Experimental and theoretical analysis of the interaction of (+/-)-cis-ketoconazole with beta-cyclodextrin in the presence of (+)-L-tartaric acid

H-1 NMR spectroscopy was used for determining the optical purity of cis-ket oconazole enantiomers obtained by fractional crystallization. The chiral an alysis was carried out using beta-cyclodextrin in the presence of (+)-L-tar taric acid. The mechanism of the chiral discrimination process, the stabili ty of the complexes formed, and their structure in aqueous solution were al so investigated by H-1 and C-13 chemical shift analysis, two-dimensional NO E experiments, relaxation time measurements, and mass spectrometry experime nts. Theoretical models of the three-component interaction were built up on the basis of the available NMR data, by performing a conformational analys is on the relevant fragments on ketoconazole and docking studies on the com ponents of the complex. The model derived from a folded conformation of ket oconazole turned out to be fully consistent with the molecular assembly fou nd in aqueous solution, as inferred from NOE experiments. An explanation of the different association constants for the complexes of the two enantiome rs is also provided on the basis of the interaction energies.