Product extraction, membrane reactors

In this case study, an enzymatic hydrolysis reaction, the racemic ibuprofen ester, i.e. (R)-and (S)-ibuprofen esters in equimolar mixture, undergoes a kinetic resolution in a biphasic enzymatic membrane reactor (EMR). In kinetic resolution, the two enantiomers react at different rates lipase originated from Candida rugosa shows a greater stereopreference towards the (S)-enantiomer. The membrane module consisted of multiple bundles of polymeric hydrophilic hollow fibre. The membrane separated the two immiscible phases, i.e. organic in the shell side and aqueous in the lumen. Racemic substrate in the organic phase reacted with immobilised enzyme on the membrane where the hydrolysis reaction took place, and the product (S)-ibuprofen acid was extracted into the aqueous phase. 

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]. 

One of the main challenges for zeolite membrane reactors is that optimal reactor operation requires that the membrane flux be in balance with the reaction rate.. Whether acting in an inert or catalytic capacity, the extractive ability of the membrane needs to keep up with the production of the species being removed in order to fully participate in improving the reaction yield [44]. 

The reaction in a homogeneous solution with a polar organic solvent in which the enzymes and substrates are both soluble, occurs often at the expense of the enzyme stability [4, 5]. Besides immobilised enzymes in organic solvents [6], emulsion reactors, especially enzyme-membrane-reactors coupled with a product separation by membrane based extractive processes [7-9] and two-phase membrane reactors [10-12], are already established on a production scale. 

Similarly, enantiomerically pure hydrophobic (S)-l-phenyl-2-propanol, (S)-4-phe-nyl-2-butanol, and (S)-6-methylhept-5-en-2-ol (sulcatol) were obtained with high purities in a dual-loop enzyme membrane reactor unit with separate membrane extraction unit (Kruse, 1996). Whereas substrate concentrations were low at 9-12 mM, space-time yields higher than 100 g (L d) 1 as well as concentrated product solutions were obtained. 

J.L. Lopez and S.L. Matson, A Multiphase/Extractive Enzyme Membrane Reactor for Production of Diltiazem Chiral Intermediate, J. Membr. Sci. 125, 189 (1997). 

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],... 

Improved selectivity in the liquid-phase oligomerization of i-butene by extraction of a primary product (i-octene C8) in a zeolite membrane reactor (acid resin catalyst bed located on the membrane tube side) with respect to a conventional fixed-bed reactor has been reported [35]. The MFI (silicalite) membrane selectively removes the C8 product from the reaction environment, thus reducing the formation of other unwanted byproducts. Another interesting example is the isobutane (iC4) dehydrogenation carried out in an extractor-type zeolite CMR (including a Pt-based fixed-bed catalyst) in which the removal of the hydrogen allows the equilibrium limitations to be overcome [36],... 

Membrane bioreactors have been reported for the production of diltiazem chiral intermediate with a multiphase/extractive enzyme membrane reactor [15, 16]. The reaction was carried out in a two-separate phase reactor. Here, the membrane had the double role of confining the enzyme and keeping the two phases in contact while maintaining them in two different compartments. This is the case of the multiphase/ extractive membrane reactor developed on a productive scale for the production of a chiral intermediate of diltiazem ((2R,3S)-methylmethoxyphenylglycidate), a drug used in the treatment of hypertension and angina [15]. The principle is illustrated in... 

The first published information on the industrial application of a hybrid system with a HF contactor for production of the drug dilthiazem intermediate was reported by Lopez and Matson [23]. An enzymatic resolution of dilthiazem chiral intermediate is realized in an extractive enzymatic membrane reactor. The enzyme is entrapped in the macroporous sponge part of the hydrophilic hollow-fiber membrane made of a... 

Lopez, J.L. and Matson, S.L. (1997) A multiphase/extractive enzyme membrane reactor for production of diltiazem chiral intermediate. Journal of Membrane Science, 125, 189. 

The first step for the design of an EMR is to select the type of reactor. Extractive membrane reactors are desirable when one of the substrates or products is poorly soluble in aqueous solution or when an undesirable by-product has to be separated, as the membrane acts as a solvent extraction step [99]. Immobilized enzyme reactors are usually applied with materials that enable enhancement of enzymatic stability or preserve enzyme from deactivation by a direct contact with an organic solvent [99]. Finally, direct-contact membrane reactors are the most versatile alternative in processes with soluble compounds. 

