constant.
3.4.3. Reduced Order Models Using the Method of Moments
The moments are deﬁned as:
Z 1
Mj ¼
vj nðvÞdv
0

mj ¼ Mj =M0

ð3:22Þ

j ¼ 0; 1; 2; . . .
Because of the variety of coalescence kernels, it is impossible to develop a generalized
structure for reduced order models using the method of moments. A special kernel
model is assumed in this work. The methodology can be extended to the development of moment models with different kernel structures. The sample kernel modelis assumed as: 0ðbaÞvb þ v0bvvðbaÞ
bðv; v0 Þ ¼ b0¼
b
þ 0a
ð3:23Þ
a
0
0 a
v
ðvv Þ
v
The discretized format of Eq. 3.23 is given by:" ðbaÞ
#
ðbaÞ
vj
vi
bi;j ¼ b0
ð3:24Þ
a þ
avivj
The one-dimensional aggregation-only population balance equation (PBE) describedby Eq. 3.20 with the kernel model given by Eq. 3.24 can be reduced to a set ofordinary differential equations as follows:dM0 ¼ b0 mðbaÞ ma M0
dt
d
M1 ¼ 0dt
ð3:25Þ
r1
i
r h
d
1 X
2
Mr ¼ b 0mðkaÞ mðrkþbaÞ þ mðkþbaÞ mðrkaÞ M0 ;dt
2 k¼1 kr ¼ 2; 3; . . .
where m is deﬁned in Eq. 3.22, for example, m(ka) ¼ M(ka)/M0. Equation 3.25
involves the determination of fractional and negative moments. If the type of particle
size distribution is more or less known, such as log-normal or G-distribution,
Eq. 3.25 is solvable with the incorporation of interpolation and extrapolation
techniques. For more general solution techniques, fractional calculus enabling thecomputation of fractional differentiations and integrations should be used, which
exceeds the scope of this chapter.
3.4.4. Multitimescale Analysis
It is often the case that in an interconnected process situation where several processes are being simulated simultaneously that processes operate on distinct timescales. Such is the case when combinations of prereaction units are combinedwith granulation devices, dryers, and screening in full process ﬂowsheet simulations.
© 2005 by Taylor & Francis Group, LLC

570

Cameron and Wang

It can also be the case within a particular processing unit that incorporates a rangeof mechanisms.
It can be observed that these processes often operate on different timescales
covering the range of microseconds to minutes or even hours. This time separationin scales provides opportunity to make assumptions that can simplify the modelingby separating the phenomena into at least three classes:
 Slow modes (long time constant behavior) Medium modes Fast modes (short time constants)
When we do this analysis, we can often use qualitative methods based on our
general understanding of physics, chemistry, and the rate processes such as heat andmass transfer. The alternative and more complex analytical approach is through theuse of eigenvalue and eigenvector analysis (37), which is based on the underlying
models of the processes. This analysis often allows us to simplify complex models
when we model for particular goals by making the following assumptions: Slow modes can be treated as being constant over the timeframe of interest.
 Medium modes are modeled in detail Fast modes are regarded as pseudosteady states, being represented by algebraic equations.
This timescale approach can simplify signiﬁcantly the complexity of the processmodels depending on the timeframe of interest in the simulation and the approachhas general application to all forms of models.

4. SOLVING AND USING POPULATION BALANCES
4.1. Solution of Population Balance Equations
4.1.1. Discretization Methods
4.1.1.1. Hounslow Discretization. Hounslow et al. (16) developed a relatively
simple discretization method by employing an M-I approach (the mean value theorem on frequency). The population balance equations, such as Eq. 3.20, are normallydeveloped using particle volume as the internal coordinate. Because of the identiﬁed
advantages of length-based models, Hounslow et al. (16) performed the coordinatetransformation to convert the volume-based model described by Eq. 3.20 to alength-based model as follows:
h
i h
i
3 1=3
3 1=3
3
3
2Z Lb L l
;
l
n
L

l
;
t
nðl; tÞ
dLnðL; tÞ ¼
dl
2=3
dt
2 0
L3  l3
ð4:1Þ
Z 1bðL; lÞnðl; tÞ dl nðL; tÞ0in which L and l denote the characteristic length of particles. The Hounslow method
is based on a geometric discretization with the following ratio between two successive size intervals:p
ﬃﬃﬃ
3
Liþ1 =Li ¼ 2; or viþ1 =vi ¼ 2
ð4:2Þ
© 2005 by Taylor & Francis Group, LLC

Granulation Process Modeling571

where L and v represent the chacteristic length and volume of particles, respectively,
the subscripts i þ 1 and i denote the size classes. The continuous population balance
equation described by Eq. 4.1 is converted into a set of discretized population balance equations in various size intervals by using this technique. That is, the changeof number density in the ith size interval is given by:
i2
X
d
i
ni ¼ ni12jiþ1 bi1; j nj þ bi1;i1 n2i1
dt
2
j¼1

 ni

i1
X

2ji bi; j nj  ni

j¼1

imax
X

bi; j nj

ð4:3Þ

j¼1

i ¼ 1; 2; . . . ; imax
The continuous binder size distribution model described by Eq. 3.21 can also bediscretized using a similar numerical scheme as follows (7):
i2
i2
X
X
d
Mi ¼ Mi12jiþ1 bi1; j nj þ ni12jiþ1 bi1; j nj
dt
j¼1
j¼1

þ ni

i1 
X


1  2ji bi; j Mj þ bi1;i1 ni1 Mi1
ð4:4Þ

j¼1

 Mi

i1
X

2ji nj  Mi

j¼1

imax
X

bi; j njj¼1

i ¼ 1; 2; . . . ; imax
4.1.1.2. Kumar and Ramkrishna’s Discretization Technique. Kumar andRamkrishna (22) developed a discretization method by using a grid with a more general and ﬂexible pattern with ﬁne or coarse discretizations in different size ranges.
The size range between two sizes vi and viþ1 is called the ith section, and the particle
size in this section is simply denoted by xi (grid point) such that vi < xi < viþ1 as seenin Figure 4.
A particle of size v in the size range xi and xi þ 1 can be represented by two
fractions a(v, xi) and b(v, xi þ 1) associated with the two grid points xi and xi þ 1,
respectively. For the conservation of two general properties f1(v) and f2(v), these fractions satisfy the following equations:aðv; xi Þf1 ðxi Þ þ bðv; xiþ1 Þf1 ðxiþ1 Þ ¼ f1 ðvÞaðv; xi Þf2 ðxi Þ þ bðv; xiþ1 Þf2 ðxiþ1 Þ ¼ f2 ðvÞ

Figure 4 General grid used with Kumar & Ramkrishna numerical technique.
© 2005 by Taylor & Francis Group, LLC

ð4:5Þ

572

Cameron and Wang

By using this composition technique for particle properties, discrete equations forcoalescence-only population balance model given by Eq. 3.20 have been formulated
as follows:
jk
X

dni
¼
dt

j;k
xi1

ðxj þxk Þ xiþ1

imax
X
1
1  dj;k Zbðj; kÞnj ðtÞnk ðtÞ  ni ðtÞbði; kÞnk ðtÞ
2
k¼1

ð4:6Þ

In Eq. 4.6, ni, b, imax are deﬁned previously, dj,k is the Dirac-delta function, and Z isdeﬁned as follows:xiþ1  v;
xiþ1  xi
v  xi1Z¼;
xi  xi1
Z¼

xi

v

xiþ1
ð4:7Þ

xi1

v

xi

The ﬁrst and second terms on the right-hand side of Eq. 4.6, respectively, represent
the birth rate and death rate of particles because of the ith size interval coalescence.
Attention should be paid to the selection of the internal coordinates. The original Kumar–Ramkrishna discretization should be applied to volume-based models
rather than length-based models. Although both are interconvertible, it is importantto check consistency in numerical computations.
4.1.2. Wavelet-Based Methods
The wavelet-based methods are relatively new numerical schemes for solving population balance equations consisting of both differential and integral functions (28).
Again, the volume-based population balance equations with particle volume as theinternal coordinate are used to demonstrate the main characteristics of the wavelet
methods. The most important advantage of these methods over other numerical
techniques is their ability to effectively deal with steep moving proﬁles. Here, we only
explain the basic algorithms of the wavelet collocation method for practical applications using the Daubechies wavelets rather than provide mathematical insights forgeneral wavelet techniques.
Similar to other collocation methods, the coordinates should be normalized
within the interval [0, 1]. For the 1-D population balance equation given by Eq. 3.11,
this can be done by introducing the linear transformation x ¼ v/vmax, where x is thedimensionless particle volume and vmax is the maximum particle size in the system.
The original integral intervals [0, v] and [0, 1] are transformed to [0, x] and [0, 1],
respectively. Consequently, Eq. 3.11 becomes:@@
nðx; tÞ ¼  ½GðxÞnðx; tÞ@t@x Zvmax xþbðx  x0 ; x0 Þnðx  x0 ; tÞnðx0 ; tÞ dx0
2 0
Z 1
 vmax nðx; tÞbðx; x0 Þnðx0 ; tÞ dx0

ð4:8Þ

0

where G(x) is deﬁned as dx/dt rather than dv/dt. For a broad class of engineering
problems, the approximate solution of a general function w(x) with J-level resolution© 2005 by Taylor & Francis Group, LLC

Granulation Process Modeling573

can be written in terms of its values in the dyadic points:
X
wJ ðxÞ wJ ð2J mÞyð2J x  mÞ

ð4:9Þ

m

where y(x) is denoted as the autocorrelation function of scaling function. We ﬁrst
solve the coalescence-only PBE with G(x) ¼ 0. If J-level wavelet method is used,
the matrix representation at the ith dyadic point is given by:
2
3
2
3
n0
n0
6 n1 7
6 n1 7@ni vmax
6
6
7
7¼
ð4:10Þ
½ n0 n1    n2J M3;i 6 .. 7  vmax ni M2i 6 .. 7
4 . 5
4 . 5
@t
2
n2 J
n2 J
where ni is the number density at the ith dyadic (collocation) point. The operational
matrix M3,i and vector Mi2 are constructed as follows. M3,i are (2J þ 1)  (2J þ 1)
operational matrices at volume points are represented as:
2 3;i
3;i
3;i 3
M0;0 M0;1   M0;2
J
6 3;i
3;i
3;i 7
6 M1;0 M1;1   M1;2J 7
76
ð4:11Þ
M3;i ¼ 6
.. 7
..
..
7
6 ..
5
4 .
.
.
.
M23;iJ ;0

M23;iJ ;1   M23;iJ ;2J

Mi2 are 1  (2J þ 1) operational vectors at volume points and are described by:
M2 i ¼ M 2 i;0 M 2 i;1    M 2 i;2J
Elements in matrix M3,i are developed as:
1
Mk3;i1 ;k2 ¼ J
2

2JXbðxi  xl ; xl Þ

l¼0

ð4:12Þ

 Olk2 ;ik1 k2 ði  k2 Þ  Olk2 ;ik1 k2 ðk2 Þ
Elements in the operational vectors Mi2 are given by:
" J
#
2
1 X
2
bðxi ; xl ÞHkl ðkÞ
Mi;k ¼ J
2 l¼0

ð4:13Þ

The required two-term integral of autocorrelation function Hk (x) and three-term
integral of autocorrelation function Oj,k(x) in Eqs. 4.12 and 4.13 are deﬁned as:
Z xyðy  kÞyðyÞdy
ð4:14Þ
Hk ðxÞ ¼
1

Oj;k ðxÞ ¼

Z x

yðy  jÞyðy  kÞyðyÞdy

ð4:15Þ

1

The autocorrelation function y (k) and its derivatives y(s)(k) are represented
as follows:Z þ1yðkÞ ¼fðxÞfðx  kÞ dx
1
ð4:16Þ
Z þ1fðxÞfðsÞ ðx  kÞ dxyðsÞ ðkÞ ¼ ð1Þs
1© 2005 by Taylor & Francis Group, LLC

574

Cameron and Wang

where j(x) is the scaling function. y(s)(k) can be evaluated by using the following
recursive algorithm with y(k) ¼ y(0)(k):yðsÞ ð2J1 kÞ ¼ 2s yðsÞ ð2J kÞ þ 2s1

