Studies on Fluconazole and Ketoconazole complexes prepared with Beta-cyclodextrin

Fluconazole (FZ) and ketoconazole (KZ) are azole derivative antifungal pharmaceutical active agents which are widely used for the therapy of micotic infections. Both of the active agents have low aqueous solubility. Preparation of cyclodextrin complexes is one of the technologies used to enhance saturated solubility. For this purpose, following phase solubility diagram studies Beta-cyclodextrin (B-CD) complexes of FZ and KZ were prepared using different preparation methods (freeze drying, spray-drying, co-evaporation and kneading).Characterization of complexes prepared with molar ratio of 1:1 was performed by yield %, thermal, aqueous solubility, particle shape, X-ray diffraction, infrared, nuclear magnetic resonance, active agent amount and antifungal activity studies against Candida albicans. In vitro dissolution from hard cellulose capsules containing FZ/B-CD complexes was compared to pure FZ and its commercial capsules while in vitro dissolution from vaginal suppositories containing KZ/B-CD complexes were compared to the pure KZ and its commercial vaginal suppositories. During comparison f1 (difference) and f2 (similarity) factors were evaluated. Paddle method defined in USP 31 together with high pressure liquid chromatographic method were used in in vitro dissolution experiments.By means of B-CD complex preparation, varying enhancements in solubilities and antifungal activities of active agents were determined depending on preparation methods. High release of active agents from B-CD complexes compared to pure active agents was attributed to the interactions between B-CD and active agents, high energetic amorphous state and decrease in the interfacial tension between insoluble active agents and dissolution media.As a conclusion, the overall of FZ/B-CD and KZ/B-CD complexes designed to be developed showed that bioavailability problems could be overcome by increasing the aqueous solubility and dissolution and also clinical doses of active agents could be decreased by increase in the antifungal activity on Candida albicans.