Complexation of Voriconazole Stereoisomers with Neutral and Anionic Derivatised Cyclodextrins

A number of native, neutral derivatised and anionicderivatised cyclodextrins (CDs) were examined aschiral electrolyte additives in capillaryelectrophoresis (CE) to separate the fourstereoisomers of the new antifungal agent,voriconazole. A very large difference in interactionbetween each diastereoisomer and the CDs was observedin the CE study, where enantioselectivity was easilyobtained for one and extremely difficult to obtain forthe other. Nuclear magnetic resonance spectroscopy(H-NMR) indicated a strong interaction betweenthe easily separated diastereoisomer and each of theCDs with enantiomeric shift nonequivalence values ofover 100 Hz obtained when using the anionicsulphobutylether-{/content/k20j5k78ut034k75/xxlarge946.gif} - CD chiral solvating agent. Inaccordance with observations from the CE study, theopposite diastereoisomer indicated no shiftnonequivalence at all. The nature of the complexationbetween the easily separated diastereoisomer and theanionic sulphobutylether{/content/k20j5k78ut034k75/xxlarge946.gif}-CD was also probedusing a two-dimensional nuclear Overhauser enhancementexperiment and a series of spin lattice relaxationtime measurements. It was found that theenantioselective interaction occurred through thepartial inclusion of a difluorophenyl group into theCD toroid which was also aided through a number ofadditional interactions between the drug molecule andthe sulphobutylether derivatives outside the CDtoroid.