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 × 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.

中文翻译：

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扩大规模的微型反应器，用于公斤级合成哌拉西林：实验和计算流体动力学模拟

在这项研究中，两个串联的膜分散微反应器用于合成公斤级低杂质含量的哌拉西林。通过结合实验和计算流体动力学模拟，膜的尺寸和截面积分别从2 mm×0.7 mm和2 mm×1 mm扩大到6.5 mm×2.5 mm和6.5 mm×3.5 mm，时间从〜10分钟延长到〜60分钟，从而使每批的合成规模从15 g增加到1 kg。随后，讨论了氨进料与4-乙基-2,3-二氧代-1-哌嗪羰基氯进料之间的距离，pH，循环流速和分散相流速对溶液浓度的影响。最终的哌拉西林产物平均产率为〜94.70％，纯度超过99.7％，杂质D含量为〜0.077％，E含量为〜0。