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

Abstract

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 desired form within a reasonable cycle time, a three-pronged approach was applied—maximize seed surface area through the use of milled seed, run the crystallization at a high temperature to increase crystal growth rate, and perform the crystallization at a high level of supersaturation relative to the desired, more stable form while keeping the concentration below the equilibrium solubility of the less stable polymorph. By carefully selecting the seed loading, we were also able to dial-in the target particle size directly via a growth-dominated crystallization, thus eliminating the need for post-crystallization product milling. As a result, a robust, efficient, and reliable crystallization process has been achieved to ensure isolation of the desired polymorph at target particle size.