Continuous Manufacturing of Rocuronium Bromide Part 2: Step 2 Process Development

Abstract

Rocuronium bromide, a neuromuscular blocking agent critical to anesthesia and emergency care, experienced severe shortages during the COVID-19 pandemic due to fragmented global supply chains and limitations of traditional batch manufacturing. To enhance supply chain resilience and responsiveness, this Part 2 manuscript details the development and optimization of the Step 2 unit operations, including the N-alkylation, continuous reaction, and crystallization. Through kinetic modeling and real-time monitoring using ReactIR and conductivity, the Step 2 N-alkylation was optimized to reduce reaction time and reagent usage. A five-stage CSTR cascade was implemented, achieving >98% rocuronium bromide purity with steady-state performance and minimal residual starting material. For crystallization, extensive solubility and solvent screening identified methyl propyl ketone (MPK) as the most effective antisolvent, enabling high-purity rocuronium bromide recovery with yields up to 94%. The process was successfully scaled to a 500 mL CSTR, and in-line particle analysis confirmed robust crystal growth dynamics. These advancements demonstrate the viability of transitioning small molecule API synthesis into continuous operation while maintaining control over reaction and solid-state quality. The work presented here makes significant progress on the second half of the process (particularly in addressing the low assay challenge), positioning this work for future integration into an end-to-end continuous manufacturing platform for rocuronium bromide.