Stephen L. Matson

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

Abstract 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.

Membranes in biotechnology: State of the art

Abstract Membranes and membrane separation processes promise to have -- and, indeed, are already having -- a major impact upon the rapidly growing field of biochemical processing. Initially, emphasis was placed on application of microfiltration, ultrafiltration, and reverse osmosis to such important bioprocessing operations as cell removal, whole-broth clarification, and downstream recovery and purification of bioproducts from invariably dilute and often complex aqueous mixtures. However, novel membrane-based bioseparation processes are increasingly being invented, developed, and applied that either replace or augment more traditional technologies. Additionally, biochemical process engineers have begun to use membranes to increase the productivity of conventional fermentation operations, focusing on techniques of cell recycle and extractive fermentation and the application of unique biosensors -- all of which are based on membranes. Finally, and perhaps most excitingly, ambitious proponents of membrane technology stand a reasonable chance of redefining the biochemical processing problem altogether. In particular, continuous immobilized cell and enzyme membrane reactors promise not only to replace the conventional batch fermentor, but also to accomplish many of the product recovery and purification tasks associated with bioconversion processes.

Membrane Reactors in Bioprocessing

Engineering research on membranes has had two prime objectives, the first and by far the more extensively investigated being the development of membranes for separation processes.’” In parallel with this work, however, other investigators have considered microporous membranes as solid-phase supports to which enzymes oi’whole cells might be attached for the purpose of catalyzing a bioconversion.M These types of enzymatically active membranes, which we refer to as “reactive membranes,” have been operated in both diffusive and convective modes. Since membranes can effect both biocatalysis and separation, and since these two operations are inextricably related in any biochemical process, we were intrigued by the possibility of combining these functions in a single membrane device, the so-called membrane bioreactor, in hopes of achieving novel and powerful device performance.