Abstract
Pharmaceutical production quality has recently been a focus for improvement through incorporation of end-to-end continuous processing. Enzymatic ß-lactam antibiotic synthesis has been one focus for continuous manufacturing, and α-amino ester hydrolases (AEHs) are currently being explored for use in the synthesis of cephalexin due to their high reactivity and selectivity. In this study, several reactors were simulated to determine how reactor type and configuration impacts reactant conversion, fractional yield toward cephalexin, and volumetric productivity for AEH-catalyzed cephalexin synthesis. The primary reactor configurations studied are single reactors including a continuous stirred-tank reactor (CSTR) and plug flow reactor (PFR) as well as two CSTRS and a CSTR + PFR in series. Substrate concentrations fed to the reactors as well as enzyme concentration in the reactor were varied. The presence of substrate inhibition was found to have a negative impact on all reactor configurations studied. No reactor configuration simultaneously allowed high substrate conversion, high fractional yield, and high productivity; however, a single PFR was found to enable the highest substrate conversion with higher fractional yields than all other reactor configurations, by minimizing substrate inhibition. Finally, to further demonstrate the impact of substrate inhibition, an AEH engineered to improve substrate inhibition was simulated and Pareto optimal fronts for a CSTR catalyzed with the current AEH were compared to Pareto fronts for the improved AEH. Overall, reduced substrate inhibition would allow for high substrate conversion, fractional yield, and productivity with only a single CSTR.
Highlights
End-to end continuous processing has recently become a target for improving production quality in the pharmaceutical industry
Substrate inhibition by phenylglycine methyl ester (PGME) had been found to have a significant impact on the synthesis potential of amino ester hydrolases (AEHs) at high concentrations of PGME through both competitive inhibition to form a nonreactive species, EPGME·PGME, as well as a partial competitive inhibition that still allows for hydrolysis of a PGME-bound acyl-enzyme complex, EAPGME, to PG (Scheme 10)
penicillin G acylase (PGA), a more readily used enzyme for synthesis of ß-lactam antibiotics, has
Summary
End-to end continuous processing has recently become a target for improving production quality in the pharmaceutical industry. SS-lactam antibiotics are promising candidates for continuous production due to the high volume of their consumption worldwide and the development of single-step enzymatic synthesis routes (Kasche 1986; Hernandez-Justiz et al, 1999; Youshko and Svedas 2000; Wegman et al, 2001; Youshko et al, 2002a; Elander 2003; Kallenberg et al, 2005; Chandel et al, 2008; Srirangan et al, 2013; Thakuria and Lahon 2013). Β-lactam antibiotics are typically synthesized enzymatically using penicillin G acylase (PGA) due to its high thermostability, efficiency, and selectivity toward antibiotic synthesis. AEH has been studied far less than PGA, and a kinetic model describing AEH-catalyzed synthesis of cephalexin has only recently been established (Lagerman et al, 2021). Cephalexin is the strongest candidate for synthesis by AEH, and understanding how AEH can be used in common reactor configurations is a prerequisite for developing AEH-catalyzed synthesis processes
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