NX

a2l1 ðyðsÞ ð2J k  2l þ 1Þ

l¼1

þ yðsÞ ð2J k  2l  1ÞÞð4:17Þ

The differential operators in the PBE can also be evaluated at the collocation
points as:@n¼ Aðyð1Þ Þn@x
ð4:18Þ
@2n
ð2Þ
¼
Bðy
Þn
@x2
where n ¼ [n1, n2, . . . , nN]T is a vector in which ni is the number density at the ith
collocation point, N ¼ 2J þ 1 is the number of collocation points, T stands for vectortranspose, A and B are square matrices computed using the values y(1)(k) and y(2)(k),respectively. An algorithm for the computation of the matrices A and B was
described in Liu et al. (27). Consequently, the growth term in Eq. 4.8 can be approximated using Eq. 4.18.
It should be pointed out that after coordinate normalization, functions of interest are evaluated in the closed intervals [0, 1], rather than in [1, 1] or other intervals. In this case, some modiﬁed interpolation functions can be constructed tointerpolate the values in dyadic points outside [0, 1] to the desired interval (6,25).
Three population balance equations with different kernel models have beensuccessfully solved by using the wavelet collocation method (28). These kernel models were: (1) size-independent kernel b ¼ b0 ¼ constant, (2) linear size-dependent
kernel bðx; x0 Þ ¼ b0 ðx þ x0 Þ, and (3) nonlinear size-dependent kernel Qðx; x0 Þ ¼
bðx1=3 þ x01=3 Þðx1=3 þ x01=3 Þ. Simulation results have shown that the wavelet collocation methods are able to achieve fast convergence with high accuracy if adequate
resolution levels are selected. The methods are particularly effective for the processes
with steep moving proﬁles that are difﬁcult to solve by using other numerical schemes.
Here, emphasis has been placed on the introduction of basic techniques for the
resolution of population balance equations using wavelets, which is required to solve
2J þ 1 ordinary equations for each population balance equation given by Eq. 4.8.
Recently, Liu and Cameron (29) have developed a new wavelet-based adaptive technique, which enables a dramatic reduction of the number of ordinary differential
equations to be solved. Furthermore, this adaptive method allows the automatic
selection of the minimum wavelet level J with acceptable accuracy. With the background knowledge described in this chapter, readers may understand the adaptive
technique through studies on the original papers without major difﬁculties.
Website on the wavelet collocation methods for the computations of population balance equations. The operational matrices M3,i and Mi2, matrices A and B,
together with the integral functions H and O at various resolution levels are available
at http://www.cheque.uq.edu.au/psdc.
4.1.3. Solving Differential-Algebraic Equation DAE Systems
Many of the previously mentioned numerical methods lead to large sets of differential equations coupled with sets of nonlinear algebraic equations. These are the© 2005 by Taylor & Francis Group, LLC

Granulation Process Modeling575

so-called DAE systems. A number of approaches are available to solve these equation sets, mainly based on implicit or semi-implicit methods such as the backward
differentiation formulae (BDF) (34) or variants of Runge–Kutta methods (9,53).
The Mathworks package MATLABTM also contains useful DAE solvers in thelatest versions that are based primarily on implicit BDF formulae. Solutions of thesetypes of problems are generally straightforward. Some issues still remain in obtaining consistent initial conditions for the solution to commence.

4.2. Monte Carlo Methods
There is a long history in studies on application of Monte Carlo methods to processengineering. The ﬁrst serious research paper on a Monte Carlo treatment for systems
involving population balances could be credited to Spielman and Levenspiel (42).
Since then, a signiﬁcant number of publications have appeared in the literature on
the resolution of population balance equations using Monte Carlo methods (35).
Comprehensive Monte Carlo treatments are described in the literature (20,35). Only
selected issues on basic techniques are addressed in this section.
4.2.1. Classiﬁcation of Monte Carlo Methods
Monte Carlo methods can be used in two ways for engineering applications.
1. Direct evaluation of difﬁcult functions. For example, the integral given by:
Z b
I¼
f ðxÞ dx
ð4:19Þ
acan be evaluated as: ðnÞ
I ¼ EðY Þ ¼ E ½ðb  aÞgðX Þ ¼ E ½YnPgðXi Þ ðnÞ ¼    ðb  aÞ i¼1
Ynð4:20Þ

where X1, X2, . . . , Xn are random variables deﬁned in the closed interval [a, b],
and E(Y) denotes the mathematical estimation of function Y.
2. Artiﬁcial realization of the system behavior (35). This method is commonly
applied to complex particulate processes, which are described in somedetail here. In the artiﬁcial realization, the direct evaluation of integral
and differential functions is replaced by the simulation of the stochastic
behavior modeled by using a randomness generator to vary the behaviorof the system (20). The important probabilistic functions in the originalmodel equations, such as coalescence kernels for granulation processes,
are still essential in Monte Carlo simulations and are shown later.
Monte Carlo methods for the artiﬁcial realization of the system behavior canbe divided into time-driven and event-driven Monte Carlo simulations. In the former
approach, the time interval Dt is chosen, and the realization of events within this timeinterval is determined stochastically. Whereas in the latter, the time interval between
two events is determined based on the rates of processes. In general, the coalescence
rates in granulation processes can be extracted from the coalescence kernel models.
The event-driven Monte Carlo can be further divided into constant volume methods© 2005 by Taylor & Francis Group, LLC

576

Cameron and Wang

in which the total volume of particles is conserved, and the constant number method
in which the total number of particles in the simulation remains constant. The main
advantage of the constant number method for granulation processes is that the
population remains large enough for accurate Monte Carlo simulations (41,52).
An additional advantage associated with the constant number methods is its ability
to reduce the renumbering effort. Consequently, the constant number method isrecommended and is further explained.
4.2.2. Key Equations for Constant Number Monte Carlo Simulation
Key equations needed in Monte Carlo simulations include the interevent time Dtq
representing the time spent from q1 to q Monte Carlo steps, coalescence kernel
Kij, normalized probability pij for a successful collision between particles i and j,
and a number of intermediate variables. The coalescence kernel can be divided into
particle property independent part Kc and dependent part kij (Xi, Xj) as follows:
Kij ¼ Kc kij Xi ; Xj

ð4:21Þ

i; j ¼ 1; 2; . . . ; N

where X denotes the vector of internal coordinates representing particle properties,
such as size and moisture content, and N is the total number in the simulation system. It can be seen that Eq. 4.21 is similar to the coalescence kernel given by bij ¼ b0
kij (vi, vj) described in the previous sections for one-dimensional systems. However, it
should be pointed out that i and j in Eq. 4.21 are used to identify the individual particles, whereas that in bij, i, j ¼ 1,2, . . . , imax are size classes rather than particle identity numbers. To avoid confusion, bij and b0 are replaced by Kij and Kc, respectively,
in Monte Carlo simulations. The normalized probability for successful collision is
given by:
pij ¼

kij
kmax

ð4:22Þ

where kmax is the maximum value of the coalescence kernel among all particles. The
ﬁnal result of the interevent time is given by:2tc 1
N
Dtq ¼  
kij N N  1qð4:23Þ

with
tc ¼

1
Kc C0

ð4:24Þ

and
N
N
P
P

kij
  i¼1 j¼1;i6¼jkij ¼
ð4:25ÞNðN  1ÞIn Eq. 4.25, C0 is the total number concentration at t ¼ 0 deﬁned by C0 ¼ N/V0
where V0 is the volume of particles at the initial time. We presented only the ﬁnal
results of the needed equations here. Interested readers are referred to Smith andMatsoukas (41) for detailed mathematical derivations.
© 2005 by Taylor & Francis Group, LLC

Granulation Process Modeling577

4.2.3. Simulation Procedure
The simulation procedure for the constant number Monte Carlo method applied tocoalescence processes consists of the following key steps:
1. Initialization of the simulation system. This includes the determination ofsample size (normally 10,000–20,000 particles) followed by assigning theidentity number and properties to each particle. The properties must satisfy
the initial property distributions, such as particle size and moisture distributions. Set t0 ¼ 0 and q ¼ 1.
2. Acceptance or rejection of coalescence. In this step, two particles, i and j,
are randomly selected and the coalescence kernel kij with normalised probability pij given by Eq 4.22 are computed, followed by the generation of arandom probability prq. If pij < prq, the coalescence is rejected, and a newpair of particles is selected again to repeat the calculation until pij > prq,
which implies a successful coalescence. When the coalescence is successful,the new agglomerated particle holds the identity number i, and anotherparticle randomly selected from the rest of the system is copied as particle
j and go to Step 3.
3. Computation of the interevent time. The interevent time for step q is computed using Eqs 4.23–4.25. Total operational time is given by:
t ¼ t0 þqX

Dtm

ð4:26Þ

m¼1

4. Set q ¼ q þ 1 and return to Step 2.
5. Simulation termination and result validation. As t reaches the prespeciﬁed
termination time tf, check the acceptance of simulation results. If acceptable, stop the simulation; otherwise, modify model parameters and start a
new simulation process.
It can be seen that the Monte Carlo methods are applicable to both one-dimensional and multidimensional coalescence processes without any theoretical andalgorithmic hurdles. However, most reported results with good agreement withexperimental data are limited to one-dimensional systems except that reported byWauters (52). This is mainly because of the lack of reliable multidimensional kernel
models rather than the applicability of Monte Carlo methods.

5. APPLICATION OF MODELING TECHNIQUES
5.1. Modeling for Closed-Loop Control Purposes
5.1.1. Development of Control Relevant, Linear Models
As the linear control theory and techniques are better developed and easier to implement than their nonlinear counterparts, it is highly desirable to use linear models forcontrol purposes. In process engineering, the nonlinear models are frequently linearized around certain operating points. The linearization technique is described brieﬂy
here. Let the general nonlinear system be described as:(
dx¼ fðx; uÞð5:1Þ
dt
y ¼ hðxÞ
© 2005 by Taylor & Francis Group, LLC

578

Cameron and Wang

where x ¼ [x1, x2, . . . , xp]T, y ¼ [y1, y2, . . . , yq]T, and u ¼ [u1, u2, . . . , us]T are vectorsof state, output,and control variables, respectively, f ¼ [f1, f2, . . . , fp]T and h ¼[h1, h2, . . . , hq]T are vectors of smooth functions, in which p, q, and s are dimensionsof the vectors of state, output and control variables, respectively. In the population
balance equations given by Eqs. 4.3, 4.6 and 4.10, x ¼ [n1, n2, . . . , np], p ¼ imax. The
conventional linearization method is based on the ﬁrst-order Taylor series expansion
around certain operational points. The resulting linear model is given by:ddx¼ Adx þ Bdu
dt
dy ¼ Cdx









@fðx; uÞ @fðx; uÞ @hðxÞ 
;B ¼
;C ¼
A¼
@xT  x ¼ xo
@uT  x ¼ xo
@xT  x ¼ xo
u¼u
u¼u
u¼u
o

o

ð5:2Þ

o

In the control literature, the symbol d in front of x, y, and u is normally omitted forsimplicity. The readers should be aware that in the models developed this way, x, y,and u denote deviations from their respective values at the speciﬁed operational
point rather than the real values. That is, the linearized model used in control studies
is represented as:dx¼ Ax þ Bu
dt
y ¼ Cxð5:3Þ

The discretized population balance equations given by Eqs. 4.3, 4.6 and 4.10, and thebinder size distribution model described by Eq. 4.4 can be linearized to obtain themodels with the format given by Eq. 5.3. The control variables are normally connected with the coalescence kernels (55).
5.1.2. ARX and ARMAX Models for Linear Model Predictive Control
For model predictive control purposes, there are two commonly used black box
models: ARX model with autoregressive (AR) part and extra (X) input, and
ARMAX model with additional moving average (MA) part accounting for disturbances. The method for the development of ARX and ARMAX models is well
explained by Ljung (30). The single input, single output ARX is given by:yðtÞ þ a1 yðt  1Þ þ    þ ana yðt  na Þ ¼ b1 uðt  1Þ þ    þ bnb uðt  nb Þ þ eðtÞð5:4Þand the ARMAX model is represented as:yðtÞ þ a1 yðt  1Þ þ    þ ana yðt  na Þ ¼
b1 uðt  1Þ þ    þ bnb uðt  nb Þ þ eðtÞ þ c1 eðt  1Þ þ    þ cnc eðt  nc Þ
ð5:5ÞIn Eqs. 5.4 and 5.5, y is the output (controlled) variable; u is the input (manipulative)
variable, e is the disturbance; a, b, and c are time varying coefﬁcients identiﬁed
on-line; na, nb, and nc are deﬁned as prediction, control, and disturbance horizons.
© 2005 by Taylor & Francis Group, LLC

Granulation Process Modeling579

The matrix format for multivariable RRX and ARMAX models is described by:AðqÞyðtÞ ¼ BðqÞuðtÞ þ eðtÞðARXÞAðqÞyðtÞ ¼ BðqÞuðtÞ þ CðqÞeðtÞ

ðARMAXÞ

ð5:6Þ
ð5:7Þ

In Eqs (5.6) and (5.7), matrices A, B, and C are deﬁned as:AðqÞ ¼ Iny þ A1 q1 þ    þ Ana qnaBðqÞ ¼ B0 þ B1 q1 þ    þ Bnb qnbCðqÞ ¼ C0 þ C1 q

