Impurity Profiling for a Scalable Continuous Synthesis and Crystallization of Carbamazepine Drug Substance

IF 3.5 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2024-05-01 DOI:10.1021/acs.oprd.4c00081

Matthew Glace, Harrison Kraus, Wei Wu, David Acevedo, Dongxia Liu, Thomas D. Roper and Adil Mohammad*,

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Abstract

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.

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用于卡马西平药物物质可扩展连续合成和结晶的杂质分析

从亚氨基二苯乙烯（ISB）合成和结晶 III 型卡马西平（CBZ）的可扩展连续生产工艺已经建立。首先使用塞流反应器（PFR）进行高产合成，然后使用连续振荡障板反应器（COBR）进行放大。采用了一种实时在线拉曼光谱方法，以确保从起始材料 ISB 到产物 CBZ 的转化率保持在 99.0% 以上。监测到的产品流被输送到一个混合悬浮混合产品结晶器（MSMPR-1）和一个过滤装置，以分离出初步的 CBZ I 型多晶体。根据显微镜测量得出的晶体生长模型设计了冷却再结晶工艺。比较了间歇式和流动式工艺的杂质净化能力和多晶型的达到率。本研究概述了工艺建模和工艺分析技术（PAT）在伸缩式连续生产工艺中杂质净化的作用。

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来源期刊

Organic Process Research & Development 化学-应用化学

CiteScore

6.90

自引率

14.70%

发文量

251

审稿时长

2 months

期刊介绍： The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.