A scalable continuous manufacturing process for the synthesis and crystallization of form III carbamazepine (CBZ) from iminostilbene (ISB) has been established. A high-yielding synthesis was first obtained using a plug flow reactor (PFR) and then scaled up using a continuous oscillatory baffled reactor (COBR). A real-time in-line Raman spectroscopy method was implemented to ensure that the conversion of the starting material ISB to the product CBZ was maintained above 99.0%. The monitored product stream was telescoped into a mixed-suspension mixed-product crystallizer (MSMPR-1) and a filtration unit to isolate the preliminary CBZ form I polymorph. A cooling recrystallization process was designed by using a crystal growth model derived from microscopy measurements. The impurity purging capacities and polymorph attainments were compared for the batch and flow processes. This study outlines the role of process modeling and process analytical technology (PAT) for impurity purging in a telescoped continuous manufacturing process.

中文翻译：

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卡马西平原料药可扩展连续合成和结晶的杂质分析

已经建立了一种可扩展的连续生产工艺，用于从亚氨基芪 (ISB) 合成和结晶 III 型卡马西平 (CBZ)。首先使用活塞流反应器 (PFR) 获得高产率合成，然后使用连续振荡挡板反应器 (COBR) 进行放大。实施实时在线拉曼光谱方法以确保起始原料ISB到产物CBZ的转化率保持在99.0%以上。将监测到的产物流放入混合悬浮液混合产物结晶器 (MSMPR-1) 和过滤装置中，以分离初步的 CBZ 晶型 I 多晶型物。通过使用从显微镜测量得出的晶体生长模型来设计冷却重结晶过程。比较了间歇式和流动式工艺的杂质净化能力和多晶型效果。本研究概述了工艺建模和工艺分析技术 (PAT) 在伸缩式连续制造工艺中杂质净化中的作用。