Chiral chromatographic resolution of antiepileptic drugs and their metabolites: a challenge from the optimization to the application

A large number of the antiepileptic drugs (AEDs) presently available for clinical practice are chiral compounds while others, although achiral, may originate pharmacologically active chiral metabolites in vivo. The well-known implications of chirality in pharmacokinetics and pharmacodynamics demand the investigation of pharmacological properties for a racemic mixture and each enantiomer. To achieve these objectives, appropriate chiral analytical methods must be available. This article provides the first review of the current state of the art in chiral chromatographic methods available for quantifying enantiomers of AEDs in distinct matrices. Particular attention is paid to the methodological aspects and optimization strategies that successfully allow enantiomeric chromatographic separation of chiral AEDs and/or metabolites. Furthermore, the relevance of these methods in supporting the discovery and development of chiral AEDs is emphasized. In parallel and whenever available, the principal validation parameters are herein considered and related to the stage of drug discovery and development. In an attempt to optimize anticonvulsant activity and simultaneously diminish toxic effects, many pharmaceutical companies have started to manufacture single enantiomers. Therefore, chiral chromatographic techniques will be essential and the information herein compiled can be used as a framework for developing them.