Complexes of fluconazole with sodium p-sulfonatocalix[n]arenes: characterization, solubility and antifungal activity

Aiming at providing new formulations capable of improving the biopharmaceutical properties of fluconazole, we studied the formation of host-guest complexes of this antifungal agent with water-soluble sodium p-sulfonatocalix[4]arene and sodium p-sulfonatocalix[6]arene. The formation of inclusion complexes was first investigated using H-1 NMR spectroscopy and TGA experiments. The complexes' stoichiometry, apparent binding constants (K-a) and the complexed populations (%p(bound)), were determined, using H-1 NMR data. The topology of the complexes were assessed by 1D ROESY experiments, and the data were corroborated by semi-empirical and DFT calculations. The activity of the fluconazole-calix[n]arene complexes against clinically relevant fungal species was investigated. Finally, the effect of complexation on the solubility of fluconazole was investigated using the phase-solubility method of Higuchi and Connors.