1

þ    þ Cnc q

ð5:8Þ

nc

where qk is the delay operator representing ‘‘delayed by k time intervals,’’ forexample:AðqÞyðtÞ ¼ yðtÞ þ A1 yðt  1Þ þ    þ Ana yðt  na Þ

ð5:9ÞThe compact format of ARX and ARMAX models given by Eqs 5.6 and 5.7 can beeasily converted into more intuitive, expanded format exempliﬁed by Eq. 5.9. With
input (u and e) and output (y) data, the matrices A, B and C can be readily identiﬁed
employing the System Identiﬁcation Toolbox for Use with MATLABTM (31). An
ARX model for a pan, granulation process was developed by Adetayo et al. (3) witha successful application for effective control of the plant.
5.1.2. Nonlinear Model Predictive Control Structure
Nonlinear model predictive control (NMPC) schemes consist of simultaneous determinations of manipulative variables and uncertain parameters. In some cases, theopen-loop dynamic optimization is carried out for the determination of desired trajectories (set-points). This integrated control strategy was developed by Miller and
Rawlings (32a) in a study on model identiﬁcation and control for batch cooling crystallizers, in which the population balance described by partial differential equation
was reduced to a low-dimensional model using method of moments. That is, thecontrol objective was of average size rather than the size distribution in Miller and
Rawlings’ work. Detailed studies on modeling and model predictive control(MPC) of particle size distribution in emulsion co-polymerization processes using
population balance models have been carried out by Immmanuel et al. (17) andCrowley et al. (10). The reported research results have shown that the NMPC
schemes using population balance equations should also be applicable to pharmaceutical granulation processes because of the similar model structure. A general
structure for nonlinear model predictive control is shown in Figure 5, which depicts
an integration of the modeling strategy originally proposed by Sanders et al. (39)with the model based control scheme.
A full implementation of NMPC in industrial granulation plants using physically based models has not been reported yet. A simulated study has been carried out
by Zhang et al. (55) to control an industrial-scale fertilizer plant using a physically
based model. The main limitation of the study was that the physically based population balance model was used to generate output data without real on-line measurements. This implies that if a severe plant-model mismatch occurs, the proposed
control strategy may fail. Further work is required to modify the model on-line,
based on the measurement data.
© 2005 by Taylor & Francis Group, LLC

580

Cameron and Wang

Figure 5 General structure of NMPC using physically based models.

5.1.3. On-Line Measurement-Based Control Schemes
In addition to model-based control schemes using population balance equations,
there are a number of practical control schemes in the pharmaceutical industry, that
do not rely on mathematical models. These include simple feedback control with orwithout feed-forward compensation, and fuzzy-logic control systems.
5.1.3.1. Simple Feedback Control with Feed-Forward Compensation. One of
the most important issues for the effective control of granulation processes is thedevelopment of fast and reliable measurement techniques for the characterizationof particulate systems. Because of the difﬁculties associated with the direct measurement of particle characteristics, such as particle size distribution, moisture content,
and deformability, some indirect monitoring parameters have been adopted as
the indicators of particle characteristics. A commonly accepted monitoring parameter in the pharmaceutical industry is power consumption, which has been successfully used to control the particle size in high-shear mixers at the end-point (12,23).
Based on a series of investigations carried out by Leuenberger, (23), the energy
dissipated per unit volume in a high-shear mixer, dW/dV, can be approximately
represented as:
dW1e¼ msc k /dVe

ð5:10Þ

where W is the power consumption, V is the granulator volume, m is the apparent
coefﬁcient of friction, sc is the cohesive stress, k is the dimensionless shear rate,and e is the porosity of the powder mass. It is easy to show that power consumption
is related to the saturation level S and is deﬁned as follows:
S¼

Hð1  eÞre

ð5:11Þ

where H is the mass ratio of liquids to solids, and r is the density of the particle relative to that of the liquid (r ¼ rS/rL). Furthermore, Kristensen and Schaefer (21)pointed out that the saturation level deﬁned by Eq. 5.11 could be related back to
the average granule size. Consequently, the power consumption, the saturation level,
and the granule particle size are inter-related, which forms a technical basis to use© 2005 by Taylor & Francis Group, LLC

Granulation Process Modeling581

Figure 6 Simple feedback control scheme with feed-forward compensation.

power consumption as a monitoring parameter for the characterization of particles
within the high-shear mixer. A detailed description of the control strategy using.
Mort et al. (33) pointed out that: ‘‘With recent development in particle sizing
technology, the agglomerate size distribution can be measured in-line at any numberof points in the process.’’ The main measurement technique is image analysis by
mounting high-speed cameras and lighting systems in appropriate locations. As
the direct measurement data of particle sizes are available, the controller design
can be based on these data without relying on the indirect indicators under the condition that the rate of binder addition is sufﬁciently slow to allow for image data to
be collected, processed, and fed back. This concept has been used for batch granulation processes in ﬂuidized beds. The same authors also proposed a feed-forward control strategy to compensate the ﬂuctuation of the recycle rate. The simple feedback
control with feed-forward compensation scheme is shown in Figure 6.
The measurement data in Figure 6 could be the indirect monitoring parameters(23) or the explicit particle size distribution (33), depending on the relative speed ofthe measurement system and process dynamics.
5.1.3.2. Fuzzy-Logic Control of High-Shear Granulation. Watano et al.
(50,51) have developed a novel system to control granule growth in a high-shear mixer.
The system basically consisted of image processing and a fuzzy controller as shown in
Figure 7.
In Figure 7, D(t) is the deviation between the desired value (Dd) and the measured value (Dm) of granule size, and DD(t) denotes the change rate of measured
values that are mathematically represented as follows:DðtÞ ¼ Dd  Dm ðtÞDDðtÞ ¼ Dm ðtÞ  Dm ðt  1Þ

ð5:12Þ

Other notations in Figure 7 are as follows. V(t) is the result of fuzzy reasoning used
to control the output power of liquid feed pump, while K1 and K2 represent gains of
the input variables.

Figure 7 Block diagram of granule size control system (after Watano et al., 2001).
© 2005 by Taylor & Francis Group, LLC

582

Cameron and Wang

In the methodology developed by Watano et al. (50,51), four fuzzy variables
were used, namely ZR (zero), PS (positive small), PM (positive medium) and PL(positive large). The values of D(t), DD(t) and V(t) were all classiﬁed into these four
categories. Ten rules were proposed to relate measured D(t) and DD(t) with V(t).
Consequently, V(t) can be quantiﬁed using the if-then statement. An example isgiven as follows:
If D(t) ¼ PS and DD(t) ¼ PL then V(t) ¼ ZR [Rule 2 in Table 2 of Watano et al. (51)].
In this way, all the combinations of D(t) and DD(t) can be connected with V(t)for the effective control of the process. The technique can be considered as highly
successful with the experimental justiﬁcations.

5.2. Modeling for Optimal Design, Operation, and Open-Loop
Optimal Control
Process optimization and open-loop optimal control of batch and continuous drum
granulation processes are described here as another important application example
of population balance modeling. Both steady-state and dynamic optimization studies
are carried out that consist of: (i) Construction of optimization and control relevant,population balance models through the incorporation of moisture content, drum
rotation rate, and bed depth into the coalescence kernels; (ii) Investigation of optimal operational conditions using constrained optimization techniques; and (iii)
Development of optimal control algorithms based on discretized population balance
equations. The objective of steady-state optimization is to minimize the recycle ratewith minimum cost for continuous processes. It has been identiﬁed that the drum
rotation rate, bed depth (material charge), and moisture content of solids are practical decision (design) parameters for system optimization. The objective for the optimal control of batch granulation processes is to maximize the mass of product-sizedparticles with minimum time and binder consumption. The objective for the optimal
control of the continuous process is to drive the process from one steady state toanother in minimum time with minimum binder consumption, which is also known
as the state-driving problem. It has been known for some time that the binder sprayrate is the most effective control (manipulative) variable. Although other process
variables, such as feed ﬂow rate and additional powder ﬂow rate can also be usedas manipulative variables, only the single input problem with the binder spay rate
as the manipulative variable is addressed here to demonstrate the methodology. It
can be shown from simulation results that the proposed models are suitable for control and optimization studies, and the optimization algorithms connected with either
steady-state or dynamic models are successful for the determination of optimal
operational conditions and dynamic trajectories with good convergence properties.
It should be pointed out that only open-loop optimal control issues for granulation processes without uncertainty are addressed here. The integration of openloop optimal control with closed-loop, nonlinear model predictive control (NMPC)
for uncertain processes is reported elsewhere by the authors (49).

5.2.1. Statement of Optimization and Open-Loop Optimal Control Problems
A typical batch drum granulation process is schematically shown in Figure 8. There
are two operational strategies: (1) premix the ﬁne particles with the proper amountof liquid binder followed by the rotating operation until the desired size distribution© 2005 by Taylor & Francis Group, LLC

Granulation Process Modeling583

Figure 8 Schematic diagram of batch drum granulation.

is achieved; and (2) simultaneous mixing and granulating by spraying liquid binder(and ﬁne powders in some cases) on the moving surface of particles inside the rotating drum. The ﬁrst strategy involves system optimization without any control action.
The optimization problem can be stated as: to determine the optimal moisture content, initial size distribution, rotating rate, and bed depth (drum charge), such thatthe desired size distribution can be obtained within a minimum time tf. Optimal control techniques can be applied to the second strategy, which can be stated as: for the
speciﬁed initial conditions, maximize the mass of product-sized particles in minimum
time with minimum energy consumption by adjusting the manipulative variables,such as binder spray rate and drum rotation speed. We discuss the optimal control
problem with the binder spray rate as the single manipulative variable in detail.
A slightly modiﬁed continuous drum granulation process with an additional
ﬁne powder stream is shown in Figure 9. As mentioned previously, the additional
ﬁne powder stream is used to improve the controllability of the process, which is
not seen in the conventional design. Our studies on continuous drum granulation
include the steady-state optimization and optimal state driving from one steady state
to another. The objective for steady-state optimization is to achieve minimum recycle
rate with minimum cost through the determination of optimal operational conditions, such as rotating rate, binder spray rate, feed ﬂow rate, bed depth, and drum
inclination angle. The optimal state driving attempts to drive the system from one
steady state to another in a minimum time with minimum energy consumption byadjusting the time-dependent manipulative variables, such as binder spray rate, feed
ﬂow rate, and optionally additional ﬁne powder ﬂow rate.
5.2.2. Optimization and Open-Loop Optimal Control Equations
The optimization and open-loop optimal control equations consist of model equations and objective functions.

Figure 9 Schematic diagram of continuous drum granulation.
© 2005 by Taylor & Francis Group, LLC

584

Cameron and Wang

5.2.2.1. Optimization and Control Relevant-Model Equations. The discretized
population balance equation for batch system can be described as follows:d@ni ¼ 
ðGni Þ þ Bi  Di
dt
@L
i ¼ 1; 2; . . . ; imax

ð5:13Þ

where ni, Bi, and Di stand for the particle number, birth rate, and death rate in the ith
size interval, respectively; and i ¼ 1,2, . . . , imax, in which imax is the total number ofsize intervals. Similarly, continuous processes can also be represented as:
d
@
nin
ni
ni ¼ 
ðGni Þ þ Bi  Di þ F in iin  F out
dt
@L
nt
nt

ð5:14Þ

i ¼ 1; 2; . . . ; imax
where F is the number ﬂow -rate, the subscript t indicates the total value, and thesuperscripts identify the inlet and outlet streams. Using Hounslow’s discretization
methods, the relevant terms in the right-hand side of Eqs. 5.13 and 5.14 are given by:
Bi ¼ ni1

i2
X
j¼1

Di ¼ nii1Xi
2jiþ1 bi1; j nj þ bi1;i1 n2i122ji bi; j nj  ni

j¼1

imax
X

bi; j nj

ð5:15Þ

ð5:16Þ

j¼1

@Gni
2G
r
r
¼
ni1 þ ni  2
niþ1
ð1 þ rÞLi r2  1
r 1
@L
p
ﬃﬃﬃ
3
r ¼ Liþ1 =Li ¼ 2

ð5:17Þ

where bi,j is equivalent to the representation b(Li, Lj). Consequently, an original
population balance equation described by a partial differential-integral equation isconverted into a set of ordinary differential equations. It is more convenient to convert the number-based population balance equations described by Eqs. 5.13–5.17 tomass-based ones, which are demonstrated by the authors (48).
A control relevant model was developed by Zhang et al. (55), in which the coalescence kernel is a function of the moisture content. In the newly developed kernel
models reported by Balliu (5) and Wang et al. (47,48), in addition to moisture content, the bed depth and drum speed are also incorporated. Two kernel models,
namely size-independent kernel and size-dependent kernel, are used in optimizationand control simulations. The size-independent kernel is given by:
bi;j ¼ b0 ¼ a0  ½ðxm Þn1 ea1 xm   ðBd Þn2 ea2 Bd  Sdn3 ea3 Sd
ð5:18Þ
where xm is the moisture content in particles, Bd is the bed depth, Sd is the drum
rotating rate, a0–a3 and n1–n3 are constants determined through parameter identiﬁcation techniques based on the measurement data. The size dependent kernel© 2005 by Taylor & Francis Group, LLC

