Chiral pharmaceutical analysis

Pettersson, C. and Persson, B., HPLC Applications for Chiral Pharmaceutical Analysis, In Handbook of HPLC, Katz, E., Eksteen, R., Schoenmakers P. and Miller, N., Eds., Dekker, New York, pp. 669-693, 1998. 

CMPAs have rarely been used for chiral analysis in biological matrixes, and have, to the authors knowledge, not been applied during the last decade. One of the reasons is probably the incompatibility between involatile CMPAs and MS detection. For recent reviews on chiral pharmaceutical analysis by LC/MS, see Refs. [114,116,119,120]. 

Although industrial laboratories shied away from the technique at first, CE is now becoming more common in these labs for a variety of analyses, including ion analysis, chiral pharmaceutical analysis, and peptide mapping [1]. With the increased prevalence of CE in industrial analytical laboratories comes the need for instrument qualification to ensure the proper functioning and performance of the instrument in order to obtain consistent, reliable, and accurate data. 

Method development remains the most challenging aspect of chiral chromatographic analysis, and the need for rapid method development is particularly acute in the pharmaceutical industry. To complicate matters, even structurally similar compounds may not be resolved under the same chromatographic conditions, or even on the same CSP. Rapid column equilibration in SFC speeds the column screening process, and automated systems accommodating multiple CSPs and modifiers now permit unattended method optimization in SFC [36]. Because more compounds are likely to be resolved with a single set of parameters in SFC than in LC, the analyst stands a greater chance of success on the first try in SFC [37]. The increased resolution obtained in SFC may also reduce the number of columns that must be evaluated to achieve the desired separation. 

Andersson, M.E. et al., Evaluation of generic chiral liquid chromatography screens for pharmaceutical analysis, J. Chromatogr. A, 1005, 83, 2003. 

D Acquarica, L, New synthetic strategies for the preparation of novel chiral stationary phases for HPLC containing natural pool selectors, presented at 8 Int. Meeting on Recent Developments in Pharmaceutical Analysis, Roma, June 29-July 3, 1999, 37. 

Chiral separation of drng molecules and of their precursors, in the case of synthesis of enantiomerically pure drugs, is one of the important application areas of HPLC in pharmaceutical analysis. Besides HPLC, capillary electrophoresis (CE) is another technique of choice for chiral separations. Chapter 18 provides an overview of the different modes (e.g., direct and indirect ones) of obtaining a chiral separation in HPLC and CE. The direct approaches, i.e., those where the compound of interest is not derivatized prior to separation, are discussed in more detail since they are cnrrently the most frequently used techniques. These approaches require the use of the so-called chiral selectors to enable enantioselective recognition and enantiomeric separation. Many different molecnles have been nsed as chiral selectors, both in HPLC and CE. They can be classified into three different groups, based on their... 

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. 

These polysaccharide-based stationary phases appear to be the most useful in organic, bio-organic and pharmaceutical analysis. Of the above-mentioned derivatives three of them, namely cellulose tris-(3,5-dimethylphenylcarbamate), amylose tris-(3,5-dimethylphenylcarbamate) and cellulose tris-(4-methylbenzoate), have very complementary properties and numerous publications have demonstrated that they have been able to achieve the chiral resolution of more than 80% of the drugs currently available on the market. " These CSPs are known under the commercial names, Chiralcel OD-H , Chiralpak AD and Chiralcel OJ , respectively (Figure 4). Their very broad enantiorecognition range is also the... 

Levin, S., Abu-Lafi, S., The Role of Enantioselective Liquid Chromatography Separations Using Chiral Stationary Phases in Pharmaceutical Analysis, In Advances in Chromatography, Grushka, E. and Brown, P. R., Eds., Vol. 33, Marcel Dekker, New York, pp. 233-266, 1993. 

CE has been applied extensively for the separation of chiral compounds in chemical and pharmaceutical analysis.First chiral separations were reported by Gozel et al. who separated the enantiomers of some dansylated amino acids by using diastereomeric complex formation with Cu " -aspartame. Later, Tran et al. demonstrated that such a separation was also possible by derivatization of amino acids with L-Marfey s reagent. Nishi et al. were able to separate some chiral pharmaceutical compounds by using bile salts as chiral selectors and as micellar surfactants. However, it was not until Fanali first showed the utilization of cyclodextrins as chiral selectors that a boom in the number of applications was noted. Cyclodextrins are added to the buffer electrolyte and a chiral recognition may... 

In Table 1, the typical validation parameters required for the different types of analytical procedures are listed. For all these analytical procedures CE might be an appropriate analytical technique. In fact numerous validated CE methods for pharmaceutical analysis have been described in literature during the last decade.In Table 2, an overview is listed of the ICH validation parameters included in several reported CE validation studies. Since chiral purity determination is an important application area of CE methods, this test is listed separately as a specific analytical procedure. In addition, the determination of drug counterions has been included as a separate application. This overview illustrates that in general the required validation parameters are addressed in reported CE validation studies. It should be noted, however, that the validation parameters included in Table 2 are not necessarily evaluated exactly according ICH requirements in the reported references. Many pharmaceutical companies apply a phase-related validation approach in which the depth of validation depends on the clinical phase of development of the product involved. 

CE is an important separation technique within the field of pharmaceutical analysis. CE may be an attractive choice as analytical procedure for identification, assay, or (chiral) purity determination. In addition, CE may provide distinct advantages over existing pharmacopoeial... 

Williams, R. C., Edwards, J. R, and Ainsworth, C. R. (1994). Analysis of diastereoisomer impurities in chiral pharmaceutical compounds by capillary electrophoresis. Chromatographia 38, 441-446. 

The first section of the book explores emerging novel aspects of HPLC and related separation methods based on the differential velocity of analytes in a liquid medium under the action of either an electric field (capillary electromigration techniques) or a gravitational field (field-flow fractionation). The section focusing on applications highlights four significant areas in which HPLC is successfully employed chiral pharmaceutical, environmental analysis, food analysis, and forensic science. 

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