Complexation of voriconazole stereoisomers with neutral and anionic derivatised cyclodextrins

A number of native, neutral derivatised and anionic derivatised cyclodextrins (CDs) were examined as chiral electrolyte additives in capillary electrophoresis (CE) to separate the four stereoisomers of the new antifungal agent, voriconazole. A very large difference in interaction between each diastereoisomer and the CDs was observed in the CE study, where enantioselectivity was easily obtained for one and extremely difficult to obtain for the other. Nuclear magnetic resonance spectroscopy (H-1-NMR) indicated a strong interaction between the easily separated diastereoisomer and each of the CDs with enantiomeric shift nonequivalence values of over 100 Hz obtained when using the anionic sulphobutylether-beta-CD chiral solvating agent. In accordance with observations from the CE study, the opposite diastereoisomer indicated no shift nonequivalence at all. The nature of the complexation between the easily separated diastereoisomer and the anionic sulphobutylether beta-CD was also probed using a two-dimensional nuclear Overhauser enhancement experiment and a series of spin lattice relaxation time measurements. It was found that the enantioselective interaction occurred through the partial inclusion of a difluorophenyl group into the CD toroid which was also aided through a number of additional interactions between the drug molecule and the sulphobutylether derivatives outside the CD toroid.