A multiphase/extractive enzyme membrane reactor for production of diltiazem chiral intermediate

Enzyme membrane reactors can be used to enhance the productivity and practicality of certain biotransformations by improving substrate/enzyme contact, by providing a simple and reversible means of enzyme ''immobilization,'' and by effecting the removal of inhibitory reaction products. This paper describes the development and eventual scale-up of a multiphase/extractive membrane reactor designed to manage reaction problems encountered in a biphasic reaction system characterized by the formation of an inhibitory reaction product. In particular, the application of this membrane reactor to an enzyme-mediated resolution of a racemic mixture is described - namely, the optical resolution of a chiral intermediate used in the production of diltiazem, a drug used in the treatment of hypertension and angina. The development process is traced from bench-scale studies of process feasibility through optimization, process reliability, and pilot-plant studies - a process that ultimately culminated in the operation of a commercial-scale membrane reactor facility that currently produces over 75 metric tons per year of diltiazem intermediate.