Improvement in the physicochemical properties of ketoconazole through complexation with cyclodextrin derivatives

Highly-soluble cyclodextrin derivatives, such as hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and methyl-beta-cyclodextrin (MEB), were tested as solubilizing agents for ketoconazole, with the aim of improving the physicochemical and biopharmaceutical properties of this lipophilic imidazole antifungal agent. Products were prepared in four molecular ratios by physical mixing, kneading and spray-drying methods. The kneaded products in a ratio of 1:2 and the spray-dried products exhibited the highest dissolution rates. The phase solubility diagrams of ketoconazole with these cyclodextrins at 25degreesC in water and in simulated intestinal medium were constructed. A solubility diagram of A(L) type was obtained with HP-beta-CD, and one of A(P) type with MEB. The complexes were characterized by thermal methods (DSC, TG, DTG and DTA). Multicomponent systems were prepared with tartaric acid. The effects of water-soluble polymers, e. g., polyvinylpyrrolidone, on the aqueous solubility of ketoconazole were investigated. Particle size distribution, surface area, partition coefficient, heat of dissolution and wettability studies were also carried out. The formation of inclusion complexes was observed by means of thermoanalytical studies.