Process Modelling, Simulation and Technoeconomic Evaluation of Conventional Batch, Batch Reactive Crystallization, and Continuous Reactive Crystallization Routes for Enzymatic Amoxicillin Synthesis

Cost-effective production of generic antibiotics remains a pressing industrial priority, particularly for high-volume β-lactam APIs where narrow profit margins and stringent environmental regulations constrain manufacturing options. This paper presents an integrated process systems engineering framework for the in-silico design, simulation, and technoeconomic comparison of three amoxicillin manufacturing routes: (i) conventional batch enzymatic synthesis followed by separate pH-swing crystallization; (ii) batch reactive crystallization integrating enzymatic synthesis with in-situ product removal; and (iii) continuous reactive crystallization in a mixed-suspension mixed-product removal (MSMPR) cascade. Kinetic models for penicillin G acylase-catalyzed synthesis are parameterized from literature data, coupled with population balance crystallization kinetics and solubility correlations. The continuous reactive crystallization route achieves the highest reactor productivity and the lowest process mass intensity (PMI = 28.2), yet batch reactive crystallization emerges as the most economically advantageous (24.98 million GBP), narrowly below the conventional batch route (25.71 million GBP), while the continuous MSMPR route is substantially more expensive at 120.55 million GBP — approximately 4.8 and 4.7 times the cost of the two batch routes. These findings suggest that continuous manufacturing is not always the better choice; its viability depends importantly on whether the productivity gains offset the added separation complexity and catalyst recovery costs. All API masses, yields, and green metrics in this work are expressed on an amoxicillin trihydrate basis unless stated otherwise.