This study compares the use of wet milling and indirect ultrasound for promoting nucleation and controlling the particle size during the continuous crystallization of a hard-to-nucleate active pharmaceutical ingredient (API). Both an immersion and an external wet mill installed on a recirculation loop were investigated. It was found that all methodologies significantly improved the nucleation kinetics, and the effects of key process parameters (e.g., mill speed, temperature, and ultrasound intensity) on particle size were experimentally investigated. A minimum d₅₀ of 27 and 36.8 μm was achieved when using the wet mill and ultrasound, respectively. The effectiveness of wet milling was demonstrated in a three-stage mixed suspension mixed product removal continuous crystallization of the API that was operated continuously for 12 h (eight residence times), achieving a steady state with minimal fouling. Strategies for improving the overall robustness of the setup in routine manufacturing are discussed.

中文翻译：

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湿磨和间接超声作为控制活性药物成分连续结晶中成核的手段的研究

本研究比较了在难以成核的活性药物成分 (API) 的连续结晶过程中，湿磨和间接超声在促进成核和控制粒径方面的应用。对安装在再循环回路上的浸入式和外部湿磨机进行了研究。发现所有方法都显着改善了成核动力学，并且通过实验研究了关键工艺参数（例如，研磨速度、温度和超声强度）对粒度的影响。最低d ₅₀当使用湿磨机和超声波时，分别达到 27 和 36.8 微米。湿磨的有效性在 API 的三级混合悬浮混合产品去除连续结晶中得到证明，该结晶连续运行 12 小时（8 次停留时间），达到稳定状态且结垢最少。讨论了提高常规制造中设置的整体稳健性的策略。