Development and scale-up of a crystallization process to improve an API’s physiochemical and bulk powder properties

A revised crystallization process for TAK-117, a selective PI3Kα inhibitor currently in Phase 1b clinical trials, was developed that greatly improved the overall purity, recovery, and physiochemical and bulk powder properties of the isolated product. The original process afforded material that was prone to agglomeration during drying, resulting in significant product losses during sieving as well as issues with drug product manufacturability. Opportunities to explore a wide array of possible crystallization routes and solvent options were limited because TAK-117 is only sparingly soluble in most commonly used organic solvents apart from dimethyl sulfoxide (DMSO) and acidic systems. However, reasonable productivities were achieved using DMSO at elevated temperatures (100 °C), and the optimized process leveraged thermal cycling to improve the aspect ratio of the isolated crystals, minimize agglomeration during drying, and improve the powder’s bulk properties. The revised process was found to produce materia...