(116g) API Crystallization Process Development and Scale-up for Particle Size Control: A Case Study of a Development Candidate

Previous results show variation in D(0.90) from 10 µm to 546 µm for a Gilead API. This variation has proved to be problematic for the drug product design and manufacturing. It is the objective of this study to improve the consistency in the API particle size. Relevant solubility studies have been designed and solubility data have been generated to guide the development of the crystallization process and control of the API particle size. Through control of the level of supersaturation at the onset of crystallization or seeding point for this hybrid anti-solvent and cooling crystallization process, a significant improvement in particle size has been observed. Coupling the supersaturation control with the use of suitable agitation rate during the crystallization process, consistent particle size control was achieved in the lab. Based on the constant power input per unit mass principle, this improved process was successfully scaled up and demonstrated at ~30 kg scale.