Continuous reactive crystallization of β-lactam antibiotics catalyzed by penicillin G acylase. Part I: Model development

A model is developed for simulating continuous manufacturing of beta-lactam antibiotics by enzymatic reactive crystallization. An amoxicillin case study using the unified model of reaction and crystallization kinetics in different reactor designs is presented. Attainable regions are constructed for conversion of amoxicillin precursors and mean crystal size. Attainable regions for conversion show that, with a 2:1 molar ratio of precursors, 98% conversion of the limiting reactant is possible with reactive crystallization while only 72% conversion can be achieved without crystallization. A well-mixed reactive crystallizer is shown to have higher productivity than a plug-flow reactive crystallizer, which is uncommon for positive-order processes like enzyme reactions and crystallization. A Pareto optimal surface is drawn for conversion, productivity, and fractional yield to inform the design of an optimal process. Additional means of optimizing production of amoxicillin, including classified crystal fines removal, are discussed to further enhance crystal size and productivity. (C) 2019 Elsevier Ltd. All rights reserved.