Precipitation of micro/nanoparticles in enhanced high energy dissipation mixing systems

PRECIPITATION OF MICRO/NANOPARTICLES IN ENHANCED HIGH ENERGY DISSIPATION MIXING SYSTEMS by Giuseppe Di Benedetto Crystallization is the most common unit operation used in the pharmaceutical industry to synthesize active ingredients. Rapid development of a drug candidate is dependent on the ability to produce a desired drug substance with consistent properties, These properties include stability and purity, which are directly affected by the crystallization process and which affect, in turn, bioavailability, drug dissolution rate, drug stability, and shelf life, The objective of this work is to produce micro/nanoparticle crystals within existent glass-lined pharmaceutical stirred-tank reactors by modifying the current reactor configuration to include features that can increase the local rate of energy dissipation in the mixing precipitation zone where crystals are formed, thus promoting the formation of micro/nanoparticles, In this work, a submerged impinging jet system placed inside the tank was used in combination with another energy dissipation device, i,e. , a sonicator, to achieve this objective, The hydrodynamics of the typical reactor used in the pharmaceutical industry for this purpose, namely a partially baffled cylindrical reactor stirred by a retreat-blade impeller, was first predicted using Computational Fluid Dynamics (CFD). Laser Doppler Velocimetry (LDV) was used to validate the CFD predictions of the velocity distribution in the reactor and especially in the mixingprecipitation zone. Then, the performance of the system was evaluated using an actual precipitation reaction of relevance to the pharmaceutical industry, namely the precipitation of griseofulvin, a common antifungal drug, from a solution in acetone using an aqueous solution as the antisolvent. Precipitation studies were conducted to determine the role on crystal size distribution of different operating parameters, such as impinging jet velocity, angle of impingement, sonication power, and the presence of different surfactants. Several characterization techniques such as Scanning Electron Microscopy (SEM), Laser Diffraction Particle Size Analysis, and X-Ray Diffraction (XRD) were utilized to determine the particle size distribution, particle shape, and crystal morphology. The submerged impinging jets system produced crystals with smaller mean particle sizes when the two jets were oriented 180 degrees apart and pointed directly at each other. The introduction of ultrasonic power at the impingement point resulted in markedly smaller mean particle size and a tighter particle size distribution. In general, the results were highly reproducible. X-Ray diffraction results showed that the crystal structure was unaffected by different operating conditions. A similar investigation was conducted on a new type of confined impinging jets system. This newly fabricated system allowed for the introduction of ultrasonics within a small, confined impinging jets chamber. The key parameters investigated in this study were the antisolvent-to-solvent mass flow ratio and the sonication power intensity. The mass flow ratio between the antisolvent stream and the solvent stream had a major effect on the resulting mean particle size and accompanying particle size distribution. The higher mass flow ratios delivered a faster precipitation process resulting in smaller mean particle size and tighter particle size distribution. The addition of sonication to the confined impinging jets apparatus resulted in a significant reduction in the mean particle size which was between 1-2 pm. PRECIPITATION OF MICRO/NANOPARTICLES IN ENHANCED HIGH ENERGY DISSIPATION MIXING SYSTEMS by Giuseppe Di Benedetto A Dissertation Submitted to the Faculty of New Jersey Institute of Technology in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Chemical Engineering Otto H. York Department of Chemical, Biological and Pharmaceutical Engineering January 2009 Copyright © 2009 by Giuseppe Di Benedetto ALL RIGHTS RESERVED APPROVAL PAGE PRECIPITATION OF MICRO/NANOPARTICLES IN ENHANCED HIGH ENERGY DISSIPATION MIXING SYSTEMS Giuseppe Di Benedetto Dr. Piero M. Armenante, Dissertation Advisor Date Distinguished Professor of Chemical Engineering, NJIT Dr. Robert Barat, Committee Member Date Professor of Chemical Engineering, NJIT br. Rajesh N. Dave, Committee Member Date Distinguished Professor of Chemical Engineering, NJIT Dr. Somenath Mitra, Committee Member Date Professor of Chemistry and Environmental Science, NJIT Dr. Paul Takhistov, Committee Member Date Associate Professor of Food Engineering, Department of Food Science Rutgers University, New Brunswick, NJ