Pirkle-type CSPs

Chiral resolution on Pirkle-type CSPs varies from one CSP to another and, therefore, it can be optimized by selecting a suitable chiral selector. Chiral resolutions on /r-acidic and -basic CSPs have been carried out under the normal phase mode. However, some reports are also available dealing with the use of reversed phase eluents, but the prolonged use of a reversed phase mobile phase is not recommended. With the development of more stable new CSPs, the use of the reversed mobile phase mode became possible. Nowadays, both mobile phase modes - that is, normal and reversed - are 

Partial resolution Optimize resolution by adjusting concentrations of  

In the chiral analysis of many drugs, pharmaceuticals and agrochemicals by HPLC, detection is mostly achieved using the UV mode [1-7], and hence this detection mode has also been used for the chiral resolution of some environmental pollutants [8], However, some organochlorine pollutants are transparent to UV radiation hence, the UV detection mode is not suitable and some other detection devices have to be used in chiral HPLC, the most of which are MS, optical detectors and so on. 

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With regard to the resolution of enantiomers, some applications can be found with modified silica gel supports. Thus, a Pirkle-type CSP was used for the separation of 200 mg of a racemic benzodiazepinone [75]. Also tris-(3,5-dimethylphenyl)carba-mate of cellulose coated on silica [91, 92] was applied successfully to the resolution of the enantiomers of 2-phenoxypropionic acid and to oxprenolol, alprenolol, propranolol among other basic drugs. However, the low efficiency of this technique and the relative high price of the CSPs limits its use to the resolution of milligram range of sample. 

Examples with other Pirkle-type CSPs have also been described [139, 140]. In relation to polysaccharides coated onto silica gel, they have shown long-term stability in this operation mode [141, 142], and thus are also potentially good chiral selectors for preparative SFC [21]. In that context, the separation of racemic gliben-clamide analogues (7, Fig. 1-3) on cellulose- and amylose-derived CSPs was described [143]. 

Utilization of intelligent systems in chiral chromatography starts with an original project called CHIRULE developed by Stauffer and Dessy [36], who combined similarity searching and an expert system application for CSP prediction. This issue has recently been reconsidered by Bryant and co-workers with the first development of an expert system for the choice of Pirkle-type CSPs [37]. 

The brush-type (Pirkle-type) CSPs have been used predominantly under normal phase conditions in LC. The chiral selector typically incorporates tt-acidic and/or n-basic functionality, and the chiral interactions between the analyte and the CSP include dipole-dipole interactions, n-n interactions, hydrogen bonding, and steric hindrance. The concept of reciprocity has been used to facilitate the rational design of chiral selectors having the desired selectivity [45]. 

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. 

Pirkle-type CSPs do not involve ionic interactions and therefore are almost exclusively operated in the normal-phase mode. The use of subcritical carbon dioxide based mobile phase, i.e., subcritical fluid... 

More recent developments in the field of the Pirkle-type CSPs are the mixed r-donor/ r-acceptor phases such as the Whelk-Of and the Whelk-02 phases.The Whelk-Of is useful for the separation of underiva-tized enantiomers from a number of families, including amides, epoxides, esters, ureas, carbamates, ethers, aziridines, phosphonates, aldehydes, ketones, carboxylic acids, alcohols and non-steroidal anti-inflammatory drugs.It has been used for the separation of warfarin, aryl-amides,aryl-epoxides and aryl-sulphoxides. The phase has broader applicability than the original Pirkle phases. The broad versatility observed on this phase compares with the polysaccharide-derived CSPs... 

TABLE I Overview of Some Pirkle-type CSPs and Their Chiral Selectors... 

New brush-type phases (donor-acceptor interactions) are appearing all the time. " Examples are stationary phases comprising quinine derivatives and trichloro-dicyanophenyl-L-a-amino acids as chiral selectors. Quinine carbamates, which are suitable for the separation of acidic molecules through an ionic interaction with the basic quinine group, are also commonly used but in general they are classified with the anion-exchange type of chiral selectors (see further) because of their interaction mechanism, even though r-donor, r-acceptor properties occur. (Some separations on Pirkle-type CSPs are shown in Table 2.)... 

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

TABLE 1 Various Commercial Pirkle-Type CSPs... 

Because of the development of the new types of CSP (rc-acidic-basic types), the use of re-acidic and re-basic types of CSP are not common. In view of this, attempts are made to describe the art of the optimization of the chiral resolution using only re-acidic-basic-type CSPs. The optimization of the chiral resolution on Pirkle-type CSPs are presented in Scheme 1. 

SCHEME 1 Protocol for the development and optimization of mobile phases on Pirkle-type CSPs under the normal phase mode. AcOH, acetic acid TEA, triethylamine. 

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.)... 

Pirkle type CSPs contain a chiral moiety having phenyl ring and, therefore, the formation of a it-it charge-transfer diastereoisomeric complex of the enantiomers (with the phenyl group) with CSP is supposed to be essential. In view of this, the re-acidic CSPs are suitable for the chiral resolution of re-donor solutes and vice versa. However, the newly developed CSPs containing both re-acidic and re-basic groups are suitable for the chiral resolution of both types of solute (i.e., re-donor and re-acceptor analytes). 

TABLE 5 Enantiomeric Resolution of Racemic Compounds on Pirkle-Type CSPs Using Sub-FC and SFC... 

In spite of the high speed and efficiency of capillary electrochromatography, the Pirkle-type CSPs could not be used frequently for chiral resolution purposes. Only a few reports are available on this issue. Cavender et al. [167] and Wolf et al. 

Pirkle-type CSPs have achieved a good status in the field of the chiral resolution by liquid chromatography. In these phases, the chiral moiety on the silica support... 

Brush or Pirkle-type CSPs show promise in the enantioseparation of many classes of compounds, and also have shown to exhibit the high efficiencies expected in CEC separations. The high efficiency of enantioseparations of these CSPs is thought to be due to more favorable mass transfer kinetics between the analytes and these CSPs. Cavender et al. [144] used these CSPs bonded to silica particles to separate 10 chirally active compounds. They used (S)-Naproxen-derived CSP as well as the more widely used (3R, 4S)-Whelk-0. They found that while the (S)-Naproxen-derived CSP gave rise to more reproducible EOF, (3R,4S)-Whelk-0 gave more efficient separations. The reproducibility of the... 

A CSP consists of a chiral selector, which either alone constitutes the stationary phase or which has been immobilised to a solid phase. The chiral selector is a low molecular weight compound or a polymer, either synthetic or natural. A broad range of CSPs has been developed. Examples of CSPs that have been used successfully include polysaccharides, such as cellulose and its derivatives [6] and cyclodex-trins [7], and proteins, e.g. bovine serum albumin, aj-acid glycoprotein, cellulase, trypsin and a-chymotrypsin [8]. Several different synthetic polymers have also proven to be useful CSPs, for example the Blaschke-type CSPs (polyacrylamides and polymethacrylamides) [9] and the Pirkle-type CSPs [10]. 

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