Inclusion complexes of ketoconazole with beta-cyclodextrin: physicochemical characterization and in vitro dissolution behaviour of its vaginal suppositories

DEMİREL M., Yurtdas G., GENÇ L.

JOURNAL OF INCLUSION PHENOMENA AND MACROCYCLIC CHEMISTRY, vol.70, pp.437-445, 2011 (SCI-Expanded) identifier identifier


Ketoconazole (KZ) is an imidazole antifungal agent which is administered topically and also orally. KZ is practically insoluble in water. Vaginal candidiasis is a common condition and up to 75% of all women have at least one episode of this infection during their lifetime. The aim of study was to prepare KZ/beta-cyclodextrin (beta-CD) complex to improve the physicochemical properties of KZ and to investigate the possibility of preparing vaginal suppositories with the complexes. A linear increase in KZ solubility as a function of beta-CD concentration was verified using the phase-solubility diagram. The resulting diagram was classified as AL-type, is generally related to the formation of a soluble complex. Complexes were prepared in a 1: 1 molar ratio by different methods, namely freeze-drying, spray-drying, co-evaporation and kneading. Characterization of the complexes prepared was performed by practical yield %, aqueous solubility, active agent amount analyses, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), powder X-ray diffractometry (PXRD) and H-1 and C-13 nuclear magnetic resonance (NMR) spectroscopy. Characterization studies provided additional evidences of complexation. The paddle method defined in USP31 was used in in vitro dissolution experiments on the prepared vaginal suppositories. It was found that solubility enhancement by preparing KZ/beta-CD complexes depends on the type of the preparation method. Dissolution of KZ from complexes was found to be faster than the active agent and the commercial suppositories. This result may be attributed to the interactions between beta-CD and active agent, high energetic amorphous state and decrease in the interfacial tension between insoluble active agent and dissolution media.