1H-NMR and molecular modelling techniques for the investigation of the inclusion complex of econazole with alpha-cyclodextrin in the presence of malic acid.

Carrying on a study where the combination of alpha-cyclodextrin and malic acid was found to be the most effective in improving the solubility of econazole, an antifungal drug very poorly water soluble, in the present work 1H-NMR and nuclear overhauser effect (NOE) experiments and molecular modelling studies were performed to gain insight into the interactions in solution between such three components and the structure of the supposed multicomponent complex. Findings demonstrated that two different complexes can be simultaneously present in solution involving, respectively, the inclusion of econazole monochloro-phenyl group within the host cavity from the primary hydroxyl side of the cyclodextrin cavity, or that of the other phenyl group through the opposite side of the cavity. It was shown that also malic acid is strictly involved in the molecular assembly of the complex, particularly through interactions with primary hydroxyl groups of the cyclodextrin molecule. Molecular modelling studies allowed to elaborate possible geometric models of the multicomponent complex and to select the more energetically favourable conformations which complied better with experimental data. Results suggested the possible formation in solution of stable oligomeric aggregates constituted by the repeated concatenation of the three components.