W1130-10-079

Excipient consistency is key tode-risk formulation development
and manufacturing
Sunil Kumar N, Bastiaan HJ Dickhoff, DFE Pharma, Goch, Germany

Contact information: dfepharma.com

Purpose

Method(s)Result(s)Continuous manufacturing (CM) gains more andPharmatose® 200M was used to map the influence

An example of continuously produced typicalInterestingly, magnitude of the variation in PSD

Utilizing excipients with tight particle size andmore interest in the pharmaceutical industry. Theof the excipient variation on the processing

Pharmatose® CM granules is visualized by SEM inas seen in the starting materials is not seen in thedensity ranges are of benefit in ContinuousInternational Conference of Harmonization (ICH)behavior of a Twin screw Extruder (TSE). ThreeFig 2. Pharmatose® CM showed the most consistent

granulated products. Probably this is due to theManufacturing, as these products will ensurestates in its Q8 ‘Pharmaceutical Development’batches of Pharmatose® CM having consistent PSD

granulation performance in terms of BD, TD, andfact that the granules were sieved using 800µm

a consistent output in end product behaviour.

guideline that the manufacturer of pharmaceuticals

characteristics along with custom made fine andPSD; where BD of granulations were within limits

and this may have caused the discriminative power

Excipients with wide size / density ranges, asshould have an enhanced knowledge of thecoarse end of Pharmatose® 200M supplied by DFE

from 0.60 to 0.67 and TD varied from 0.82 to 0.92.

between the products in terms of PSD to diminish.

described in this study as fine and coarse end are

product performance over a range of raw material

Pharma were used. The different products wereThe three tier PSD ranged as follows: X10 - fromPharmatose® CM granules shows good tabletability

expected to cause a wide output product behavior.

attributes, manufacturing process options (including

processed using TSE from Leistritz , model-ZSE 18

47 to 60µm; X50 - from 188 to 289µm; and X90(Fig 4, orange line). The black dotted line represents

continuous manufacturing) and process parameters.

HPe-VA. The product (solid) was fed to the TSE using- from 735 to 885µm. Fig 3 shows the cumulative

granulated Pharmatose® 200M fine end, whereasDFE Pharma offers QbD support and consistenta loss in weight twin screw feeder (K-Tron, K-PH-

volume distribution. The green line and the green

black line represents granulated Pharmatose® 200M

pharmaceutical excipients for pharmaceutical

Stringent controls on Particle Size Distributions

CL-24-KT20). The binder-water 8,25%w/w, was fed

dotted line represents the starting material andcoarse end.

development and manufacturing and suitable for(PSD) of starting materials are of key importanceusing a peristaltic liquid feed pump (Watson Marlow,

the granulated fine end of Pharmatose® 200M,520Du) and TSE was run at solid feed addition rate

respectively. The blue line and the blue dotted line

this purpose the PSD of Pharmatose CM (a newof 5kg for 30min. The granules obtained were dried

represents the starting material and the granulated

excipient) has been evaluated in comparison withusing Rapid dryer (Retsch, Germany). Dried granules

coarse end of Pharmatose 200M , respectively. The

custom made grades of the fine and coarse ends ofwere sieved using a 800µm sieve and the undersize

orange line shows the starting material, whereas thePharmatose® 200M. Furthermore, Pharmatose® CMgranules were lubricated by blending with 0.5%

dark orange line represents the granulated

was chosen to identify the influence of variation inMagnesium Stearate using Turbula mixer for 2 minPharmatose® CM.

®

the excipient PSD on the final granule size and on
tablet properties.

®

Continuous Manufacturing.
100%% Cumulative volume

in continuous manufacturing of granules. For

Conclusion(s)60%

way and gave comparable results.

40%

Acknowledgement

20%

0110100

1000

10000

Particle size(um)at 90 rpm. Lubricated granules were tableted usingPharmatose® CM granulated

9mm round flat faced punch sets.

Fine end granulated

Coarse end granulated

Pharmatose® 200CM

Coarse end

Coarse end

The authors would like to thank Kathrin Nickel andAlbert Huber from Leistritz Extrusiontechnik GMBH;
without their help this work would not have been

Fig 3: Cumulative PSD graph of Pharmatose® CM along with fine and coarse end

possible.
2,0Tablet Tensile Strenght (Mpa)

To showcase the consistent performance ofcontinuous wet granulation with granules from threebatches of Pharmatose® CM (a new excipient grade)along with a fine and coarse end of Pharmatose®
200M, these batches were analyzed for Bulk
Distribution (PSD) and tabletability.

SuperTab® 21AN DFE Pharma was used in the same0%

Objective(s)Density (BD), Tapped Density(TD), Particle Size80%

1,51,0Pharmatose® 200CM

0,5Pharmatose® 200CM Fine
Pharmatose® 200CM Coarse

Fig 1: Manufacturing of granules using Leistritz ZSE 18 HPe-VA

Fig 2: Typical SEM of Pharmatose CM granules using TSE®

0,00510152025Compaction Force (kN)Fig 4: Tablet tensile strength vs Compaction force data of lubricated granules

Contact information
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In pursuit of excipient excellence