Ligand-exchange type CSPs

Metal Complexation/Ligand Exchange Type CSPs... 

ENANTIOSEPARATION OF PHARMACEUTICALLY RELEVANT CHIRAL COMPOUNDS USING LIGAND-EXCHANGE TYPE CSPs... 

A variety of CSPs operating on ligand-exchange-type principles are commercially available from Daicel Chemical Industries, Ltd (Japan). Among these, CHIRALPAK MA(-i-), based on N,N-dioclyl-L-alanine, and the proline-type CHIRALPAK WH appear to be the most broadly applicable CSPs. 

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. 

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. 

It is well known that the chiral resolution of these CSPs occurred as a result of the exchange of ligands and enantiomers on the same metal ion. Therefore, these CSPs are suitable only for those racemates which can coordinate with the metal ion. Therefore, racemates like amino acids, amines, and hydroxy acids have been resolved successliilly by the ligand-exchange process. As mentioned earlier, either the individual chiral ligand or one complexed with a metal ion is bonded onto silica gel support. Therefore, in the case of the first type of CSP, the metal ion is used in the mobile phase no metal ion is required in the mobile phase in the latter case. 

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. 

Type IV includes chiral phases that usually interact with the enantiomeric analytes through the formation of metal complexes. There are usually used to separate amino acid enantiomers. These types of phases are also called ligand exchange phases. The transient diastereomeric complexes are ternary metal complexes between a transitional metal (usually Cu +), an amino acid enantiomeric analyte, and another compound immobilized on the CSP which is able to undergo complexation with the transitional metal (see also the ligand exchange section. Section 22.5). The two enantiomers are separated based on the difference in the stability constant of the two diastereomeric species. The mobile phases used to separate such enantiomeric analytes are usually aqueous solutions of copper (II) salts such as copper sulfate or copper acetate. To modulate the retention, several parameters—such as the pH of the mobile phase, the concentration of the copper ion, or the addition of an organic modifier such as acetonitrile or methanol in the mobile phase—can be varied. 

Several books are devoted to the chiral separations in HPLC [69,93,104,108,110]. Among several hundreds of CSPs described, ligand-exchange [105], Pirkle-type [113], protein and peptide [114], polysaccharide [115], macrocyclic [93,116], and synthetic polymeric [117-119] CSPs are most widely used. 

Since enantiomer separation requires the Intervention of some chiral agent, one may utilize either chiral mobile phase additives (CMPA) or chiral stationary phases (CSPs). While the requirement that one add a chiral substance to the mobile phase has obvious limitations for preparative separations, it is not a serious problem for analytical separations. Indeed, for some types of compounds (e.g. amino acids) this approach may be preferred. Quite an extensive literature exists for the use of mobile phases containing chiral bidentate ligands and copper ions for the "ligand exchange" resolution of underlvatized amino acids (1, 2) and for N-dansyl derivatives of amino acids Tartaric acid derivatives have also been used as CMPAs (5). 

---