production of maltose syrups from starch, and glucoamylase/glucose oxidase for the
conversion of maltose into into hydrogen peroxide (Bardeletti & Coulet, 1987).
Optical Resolutions and Synthesis of PeptidesOther reactions that have been increasingly studied in membrane reactors are the
production of optically pure compounds and the synthesis of oligopeptides for
pharmaceutical and fine chemical uses (Table 6.7).
The ability of enzymes to discriminate between enantiomers in racemic substrates has
made enzymatic synthesis an alternative to conventional chemical synthesis in the
preparation of chiral pharmaceuticals (Margolin, 1993). Although the increasing use of
enzymes (e.g. lipases) for the synthesis of optically pure drugs has not been accompanied
by a comparable development of adequate enzyme reactors, membrane reactors have
been emerging as one of the most appropriate configurations for large-scale optical
resolutions. The majority of the applications described uses lipases as the biocatalyst in
two-phase membrane reactors.
The Tanabe Seiyaku Company in cooperation with Sepracor Inc. (Tosa & Shibatani,
1995) industrialized one of the most successful processes developed. The process uses a
lipase in a two-phase hollow fibre reactor, to perform the resolution of (±)-
methoxyphenylglycidate methyl ester, an intermediate of the pharmaceutical diltiazem.
The enzyme is immobilised by adsorption on the shell side of the module where toluene
flows with the substrate and water is circulated in the lumen of the fibres. Biproducts of
the reaction that inhibit the enzyme are extracted to the aqueous phase (Matsumae et al.,
1994; Tosa & Shibatani, 1995). One of the disadvantages of this reactor at the industrial
level is the low level of productivity due to the use of substrate in the soluble form. An
attempt to overcome this drawback was made by coupling a crystalUser to the membrane
reactor at the lab scale. This unit was used as a reservoir for highly concentrated slurry of
substrate and to recover product, which crystalUsed simultaneously during reaction
(Furui et al., 1996).
Other applications developed at Sepracor Inc. with two phase hollow fiber reactors
were the racemic resolution of an ester (glycidyl butyrate) catalyzed by a lipase (López et
al., 1990) and the resolution of racemic amino acids by β-chymotrypsin (Matson &
Quinn, 1986; Matson & López, 1990; López et al., 1991).
The production of short chain peptides (2–32 amino acids) and their derivatives is of
increasing importance in areas such as biomedical research, the development of
pharmaceuticals and the food industry (Kelley, 1996). The interest in the protease
catalysed synthesis of these compounds as opposed to traditional chemical synthesis, is
due to the known advantages of the enzymatic approach: no racemisation, lower
purification costs, higher yields, no need for side-chain protection and use of mild
reaction conditions (pH, temperature, pressure) that lead to lower energy consumption.
Membrane reactors have been used up to now especially to promote the synthesis of
different dipeptides (Table 6.8). The literature describes for example the use of α-
chymotrypsin in the large scale synthesis of kyotorphin (Tyr-Arg) (Herrmann et al.,
1991) or the use of α-chymotrypsin in reversed micelles to synthesise Phe-Leu, an
intermediate of the pharmacological dipeptides enkephalin and dynorphin (Serralheiro et
al., 1994; 1999; Prazeres et al., 1995).
Multiphase bioreactor design 172