Process Development for the ICM of Rocuronium Bromide

Stephen Born from Continuus Pharmaceuticals presents Process Development for the ICM of Rocuronium Bromide, detailing process intensification, solvent and reagent optimization, continuous crystallization, and significant reductions in processing time and solvent use. Stephen describs the conversion of batch acylation and alkylation steps to continuous flow, optimizing reagent stoichiometry, solvent volumes, and base selection, and using inline extraction and thin film evaporation to streamline workup and reduce DCM usage. A two-stage MSMPR cascade with anti-solvent addition and seeding was implemented for crystallization, with process modeling guiding anti-solvent selection and volume, and inline particle monitoring ensuring steady operation and impurity control. The N-alkylation was optimized by reducing solvent and increasing temperature, with a five-stage CSTR cascade achieving full conversion in reduced time, and PAT tools such as conductivity probes and ReactIR used for real-time monitoring of reaction progress and product formation. The integrated continuous process reduced the total processing time for both reaction and crystallization steps from several days to under ten hours, with improved control, yield, and impurity profiles, demonstrating scalability and compatibility with plant-wide control systems.