| Crystallization processes in the pharmaceutical industry are usually designed to obtain crystals with controlled size, shape, purity, and polymorphic form. Knowledge of the process conditions required to fabricate crystals with controlled characteristics is critical during process development. This research work focuses on the study of size distribution and polymorphic form. In the first part, continuous crystallization of Ketoconazole, Flufenamic Acid, and L-Glutamic Acid in a non-conventional plug flow crystallizer was investigated. Kenics type static mixers were used to promote homogeneous mixing of active pharmaceutical ingredient solution and antisolvent. A strategy of multiple points of addition of antisolvent along the crystallizer was evaluated to control the size of the crystals. Interestingly, it was found that crystal size can be increased or decreased with increased number of antisolvent addition points, depending on the kinetics of the system. It was also found that smaller crystals with narrower size distribution can be obtained with the static mixers. A model to describe the continuous crystallization process was developed through the simultaneous solution of a Population Balance Equation, kinetics expressions for crystal growth and nucleation, and a mass balance. The comparison of experimental and calculated values for crystal size distribution revealed that a growth rate dispersion model could describe accurately the continuous crystallization process. Collision of crystals with each other and with mixing elements inside the crystallizer may be the source of random fluctuation of the growth rate in the non-conventional plug flow crystallizer with static mixers.;Polymorph screening studies of Mefenamic Acid, Acetaminophen, and Flufenamic Acid were carried out using a semi-automated apparatus. Cooling crystallization and slurry aging experiments were conducted under different process conditions and a selection of 16 diverse solvents to find as many polymorphic forms as possible. Results yielded both known polymorphs and a solvate of Mefenamic Acid, as well as the two most commonly encountered polymorphs and a solvate of Flufenamic Acid. Thus, the simple semi-automated approach described in this work is suitable for early stage polymorph screening as it was able to reproduce effectively the diversity of polymorphs in model compounds. |
