A kinetic study and model-based design space determination for drug substance flow synthesis using an amination reaction are presented. A flow experiment was conducted to synthesize 3-fluoro-4-morpholinobenzonitrile from 3,4-difluorobenzonitrile, morpholine, and diazabicycloundecene. Concentrations, residence time, temperature, and reactor inner diameter were varied to gather the kinetic data. A set of equations was defined to describe the mass and energy balances, and the developed model could reproduce the experimental profiles with high accuracy. By incorporating the Reynolds number into the pre-exponential factor, the developed one-dimensional model could account for performance variations in different inner diameter conditions. The model was then used to identify the design space, considering yield, temperature, productivity, and environment. The study also evaluated the process robustness given pulse disturbances, which could help identify the required sensor monitoring. Finally, a method for facilitating regulatory processes was proposed. The presented model-based approach can aid in producing high-quality pharmaceuticals in an efficient, sustainable, and cost-effective way by utilizing digital power.

中文翻译：

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使用亲核芳香取代的胺化反应进行药物流合成的动力学研究和基于模型的设计空间确定

提出了使用胺化反应进行药物流合成的动力学研究和基于模型的设计空间确定。进行流动实验，由3,4-二氟苯甲腈、吗啉和二氮杂双环十一碳烯合成3-氟-4-吗啉代苯甲腈。改变浓度、停留时间、温度和反应器内径以收集动力学数据。定义了一组方程来描述质量和能量平衡，并且开发的模型可以高精度地再现实验曲线。通过将雷诺数纳入指前因子，开发的一维模型可以解释不同内径条件下的性能变化。然后使用该模型来确定设计空间，同时考虑产量、温度、生产率和环境。该研究还评估了脉冲干扰下的过程鲁棒性，这有助于确定所需的传感器监控。最后，提出了一种促进监管流程的方法。所提出的基于模型的方法可以帮助利用数字电源以高效、可持续和具有成本效益的方式生产高质量的药品。