(233v) Development and Optimization of a Mixed Suspension Mixed Product Removal (MSMPR) Crystallization Process Incorporating Wet-Milling 

In recent years, there has been an increased interest in moving pharmaceutical manufacturing from batch to continuous processing. The potential to reduce cost, simplify production and improve product quality have driven significant investment in continuous manufacturing. While crystallization is an important separation and purification unit operation, continuous crystallization processes have not been widely studied within the pharmaceutical industry primarily because of the design complexity and difficulty of robust operation. The MSMPR crystallizer is arguably one of the most promising technologies as its operation is conceptually simpler than for e.g. tubular crystallizers and it is easy to convert batch crystallizers to continuous operation. However, issues such as fouling and encrustation, transfer line blockage, and classification due to limited nucleation are frequently experienced with numerous reports in the literature.

The work presented herein solves the fouling and classification issues encountered for one of Takedaâ??s APIs by adding wet-milling to the first stage of an MSMPR crystallizer. The API studied was found to be characterized by slow nucleation kinetics resulting in a prolonged wash out period. During this period, large (>1mm) particles were formed that were unable to be transferred leading to classification issues, build up of supersaturation and severe fouling.

The high shear imparted by the wet-mill was found to control particle size and increase both primary and secondary nucleation rates. This reduced supersaturation and therefore fouling and encrustation. The wet-mill was incorporated in the first stage of the cascade which was then experimentally optimized investigating factors such as solvent composition, types and materials of construction of the impeller, wet-mill rotational speed, wet-mill turnover numbers, residence time and start-up methods. Finally, a multi-stage system was developed to optimize productivity.