Racemates versus enantiomerically pure drugs: putting high-performance liquid chromatography to work in the selection...

In view of the current negative attitude towards pharmaceutical preparations containing two or more drug substances, it is not surprising that the stereoisomeric composition of drugs has become a key issue in their development, regulatory approval and marketing. As the requirements placed on the purity of drugs become more and more stringent, the question arises of whether a racemic mixture should be automatically considered as being 50% impure. The answer is complex and requires careful comparative evaluations of the activities, toxicities and pharmacokinetics of the two enantiomers. In addition to the risk-benefit factors, the cost-benefit factors should also be carefully weighed in order to reach a decision which will guarantee drug safety. Excessive development costs and an unnecessary regulatory burden resulting from systematic demands for enantiomerically homogeneous drugs can be avoided with very potent drugs administered at low dosages and low-potency drugs for which the "inactive" isomer is not considerably more toxic than the active isomer. Regardless of the final decision taken, during the preclinical and clinical drug development it is important to have analytical methods suitable for conducting pertinent studies. This paper discusses the importance of stereochemistry in drug development and the role of high-performance liquid chromatography as a pre-eminent tool for analytical and preparative enantioselective separations.