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Scaling up microreactors for kilogram‐scale synthesis of piperacillin: Experiments and computational fluid dynamics simulations
Author(s) -
Xie Yu,
Chen Qiang,
Huang Guoming,
Wang Yujun,
Hu Weiguo,
Yan Zhengren,
Wang Xin,
Huang Juan,
Gao Mingtang,
Fei Weiyang,
Luo Guangsheng
Publication year - 2021
Publication title -
aiche journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.958
H-Index - 167
eISSN - 1547-5905
pISSN - 0001-1541
DOI - 10.1002/aic.17231
Subject(s) - microreactor , chemistry , volumetric flow rate , yield (engineering) , scaling , analytical chemistry (journal) , impurity , chromatography , nuclear chemistry , thermodynamics , organic chemistry , mathematics , physics , geometry , catalysis
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.