Pitfalls in the Enantioselective Analysis of Chiral Drugs

Abstract

There is currently considerable interest in the stereochemical aspects of biochemical pharmacology, largely originating from analytical developments permitting the determination of the enantiomeric composition of chiral drugs in biological media. These new methods allow new types of experiments to be carried out, but there is a need for them to be used critically: a number of pitfalls await those who use them inappropriately. These particularly present themselves in metabolic studies where authentic standards are not available for method validation. Both of the major methods for determining enantiomeric composition can give rise to errors. The formation of diastereoisomers may exhibit stereoselectivity, while the use of chiral columns is fraught with difficulties. In both cases, calibration lines for the two enantiomers are frequently different. Additionally, enantiodifferentiation may occur during sample work-up, as a consequence of achiral processes such as solvent extraction. The importance of proper method validation, with each of a pair of enantiomers, cannot be stressed too highly. If standards of appropriate enantiomeric purity are not available, individual methods cannot be acceptably validated, and data can be accepted only when the same result is obtained with two methods relying on different principles, e.g. a chiral column plus a diastereomeric derivatization, or a Chromatographic method plus NMR.⊗

This Forum Abstract has been married up with a provisional text MS., without a proof-correcting stage.-Editor.