Hollow-Fibers Membrane Reactors

Compared to batch processes, continuous processes often show a higher space-time yield. Reaction conditions may be kept within certain limits more easily. For easier scale-up of some enzyme-catalyzed reactions, the Enzyme Membrane Reactor (EMR) has been developed. The principle is shown in Fig. 7-26 A. The difference in size between a biocatalyst and the reactants enables continuous homogeneous catalysis to be achieved while retaining the catalyst in the vessel. For this purpose, commercially available ultrafiltration membranes are used. When continuously operated, the EMR behaves as a continuous stirred tank reactor (CSTR) with complete backmixing. For large-scale membrane reactors, hollow-fiber membranes or stacked flat membranes are used 129. To prevent concentration polarization on the membrane, the reaction mixture is circulated along the membrane surface by a low-shear recirculation pump (Fig. 7-26 B). 

Finally, possible causes for deactivation of catalytic membranes are described and severad aspects of regenerating catalytic membrane reactors are discussed. A variety of membrane reactor configurations are mentioned and some unique membrane reactor designs such as double spiral-plate or spiral-tube reactor, fuel cell unit, crossflow dualcompartment reactor, hollow-fiber reactor and fluidized-bed membrane reactor are reviewed. 

The most important technique for perfusion culture methods is to separate the concentrated cells and conditioned medium from the suspended culture broth. As noted above, the separation methods chiefly used are filtration with tubular and flat membranes as well as ceramic macroporous filters. These membrane reactors can be employed for both anchorage-dependent and suspension growing cells. Static maintenance type systems are commercially available for disposable reactors, and small size unit reactors from 80 ml to 1 liter are used for continuous production of monoclonal antibodies with hybridoma cells. The maintainable cell densities are about 10 -10 cells/ ml which is essentially mouse ascites level. However, in these systems, the cell numbers cannot be counted directly because the cells adhere to membranes or hollow fibers. Therefore, the measurement of cell density must use indirect methods. Such indirect methods include the assaying of the quantities of glucose consumption and the accumulation of lactate. The parameters of scale-up have not yet been established for these static methods. 

Depending on the flow dynamics of the reaction vessel, it is possible to distinguish between reactors equipped with flat UF membranes or hollow fibers. 

Hollow fiber reactors [7] and dialysis reactors [8] avoid shear stress by separating cells and flowing media. In both reactors nutrient supply takes place by diffusion through the capillary wall or the dialysis membrane. 

The main disadvantage of all these systems is the Hmitation of scale-up. Monoclonal antibodies are produced by multiplying the hollow fiber systems and stirred tank reactors with membrane aeration are known up to 100 liter. Small quantities of product can be produced by these systems but they are not suitable for real industrial scale-up. 

Cross-flow ultrafdtration equipment.—The device used is shown in Figure 1. It included a glass reactor (R) with temperature, pH and stirring control, a Minitan pump (P) (Millipore, Bedford, USA), a Harp hollow fiber membrane cartridge (M) (Romicon-Supelco, Bellefonte, USA) with a cut-off of 2000 daltons, and a permeate exit (f) for fraction collection. The retentate (r) was returned to the reactor. 

Hollow-fiber membrane reactor Hydrolysis of sunflower oil Lipase from Rhizopus sp. 122... 

The production process for (S)-phenylalanine as an intermediate in aspartame perpetuates the principle of reracemization of the nondesired enantiomer (Figure 4.5) in a hollow fiber/ liquid membrane reactor. Asymmetric hydrolysis of the racemic phenylalanine isopropylester at pH 7.5 leads to enantiopure phenylalanine applying subtilisin Carlsberg. The unconverted enantiomer is continuously extracted via a supported liquid membrane [31] that is immobilized in a microporous membrane into an aqueous solution of pH 3.5. The desired hydrolysis product is charged at high pH and cannot, therefore, be extracted into the acidic solution [32]. 

Enzyme membrane reactor for production of diltiazem intermediate. A solution of the racemic ester in organic solvent enters the port at the bottom of the reactor and flows past the strands of microporous, hollow-fiber membrane that contain an enzyme. The enzyme catalyzes hydrolysis of one enantiomer of the ester that undergoes decarboxylation to 4-methoxyphenylacetaldehyde (which in turn forms a water-soluble bisulfite complex that remains in the aqueous phase). The other enantiomer of the ester remains in the aqueous stream that leaves the reactor via the port at the top. Courtesy of Sepracor, Inc. 

In a comparable system, (I ,S)-ibuprofen can be separated by a membrane reactor [83], see Fig. 13.10. The technique comprises a stereo-specific hydrolysis by an enzyme. Subsequently, the enantiomeric ester is extracted into the organic phase on the other side of the membrane. In the system developed by Sepracor Inc., (i )-ibuprofen is selectively hydrolyzed by proteases in a hollow-fiber unit and the (S)-ibuprofen ester can be isolated at 100% yield. This configuration also applies for enantioseparation of other acids such as naproxen and 2-chloropropionic acid. 

