High performance liquid chromatography for direct and indirect enantiomeric separations of chiral drugs

This thesis deals with some analytical and pharmaceutical problems associated with chiral drugs. Although there can be marked differences between enantiomers in their pharmacological profile, many chiral drugs are still marketed as racemic mixtures. As has been indicated in the previous chapters, there is a variety of reasons that make it essential to have analytical methods available that can discriminate between the individual enantiomers. Therefore analytical methods, based on liquid chromatography, were studied towards their applicability to the separation of enantiomers. Both direct and indirect chromatographic separation methods were studied. In the indirect separation method the emphasis was on the development of chiral derivatization reagents for tertiary amines. Because of the low reactivity of tertiary amines very few chiral derivatization reagents are known for drugs with this functional group. (-) Menthylchloroformate was used as a chiral derivatization agent for tertiary dimethylamines. (+)-1-(9-F1uorenyl)ethylchloroformate was used for the derivatization of a secondary amine. The enantiomeric separation of chiral aminotetralins was studied using direct chromatographic methods. Direct enantiomeric separations are often based on trial and error experiments. Optimization of the working conditions for chiral columns, e.g. mobile phase, flow velocity, eluent composition and column temperature is seldomly seen in the literature. Therefore, we applied chemometrics to study the influence of these parameters on the separation of the aminotetralins on a commercially available chiral Chiralcel OD column. This resulted not only in optimal working conditions and much better separations, but also in a better understanding of the chiral recognition mechanism of the column