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

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.