Bulk powder properties (BPPs) of small molecule pharmaceuticals are intricately regulated in the latter stages of API process development. These properties include critical factors such as solubility, density, flowability, and hygroscopicity, each influenced by a combination of particle characteristics, including particle size distribution (PSD), particle shape, moisture content, and chemical composition. The pursuit of optimal BPPs for specific APIs demands rigorous development efforts and judicious experimental design. Serabelisib (TAK117), a PI3K inhibitor discovered and developed by Takeda, represents one of the most challenging compounds in BPP optimization. Following an iterative crystallization process development, a scalable crystallization medium using DMSO as a solvent was emerged as the preferred choice among the three systems screened.
Key Takeaways:
• Serabelisib (TAK117) is a PI3K inhibitor developed by Takeda and underwent an investigational experimental study.
• Its production had been complicated by the agglomeration problem, which was partially solved in another article (OPRD 2016, 20, 1500) by screening the washing solvents with the utilization of LabRAM.
• This article showed a comprehensive overview of the improvement of physicochemical and bulk powder properties.
• TAK117 has sparing solubility in most solvents, moderate solubility in DMSO (5.33 mg/mL at 20 °C, 11.22 mg/mL at 50 °C), and better solubility in acidified media, in which the API exhibits unexpected stability.
• The original manufacturing process used acidified MeOH as the solvent to purify and crystallize the crude API. Several drawbacks were found, including instability, low yield, and agglomeration.
• Although the second generation of the process employing aqueous formic acid with an appropriate co-solvent was able to improve stability and yield, and reduce agglomeration, it failed to reproduce the particle morphology and size, offering no benefit to the impurity.
• DMSO was realized as an alternative solvent system for the crystallization process. After two generations of process development, an ideal crystallization protocol was identified to provide six batches of material at 15 and 30 kg scales with minimized agglomeration, and consistent quality and powder bulk properties.