Granulation Process Modeling585

is represented as (13):bi;j ¼ b0

Li þ Lj
Li Lj

2

ð5:19Þ

where b0 is also deﬁned in Eq. 5.18.
As the main mechanism determining the growth rate G in Eqs. 5.13 and 5.14
is the layering of the ﬁne powders on the surface of particles, it can be deduced thatthe growth rate is a strong function of the powder fraction and moisture content.
The following correlation is used to calculate the growth rate:hi
Mpowder
G ¼ Gm  P exp aðxw  xwc Þ2
ð5:20Þ
k  Mi þ Mpowder
where Gm is the maximum growth rate, Mpowder is the mass of ﬁne powder below
the lower bound of the particle classes, Mi is the mass of particles in the ith size class,xwc is the critical moisture, k and a are ﬁtting parameters. Studies on powder massbalance lead to the following equations for batch processes:
Z 1
dMpowderMðLÞindL
ð5:21Þ
¼ Fpowder  3GL
dt0
and continuous processes:
dMpowderMpowderin¼ Fpowder

 3G
dt
tR

Z 1
0

MðLÞ
dL
L

ð5:22Þ

inwhere Fpowder
represents the ﬂow rate of additional powder stream in both batch andcontinuous cases. It can be used as an additional manipulative variable.
The liquid mass balance for batch processes is given by:

dxw
1
¼
Rw
Mt
dt

ð5:23Þ

where Mt is the total mass of solids in the drum and Rw is the binder spray rate.
Similarly, we can develop the liquid mass balance for the continuous process as:dxw
1  in in¼
F x  FM xw þ Rw
Mt M wdt

ð5:24Þ

inFM are inlet and outlet mass ﬂow rates, respectively, and Xwin is thewhere and FM
moisture content in the feed solids.
In summary, the equations in the control relevant model for batch systems are
discretized population balance equations given by Eq. 5.13, powder dynamics
described by Eq. 5.21, and liquid dynamics represented by Eq. 5.23. The corresponding equations for continuous processes are Eqs. 5.14, 5.22 and 5.24. Both cases sharethe same kernel models given by Eqs. 5.18 and 5.19, and the growth-rate model
described by Eq. 5.20.
5.2.2.2. Objective Functions for System Optimization and Open-Loop OptimalControl. The objective function for system optimization of batch granulation is:w1 Mp tf
Minimize J ¼
Sd ;Bd ;xw
tf
ð5:25Þ
Subject to : Equation 5:13
© 2005 by Taylor & Francis Group, LLC

586

Cameron and Wang

The objective function for batch granulation with the binder spray rate as the
only manipulative variable is given by:()
Rt
w1 Mp tf þ w2 0f Rw dt
MimimizeRw
tf
ð5:26Þ
Subject to : Equations 5:13; 5:21; and 5:23
In Eqs. 5.25 and 5.26 , Mp is the mass of product sized particles, w1 and w2 areweighting functions.
The objective function for steady-state optimization of continuous granulationis:
Minimize w1 Fp þ w2 Rw
Sd ;Bd ;F in ;Rw

Subject to :Equations 5:14; 5:22; 5:24 with left hand sides replaced by zero

ð5:27Þ

where Fp is the mass ﬂow rate of product sized particles.
For the state-driving study, we carry out steady-state optimizations fortwo different product speciﬁcations: the product range for steady state 1 (SS1) is
2.0–3.2 mm, whereas that for steady state 2 (SS2) is 3.2–5.0 mm. The objective function for this optimal state-driving problem is described as:


Z tf
i
Xh
2
Minimize J ¼
w1;i Mi tf  MiSS2
Rw dt þ w3 tf
þ w2
Rw

0

Subject to :Equations 5:14; 5:22; 5:24 and zero derivatives at final time

ð5:28Þ

where Mi(tf) and Mi ss2 denote the mass of particles in the ith size interval at the ﬁnal
time and for steady state 2, respectively.
5.2.3. Dynamic Optimization Algorithm
It is not difﬁcult to solve the steady-state optimization problems with constraints
represented by algebraic equations by using commercial software packages. We
mainly explain the dynamic optimization methods used in this work. The basic structure of the algorithm employed in this paper is shown in Figure 10.
In the dynamic optimization algorithm depicted in Figure 10, a control parameterization technique (44) is used to discretize the originally continuous control
variables. That is, a control (manipulative) variable u(t) is represented by a set ofpiece-wise constants, ui, i ¼ 1, 2, . . . , q. These constants are treated as parameters
to be determined by using dynamic optimization algorithms.
As the MATLAB software packages with Optimisation Toolbox provides both
effective ordinary differential equation (ODE) solvers as well as powerful optimization algorithms, the dynamic simulations reported in this paper are carried out by
using the MATLAB Optimisation Toolbox (8).
5.2.4. Selected Simulation Results and Discussion
Simulations for both batch and continuous granulation processes are based ona pilot plant drum granulator with the following parameters: length ¼ 2 m, diameter ¼ 0.3 m, nominal hold up ¼ 40 kg, rotation rate ¼ 25–40 rpm, retention time© 2005 by Taylor & Francis Group, LLC

Granulation Process Modeling587

Figure 10 Basic structure of the dynamic optimization algorithm.

range ¼ 6–10 min. Other process parameters are available in a recent paper by theauthors (48).
The simulated optimal proﬁles for the batch processes are shown in Figure 11(a–c) with two data sets with and without constraints on control action. The control
constraints restrict lower and upper bounds on the control variables (lower
bound ¼ 0 kg/s, upper bound ¼ 0.015 kg/s), as well as the gradient of the control
actions (jdRwjdtj .0.0003 kg/s2). It can be seen from Figure 11d that if the normal
constraints on the control variable are replaced by a high upper bound of control
variable (0.036 kg/s) as the only constraint, very high spray rates at the early operating stage with very short spray time leads to the minimum objective function given
by Eq. 5.26. However, if the normal constraints are activated, the control variable
moves smoothly rather than suddenly with the price of a longer operational time.
The difference between ﬁnal times in the two cases is about 104 seconds (283–179 s),
which is quite signiﬁcant. The results clearly have implications on equipment designand speciﬁcations that could allow the constraints to be moved out, thus approaching the best operating policy.
Through steady-state optimizations using the objective function described by
Eq. 5.27, optimal binder spray rates for two different speciﬁcations on product size
ranges are obtained. These are: Rw ¼ 0.050 kg/s for 2.0–3.2 mm as the product size
range, and Rw ¼ 0.075 kg/s for 3.2–5.0 mm as the product size range. Figures 12aand 12b show the proﬁles using an optimal control policy and a constant spray rate
policy. The change of the cumulative mass between initial and ﬁnal times under optimal control policy is shown in Figure 12c. The control proﬁles are depicted in Figure
12d. The optimal control policy leads to about 50% reduction on the objective function given by Eq. 5.28. The optimal spray policy can be stated as: ‘‘Gradually© 2005 by Taylor & Francis Group, LLC

588

Figure 11 Optimal control of batch drum granulation.

Figure 12 Optimal control of continuous drum granulation.
© 2005 by Taylor & Francis Group, LLC

Cameron and Wang

Granulation Process Modeling

589

Figure 13 Effects of constraint tightness on optimal control of drum granulation.

increase the spray rate from the ﬁrst steady state (0.005 kg/s) to achieve a relatively
high spray rate (0.0084 kg/s) followed by gradual reduction of the spray rate until
the spray rate of the second steady-state value (0.0075 kg/s) is reached, which will
be maintained for the rest of the operational period.’’ From Figure 12, the signiﬁcance of optimal control studies can be demonstrated by observing the fact thatthe optimal proﬁles approach the second steady state faster, and the optimal control
strategy is easy to implement with smooth movement. It should be pointed out thatthe small difference between two control policies shown in Figure 12 is because of
the small difference between two product speciﬁcations (product ranges from
2.0–3.2 mm to 3.2–5.0). It can be predicted that if the two steady states are far away,
profound economic beneﬁt can be achieved. Optimal control strategies are particularly important to plant start up and shut down operations.
Figure 13 shows the dynamic proﬁles of optimal state driving from steady state
1 to steady state 2 with different levels of constraints. Dynamic changes of productmass, undersized mass, and moisture content are shown in Figure 13 a, b, and c,
respectively, under two constraint levels. Figure 13d depicts control proﬁles for thesetwo cases. In addition to the constraints on control actions, the ﬁnal time constraints
to ensure the ﬁnal steady-state status is imposed on the system. That is, the left-handside of Eqs 5.14, 5.22, and 5.24 should be zero at the ﬁnal time. However, it is notnecessary to achieve zero exactly for the derivatives at the ﬁnal time. We normally
impose the ﬁnal time constraints as jdxðtf Þ=dtj < e in which x represents generalstate variables such as the number of particles, mass of powder, and moisture© 2005 by Taylor & Francis Group, LLC

590

Cameron and Wang

content; and e is a very small positive number for practical applications with thevalue depending on the tightness of constraints. The e values are chosen as 106
and 103 for tight and loose constraints indicated in Figure 13, respectively. It canbe shown from Figure 13 that the control strategy with loose constraints leads toshorter operational time than that with tight constraints (1827 vs. 1925s). However,
the moisture dynamics shows severe offset and oscillation. In optimization simulations, only ﬁnal time constraints are changed for the two cases. It is interesting tonote that the program with tight constraints leads to small and smooth controller
movements even though the constraints on the control variable are not altered explicitly. It seems that the loose constraints allow too much manipulative variation thatdrives the system into a region (Xw  0.1) where moisture variations have signiﬁcant
impact on the granulation performance. A marginal beneﬁt identiﬁed by 5% time
reduction is achievable using loose constraints with a price of process oscillations.
Consequently, control strategy with tight ﬁnal time constraints is superior to thatwith loose constraints in this particular application.
Through an analysis on the simulation results, the following conclusions can be
drawn.
1. Population balance modeling provides an important basis for optimal
design and operations for both batch and continuous granulation processes.
2. The effects of liquid content, bed depth, and drum rotation rate on the coalescence behavior can be quantiﬁed through the development of new kernel
models with the structure described by Eqs 5.18 and 5.19. The simulation
results are qualitatively consistent with industrial experience in large-scalefertilizer production.
3. An optimal control strategy and algorithm using commercial optimization
software packages connected to reliable DAE/ODE solvers are successful
for the determination of optimal trajectories with good convergence properties. This implies that under certain conditions, the more complicatedoptimal control algorithms, such as that based on the well-known Pontryagin’s maximum principle, could be avoided.
4. As start-up and shutdown operations are frequently encountered in granulation plants with huge ﬁnancial impacts, studies on optimal control strategies can lead to signiﬁcant economic beneﬁts.

6. CONCLUSION
Granulation modeling is an area of growing importance. It is dominated by the
population balance approach for developing mechanistic models. However, it
requires an improved understanding of the key factors involved in particle growthand breakage. This is currently improving. The growing importance of particulate
ﬂow patterns is being addressed through approaches such as discrete element methods (DEM), which will hopefully provide a microscale view of particle motions in the
granulation device. The challenge is in addressing the multiscale nature of granulation modeling that spans from particle interactions up to the plant level.
The development of empirically based models has provided a simple means ofaddressing quickly a number of control-related applications. This will continue to bea useful approach for such problems.
© 2005 by Taylor & Francis Group, LLC

Granulation Process Modeling

591

Application of models to design, advanced control, and diagnosis will require
mechanistic models that continue to incorporate the latest understanding of theunderlying mechanisms. Much work is currently underway in these areas and theincorporation into existing models of new knowledge will help extend the applicability of process models for granulation.

