Liquid enantiomers

A pure liquid enantiomer or a pure solid enantiomer in (homogeneous) solution is said to be isotropic (the same throughout). However, when different results are obtained in different directions (as with a crystalline material) the substance is anisotropic. 

In the absence of special syimnetry, the phase mle requires a minimum of tliree components for a tricritical point to occur. Synnnetrical tricritical points do have such syimnetry, but it is easiest to illustrate such phenomena with a tme ternary system with the necessary syimnetry. A ternary system comprised of a pair of enantiomers (optically active d- and /-isomers) together with a third optically inert substance could satisfy this condition. While liquid-liquid phase separation between enantiomers has not yet been found, ternary phase diagrams like those shown in figure A2.5.30 can be imagined in these diagrams there is a necessary syimnetry around a horizontal axis that represents equal amounts of the two enantiomers. 

The resolution of optically active compounds by gas chromatography with chiral phases is a well-established procedure, and the separation of Al-perfluoto-acetylated ammo acid ester enantiomers m 1967 was the first successful application of enantioselective gas-liquid chromatography [39] Ammo acids have been resolved as their A -trifluoroacetyl esters on chiral diamide phases such as N-lauroyl-L-valineferf-butylamideorAl-docosanoyl-L-valme /ez-r-butylamide [40,41,... 

M. Tanaka and H. Yamazaki, Dkect detemination of pantoprazole enantiomers in human serum by reversed-phase liigh peifomance liquid chi omatography using a cellulose-based cliiral stationaiy phase and column-switching system as a sample cleanup procedure , Aim/. Chem. 68 1513-1516(1996). 

L. Liu, H. Cheng, J. J. Zhao and J. D. Rogers, Determination of montelukast (MK-0476) and its 5-enantiomer in human plasma by stereoselective high performance liquid cliromatography with column-switching , ]. Pharm. Biomed. Anal. 15 631-638 (1997). 

Figure 11.4 Chromatograms of plasma samples on a silica-chiralcel OJ coupled column system (a) plasma spiked with oxprenolol (internal standard) (b) plasma spiked with 040 p-g/ml metyrapone and 0.39 p-g/ml metyrapol (racemate) (c) plasma sample obtained after oral administration of 750 mg metaiypone. Peaks are as follows 1, metyrapone 2, metyrapol enantiomers 3, oxprenolol. Reprinted from Journal of Chromatography, 665, J. A. Chiarotto and I. W. Wainer, Determination of metyrapone and the enantiomers of its chfral metabolite metyrapol in human plasma and urine using coupled achfral-chfral liquid cltro-matography, pp. 147-154, copyright 1995, with permission from Elsevier Science.

J. A. Chiar otto and I. W. Wainer, Determination of metyrapone and the enantiomers of its chiral metabolite metyrapol in human plasma and urine using coupled achhal-chhal liquid cliromatogruphy , J. Chromatogr. 665 147-154 (1995). 

C. L. Hsu and R. R. Walters, Assay of the enantiomers of ibutilide and artilide using solid-phase extraction, derivatization and achhal-cliiral column-switcliing high-performance liquid cliromatography , J. Chromatogr. B 667 115-128 (1995). 

C.-Y. Hsieh and J.-D. Huang, Two-dimensional high-performance liquid cliromato-grapliic method to assay p-hydroxyphenylphenylhydantoin enantiomers in biological... 

Y. Oda, N. Asakawa, Y. Yoshida and T. Sato, On-line determination and resolution of the enantiomers of ketoprofen in plasma using coupled achiral-cliiral high-performance liquid chromatography , 7. Pharm. Biomed. Anal. 10 81-87 (1992). 

H. Fujimoto, I. Nishino, K. Ueno and T. Umeda, Determination of the enantiomers of a new 1,4-dihydropyridine calcium antagonist in dog plasma achiral / chiral coupled high performance liquid cliromatography with electrochemical detection , 7. Pharm. Sci. 82 319-322(1993). 

D. Masurel and F W. Wainer, Analytical and preparative high-performance liquid cliromatographic separation of the enantiomers of ifosfamide, cyclophosphamide and ti ofosfamide and their determination in plasma , 7. Chromatogr. 490 133-143 (1989). 

