Continuous Manufacturing of Beta-Lactam Antibiotics

Crystallization usually is thought of as a final step in the production of a desired chemical species, especially if the purity and morphology of the product are important. In the present work, an entire process is enhanced by coupling crystallization to a synthesis reaction, thereby improving process yield and selectivity. The research focuses on the enzymatically catalyzed synthesis of beta-lactam antibiotics, which are among the most consumed pharmaceuticals on a global basis. Besides kinetically controlling the system to avoid hydrolysis, another way to improve the process yield and selectivity is by combining the synthesis of the target with crystallization, which maintains the concentration of the target species at a low value, effectively reducing the rate of undesired reactions and stabilizing the product species. Performing these steps in a continuous vessel provides many opportunities unique to continuous manufacturing such as easier process control, higher productivity, and elimination of batch-to-batch variations.

In the work described in this presentation, a process model was developed for a pilot plant that included an MSMPR reactor-crystallizer by coupling relevant reaction and crystallization kinetic models, informed by process analytical technologies (FBRM, ReactIR, PVM). Process simulations were then used to assess the interaction between different process attributes such as productivity and reactant conversion under different conditions. In the next step, a pilot plant including feed reservoirs, an MSMPR reactor-crystallizer, a separator, and a filtration unit was constructed for the continuous production of beta-lactam antibiotic crystals with a production rate of 2-10 g/h. A critical challenge specific to this system included the separation of the solid-supported biocatalyst from product crystals. The former must be retained in the system while the latter (crystal product) must be removed.