REFERENCES
1. Adetayo AA, Litster JD, Pratsinis SE, Ennis BJ. Population balance modelling of drum
granulation of materials with wide size distribution. Powder Technol 1995; 82:37–49.
2. Adetayo AA, Ennis BJ. A unifying approach to modelling granulation processes coalescence mechanisms. AIChE J 1997; 43(1):927–934.
3. Adetayo AA, Pottman M, Ogunnaike B. Effective control of a continuous granulation
process, Proc. Control of Particulate Processes IV, 23–28, Engineering Foundation,
NY, 1997.
4. Adetayo AA, Ennis BJ. A new approach to modelling granulation processes for simulation and control purposes. 2000; 108:202–209.
5. Balliu N. An object oriented approach to the modelling and dynamics of granulation circuits, PhD Thesis, School of Engineering, The University of Queensland, Australia 2004.
6. Bertoluzza S. A wavelet collocation method for the numerical solution of partial differential equations. Appl Comput Harmonic Anal 1996; 3:1–9.
7. Biggs CA, Sanders C, Scott AC, Willemse AW, Hoffman AC, Instone T, Salman AD,
Hounslow MJ. Coupling granule properties and granulation rates in high-shear granulation. Powder Technol 2003; 130:162–168.
8. Branch MA, Grace A. MATLAB Optimization Toolbox User’s Guide, The Math Works
Inc., Natick, 1996.
9. Cameron IT. Solution of Differential–Algebraic Systems using Diagonally Implicit
Runge-Kutta Methods. IMA J of Numerical Analysis 1983; 3:273–289.
10. Crowley TJ, Meadows ES, Kostoulas A, Doyle III FJ. Control of particle size distribution described by a population balance model of semi-batch emulsion polymerisation.
J Process Control 2000; 10:419–432.
11. Ennis BJ, Litster JD. Size enlargement, in Perry’s Chemical Engineering Handbook, 7thEd., Chapter 8. McGraw-Hill, NY, 1997.
12. Faure A, York P, Rowe RC, Process control and scale-up of pharmaceutical wet granulation processes: a review. European J Pharm Biopharm 2001; 52:269–277.
13. Friedlander SK, Smoke, Dust and Haze, 1st Ed., Wiley, NY, 1977; 2nd Ed., Oxford
University Press, NY, 2000.
14. Golovin AM. Sov. Phys. Dokl 1963; 8:191.
15. Hangos KM, Cameron IT. Process Modelling and Model Analysis, Academic Press,
London, ISBN 0–12–156931–4, 2001.
16. Hounslow MJ, Ryall RL, Marshall VR. A discrete population balance for nucleation,
growth and aggregation. AIChE J 1998; 34(11):1821–1832.
17. Immanuel CD, Cordeiro CF, Meadows ES, Crowley TJ, Doyle FJ. Modelling of particle
size distribution in immulsion co-polymerisation: Comparison with experimental data andparametric sensitivity studies. Computers & Chemical Engineering 2002; 26:1133–1152.
18. Kapur PC, Fuerstenau DW. Coalescence model for granulation. Ind Eng Chem Pro Des
Dev. 1969; 8:56–62.
19. Kapur PC. Kinetics of granulation by non-random coalescence mechanism, Chem Eng
Sci 1972; 27:1863–1869.
20. Kaye BH, Powder Mixing, Chapman & Hall, London, 1997.
21. Kristensen HG, Schaefer T. Granulation: A review on pharmaceutical wet granulation.
Drug Dev Ind Pharm 1987; 13:803–872.
© 2005 by Taylor & Francis Group, LLC

592

Cameron and Wang

22. Kumar S, Ramkrishna D. On the solution of population balance equations by discretization – I: A ﬁxed pivot technique. Chem Eng Sci 1996; 51(8):1311–1332.
23. Leuenberger H. Moist agglomeration of pharmaceutical processes. In: Chulia D, Deleuil
M, Pourcelot Y, Eds. Powder Technology and Pharmaceutical Processes, Handbook of
Powder Technology. Elsevier: Amsterdam, 1994 9:337–389.
24. Litster JD. Scale-up of wet granulation processes: science not art, Powder Technol, 2003;
130:5–40.
25. Liu LX, Litster JD, Iveson SM, Ennis BJ. Coalescence of deformable granules in wet
granulation processes. AIChE J 2000; 46(3):529–539.
26. Liu LX, Litster JD. Population balance modelling of granulation with a physically based
coalescence kernel, Chem Eng Sci 2002; 57:2183–2191.
27. Liu Y, Cameron IT, Wang FY. The wavelet collocation method for transient problems
with steep gradients. Chem Eng Sci 2000; 55:1729–1734.
28. Liu Y, Cameron IT. A new wavelet-based method for the solution of the population
balance equation. Chem Eng Sci 2001; 56:5283–5294.
29. Liu Y, Cameron IT. A new wavelet-based adaptive method for solving population
balance equations. Powder Technol 2003; 130:181–188.
30. Ljung L. System Identiﬁcation: Theory for the user. Prentice Hall, NJ: Upper Saddle
River, 1987.
31. Ljung L. System Identiﬁcation Toolbox for Use with MATLAB. The Math Works,
Natick, MA, 2000.
32. Michaels JN. Toward rational design of powder processes. Powder Technol 2003; 138:
1–6.
32a. Miller SM, Rawlings JP. Model identiﬁcation and control strategies for batch coolingcrystallisers. AIChE J 1994; 40(8):1312–1326.
33. Mort PR, Capeci SW, Holder JW. Control of agglomerate attributes in a continuous
binder-agglomeration process. Powder Technol 2001; 117:173–176.
34. Petzold L. A description of DASSL: A differential-algebraic system solver, Proc. IMACSWorld Congress, Montreal, Canada, 1982.
35. Ramkrishna D. Population Balances: Theory and Applications to Particulate Systems in
Engineering. San Diego: Academic Press, 2000.
36. Randolph AD, Larson MA. Theory of Particulate Processes: Analysis and Techniques ofContinuous Crystallization, 2nd Ed., Academic Press, San Diego 1988.
37. Robertson GA, Cameron IT. "Analysis of Dynamic Process Models for Structural
Insight and Model Reduction–Part 1. Structural Identiﬁcation Measures’’. Computers& Chemical Engineering 1997; 21(5):455–473.
38. Salman AD, Fu J, Gorham DA, Hounslow MJ. Impact breakage of fertilizer granules.
Powder Technol 2002; 130:359–236.
39. Sanders CFW, Willemse AW, Salman AD, Hounslow MJ. Development of a predictive
high-shear granulation model. Powder Technology 2003; 138:18–24.
40. Sastry KVS. Similarity size distribution of agglomerates during their growth by coalescence in granulation or green pelletization. Int J Mineral Process 1975; 2:187–203.
41. Smith M, Matsoukas T. Constant number Monte Carlo simulation of population
balances. Chem Eng Sci 1998; 53(9):1777–1786.
42. Spielman LA, Levenspiel O. A Monte Carlo treatment for reaction and coalescing
dispersed systems. Chem Eng Sci 1965; 20:247.
43. Tardos GI, Khan MI, Mort PR. Critical parameters and limiting condition in binder
granulation of ﬁne powders. Powder Technol 1997; 94:245–258.
44. Teo KL, Goh CJ, Wong KH. A Uniﬁed Computational Approach for Optimal Control
Problems. Longman Scientiﬁc and Technical, New York, 1991.
45. van den Dries K, de Vegt O, Girard V, Vromans H. Granulae breakage phenomena ina high shear mixer: inﬂuence of process and formulation variables and consequenceson granule homogeneity. Powder Technol 2003; 130:228–236.

© 2005 by Taylor & Francis Group, LLC

Granulation Process Modeling593

46. Wang FY, Cameron IT. Review and future directions in the modelling and control ofcontinuous drum granulation. Powder Technol 2002; 124:238–253.
47. Wang FY, Ge XY, Balliu N, Cameron IT. Optimal control and operation of drum
granulation, Proc. 2nd International Conference on Population Balance Modelling(PBM 2004). Valencia, Spain, May 2004.
48. Wang FY, Ge XY, Balliu N, Cameron IT, Optimal control and operation of drum granulation. Chem Engi Sci In press (2005).
49. Wang FY, Cameron IT. Multi-level optimal control of particulate process with on-line
identiﬁcation, to be presented at The 7th World Congress of Chemical Engineering(WCCE 7), Glasgow, Scotland 10–14 July (2005).
50. Watano S, Numa T, Koizumi I, Osako Y. Feedback control in high shear granulationof pharmaceutical powders. Eur J Pharm Biopharma 2001a; 52:337–345.
51. Watano S, Numa T, Miyanami K, Osako Y. A fuzzy control system of high shear
granulation using image processing. Powder Technol 2001b; 115:124–130.
52. Wauters PAL. Modelling and Mechanisms of Granulation, PhD thesis, The Delft
University of Technology The Netherlands, 2001.
53. Williams R, Burrage RK, Cameron IT, Kerr M. A four-stage index 2 diagonally implicit
Runge-Kutta method. Applied Numerical Mathematics 2002; 40:415–432.
54. Yekeler M, Ozkan A. Determination of the breakage and wetting parameters of calcite
and their correlations. Part Part Syst Charact 2002; 19:419–425.
55. Zhang J, Lister JD, Wang FY, Cameron IT. Evaluation of control strategies for fertiliser
granulation circuits using dynamic simulation. Powder Technol 2000; 108:122–129.

© 2005 by Taylor & Francis Group, LLC

22Regulatory Issues in Granulation
Prasad Kanneganti
Quality Operations, Pfizer Global Manufacturing, Pfizer Asia Pacific Pte. Ltd., Singapore

1. INTRODUCTION
The pharmaceutical industry is one of the most regulated consumer industries today.
Concerned with the safety of its citizens, governments across the world have set up regulations that govern the manufacturing and distribution of ﬁnished pharmaceuticals forhuman consumption. Like the industry, the regulations are also evolving to meet current business needs and future technological challenges. With the widespread use of
the Internet, consumers have become better informed about drugs, therapies, and healthrisks. Current Good Manufacturing Practices (cGMPs) that were initially well established within the pharmaceutical industry in USA are now widely used across the globe.
Globalization of the pharmaceutical industry has taken place rapidly in recent times
fueled by mergers and acquisitions within the industry and also by economic, political,
and regulatory factors. Harmonization initiatives seeking to develop common regulatory standards have become increasingly relevant and necessary.
2. PHARMACEUTICAL QUALITY MANAGEMENT
Quality management is that aspect of management function that establishes andimplements the quality policy formally authorized by senior management. The fundamental elements of quality management are an appropriate infrastructure or quality
system and systematic actions known as quality assurance taken to ensure adequate
conﬁdence that the product or service will satisfy established requirements for quality.
Thus, quality assurance is a management tool covering all matters that individually orcollectively inﬂuence the quality of a product. It incorporates cGMP as well as otherfactors such as product design and development. Quality control is a subset of cGMP
and is concerned mainly with sampling, speciﬁcations, and testing of raw materials
and ﬁnished pharmaceutical products. The concepts of quality assurance, cGMP,
and quality control are thus interrelated aspects of quality management.
2.1. Current Good Manufacturing Practices
cGMP is that part of the quality assurance system which ensures that medicinal products are consistently produced and controlled to the quality standards appropriate
595© 2005 by Taylor & Francis Group, LLC

596

Kanneganti

to their intended use and as required by the marketing authorization provided by theregulatory agencies. The production of pharmaceutical products involves some risks,e.g., cross-contamination, label mix-ups, etc., that cannot be prevented entirely
through end product testing and cGMPs diminish such risks. This quality assurance
element is mandated by law around the world for the manufacturing, storage, anddistribution of pharmaceuticals. Although the standards set by the United States
Food and Drug Administration (FDA) (1,2) are well recognized as an industry
benchmark, standards from other countries and regions are also gaining global
recognition (3,4).
One of the cGMP standards that is gaining worldwide recognition is that set upby the Pharmaceutical Inspection Convention (PIC) and the Pharmaceutical Inspection Co-operation Scheme (PIC Scheme) commonly known as PIC/S. The purposeof PIC/S is to facilitate the networking between participating authorities and themaintenance of mutual conﬁdence, the exchange of information and experience inthe ﬁeld of GMP and related areas, and the mutual training of GMP inspectors(5). PIC/S became operational in November 1995 when the PIC Scheme commenced
operating in conjunction with PIC, which had already been operating since 1970.
The need to form the PIC Scheme became necessary when it was realized thatan incompatibility between PIC and European law did not permit individual EU
countries that were members of PIC to sign agreements with other countries seeking
to join PIC. Only the European Commission was permitted to sign agreements withcountries outside Europe, and the Commission itself was not a member of PIC.
Therefore, a less formal and more ﬂexible cooperation scheme was developed to continue and enhance the work of PIC. Unlike PIC, which is a legal treaty between
countries, the PIC Scheme is a cooperative arrangement between Health authorities.
2.2. International Conference on Harmonization
The International Conference on Harmonization (ICH) of technical requirements
for registration of pharmaceuticals for human use is a project that brings together
the regulatory authorities of Europe, Japan, and the United States and experts fromthe pharmaceutical industry in these regions to discuss the scientiﬁc and technicalaspects of product registration. With its secretariat in Geneva, Switzerland, ICH
aims to achieve greater harmonization in the interpretation and application of technical guidelines and product registration requirements thus avoiding unnecessary
duplication of testing carried out during the R&D phase for new medicines (6).
Guidelines issued by ICH are very useful reference documents for both industry and regulatory bodies. The topics for these guidelines are divided into four major
categories, each with a speciﬁc topic code: Quality Topics (Q), e.g., Stability Testing (Q1), Impurity Testing (Q3)
 Safety Topics (S), e.g., Carcinogenicity Testing (S1), Genotoxicity Testing(S2)
 Efﬁcacy Topics (E), e.g., Dose Response Studies (E4), Good Clinical
Practices (E6) Multidisciplinary Topics (M), e.g., Medical Terminology (M1), The
Common Technical Document (M4).
There is no speciﬁc ICH guideline for granulation; however, guidelines suchas the Common Technical Document (CTD) highlight the requirements for speciﬁcations, testing, impurities, stability, and validation in drug product regulatory© 2005 by Taylor & Francis Group, LLC

