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.

中文翻译：

---

通过集成的结晶，湿磨和退火再循环系统有效控制晶体尺寸

对于原料药的生产，必须具有可靠的结晶过程，该过程可以分离出具有所需晶体尺寸分布（CSD）的优质活性药物成分。这项研究提出了一种新型的集成结晶器，该结晶器将冷却和反溶剂结晶与湿磨和退火操作相结合，以生产出具有窄尺寸分布的晶体。分别加入湿磨机和随后的退火容器以减小尺寸和溶解细粉。通过使用集成系统研究verubecestat的结晶，确定了对CSD的影响工艺参数。通过实施过程分析技术，可以实现丰富的数据实验和对过程的理解，例如衰减的全反射-傅立叶变换红外和聚焦光束反射率测量。结果表明，可以通过轧机配置，轧机速度和退火温度来紧密调节CSD。提高轧机转速并使用更密的转子-定子齿布置可减小晶体尺寸，而更高的溶解温度则有利于通过溶解细粉并为晶体生长产生额外的过饱和度来收紧CSD。完整集成系统的结果与没有退火容器的配置进行了比较，这表明铣削引起的断裂，磨损和二次成核导致了更宽的CSD。提高轧机转速并使用更密的转子-定子齿布置可减小晶体尺寸，而更高的溶解温度则有利于通过溶解细粉并为晶体生长产生额外的过饱和度来收紧CSD。完整集成系统的结果与没有退火容器的配置进行了比较，这表明铣削引起的断裂，磨损和二次成核导致了更宽的CSD。提高轧机转速并使用更密的转子-定子齿布置可减小晶体尺寸，而更高的溶解温度则有利于通过溶解细粉并为晶体生长产生额外的过饱和度来收紧CSD。完整集成系统的结果与没有退火容器的配置进行了比较，这表明铣削引起的断裂，磨损和二次成核导致了更宽的CSD。