Malcata, F.X. and Hill Jr., C.G. (1995) Indnstrial ntihzation of a hollow-fiber membrane reactor for the controlled lipolysis of bntterfat. Enzyme EngineeringXII, edited by M.-D. Legoy and D. N.Thomas. Annals of the New York Academy of Science, Vol. 750, 401-407. 

Matsumae, H., Fumi, M., Shibatani, T. and Tosa. T. (1994) Prodnction of optically-active 3-phenylglycidyl acid ester by the lipase from Serratia marcescens on a hollow-fiber membrane reactor. Journal ofEermentation and Bioengineering, 78(1), 59-64. 

Membrane reactors, using semi-permeable membranes, usually of sheet or hollow fiber type... 

HOLLOW-FIBER MEMBRANES. A hollow-fiher membrane is a capillary having an inside diameter of - inn and an outside diameter < I mm and whose wall functions as a semipermeahlc membrane. The fibers can he employed singly or grouped into a bundle which may contain tens of thousands of fibers and up to several million libers as in reverse osmosis (Fig. 11. In most eases, hollow fibers are used as cylindrical membranes that permit selective exchange of materials across (heir walls. However, they can also he used as containers to effect the controlled release of a specific material, or as reactors to chemically modify a permeate as il diffuses through a chemically activated hollow-liher wall. e g., loaded with immobilized enzyme. 

Lipases (E.C. 3.1.1.3.) catalyze the hydrolysis of lipids at an oil/water interface. In a membrane reactor, the enzymes were immobilized both on the side of the water phase of a hydrophobic membrane as well as on the side of the organic phase of a hydrophilic membrane. In both cases, no other means for stabilization of the emulsion at the membrane were required. The synthesis reaction to n-butyl oleate was achieved with lipase from Mucor miehei, which had been immobilized at the wall of a hollow fiber module. The degree of conversion reached 88%, but the substrate butanol decomposed the membrane before the enzyme was deactivated. 

Figure 13.24 Cut through a hollow-fiber membrane of a multi-phase reactor.

Chiral amines, here (R)-l-aminotetralin, were obtained from racemic amine and pyruvate in a 39 mL hollow-fiber membrane reactor with (SJ-cotransaminases (ft>TA) (Shin, 2001). The substrates were recirculated until the e.e. value exceeded 95%. Simulations suggested residence times should be short to minimize product inhibition. 

Another type of microbiological reactor is the hollow fiber membrane bioreactor shown in Figure 13.19. In this device, the microbial cells are trapped on... 

Figure 13.19 A hollow fiber membrane reactor. Nutrients (S) diffuse to the microbial cells on the shell side of the reactor and undergo reaction to form products (P) such as monoclonal antibodies [31]. Reprinted from J. Membr. Sci. 39, K. Schneider, W. Holz, R. Wollbeck and S. Ripperger, Membranes and Modules for Transmembrane Distillation,...

The lipase enzyme stereospecifically hydrolyzes the (+) isomer of naproxen ester. The enzyme is immobilized in the wall of an inside-skinned hollow fiber membrane. The racemic d and / naproxen ester mixture, dissolved in methyl isobutyl ketone, is introduced on the shell side of the fiber and an aqueous buffer solution is circulated through the fiber lumen. The lipase enzyme hydrolyzes the d form of naproxen ester, forming ethanol and naproxen d. Naproxen d is a carboxylic acid soluble in aqueous buffer but insoluble in methyl isobutyl ketone. Consequently naproxen d is removed from the reactor with the buffer solution. The naproxen / ester remains in the methyl isobutyl ketone solution. This technique achieves an essentially complete separation of the d and Z forms. In a clever final step... 

HOLLOW-FIBER MEMBRANE REACTOR FOR THE LIPASE CATALYZED HYDROLYSIS SYNTHESIS OF DILTIAZEM... 

Figure 9. Optical resolution of 3-phenylglycidic acid methyl ester (MPGM) by lipase and separation of the optically active product, (-)-MPGM, from unnecessary acid using Hollow-Fiber membrane reactor...

In a multiphase membrane reactor, the conversion of benzylpenicillin to 6-aminopenidllinic acid is performed. The type of microstructured reactor used is a fermentation reactor which contains the enzyme penicillin acylase immobilized on the wall of a hollow-fiber tube. The hollow-fiber tube extracts 6-aminopenicillinic acid at the same time selectively. Benzylpenicillin is converted at the outer wall of the hollow fiber into the desired product, which passes into the sweep stream inside the fiber where it can be purified, e.g. by ion exchange. The non-converted benzylpenicillin is recycled back through the reactor [84],... 

Wang, h., Tablet, C., Schiestel, T., Werth, S. and Caro, J. (2006) Partial oxidation of methane to syngas in perovskite hollow fiber membrane reactor. Catalysis Communications, 7, 907-912. 

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