Crown-ether type CSPs

Figure 17. Schematized structure of a chiral crown ether type CSP used for chromatographic resolution or methyl phenylalaninate hydrochloride. Reprinted with permission from ref 122b.

ENANTIOSEPARATION OF PHARMACEUTICALLY RELEVANT CHIRAL COMPOUNDS USING CYCLODEXTRIN, MACROCYCLIC ANTIBIOTIC. AND CROWN-ETHER TYPE CSPs... 

Chiral crown-ethers were originally developed to be used as chiral carriers in enantios-elective liquid-liquid extraction and/or as chiral phase transfer catalysts. The principle of stereoselective host-guest complexation with a chiral crown-ether type host and its application to LC has been first described in 1978 by Cram and co-workers [ 12. Currently, crown-ether type CSPs. which incorporate atropisomeric binaphthyl derivatives as chiral units incorporated in a 18-crown-6 type backbone with substituents that enforce discrimination between enantiomers are commercially available as Crownpak CR (-I-) and (—) (Daicel Chemical Ind.) (see Fig. 9.23a). 

A new crown-ether type CSP, based on (- -)-(18-crown-6)-2,3,l 1,12-tetracarboxylic acid (see Fig. 9.23b), has recently been developed [290- 2]. The use of this type of chiral crown-ether as a selector for LC enantioseparation has been triggered by its previous success in capillary electrophoretic enantioseparations [293,294]. 

Fig. 9.2.. (a) Structure of the chiral SO of Crownpak CR, the commercially available crown-ether type CSP having binaphthyl unit, and separation of the four stereoisomers of I-aminoindan-2-oI (reprinted with permission from Ref. [87]). (b) Structure of a novel crown ether type CSP with the l8-crown-6 letracarboxylic acid SO (reprinted with permis.sion from Ref. [290]). 

Shinbo s group introduced CSPs comprising (3,3 -diphenyl-l,T-binaphthyl)-20-crown-6 (for chemical structure see Fig. 7. ISA) dynamically coated on octadecyl silica gel [227], which proved efficient tools for resolving a broad range of racemic amino acids and related compounds. A related CSP has been commercialized under the tradename CROWNPAK CR by Daicel Chemical Industries,Tokyo, Japan. Coated crown ether-type CSPs have been successfully employed for enantiomer... 

Fig. 7.19 Representative chromatograms forthe resolution of (a) gemifloxacin (methanesulfonate form) and the (b) O-ethyloxime analogue of gemifloxacin on an immobilized crown ether-type CSP. Column (250 x 4.6 mm i.d.) mobile phase 80% acetonitrile in H2O4-H2SO4...

Different classifications for the chiral CSPs have been described. They are based on the chemical structure of the chiral selectors and on the chiral recognition mechanism involved. In this chapter we will use a classification based mainly on the chemical structure of the selectors. The selectors are classified in three groups (i) CSPs with low-molecular-weight selectors, such as Pirkle type CSPs, ionic and ligand exchange CSPs, (ii) CSPs with macrocyclic selectors, such as CDs, crown-ethers and macrocyclic antibiotics, and (iii) CSPs with macromolecular selectors, such as polysaccharides, synthetic polymers, molecular imprinted polymers and proteins. These different types of CSPs, frequently used for the analysis of chiral pharmaceuticals, are discussed in more detail later. 

However, other separations with a CSP based on (-l-)-(18-crown-6)-2,3,11,12-tetracarboxylic acid are also described. ° This CSP allows a larger organic modifier content in the mobile phase. Some separations obtained on this CSP are shown in Table 7. This type of CSP was recently commercialized by RSTech (Daejon, Korea) under the name Chirolsil RCA(-e). The CSP with the ( —) form of this crown ether exists under the name Chirolsil SCA( —). ... 

In contrast, CSPs have achieved great repute in the chiral separation of enantiomers by chromatography and, today, are the tools of the choice of almost all analytical, biochemical, pharmaceutical, and pharmacological institutions and industries. The most important and useful CSPs are available in the form of open and tubular columns. However, some chiral capillaries and thin layer plates are also available for use in capillary electrophoresis and thin-layer chromatography. The chiral columns and capillaries are packed with several chiral selectors such as polysaccharides, cyclodextrins, antibiotics, Pirkle type, ligand exchangers, and crown ethers. 

