Selectors membranes

The first successful chiral resolutions through enantioselective membranes have been published recently, but few cases are applicable to the preparative scale, mainly due to mechanical and technical limitations. Low flow rates, saturation of the chiral selectors and loss of enantioselectivity with time are some of the common problems encountered and that should be solved in the near future. 

Liquid membranes can be constituted by liquid chiral selectors used directly [170] or by solutions of the chiral molecules in polar or apolar solvents. This later possibility can also be an advantage since it allows the modulation of the separation con-... 

Another possibility of constructing a chiral membrane system is to prepare a solution of the chiral selector which is retained between two porous membranes, acting as an enantioselective liquid carrier for the transport of one of the enantiomers from the feed solution of the racemate to the receiving side (Fig. 1-5). This system is often referred to as membrane-assisted separation. The selector should not be soluble in the solvent used for the elution of the enantiomers, whose transport is driven by a gradient in concentration or pH between the feed and receiving phases. As a drawback common to all these systems, it should be mentioned that the transport of one enantiomer usually decreases when the enantiomer ratio in the permeate diminishes. Nevertheless, this can be overcome by designing a system where two opposite selectors are used to transport the two enantiomers of a racemic solution simultaneously, as it was already applied in W-tube experiments [171]. 

Most of the chiral membrane-assisted applications can be considered as a modality of liquid-liquid extraction, and will be discussed in the next section. However, it is worth mentioning here a device developed by Keurentjes et al., in which two miscible chiral liquids with opposing enantiomers of the chiral selector flow counter-currently through a column, separated by a nonmiscible liquid membrane [179]. In this case the selector molecules are located out of the liquid membrane and both enantiomers are needed. The system allows recovery of the two enantiomers of the racemic mixture to be separated. Thus, using dihexyltartrate and poly(lactic acid), the authors described the resolution of different drugs, such as norephedrine, salbu-tamol, terbutaline, ibuprofen or propranolol. 

Liquid-liquid extraction is a basic process already applied as a large-scale method. Usually, it does not require highly sophisticated devices, being very attractive for the preparative-scale separation of enantiomers. In this case, a chiral selector must be added to one of the liquid phases. This principle is common to some of the separation techniques described previously, such as CCC, CPC or supported-liquid membranes. In all of these, partition of the enantiomers of a mixture takes place thanks to their different affinity for the chiral additive in a given system of solvents. 

Addition of a chiral carrier can improve the enantioselective transport through the membrane by preferentially forming a complex with one enantiomer. Typically, chiral selectors such as cyclodextrins (e.g. (4)) and crown ethers (e.g. (5) [21]) are applied. Due to the apolar character of the inner surface and the hydrophilic external surface of cyclodextrins, these molecules are able to transport apolar compounds through an aqueous phase to an organic phase, whereas the opposite mechanism is valid for crown ethers. 

Armstrong and Jin [15] reported the separation of several hydrophobic isomers (including (l-ferrocenylethyl)thiophenol, 1 -benzylnornicotine, mephenytoin and disopyramide) by cyclodextrins as chiral selectors. A wide variety of crown ethers have been synthesized for application in enantioselective liquid membrane separation, such as binaphthyl-, biphenanthryl-, helicene-, tetrahydrofuran and cyclohex-anediol-based crown ethers [16-20]. Brice and Pirkle [7] give a comprehensive overview of the characteristics and performance of the various crown ethers used as chiral selectors in liquid membrane separation. 

In general, high selectivities can be obtained in liquid membrane systems. However, one disadvantage of this technique is that the enantiomer ratio in the permeate decreases rapidly when the feed stream is depleted in one enantiomer. Racemization of the feed would be an approach to tackle this problem or, alternatively, using a system containing the two opposite selectors, so that the feed stream remains virtually racemic [21]. Another potential drawback of supported enantioselective liquid membranes is the application on an industrial scale. Often a complex multistage process is required in order to achieve the desired purity of the product. This leads to a relatively complicated flow scheme and expensive process equipment for large-scale separations. 

For the separation of D,L-leucine, Ding et al. [62] used poly(vinyl alcohol) gel-coated microporous polypropylene hollow fibers (Fig. 5-11). An octanol phase containing the chiral selector (A-n-dodecyl-L-hydroxyproline) is flowing countercur-rently with an aqueous phase. The gel in the pores of the membrane permits diffusion of the leucine molecules, but prevents convection of the aqueous and octanol phase. At a proper selection of the flow ratios it is possible to achieve almost complete resolution of the D,L-leucine (Fig. 5-12). 

As described above, the application of classical liquid- liquid extractions often results in extreme flow ratios. To avoid this, a completely symmetrical system has been developed at Akzo Nobel in the early 1990s [64, 65]. In this system, a supported liquid-membrane separates two miscible chiral liquids containing opposite chiral selectors (Fig. 5-13). When the two liquids flow countercurrently, any desired degree of separation can be achieved. As a result of the system being symmetrical, the racemic mixture to be separated must be added in the middle. Due to the fact that enantioselectivity usually is more pronounced in a nonaqueous environment, organic liquids are used as the chiral liquids and the membrane liquid is aqueous. In this case the chiral selector molecules are lipophilic in order to avoid transport across the liquid membrane. 

Fig. 5-13. Schematic representation of the Akzo Nobel enantiomer separation process. Two liquids containing the opposing enantiomers of the chiral selector (FI and K) are flowing countercurrently through the column (4) and are kept separated by the liquid membrane (3). The racemic mixture to be separated is added to the middle of the system (1), and the separated enantiomers are recovered from the outflows of the column (2a and 2b) [64],...

Kcurentjes et al. (1996) have also reported the separation of racemic mixtures. Two liquids are made oppositely chiral by the addition of R- or S-enantiomers of a chiral selector, respectively. These liquids are miscible, but are kept separated by a non-miscible liquid contained in a porous membrane. These authors have used different types of hollow-fibre modules and optimization of shell-side flow distribution was carried out. The liquid membrane should be permeable to the enantiomers to be separated but non-permeable to the chiral selector molecules. Separation of racemic mixtures like norephedrine, ephedrine, phenyl glycine, salbutanol, etc. was attempted and both enantiomers of 99.3 to 99.8% purity were realized. 

Fig. 3.2. The cycle of membrane equilibria for potential development. [E] is the enantiomer, [CS] is the chiral selector from the membrane, [E-CS] is the complex, (s) and (i) define the bulk solution and the membrane-solution interface, respectively.

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