Application of New Technology to a Mature Piroxicam Crystallization Process To Gain Process Understanding and Control, via Industrial-Academic Collaboration

摘要

The established industrial seeded-cooling crystallization of piroxicam was interrogated to gain an understanding of increased batch failures due to polymorph contamination at commercial manufacturing scale. Alternative analysis of plant seed material revealed the presence of the undesired polymorph on the surface of seed batches that had been used in the failed crystallizations, identifying the root cause of the polymorph contamination. Additionally, analysis of the crystallization process with online process analytical technologies identified that a number of the seeding points lay in the undersaturated region of the solubility space and that these seed charges were dissolving. A number of process changes were investigated at lab scale to increase process robustness and eliminate batch failure while maintaining the filed process conditions. Implementation of the selected changes at commercial manufacturing scale resulted in a dramatic shift in process performance.