Scaling Up Microreactors For Kilogram-Scale Synthesis Of Piperacillin: Experiments And Computational Fluid Dynamics Simulations

In 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 x 0.7 mm and 2 mm x 1 mm to 6.5 mm x 2.5 mm and 6.5 mm x 3.5 mm, respectively, and the reaction time is extended from similar to 10 to similar 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 similar to 94.70%, a purity exceeding 99.7%, the impurity D content similar to 0.077% and E content similar to 0.045%, satisfies the requirements of pharmacopeia regarding antibiotic impurities.