(290d) Improving the Synthesis-to-Hydrolysis Ratio for Beta-Lactam Antibiotics Using Membrane Reactors

Beta-lactam antibiotics, such as ampicillin and amoxicillin, comprise 65% of the total antibiotics market with annual sales of $15 billon (Chandel:2008). Currently, ampicillin and amoxicillin are produced on large scale by condensation of D-phenylglycine ester and p-hydroxy-D-phenylglycine ester, respectively, with the beta-lactam nucleus (6-aminopenillanic acid, 6-APA) catalyzed by penicillin G acylase (PGA) (Arroyo: 2003). The condensation reaction can be carried out under thermodynamic or kinetic control, but typically kinetic control is preferred as it results in higher product yield. A potential disadvantage of the kinetically controlled process is the hydrolysis of the side chain ester and secondary hydrolysis of the semi-synthetic beta-lactam. For ampicillin, the synthesis-to-hydrolysis ratio is about 2.8 in water at 20°C and a pH value of 7.5 (Bruggink:1998). Finding a method to increase the synthesis-to-hydrolysis ratio would contribute to increasing the availability of effective antibiotics while enhancing the environmental friendliness of the process.

Our goal is to improve the synthesis-to-hydrolysis ratio of ampicillin to 5 (in case of kinetically-controlled synthesis) or the degree of conversion to ampicillin (in case of thermodynamically-controlled synthesis) with the use of a membrane reactor system. The system under investigation consists of a packed bed of immobilized PGA in series with a selective membrane that allows us to control the amount of water in the reaction mixture. The nonporous high-flux perfluoro membranes that we employ have a large free volume space, which results in high permeation rates, but are only permeable to water, hydrogen, and other small molecules. While removing water from the reaction system suppresses the hydrolysis reaction, it is necessary to maintain a certain amount of water for enzyme function. Therefore, the amount of water in the system is carefully monitored using known membrane properties and transmembrane pressure.

The presentation will focus on the condensation of phenylacetic acid and 6-APA to ampicillin. We will report the dependence of reaction rate and yield on solvent composition, especially water content, and compare our system with the conventional process.