Pirkle-type CSPs structure

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. 

FIGURE 2 The chemical structures of some Pirkle-type CSPs. 

TABLE 3 Effect of the Structures of Pirkle-Type CSPs on the Chiral Resolution of... 

FIGURE 8 The chemical structures of (a) Pirkle-type CSPs with small and large alkyl chains (from Ref. 144) and (b) different Sumichiral OA CSPs. (From Ref. 20.)... 

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]. 

Most chiral HPLC analyses are performed on CSPs. General classification of CSPs and rules for which columns may be most appropriate for a given separation, based on solute structure, have been described in detail elsewhere. Nominally, CSPs fall into four primary categories (there are additional lesser used approaches) donor-acceptor (Pirkle) type, polymer-based carbohydrates, inclusion complexation type, and protein based. Examples of each CSP type, along with the proposed chiral recognition mechanism, analyte requirement(s), and mode of operation, are given in Table 3. Normal-phase operation indicates that solute elution is promoted by the addition of polar solvent, whereas in reversed-phase operation elution is promoted by a decrease in mobile-phase polarity. 

Chiral stationary phases (CSPs) developed on the basis of the strategy devised by Pirkle et al. (Pirkle 1980, 1984, 1988, 1992 Wolf 2002) depend on an explicit recognition of the three-dimensional fit between the CSP molecule and the enantiomers of the analyte. This strategy is based on Piride s Principle of Reciprocity (Figure 4.14), namely, that a single enantiomer of a racemate which separates well on one CSP will, when used to produce a second CSP, usually afford separation of the enantiomers of analytes that are structurally similar to the chiral selector of the first CSP. Figure 4.14 also shows two chiral selectors that do exhibit reciprocity, as well as a representation of how the specific interaction between the (S)-form of the first CSP can select for one enantiomer of the second. This is a typical example of the Pirkle-type chiral selectivity. 

Section 7.5 outlined how silica can be derivatized with almost any functional group the resulting monomer structures are known as brushes . The first broadly used and still very important CSP is the brush-type dinitrobenzoylphenylglycine (DNBPG), the first one shown in Table 22.1. According to its inventor, William H. Pirkle, it is often called Pirkle-phase , although a more correct name is Pirkle T because it is not the only one of his phases that is on the market. 

Other types of CSPs, known as brush type, have been constructed synthetically. A chiral structure, usually an amide, is linked to silica by a tether molecule. This approach has the potential for design of the chiral recognition elements. The ability to synthetically manipulate the structures also permits investigation of the role of specific structural elements in chiral selectivity. Several synthetic CSPs were developed by W. H. Pirkle and co-workers at the University of Illinois. An important example is the 3,5-dinitrobenzoyl (3,5-DNB) derivative of 7 -phenylglycine, which is attached to silica by aminopropyl tethers (CSP 2). The 3,5-DNB derivatives of several other amino acids (e.g., CSP 4) and diamines have also been explored. ... 

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