Scaling up microreactors for kilogram‐scale synthesis of piperacillin: Experiments and computational fluid dynamics simulations

Abstract

AbstractIn this study, two membrane dispersion microreactors in series are used to synthesize piperacillin with low impurity content in kilogram scale. By combining experiments and computational fluid dynamics simulations, the membrane size and cross‐sectional area are scaled up from 2 mm × 0.7 mm and 2 mm × 1 mm to 6.5 mm × 2.5 mm and 6.5 mm × 3.5 mm, respectively, and the reaction time is extended from ~10 to ~60 min, which achieves that the synthesis scale of each batch is increased from 15 g to 1 kg. Subsequently, the effects of distance between ammonia feed and 4‐ethyl‐2,3‐dioxo‐1‐piperazine carbonyl chloride feed, pH, circulation flow rate, and dispersed phase flow rate on solution concentration are discussed. The final piperacillin product with an average yield of ~94.70%, a purity exceeding 99.7%, the impurity D content ~0.077% and E content ~0.045%, satisfies the requirements of pharmacopeia regarding antibiotic impurities.