Processes for production of ethanol and acetone-butanol-ethanol mixture from fermentation products in membrane contactor devices were presented in Refs. [88,89]. Recovery of butanol from fermentation was reported in Ref. [90]. Use of composite membrane in a membrane reactor to separate and recover valuable biotechnology products was discussed in Refs. [91,92]. A case study on using membrane contactor modules to extract small molecular weight compounds of interest to pharmaceutical industry was shown in Ref. [93]. Extraction of protein and separation of racemic protein mixtures were discussed in Refs. [94,95]. Extractions of ethanol and lactic acid by membrane solvent extraction are reported in Refs. [96,97]. A membrane-based solvent extraction and stripping process was discussed in Ref. [98] for recovery of Phenylalanine. Extraction of aroma compounds from aqueous feed solutions into sunflower oil was investigated in Ref. [99]. 

An interesting application of catalytic membrane reactors [14,136] relates to the production of tritium which together with deuterium will be the fuel for the fusion reactors of the future. Tritium is produced by mearts of a nuclear reaction between neutrons and lithium atoms in a breeder reactor. The tritium thus produced must be further purified to reach the purity levels that are required in the fusion reactor. For the extraction and purification process Basile and... 

Sometimes reaction rates can be enhanced by using multifunctional reactors, i.e., reactors in which more than one function (or operation) can be performed. Examples of reactors with such multifunctional capability, or combo reactors, are distillation column reactors in which one of the products of a reversible reaction is continuously removed by distillation thus driving the reaction forward extractive reaction biphasing membrane reactors in which separation is accomplished by using a reactor with membrane walls and simulated moving-bed (SMB) reactors in which reaction is combined with adsorption. Typical industrial applications of multifunctional reactors are esterification of acetic acid to methyl acetate in a distillation column reactor, synthesis of methyl-fer-butyl ether (MTBE) in a similar reactor, vitamin K synthesis in a membrane reactor, oxidative coupling of methane to produce ethane and ethylene in a similar reactor, and esterification of acetic acid to ethyl acetate in an SMB reactor. These specialized reactors are increasingly used in industry, mainly because of the obvious reduction in the number of equipment. These reactors are considered by Eair in Chapter 12. 

A membrane cell recycle reactor with continuous ethanol extraction by dibutyl phthalate increased the productivity fourfold with increased conversion of glucose from 45 to 91%.249 The ethanol was then removed from the dibutyl phthalate with water. It would be better to do this second step with a membrane. In another process, microencapsulated yeast converted glucose to ethanol, which was removed by an oleic acid phase containing a lipase that formed ethyl oleate.250 This could be used as biodiesel fuel. Continuous ultrafiltration has been used to separate the propionic acid produced from glycerol by a Propionibacterium.251 Whey proteins have been hydrolyzed enzymatically and continuously in an ultrafiltration reactor, with improved yields, productivity, and elimination of peptide coproducts.252 Continuous hydrolysis of a starch slurry has been carried out with a-amylase immobilized in a hollow fiber reactor.253 Oils have been hydrolyzed by a lipase immobilized on an aromatic polyamide ultrafiltration membrane with continuous separation of one product through the membrane to shift the equilibrium toward the desired products.254 Such a process could supplant the current energy-intensive industrial one that takes 3-24 h at 150-260X. Lipases have also been used to prepare esters. A lipase-surfactant complex in hexane was used to prepare a wax ester found in whale oil, by the esterification of 1 hexadecanol with palmitic acid in a membrane reactor.255 After 1 h, the yield was 96%. The current industrial process runs at 250°C for up to 20 h. 

When producing high value biochemicals, the economic analysis is, generally, more favorable for the MBR systems, when compared with the more conventional units. Often selectivity rather than conversion may be the key, since higher selectivities typically result in the elimination of some of the purification steps which have a strong influence on the total production costs. The application of the multiphase/extractive enzyme membrane reactor for the production of a diltiazem chiral intermediate was reported in Chapter 4... 

Taking advantage of the enormous differences in molecular weight (and hydro-dynamic volume) between the catalyst (an enzyme) and the substrates or the products, it is possible to confine the catalyst in a membrane reactor while the reagents and products can be selectively extracted from the reaction mixture without modifying the catalytic active intermediate. Remarkably, the Chemzyme membrane reactor concept allows a productivity per gram of catalyst which could be higher than in the case of enzymes because the polymers can be multifunctionalized with several active centers [1]. 

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