(381al) Application of High-Shear Wet Milling to an API Crystallization Process

High-shear wet milling was applied to the crystallization of a drug substance to reduce particle size. In this case study, ester hydrolysis under basic conditions followed by acidic pH adjustment crystallized the resulting API with large particle size. To generate API of smaller PSD for drug product evaluation, high-shear wet milling was investigated in conjunction with other crystallization factors such as seeding, temperature, concentration, and rate of pH adjustment. This application of in-situ particle size reduction avoided the dry milling of a potent compound, thus mitigating risk of exposure to plant operators. In developing the high-shear wet milling process, parameters such as shear frequency, tip speed, and turnover rate were investigated in the laboratory using scale-down calculations to simulate wet milling performance in a large-scale or production setting. These scale-down experiments comprised a series of multi-hundred gram batches to evaluate trends in API crystal growth and particle size distribution. During these studies, API particle size was monitored throughout the crystallization process from initial seeding to isolation using an in-situ FBRM probe in combination with PSD analysis of filtered slurry samples. In addition to reducing particle size, the solubility data showed that milling also increased the rate of API crystallization. These studies contributed to the development of a crystallization process with high-shear wet milling to provide API with the desired physical properties.