(302b) Control of Crystallization Process and Crystal Form of Pharmaceutical Intermediates

Isolating the preferred polymorph or crystal form of pharmaceutical ingredients has been a long-term challenge in industrial crystallization, which often targets acceptable physical properties, overall yield, and process economics. An intermediate of a drug-inker exhibits three known polymorphs, which can differ significantly by their purity, particle size and morphology. Additionally, the enantiotropic forms presented a challenge to isolate due to their very similar solubilities. In this work, crystallization conditions of the intermediate were optimized to consistently achieve the fastest filtration, lowest residual solvents and best flowability of the desired polymorph. Antisolvent crystallization and constant-volume distillation were used to isolate the desired polymorph. Modeling of the distillation process and solubility predictions were combined with process analytical technologies (PATs) such as IR and Raman spectroscopies and solid-state characterizations to study crystallization kinetics and phase transformations. The effects of crystallization parameters, including distillation temperature, antisolvent addition, supersaturation, and seeding were investigated and the control strategy was defined. The design was confirmed in industrial runs. This work demonstrates the integration of process modeling and PATs on achieving the mechanistic understanding of crystallization processes and provides insights into the control of polymorphs with similar solubility.