Preparation of the HIV Attachment Inhibitor BMS-663068. Part 9. Active Pharmaceutical Ingredient Process Development and Powder Properties

This final communication, of a nine part publication series, details the process development history for the final synthetic step to prepare the drug substance BMS-663068 tris(hydroxymethyl)aminomethane (TRIS) salt. The challenge of developing a robust commercial process to prepare BMS-663068-TRIS salt (active pharmaceutical ingredient, API) was achieved by studying the underlying mechanisms that governed key processing characteristics. Eliminating a slurry-to-slurry transformation results in predictable reaction kinetics and control of impurity formation. Key powder property aspects, such as specific surface area and bulk density, were controlled by examining the impact of seed age, crystallization relative supersaturation (RSS), and particle attrition due to agitation during drying. Ultimately, the processing parameters established for preparation of this drug substance resulted in the generation of the target compound with consistent quality, powder properties, and yield across multiple batches.