Regulatory Issues in Granulation

597

submissions. In view of the wide international acceptance of these guidelines, itwould be prudent to check compliance with requirements speciﬁed in them while
putting together documentation dossiers to support regulatory ﬁlings or technology
transfers.
2.3. ISO 9000 Standards
The International Organization for Standardization (ISO) is the world’s largest
developer of standards. ISO’s principal activity is the development of technicalstandards. These are very useful to the industry, regulatory bodies, trade ofﬁcials,
suppliers and customers of products and services. With its Central Secretariat in
Geneva, Switzerland, ISO coordinates a network of the national standards institutesof 148 countries (7). Each country is represented by one member that, unlike in thecase of the United Nations, need not be a delegation of the national government.
ISO has gained wide acceptance internationally as a commonly understoodbaseline for quality, safety, and environment standards. It ensures fair play andfacilitates cross-border trade. ISO standards are voluntary and being a nongovernmental organization, it has no legal authority to enforce their implementation. Thisis an essential difference with cGMPs that have been legislated into law in several
countries.
One of the most popular standards is ISO 9000, which is a generic management
system standard that has become an international reference for quality requirements
in business-to-business dealings. The latest standard is the ISO 9000: 2000 series,
which was launched on December 15, 2000, and constitutes the most thorough overhaul of this standard since it was ﬁrst published in 1987. Businesses complying withthe older standards of ISO 9001 through 9003 were provided 3 years to make thetransition to the new version. ISO 9000: 2000 takes into account the developmentsin the ﬁeld of quality management and introduces eight quality management
principles on which the quality management system standards are based. Senior
management can use these principles as a framework to guide their organizations
toward improved performance. The eight principles are customer focus, leadership,
involvement of people, process approach, system approach to management, continual improvement, factual approach to decision making, and mutually beneﬁcial
supplier relationship.
Several ingredients in a drug product formulation may be common chemicals
also used in the food and cosmetic industries. For manufacturers of such chemicals,
if cGMP is not mandated by law, compliance with ISO 9000 is generally expected bypharmaceutical manufacturers as part of their supplier management program.
3. POSTAPPROVAL CHANGE CONSIDERATIONS
Scale-up of manufacturing is required during transfer of production processes fromdrug product development laboratories to commercial manufacturing centers or
between manufacturing centers. Much of the industry is undergoing mergers andacquisitions that is leading to the globalization of manufacturing and supply chain.
To make manufacturing processes efﬁcient, companies are grouping key products
into regional manufacturing centers. In the past, global trade was hindered byregulatory and importation barriers. With the recent success of global initiatives
to improve trade, such barriers are eroding away, giving way to large-scale global
manufacturing facilities.
© 2005 by Taylor & Francis Group, LLC

598

Kanneganti

During the manufacture of clinical batches, the amount of active ingredientavailable is limited and the process equipment available are often scaled-down versions of those used for the production of commercial batches. Batch sizes, thus,
are smaller than those used during the manufacture of routine commercial batches.
Process scale-up and commercial manufacturing are expedited as the industry
attempts to maximize the commercial beneﬁts afforded by patent protection for
new drug molecules. Most companies formally record the scientiﬁc data that are generated into product development reports. These form the basis for establishing the
manufacturing process, speciﬁcations, in-process controls, and validation acceptancecriteria used during commercial production of the drug product. Product development reports also provide a link between the biobatch/clinical batch and commercial
process through development and scale-up. Information from the development
phase is used to prepare the chemistry, manufacturing, and controls (CMC) sectionof an application such as a new drug application (NDA) ﬁled with the FDA (8).
Where applicable, reference is also provided to other documents such as drug masterﬁles (DMFs) submitted earlier to the FDA by the manufacturer or their vendors (9).
The FDA with input from the industry developed guidance for scale-up andpostapproval changes (SUPAC) for drug products. SUPAC covers components orcomposition, site of manufacture, scale of manufacture, and manufacturing
process/equipment. These guidelines represent the agency’s current thinking on
the topic and are not binding on the industry or agency, with alternative approaches
being acceptable. The guidance documents have been found by the pharmaceuticalindustry to enhance its ability to plan and implement change and manage resources
efﬁciently.
The SUPAC-IR guidance for immediate release solid oral dosage forms (10)provides recommendations to sponsors of NDAs, abbreviated new drug applications(ANDAs), and abbreviated antibiotic applications (AADAs) who intend, during thepostapproval period, to make changes. This guidance was the result of a workshop
on the scale-up of immediate release products conducted by the American Association of Pharmaceutical Scientists (AAPS) in conjunction with the United States
Pharmacopoeial Convention (USP) and the FDA (11). It deﬁnes the levels of change,
recommended CMC tests for each level of change, in vitro dissolution tests, and invivo bioequivalence tests for each level of change and ﬁling documentation thatshould support the change (Figures 1 and 2).
Notiﬁcation to FDA of postapproval changes to NDAs are made using change
documentation known as supplements (12). The regulations describe the type ofchanges that require prior approval from the FDA before the change can be implemented (preapprovable changes). Under some circumstances, changes can be madebefore approval from FDA [changes being effected (CBEs)] or described in theannual report to the FDA. In the case of CBE supplements, the FDA may, after
a review of the information submitted, decide that the changes are not approvable.
The SUPAC guidance documents list information that should be provided to the
FDA to ensure that product quality and the performance characteristics of the drug
products are not adversely affected by the changes proposed to be carried out.

3.1. Component and Composition Changes
The SUPAC guidance focuses on changes in excipients in the drug product. Changes
in the amount of drug substance are not addressed by this guidance. The changes are© 2005 by Taylor & Francis Group, LLC

Regulatory Issues in Granulation

599

Figure 1 Development of SUPAC guidance documents.

categorized into three levels according to the increasing impact on product quality
and performance expected.
3.1.1. Level 1 Changes
Level 1 changes are those that are unlikely to have any detectable impact on formulation quality and performance. Examples of such changes are deletion or partial
deletion of an ingredient intended to affect the color or ﬂavor of the drug product,changes in the composition of the printing ink to another approved ingredient, etc.
Changes in excipients, expressed as percentages (w/w) of total formulation, less thanor equal to the percent ranges shown in Table 1 are also Level 1 changes. The total
additive effect of all excipients changes should not be more than 5%.
The documentation necessary to support this type of change are application/compendial release requirements and stability data for one batch on long-term stability. No in vivo bioequivalence data or additional dissolution data other than those

Figure 2 Format of SUPAC guidance documents.
© 2005 by Taylor & Francis Group, LLC

600

Kanneganti

Table 1 SUPAC-IR: Component or Composition Change Levels% Excipient (w/w of total dosage unit)
Excipient

Level 1

Level 2

Level 3

FillerDisintegrantStarchOther
BinderLubricantCa or Mg stearate
Other
Glidant
Talc
Other
Film coat
Total drug excipient change (%)

5

10

> 10

3
1
0.5

6
2
1

>6
>2
>1

0.25
1

0.5
2

> 0.5
>2

1
0.1
1
5

2
0.2
2
10

>2
> 0.2
>2
N/A

Source: From Ref. 10.

required by the application/compendia are necessary for this submission. The entire
documentation package including long-term stability data for the Level 1 change is
ﬁled with the FDA through the annual report mechanism.
3.1.2. Level 2 Changes
Level 2 changes are those that could have a signiﬁcant impact on formulation quality
and performance. The testing and ﬁling requirements for Level 2 changes varydepending on three factors—therapeutic range, solubility, and permeability. Therapeutic ranges are deﬁned as narrow or non-narrow and drug solubility and drug permeability are deﬁned as either low or high. A list of narrow therapeutic range drugs
is provided in the guidance document. Solubility is calculated based on the minimum
concentration of drug, milligram/milliliter (mg/mL), in the largest dosage strength,
determined in the physiological pH range (pH 1–8) and temperature (37  0.5 C).
Permeability (Pe, cm/sec) is deﬁned as the effective human jejunal wall permeabilityof a drug and includes an apparent resistance to mass transport to the intestinal
membrane.
An example of a Level 2 change is change in the technical grade of an excipient,e.g., Avicel PH102 vs. Avicel PH200. Changes in excipients, expressed as a percentage (w/w) of the total formulation, greater than those listed earlier for Level 1changes but less than or equal to a percent range representing a twofold increaseover Level 1 changes (Table 1) are also deemed as Level 2 changes. The total additiveeffect of all excipients changes should not be more than 10%.
The documentation necessary to support this type of change are application/compendial release requirements, batch records, and stability data for one batchwith 3 months’ accelerated stability data in supplement and one batch on long-term
stability. Dissolution data requirements depend on three scenarios known as casesthat cover a high/low permeability and a high/low drug solubility, as shown in
Table 2. No in vivo bioequivalence data are necessary for this submission if the© 2005 by Taylor & Francis Group, LLC

Regulatory Issues in Granulation

601

Table 2 SUPAC-IR: Dissolution Testing Categories
Category

Nature of drug

Case AHigh permeability,
high solubility
Low permeability,
high solubility

Case B

Case CHigh permeability,
low solubility

Dissolution
mediumTime points(min)Speciﬁcation

0.1 N HCl

15

85%

As stated inapplication/compendia

15, 30, 45, 60,
120, or until
asymptote isreached15, 30, 45,
Water, 0.1 N HCl,60, 120
USP buffer media
at pH 4.5, 6.5, and7.5 (plus
surfactant if
justiﬁed)

Dissolution proﬁlesimilar tocurrent
formulation
90% or asymptote
is reached;
proﬁle similar tocurrent productSource: From Ref. 10.

situation falls within one of the cases shown in Table 2. A prior approval supplementthat contains all information including accelerated stability data is to be ﬁled. The
long-term stability data are ﬁled through the annual report mechanism.
3.1.3. Level 3 Changes
Level 3 changes are those that are likely to have a signiﬁcant impact on formulation
quality and performance. Similar to Level 2 changes, the testing and ﬁling documentation requirements vary depending on therapeutic range, solubility, and permeability. Examples of Level 3 changes are any qualitative and quantitative excipientschange to a narrow therapeutic drug beyond the ranges stated for Level 1 changes(Table 1) and all drugs not meeting the dissolution criteria listed for Level 2 changes(Table 2).
A change in granulating solution volume is not covered under SUPAC-IR as it
is a minor change to a normal operating procedure and should be included in thebatch record after undergoing validation and manufacturer’s site change control
procedure. A change in the granulating solvent, e.g., from alcohol to water, canbe expected to alter the composition of the drug product even though it may beremoved during manufacturing and hence it is a Level 3 change that requires a priorapproval supplement.
The documentation required to support Level 3 changes are application/compendial release requirements and batch records. If a signiﬁcant body of information is available, one batch with 3 months’ accelerated stability data is to be includedin the supplement and one batch on long-term stability data reported in the annual
report. Where a signiﬁcant body of information is not available, up to three batcheswith 3 months’ accelerated stability data are to be included in the supplement andone batch on long-term stability data reported in the annual report.
Dissolution data requirements for Level 3 changes are as speciﬁed for Case B in
Table 2. In addition, a complete in vivo bioequivalence study is required. This study
may be waived if an acceptable in vivo/in vitro correlation has been veriﬁed. A priorapproval supplement that contains all information including accelerated stability
data is to be ﬁled.
© 2005 by Taylor & Francis Group, LLC

