Chiral enantioseparations

TABLE 23. Factors and their levels investigated during the optimization phase in the development of a chiral enantioseparation method for a nonsteroidal antiinflammatory dmg (28)... 

TABLE 2.18. Responses studied in the circumscribed central composite design (Table 2.14 with lal = 1.68, five center point replicates (exp 15-19)) applied during the optimization phase of the development of a chiral enantioseparation method in Reference 28 migration time of the first and the second enantiomer (t i and t j), and resolution between the two enantiomers Rs... 

An alternative model has been proposed in which the chiral mobile-phase additive is thought to modify the conventional, achiral stationary phase in situ thus, dynamically generating a chiral stationary phase. In this case, the enantioseparation is governed by the differences in the association between the enantiomers and the chiral selector in the stationary phase. 

G. Subiamanian, ed., A Practical Approach to Chiral Separations by Liquid Chmmatofpa/ihy, VCH Publishers, Vifeinheim, 1994 S. G. AUatmarit. Chromutographic Enantioseparation Methods and Applications, Ellis Horwood, New Yoik, 1991. 

R.-M. Nicoud, G. Fuchs, P Adam, M. Bailly, E. Kusters, F. D. Antia, R. Reuille and E. Sclimid, Prepar ative scale enantiosepar ation of a cliiral epoxide compar ison of liquid cliromatography and simulated moving bed adsorption technology . Chirality 5 267-271 (1993). 

Early examples of enantioselective extractions are the resolution of a-aminoalco-hol salts, such as norephedrine, with lipophilic anions (hexafluorophosphate ion) [184-186] by partition between aqueous and lipophilic phases containing esters of tartaric acid [184-188]. Alkyl derivatives of proline and hydroxyproline with cupric ions showed chiral discrimination abilities for the resolution of neutral amino acid enantiomers in n-butanol/water systems [121, 178, 189-192]. On the other hand, chiral crown ethers are classical selectors utilized for enantioseparations, due to their interesting recognition abilities [171, 178]. However, the large number of steps often required for their synthesis [182] and, consequently, their cost as well as their limited loadability makes them not very suitable for preparative purposes. Examples of ligand-exchange [193] or anion-exchange selectors [183] able to discriminate amino acid derivatives have also been described. 

J. Dingenen, Polysaccharide phases in enantioseparations in A practical approach to chiral separations by liquid chromatography, G. Subramanian, VCH, Weinheim (1994) Chapter 6. 

A chiral separation medium is a complex system. Ideally, interactions that lead to enantioseparation are maximized while nonspecific interactions should be completely suppressed. Typically, a medium for chromatographic separations involves the solid support, the selector, and the linker connecting the two, as shown in scheme 3-1. 

Inspired by the separation ability of cyclic selectors such as cyclodextrins and crown ethers, Malouk s group studied the synthesis of chiral cyclophanes and their intercalation by cation exchange into a lamellar solid acid, a-zirconium phosphate aiming at the preparation of separation media based on solid inorganic-organic conjugates for simple single-plate batch enantioseparations [77-80]. 

Nieoud R. M., Euehs G., Adam P, Bailly M., Kusters E., Antia E, Reuille R., Sehmid E. (1993) Preparative Seale Enantioseparation of a Chiral Epoxide Comparison of Liquid Chromatography and Simulated Moving Bed Adsorption Teehnology, Chirality 5 267-271. 

Kusters E., Gerber G., Antia E. D. (1995) Enantioseparation of a Chiral Epoxide by SMB Chromatography using Chiraleel-OD, Chromatographia 40 387-393. 

