Abstract Crystallization is one of the most important unit operations for production of active pharmaceutical ingredients (API) in pharmaceutical industry. This work studied the impact of solvent chemical composition on fesoterodine fumarate dissolution in 2-butanone/cyclohexane mixtures and seeded cooling crystallization, combining population balance equation (PBE) modelling with experiments. Thermodynamics, transport phenomena and kinetics of nucleation, crystal growth, agglomeration, and dissolution were taken into account, two in-line process analytical technologies (PAT) – attenuated total reflectance Fourier-transform infrared spectroscopy (ATR–FTIR) and focused beam reflectance measurement (FBRM) – were used for monitoring seeded experiments, and non-linear regression analysis was applied for parameter estimation. Cyclohexane not only decreased solute saturated solubility, but increased rates of all mechanisms. Model validation by temperature cycling showed a good agreement between results and simulations which opens up possibilities for further engineered optimization and control. Combined cooling & antisolvent crystallization (CCAC) experiment revealed a complex antisolvent impact on particle dynamics.

中文翻译：

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基于过程分析技术 (PAT) 的活性药物成分 (API) 冷却、晶种和抗溶剂结晶组合模型模拟

摘要 结晶是制药行业生产活性药物成分（API）最重要的单元操作之一。这项工作研究了溶剂化学成分对富马酸非索罗定在 2-丁酮/环己烷混合物中溶解和种子冷却结晶的影响，结合群体平衡方程 (PBE) 建模与实验。考虑了成核、晶体生长、团聚和溶解的热力学、传输现象和动力学，两种在线过程分析技术 (PAT)——衰减全反射傅里叶变换红外光谱 (ATR-FTIR) 和聚焦光束反射测量(FBRM) – 用于监测种子实验，非线性回归分析用于参数估计。环己烷不仅降低了溶质饱和溶解度，而且增加了所有机制的速率。通过温度循环进行的模型验证表明结果与模拟之间具有良好的一致性，这为进一步工程优化和控制开辟了可能性。联合冷却和抗溶剂结晶 (CCAC) 实验揭示了复杂的抗溶剂对粒子动力学的影响。