602

Kanneganti

3.2. Site Changes
Site changes consist of changes in location of the site of manufacture for bothcompany-owned and contract manufacturing facilities. These do not include any
scale-up changes, changes in manufacturing process or equipment, or changes incomponents or composition. The new manufacturing locations are expected to havea satisfactory cGMP inspection. Similar to those for component and compositionchanges, site changes are also categorized into three different levels that requirediffering depth of test and ﬁling documentation. Level 1 changes are site changes
within a single facility while Level 2 changes are site changes within the same campus.
Level 3 changes consist of a change in manufacturing site to a different campus, i.e.,
the facilities are not on the same original contiguous site or in adjacent city blocks.
These requirements are summarized in Table 3.
3.3. Changes in Batch Size
Postapproval changes in the size of a batch (scale-up/scale-down) from the pivotal/
pilot scale biobatch material to a larger or smaller production batch require additional information to be submitted with the change application. Scale-down below
100,000 dosage units is not covered by the SUPAC guidance. All scale-up changes
are required to undergo suitable process validation and regulatory inspection. There
are two levels of batch size changes that cover batch size increases up to and including a factor of 10 times the size of the pilot/biobatch and increases beyond a factorof 10 times, respectively (Table 3).
3.4. Manufacturing Equipment/Process Changes
Equipment changes consist of changes from nonautomated or nonmechanical equipment to automated or mechanical equipment or changes to alternative equipment
either of the same or different design and operating principles or of a different capacity. Process changes include changes such as mixing time and operating speeds
either within or outside application/validation ranges. A change in the process usedin the manufacture of the drug product, e.g., change from wet granulation to directcompression is also included. Table 3 provides a summary of the documentation
requirements to ﬁle changes to manufacturing equipment and process.
3.5. Modified Release Solid Dosage Form
Modiﬁed release solid dosage forms include both delayed and extended release drug
products. Delayed release is the release of a drug (or drugs) at a time other than
immediately following oral administration. Extended release products, on the other
hand, are formulated to make the drug available over an extended period after ingestion so that a reduction in the dosing frequency compared to an immediate release
dosage form is achieved.
Following the successful release of the guidance document for immediate
release solid oral dosage forms (SUPAC-IR), the FDA issued a speciﬁc guidance,
the SUPAC-MR, for scale-up and postapproval changes affecting modiﬁed releasesolid dosage forms (13,14) in 1997. This guidance covers postapproval changes for
modiﬁed release solid oral dosage forms that affect components and composition,
scale-up/scale-down, site change, and manufacturing process or equipment changes.
© 2005 by Taylor & Francis Group, LLC

Regulatory Issues in Granulation603

It permits less burdensome notice of certain postapproval changes within the meaning of 21CFR 314.70.
In the case of components and composition, SUPAC-MR covers changes in
non-release controlling excipients and release controlling excipients separately. The
criticality of excipients to drug release is to be established and appropriate justiﬁcations provided if an excipient is claimed as a non-release controlling excipient in
the formulation of the modiﬁed release solid dosage form. The change level classiﬁcation, therapeutic range, test and ﬁling documentation for components andcomposition changes, site changes, changes in batch size (scale-up/scale-down),
manufacturing equipment changes, and manufacturing process changes for extended
release solid dosage forms and delayed release solid dosage forms are summarized inthis guidance document.

3.6. Changes to Granulation Equipment
The FDA released in January 1999 another guidance document that speciﬁcallyaddressed documentation requirements for ﬁlings addressing changes to pharmaceutical manufacturing equipment (15). This is the manufacturing equipment addendum
developed with the assistance of the International Society of Pharmaceutical Engineering (ISPE) and is used in conjunction with the SUPAC-IR and SUPAC-MR guidance documents. It includes a representative list of equipment commonly used in
the industry but does not include equipment modiﬁed by a manufacturer to meet
speciﬁc needs. Deﬁnitions and classiﬁcation for broad categories of unit operations
such as blending and mixing, drying, particle size reduction/separation, granulation,
unit dosage, coating, printing, and soft gelatin encapsulation are provided. For each
unit operation, a table categorizing process equipment by class (operating principle)
and subclass (design characteristics) along with examples of commercially available
equipment is presented.
Granulation is deﬁned as the process of creating granules either by using aliquid that causes particles to bind through capillary forces or by dry compaction
forces. Granulation is stated to impact on one or more of the powder properties suchas enhanced ﬂow; increased compressibility; densiﬁcation; alteration of physicalappearance to attain more spherical, uniform, or larger particles; and or enhancedhydrophilic surface properties.
The operating principles listed in the SUPAC manufacturing equipment
addendum (15) are
1. Dry granulation: Dry powder densiﬁcation and/or agglomeration by direct
physical compaction.
2. Wet high-shear granulation: Powder densiﬁcation and/or agglomerationby the incorporation of a granulation ﬂuid into the powder withhigh-power-per-unit mass, through rotating high-shear forces.
3. Wet low-shear granulation: Powder densiﬁcation and/or agglomerationby the incorporation of a granulation ﬂuid into the powder with lowpower-per-unit mass, through rotating low-shear forces.
4. Low-shear tumble granulation: Powder densiﬁcation and/or agglomerationby the incorporation of a granulation ﬂuid into the powder with lowpower-per-unit mass, through rotation of the container vessel and/or
intensiﬁer bar.
© 2005 by Taylor & Francis Group, LLC

604

Table 3 SUPAC-IR: Site Equipment and Process Change Requirements by Category
Documentation
Type/level

Change permitted

Exclusions

Chemistry

Dissolution

Bioequivalence Filing

LTSSa commitment

Application/compendial only
Varies (Table 2)

None

Annual report

None

Case B (Table 2)

Full

Prior approval
supplement
Prior approval
supplement

Application/compendial only
Application/compendial only
Case B (Table 2)

None

Annual report

None

CBE
supplement
CBE
supplement

Component/composition
Level 1
Level 2
Level 3

Table 1: total change No change beyond
5%approved target ranges
Table 1: total change No narrow therapeutic
10%range drugs
Table 1
None

Accelerated stability dataplus LTSS commitment
Accelerated stability dataplus LTSS commitment

Site change
Level 1

Single facility

No scale or process changes None

Level 2

Contiguous campus

No scale or process changes None

Level 3Different campus

No scale or process changes Accelerated stability dataand LTSS commitment

None

Scale-up/scale-down

Level 2

10-fold increase in No change in site, controls, LTSS commitment
batch sizeor equipment> 10-fold increase in No change in site, controls, Accelerated stability data
batch sizeor equipment
and LTSS commitment© 2005 by Taylor & Francis Group, LLC

Application/compendial only
Case B (Table 2)

None

Annual report

None

CBE
supplement

Kanneganti

Level 1Level 1

Level 2

Non-to-automated/ No change in operating
principle
non-to-mechanical;
new equipment
design w/wo same
capacity
New design orNoneoperating principle

LTSS commitment

Application/compendial only

None

Annual report

Accelerated stability dataand LTSS commitment

Case C (Table 2)

None

Prior approval
supplementwith change
justiﬁcation

None

None

None

Annual report

None

LTSS commitment

Application/compendial only
Case B (Table 2)

None

None

Accelerated stability dataand LTSS commitment

Case B (Table 2)

Full

CBE
supplement
Prior approval
supplementwith change
justiﬁcation

Manufacturing process
Level 1
Level 2
Level 3Operating within
validation ranges
Operating outside
validation ranges
New process(e.g., wet-to-dry
granulation)

Regulatory Issues in Granulation

Manufacturing equipmenta
LTSS, long-term stability study.
Source: From Ref. 10.

605© 2005 by Taylor & Francis Group, LLC

606

Kanneganti

5. Extrusion granulation: Plasticization of solids or wetted mass of solids andgranulation ﬂuid with linear shear through a sized oriﬁce using a pressure
gradient.
6. Rotary granulation: Spheronization, agglomeration, and/or densiﬁcationof a wetted or nonwetted powder or extruded material. This is accomplished by centrifugal or rotational forces from a central rotating disk,
rotating walls, or both. The process may include the incorporation and/or drying of a granulation ﬂuid.
7. Fluid bed granulation: Powder densiﬁcation and/or agglomeration with little
or no shear by direct granulation ﬂuid atomization and impingement onsolids, while suspended by a controlled gas stream, with simultaneous drying.
8. Spray dry granulation: A pumpable granulating liquid containing solids (insolution or suspension) is atomized in a drying chamber and rapidly driedby a controlled gas stream, producing a dry powder.
The classiﬁcation of granulation equipment in the SUPAC manufacturing
equipment addendum (15) is as follows:
1. Dry granulator: Dry granulator subclasses primarily are distinguished by
the densiﬁcation force application mechanism:

Slugging
Roller compaction

2. Wet high-shear granulator: Wet high-shear granulator subclasses primarily
are distinguished by the geometric positioning of the primary impellers;
impellers can be top, bottom, or side driven.


Vertical (top or bottom driven)
Horizontal (side driven)

3. Wet low-shear granulator: Wet low-shear granulator subclasses primarily
are distinguished by the geometry and design of the shear inducing components; shear can be induced by rotating impeller, reciprocal kneading
action, or convection screw action.
Planetary
Kneading
Screw

4. Low-shear tumble granulator: Although low-shear tumble granulators may
differ from one another in vessel geometry and type of dispersion or intensiﬁer bar, no low-shear tumble granulator subclasses have been identiﬁed.
5. Extrusion granulator: Extrusion granulator subclasses primarily are
distinguished by the orientation of extrusion surfaces and driving pressure
production mechanism:Radial or basket
Axial
Ram
Roller, gear, or pelletizer

6. Rotary granulator: Rotary granulator subclasses primarily are distinguishedby their structural architecture. They have either open top architecture,© 2005 by Taylor & Francis Group, LLC

Regulatory Issues in Granulation

607

such as a vertical centrifugal spheronizer, or closed top architecture, such asa closed top ﬂuid bed dryer: Open Closed
7. Fluid bed granulator: Although ﬂuid bed granulators may differ from one
another in geometry, operating pressures, and other conditions, no ﬂuid
bed granulator subclasses have been identiﬁed.
8. Spray dry granulator: Although spray dry granulators may differ from one
another in geometry, operating pressures, and other conditions, no spraydry granulator subclasses have been identiﬁed.
Table 4 shows a listing of granulation equipment classes and subclasses. Equipment within the same class or subclass would be considered to have the same designand operating principle under SUPAC-IR and SUPAC-MR. As an example, achange from one type of wet high-shear granulator (e.g., vertical type from manufacturer A) to another type of wet high-shear granulator (e.g., vertical type frommanufacturer B) generally would not represent a change in operating principle
and would, therefore, be considered to be the same under either SUAPC-IR or
SUPAC-MR.
A change from equipment in one class to equipment in a different class would
usually be considered a change in design and operating principle. Thus, a change
from a wet high-shear granulator to a ﬂuid bed granulator demonstrates a change
in the operating principle from powder densiﬁcation by wet agglomeration using
high shear to powder densiﬁcation with little or no shear. Such a change would beconsidered to be different under either SUPAC-IR or SUPAC-MR.
The FDA advises change applicants to carefully consider and evaluate on acase-by-case basis changes in equipment that are in the same class, but different
subclass. For example, a change from a horizontal (side driven) wet high-shear granulator to a vertical (top or bottom driven) wet high-shear granulator represents achange within a class and between subclasses. This change would not require a preapproval supplement provided the manufacturing process with the new equipment isvalidated. The data and rationale used to make this determination can be reviewed
by the FDA at its discretion. In the event a single piece of equipment is capable ofperforming multiple discrete unit operations, e.g., mixing, granulation, drying, etc.,
the unit is evaluated solely for its ability to granulate.

3.7. International Change Notification
The manufacturing process and equipment change notiﬁcation outside the UnitedStates varies from region to region. A brief description of the manufacturing process
is required as part of the ﬁling requirements for marketing a drug product. Somecountries require master batch records to be ﬁled but most others do not require
much detail. In addition, a site master ﬁle that provides information on the production and control of the manufacturing operations including major process equipment
at the site is sometimes required (16).
Regulatory agencies in countries that form the European Community (EC)have adopted a common approach to the procedures for variations to the terms ofa marketing authorization. Variations can be by notiﬁcation such as Type IA andType IB that are categorized as minor variations that fulﬁll the conditions set forth© 2005 by Taylor & Francis Group, LLC

608

Kanneganti

Table 4 Unit Operation—GranulationClass

Subclass

Dry granulator

Slugging
Roller compaction

ExamplesVariousAlexanderwerk
Bepex (Hosokawa)Fitzpatrick
FreundVector
Wet high-shear granulator Horizontal (side driven)
Littleford Day
LodigeProcessall
VerticalAeromatic-Fielder (GEA-Niro)(top or bottom driven) APV
Baker-Perkins
L.B. Bohle
Dierks & Shone
Diosna (Fluid Air)GEI-Collette (GEI International)
Key International
Littleford Day
LodigePowrex (Glatt)Processall
Werner & Pfeiderer
Zanchetta (Romaco)
Wet low shear granulator Planetary
Aaron
AeschbachAMF
GEI-Collette (GEI International)
HobartJaygo
Littleford Day
Ross
VriecoKneading
Aaron
Paul O. Abbe
Custom Metal Craft
Dynamic Air
Jaygo
Kemutec
Littleford Day
Processall
Ross
Sigma
Teledyne Readco
Screw
Vrieco-Nauta (Hosokawa)
Low-shear tumble
Slant cone, or double cone, Paul O. Abbe
granulatoror V-blender
Gemco
Patterson-Kelley
Extrusion granulator
Radial or basket
Alexanderwerk
GEA Niro(Continued)© 2005 by Taylor & Francis Group, LLC

Regulatory Issues in Granulation

Table 4609

Unit Operation—Granulation (Continued )Class

Subclass

Axial

Ram
Roller, gear, or pelletizer
Rotary granulator

Open

ClosedFluid bed granulator

None identiﬁed

Spray dry granulator

None identiﬁed

Examples
LCI
Luwa
Ross
Bepex (Hosokawa)
GablerLCI
LCI
Alexanderwerk
Bepex (Hosokawa)
Freund (Vector)
GEA Niro
LCI
Luwa
Aeromatic-Fielder (GEA Niro)
Glatt
LCI
Luwa
Aeromatic-Fielder (GEA Niro)
APV
BWI Hüttlin (Thomas Engineering)
DiosnaFitzpatrick
Fluid Air
Glatt
HeinenVectorAllgaier
GEA Niro
Glatt
HeinenSource: Ref. 15.

in an annex to the EC regulations (17). A major variation of Type II is a variation
which cannot be deemed to be a minor variation or an extension of the marketing
authorization and requires prior approval. A downscaling of batch size by 10 times
or an increase that results in up to 10 times the original batch size approved at the
grant of the marketing authorization is a Type IA change (18). All other batch size
decreases/increases or minor changes in the manufacturing process for the ﬁnishedproduct require a Type IB ﬁling. A minor change to the manufacture is one where
the overall manufacturing principle remains the same and the new process leads toan identical product regarding all aspects of quality, safety and efﬁcacy.