Some of the initial enthusiasm surrounding chiral SFC was tempered by the fact that many of the same separations had already been achieved by LC [29]. Therefore, researchers were reluctant to add SFC to their analytical laboratories. In some instances, SFC does yield separations that can not be achieved on the same CSP in LC [30, 31]. The enantioseparation of primaquine, an antimalarial compound, on a Chiralcel OD CSP is illustrated in Fig. 12-1 [32]. This compound was not resolved on the same CSP in LC [33]. The reverse situation, where a separation obtained in LC may not be observed on the same CSP in SFC, can also occur [34]. These disparities seem to be related to differences in analyte-eluent and eluent-CSP interac-... 

The versatility of chiral stationary phases and its effecitve application in both analytical and large-scale enantioseparation has been discussed in the earlier book A Practical Approach to Chiral Separation by Liquid Chromatography" (Ed. G. Sub-ramanian, VCH 1994). This book aims to bring to the forefront the current development and sucessful application chiral separation techniques, thereby providing an insight to researchers, analytical and industrial chemists, allowing a choice of methodology from the entire spectrum of available techniques. 

Following these announcements, the first wave of publications addressing the use of SMB for the manufacture of pharmaceutical products of interest was published. The separation of a chiral hetrazepine [26], WEB 2170 6-(2-chlorophenyl)-8-9-di-hydro-l-methyl-8-[(morpholinyl)-carbonyl]-4H,7H-cyclopenta[4,5]-thieno[3,2-f][l,2,4]triazolo[4,3-a][l,4]diazepine. WEB 2170 is a chiral hetrazepine from Boehringer-Ingelheim. The enantioseparation of WEB 2170 was performed using cellulose triacetate (CTA) from Merck (Darmstadt) as the CSP and with pure methanol as eluent. 

In this study, Ali and Aboul-Enein [80] used cellulose tr is (3,5-d ich Ioropheny 1 carbamate) chiral stationary phase for the enantioseparation of miconazole and other clinically used drugs by high performance liquid chromatography. The mobile... 

Barretta and coworkers63 reported a direct determination of the enantiomeric purity of chiral trisubstituted allenes by using permethylated cyclodextrin as a chiral solvating agent. They found that the heptakis ft-cyclodextrin TRIMEB discussed above can be successfully used as a chiral solvating agent (CSA) for the NMR determination of the enantiomeric purity of trisubstituted allenes llOa-f. An accurate analysis of the experimental conditions (molar ratio aliene/TRIMEB, temperature and solvent) required to optimize the enantioseparation has been carried out. The XH NMR spectra of TRIMEB, allenes llOa-f, and the mixtures TRIMEB/allene have been recorded at 300 MHz in CD3OD as solvent. 

Avery recent study [128] deals with the comparison of two commercially available vancomycin-based CSPs with different surface coverage of the chiral selector in the enantioseparation of P-blockers and profens, by RP and POM separation modes. Higher retention and better resolution were obtained on the CSP with higher coverage of vancomycin in both the separation modes. However, in the case of pro fens, higher retention was not always accompanied by an improvement of the enantioselectivity in the RP mode. An accurate study of the influence of the mobile phase composition was also performed in both the separation modes. 

The [ -adrenoreceptors antagonists (also called [)-blockers) comprise a group of chiral drugs that are mostly used in the treatment of cardiovascular disorders such as hypertension, cardiac arrhythmia, or ischemic heart disease. Teicoplanin is the chiral selector most exploited for the enantioseparation of this class of compounds, followed by vancomycin. Several P-blockers have been analyzed, particularly in the... 

Petrusevska, K. et al.. Chromatographic enantioseparation of amino acids using a new chiral stationary phase based on a macrocyclic glycopeptide antibiotic, J. Sep. ScL, 29, 1447, 2006. 

Armstrong, D.W., Liu, Y., and Ekborg-Ott, K.H., A covalently bonded teico-planin chiral stationary phase for HPLC enantioseparations. Chirality, 7, 474, 1995. 

Aboul-Enein, H.Y and Ali, I., Optimization strategies for HPLC enantioseparation of racemic drugs using polysaccharides and macrocyclic antibiotic chiral stationary phases, II Farmaco, 57, 513, 2002. 

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