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For drug substance manufacturing, it is necessary to have a robust crystallization process that can isolate quality active pharmaceutical ingredients with the desired crystal size distribution (CSD). This study presents a novel integrated crystallizer that combines cooling and antisolvent crystallization with wet milling and annealing operations to produce crystals with narrow size distributions. The incorporation of a wet mill and subsequent annealing vessel were carried out for size reduction and fines dissolution, respectively. The influential process parameters on CSD were identified by investigating the crystallization of verubecestat with the integrated system. Data-rich experimentation and enhanced process understanding were achieved by implementing process analytical technologies, such as attenuated total reflectance-Fourier transform infrared and focused beam reflectance measurement. Results show that the CSD can be tightly tuned through mill configuration, mill speed, and annealing temperature. Increasing mill rotational speed and using a denser rotor–stator teeth arrangement reduced crystal size, while a higher dissolution temperature was conducive to tightening CSD by dissolving fines and creating additional supersaturation for crystal growth. Results from the complete integrated system were compared to configurations without annealing vessel, which revealed that breakage, attrition, and secondary nucleation induced by milling led to wider CSD.

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