4. VALIDATION OF GRANULATION PROCESSES
Validation is deﬁned by the FDA as establishing documented evidence which provides a high degree of assurance that a speciﬁc process will consistently produce a
product meeting its predetermined speciﬁcations and quality attributes (19). Process© 2005 by Taylor & Francis Group, LLC

610

Kannegantivalidation is required both in general and speciﬁc terms by cGMPs for ﬁnishedpharmaceuticals—21 CFR Parts 210 and 211. The WHO deﬁnes validation as thecollection and evaluation of data, beginning at the process development stage andcontinuing through the production phase, which ensure that the manufacturing
processes, including equipment, buildings, personnel, and materials, are capable ofachieving the intended results on a consistent and continuous basis (20).
For a manufacturing facility, process knowledge is provided through technology transfer dossiers. Granulation is a critical process step that has a direct impact
on the quality of the drug product manufactured and hence requires validation. The
overall validation activity at a manufacturing facility is detailed in a document
known as the validation master plan (VMP). The validation of the granulation process is described in the VMP. Critical process parameters for granulation such as therate and amount of granulation ﬂuid added, impeller and chopper speed, and mixing
time are identiﬁed and in-process controls such as moisture content and granulation
end point measurement are established during the product development phase.

4.1. Equipment/Utilities Qualification
The qualiﬁcation of the manufacturing equipment and control instrumentation is aprerequisite to the validation of the granulation process. Critical utilities such as
puriﬁed water, compressed air, gaseous nitrogen, etc., required for granulation are
also validated to ensure that they meet the required quality speciﬁcation at the pointof delivery to the granulation equipment.
The qualiﬁcation of granulation equipment is carried out sequentially beginning with design qualiﬁcation (DQ) followed by installation qualiﬁcation (IQ) andoperational qualiﬁcation (OQ) (Fig. 3). The quality of process equipment depends
on the effort put into its design and DQ provides evidence that quality is built into
the design of the equipment. Quite often a design rationale instead of a DQ is prepared. This document addresses why a speciﬁc piece of equipment was chosen highlighting its quality and safety considerations and provides evidence of the assessment
carried out to judge its suitability for the manufacturing of the drug product.
IQ provides documented evidence that the equipment is installed as designed
and speciﬁed and correctly interfaced with other systems such as electrical supply
and utilities. During this phase of qualiﬁcation, equipment manuals/drawings, speciﬁcations, manufacturers test records, etc., together with installation documents and‘‘as-built’’ drawings are compiled and veriﬁed. Calibration of instrumentation andmaintenance checks are also established. OQ is a documented demonstration thatthe process equipment as installed operates well. At this stage, generally a manufacturing process simulation is carried out using a placebo formulation instead of theactual drug product recipe. For each qualiﬁcation phase, a protocol detailing theactivity and acceptance criteria is prepared. At the conclusion of the testing activity,
a summary report that discusses the results and the readiness to proceed to the next
phase of qualiﬁcation is issued.

4.2. Performance Qualification
Performance Qualiﬁcation (PQ) is a documented program that demonstrates that the
granulation process when carried out within deﬁned parameters will consistently perform its intended function to meet its pre-established acceptance criteria. Thus, PQ is© 2005 by Taylor & Francis Group, LLC

Regulatory Issues in Granulation

611

Figure 3 Documentation hierarchy for pharmaceutical process validation.

dynamic testing that combines the equipment, utilities, and manufacturing process to
produce the product under routine operational conditions.
Product speciﬁcations that become the basis for the acceptance criteria at PQ
stage are established during the development of the process with the biobatch or
pivotal clinical batch serving as the reference batch. Prospective validation of the
granulation process is generally carried out for new products and the data included
in regulatory submissions, if necessary. The norm is to manufacture at least threeconsecutive PQ batches; however, a process capability study can establish the actual
number of batches required based on the natural variability of a process (21). Revalidation may be required after changes that signiﬁcantly impact product quality are
made or on a periodic basis at scheduled intervals.
A FDA ﬁeld inspection guide for validation of oral solid dosage forms lists
granulation/mix analysis as a major area for investigation (22). It discusses various
types of mixers and granulation equipment and highlights their design features aswell as problems associated with their efﬁciency and validation. Blending validationand content uniformity failures due to poor mixing are of chief concern for mostconventional mixers (Table 5). This guide also compares dryers and notes that theﬂuid bed dryer is superior to the oven dryer as it yields a more uniform granulation
with spherical particles.

4.3. Computer Validation
Granulation equipment is supported by computer control systems that are getting
increasingly sophisticated. Most commercial equipment has programmable logic
controllers or embedded microprocessors. International forums with representationfrom users and the vendors of equipment and software have been set up to address
the software life cycle documentation requirements. GAMP 4 is a globally accepted© 2005 by Taylor & Francis Group, LLC

612

Kannegantiguidance document developed by ISPE and the GAMP Forum to address computervalidation (23). The PIC/S Guide to Good Practices for computerized systems inregulated ‘‘GXP’’ environments developed by international regulatory agencies isalso a useful reference document for manufacturers and other users (24).
Electronic records and electronic signatures that have cGMP implications are
generally expected by regulatory agencies to be equivalent to paper records andhandwritten signatures executed on paper (25). A new guidance that represents
FDA’s current thinking on electronic records and electronic signatures was releasedin August 2003 (26). The agency took a narrower interpretation of the requirements
stated in 21 CFR Part 11 following feedback from the pharmaceutical industry andvendors that the regulations could stiﬂe technological advances by restricting the useof electronic technology and increasing the cost of compliance. PIC/S also requires
the regulated user to validate the system for storage of the information electronicallyfor the required time and to ensure that the data are protected from damage or loss
and can be easily retrieved in a legible form (24).

Table 5 Typical Problems Associated with Mixing Equipment
Mixer Type

Design Feature

Limitations/problems

Planetary (pony pan)Open pan/pot
Horizontal blending

Ribbon blender

Top loading
Horizontal and verticalblending
Discharge valve
Blade clearance

Tumble blender

Twin shell/double cone
Mild mixing action

High shear

High-energy chopper

Dusty operation
Cross-contamination problem
Poor vertical mixing
Segregation or nonmixing ofcomponents
Difﬁcult to validate
Moderately dusty operation
Cross-contamination problem‘‘Dead spot/zone’’ at the discharge
valve
Poor mixing at ends of the center
horizontal mixing bar and shellwall
Cleaning problems with seals/
packing
Risk of overﬁll leading to poor
mixingMild mixing action
Powder lumps will not break up
Low humidity results in static
charge buildup
High humidity leads to lumping
Different mixing time compared toconventional mixers
Drug substance may partiallydissolve or recrystallize
Charring due to heat generation
Cleaning requires disassembly of
chopper

Source: From Ref. 22.
© 2005 by Taylor & Francis Group, LLC

Regulatory Issues in Granulation

613

5. CONCLUSION
The globalization of pharmaceutical manufacturing is proceeding rapidly, driven bymergers and acquisitions within the industry and the freeing up of cross-border trade.
In addition to known global quality standards such as ISO 9000, harmonization ofcGMPs and regulatory ﬁling requirements is making progress driven by ICH andregional forums such as PIC/S. Simpliﬁcation of existing regulations for notiﬁcationof postapproval changes to regulatory ﬁlings has also been achieved through workshops representing regulatory bodies such as the FDA, the pharmaceutical industry,
and academia. Such guidance has been found to be very useful by manufacturers as it
gives them greater ﬂexibility of operations, cost savings, and efﬁcient management of
resources. The manufacturer is however, expected to carry out a thorough scientiﬁcreview to evaluate the impact of all changes on product quality and performance.
Granulation is a critical process step and hence requires to be validated as part ofthe overall validation of the manufacturing process. Computer validation becomesincreasingly relevant with the use of control systems in granulation equipment,
electronic records, and electronic signatures. Process engineers and product development researchers today require a sound understanding of regulations governing drug
product approval, validation, and change management.

REFERENCES
1. 21 CFR Part 210. Current Good Manufacturing Practice in Manufacturing, Processing,Packing, or Holding of Drugs; General.
2. 21 CFR Part 211. Current Good Manufacturing Practice for Finished Pharmaceuticals.
3. PIC/S Guide to Good Manufacturing Practice for Medicinal Products (PE 009-1), Sep 1,
2003.
4. WHO expert committee on speciﬁcations for pharmaceutical preparations, 32nd report.
Good Manufacturing Practices for Pharmaceutical Products (Annex 1). Geneva: World
Health Organization, 1992.
5. Pharmaceutical Inspection Co-operation Scheme (PIC/S). http://www.picscheme.org.
6. International Conference on Harmonization (ICH). http://www.ich.org.
7. International Organization for Standardization (ISO). http://www.iso.ch.
8. FDA Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application, Feb 1987.
9. FDA Guideline for Drug Master Files, Sep 1989.
10. FDA Guidance for Industry: Scale-up and Postapproval Changes for Immediate Release
Solid Oral Dosage Forms, Nov 1995.
11. Skelly JP, et al. Workshop report: scale up of immediate release oral solid dosage forms.
Pharm Res 1993; 10(2):313–316.
12. 21 CFR Part 314.70. Supplements and Other Changes to an Approved Application.
13. FDA Guidance for Industry: Scale-up and Postapproval Changes for Modiﬁed Release
Solid Oral Dosage Forms, Sep 1997.
14. Skelly JP, et al. Workshop report: scale-up of oral extended-release dosage forms. Pharm
Res 1993; 10(12):1800–1805.
15. FDA Guidance for Industry: Scale-up and Postapproval Changes for Immediate Releaseand Modiﬁed Release Solid Oral Dosage Forms (Manufacturing Equipment Addendum), Jan 1999.
16. Health Sciences Authority (Singapore). Guidance Notes on Preparation of a Site Master
File, May 1999.
17. European Commission regulation (EC) No. 1084/2003, Jun 3, 2003.
© 2005 by Taylor & Francis Group, LLC

614

Kanneganti

18. Guideline on Dossier Requirements for Type IA and Type IB Notiﬁcations, European
Commission, Jul 2003.
19. FDA Guideline on General Principles of Process Validation, May 1987.
20. WHO expert committee on speciﬁcations for pharmaceutical preparations, 34th report.
Good Manufacturing Practices: Guidelines on Validation of Manufacturing Processes(Annex 6). Geneva: World Health Organization, 1996.
21. Kieffer R, Torbeck L. Validation and process capability. Pharm Technol 1998:66–76.
22. FDA Guide to Inspections of Oral Solid Dosage Forms Pre/Post Approval Issues forDevelopment and Validation, Jan 1994.
23. Good Automated Manufacturing Practice Guide (GAMP 4). International Society of
Pharmaceutical Engineering (ISPE), Dec 2001. http://www.ispe.org.
24. PIC/S Guide to Good Practices for Computerized Systems in Regulated ‘‘GXP’’ Environments (PE 011-1), Aug 20, 2003.
25. 21 CFR Part 11. Electronic Records; Electronic Signatures.
26. FDA Guidance for Industry on Part 11, Electronic Records; Electronic Signatures—
Scope and Application, Aug 2003.

© 2005 by Taylor & Francis Group, LLC