In view of the importance of chiral resolution and the efficiency of liquid chromatographic methods, attempts are made to explain the art of chiral resolution by means of liquid chromatography. This book consists of an introduction followed by Chapters 2 to 8, which discuss resolution chiral stationary phases based on polysaccharides, cyclodextrins, macrocyclic glyco-peptide antibiotics, Pirkle types, proteins, ligand exchangers, and crown ethers. The applications of other miscellaneous types of CSP are covered in Chapter 9. However, the use of chiral mobile phase additives in the separation of enantiomers is discussed in Chapter 10. 

The CSPs based on chiral crown ethers were prepared by immobilizing them on some suitable solid supports. Blasius et al. [33-35] synthesized a variety of achiral crown ethers based on ion exchangers by condensation, substitution, and polymerization reactions and were used in achiral liquid chromatography. Later, crown ethers were adsorbed on silica gel and were used to separate cations and anions [36-39]. Shinbo et al. [40] adsorbed hydrophobic CCE on silica gel and the developed CSP was used for the chiral resolution of amino acids. Kimura et al. [41-43] immobilized poly- and bis-CCEs on silica gel. Later, Iwachido et al. [44] allowed benzo-15-crown-5, benzo-18-crown-6 and benzo-21-crown-7 CCEs to react on silica gel. Of course, these types of CCE-based phases were used in liquid chromatography, but the column efficiency was very poor due to the limited choice of mobile phases. Therefore, an improvement in immobilization was realized and new methods of immobilization were developed. In this direction, CCEs were immobilized to silica gel by covalent bonds. 

The most popular and commonly used chiral stationary phases (CSPs) are polysaccharides, cyclodextrins, macrocyclic glycopeptide antibiotics, Pirkle types, proteins, ligand exchangers, and crown ether based. The art of the chiral resolution on these CSPs has been discussed in detail in Chapters 2-8, respectively. Apart from these CSPs, the chiral resolutions of some racemic compounds have also been reported on other CSPs containing different chiral molecules and polymers. These other types of CSP are based on the use of chiral molecules such as alkaloids, amides, amines, acids, and synthetic polymers. These CSPs have proved to be very useful for the chiral resolutions due to some specific requirements. Moreover, the chiral resolution can be predicted on the CSPs obtained by the molecular imprinted techniques. The chiral resolution on these miscellaneous CSPs using liquid chromatography is discussed in this chapter. 

Chiral separations can be considered as a special subset of HPLC. The FDA suggests that for drugs developed as a single enantiomer, the stereoisomeric composition should be evaluated in terms of identity and purity [6]. The undesired enantiomer should be treated as a structurally related impurity, and its level should be assessed by an enantioselective means. The interpretation is that methods should be in place that resolve the drug substance from its enantiomer and should have the ability to quantitate the enantiomer at the 0.1% level. Chiral separations can be performed in reversed phase, normal phase, and polar organic phase modes. Chiral stationary phases (CSP) range from small bonded synthetic selectors to large biopolymers. The classes of CSP that are most commonly utilized in the pharmaceutical industry include Pirkle type, crown ether, protein, polysaccharide, and antibiotic phases [7]. 

In type 111 CSPs, the solute enters into chiral cavities within the CSP to form inclusion complexes and the relative stabilities of the resulting dia-stereomeric complexes are based on secondary attractive (e.g., hydrogenbonding) or steric interactions. The driving force for the insertion can be hydrophobic (cydodextrin and polymethacrylate CSPs) or electrostatic (crown ether CSP). The commerdally available CSPs based on these mechanisms are presented in Table 3. 

According to their chemical structures, CSPs can be divided into three different groups. A multitude of chiral stationary phases is derived from (modified) natural or synthetic polymers, e.g., the polysaccharides, proteins or polyacrylamides. A second type of selectors is based on large chiral ring systems, such as cyclo-dextrins, macTocycKc antibiotics, and crown ethers. The last group comprises moleailes of small and medium size, such as amino acids and their derivatives, alkaloids, and fuUy synthetic selectors. 

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