A Novel Crystallization Methodology To Ensure Isolation of the Most Stable Crystal Form

It is critical to consistently achieve the desired crystal form for an active pharmaceutical ingredient (API) because crystal form may affect the compound’s chemical stability, bioavailability, and pharmaceutical processing performance. The extent to which a crystallizing system is driven by growth vs nucleation is dependent upon the level of supersaturation, defined as the difference between solution concentration and solubility. We describe a method for the accurate measurement of real-time supersaturation, which enabled us to develop and optimize an API crystallization via a feedback-control loop based on concentration measurement with online FTIR. In this contribution we discuss a novel extension of the published work [Zhou, G. X.; et al. Cryst. Growth Des. 2006, 6, 892−898] which ensured robust isolation of the thermodynamically most stable crystal form of an API. The system of interest is a monotropic polymorphic system with overlapping metastable zones. In order to ensure exclusive isolation of the...