(341e) Enabling Crystallization for a Challenging Active Pharmaceutical Ingredient through Use of a Wet-Milling Crystallization Process at Elevated Temperature

Direct crystallization of the desired polymorph of an active pharmaceutical ingredient (API) is an important step in a pharmaceutical manufacturing process. In this work, development to enable direct crystallization for an API that had proven particularly challenging due to the exceptionally slow crystal nucleation and growth kinetics is presented. The first-generation process was composed of two steps, a chiral upgrade crystallization of a different polymorph of the API and then a slurry turnover step to deliver target polymorph. Despite significant development efforts, a direct crystallization of the desired polymorph was hampered by slow crystal growth at moderate supersaturation and oiling risk at high supersaturation.

Additional development work led to the discovery of multiple conformations of the molecule in solution and the effect of these conformations on crystallization kinetics. Proton NMR detected presence of two conformations in solution while variable temperature NMR indicated those two sets of signals merged with increased temperature. This insight enabled direct crystallization of the desired polymorph, leveraging increased temperature to address the molecular conformation, and using in-situ wet milling to provide sufficient surface area for growth. Process development was accelerated using information from inline Process Analytical Technologies. The redeveloped direct crystallization has been demonstrated up to 100 g scale and will be implemented at ~100 kg-scale in the near future.