HPLC separations are one of the most important fields in the preparative resolution of enantiomers. The instrumentation improvements and the increasing choice of commercially available chiral stationary phases (CSPs) are some of the main reasons for the present significance of chromatographic resolutions at large-scale by HPLC. Proof of this interest can be seen in several reviews, and many chapters have in the past few years dealt with preparative applications of HPLC in the resolution of chiral compounds [19-23]. However, liquid chromatography has the attribute of being a batch technique and therefore is not totally convenient for production-scale, where continuous techniques are preferred by far. 

From the pioneering studies of Ito et al. [117], CCC has been mainly used for the separation and purification of natural products, where it has found a large number of applications [114, 116, 118, 119]. Moreover, the potential of this technique for preparative purposes can be also applied to chiral separations. The resolution of enantiomers can be simply envisaged by addition of a chiral selector to the stationary liquid phase. The mixture of enantiomers would come into contact with this liquid CSP, and enantiodiscrimination might be achieved. However, as yet few examples have been described in the literature. 

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. 

Proteins (BSA or ovomucoid, OVM) have also been successful in the preparative resolution of enantiomers by liquid-liquid extraction, either between aqueous and lipophilic phases [181] or in aqueous two-phase systems (ATPS) [123, 180]. The resolution of d,l-kynurenine [180] and ofloxacin and carvediol [123] were performed using a countercurrent extraction process with eight separatory funnels. The significant number of stages needed for these complete resolutions in the mentioned references and others [123, 180, 189], can be overcome with more efficient techniques. Thus, the resolution of d,l-kynurenine performed by Sellergren et al. in 1988 by extraction experiments was improved with CCC technologies 10 years later [128]. 

It is worth noting that the extractive process can be performed continuously. Thus, the separation of ( )-mandelic acid into its enantiomers was achieved with a liquid particle extractor described by Abe et al. [190-192] using A-docecyl-L-proline as chiral selector. 

W. H. Pirkle and B. C. Hamper, The direct preparative resolution of enantiomers by liquid chromatography on chiral stationary phases in Preparative Liquid Chromatography, B. A. Bidling-meyer (Ed.), Journal Chromatography Library Vol. 38, 3 Edition, Elsevier Science Publishers B. V, Amsterdam (1991) Chapter 7. 

S. G. Allenmark, Separation of enantiomers by protein-based chiral phases in A practical approach to chiral separations by liquid chromatogra.phy, G. Subramanian, VCH, Weinheim (1994) Chapter 7. 

Despite the difficulties caused by the rapidly expanding literature, the use of chiral stationary phases (CSPs) as the method of choice for analysis or preparation of enantiomers is today well established and has become almost routine. It results from the development of chiral chromatographic methods that more than 1000 chiral stationary phases exemplified by several thousands of enantiomer separations have been described for high-performance liquid chromatography (HPLC). 

For the separation of racemic mixtures, two basic types of membrane processes can be distinguished a direct separation using an enantioselective membrane, or separation in which a nonselective membrane assists an enantioselective process [5]. The most direct method is to apply enantioselective membranes, thus allowing selective transport of one of the enantiomers of a racemic mixture. These membranes can either be a dense polymer or a liquid. In the latter case, the membrane liquid can be chiral, or may contain a chiral additive (carrier). Nonselective membranes can also... 

In general, a liquid membrane for chiral separation contains an enantiospecific carrier which selectively forms a complex with one of the enantiomers of a racemic mixture at the feed side, and transports it across the membrane, where it is released into the receptor phase (Fig. 5-1). 

In the classical set-up of bulk liquid membranes, the membrane phase is a well-mixed bulk phase instead of an immobilized phase within a pore or film. The principle comprises enantioselective extraction from the feed phase to the carrier phase, and subsequently the carrier releases the enantiomer into the receiving phase. As formation and dissociation of the chiral complex occur at different locations, suitable conditions for absorption and desorption can be established. In order to allow for effective mass transport between the different liquid phases involved, hollow fiber... 

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. 

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