Characterization and in vitro dissolution behaviour of ketoconazole/β- and 2-hydroxypropyl-β-cyclodextrin inclusion compounds

Abstract

The effect of β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin on the solubility of ketoconazole in different media were studied. A type A L solubility diagram was obtained for ketoconazole and the two cyclodextrins in buffer solution, pH 5 and pH 6. The stability constants between ketoconazole and the two cyclodextrins were calculated from the phase solubility diagrams. Increased ionization of the imidazole derivative decreased the values of the stability constants. The formation of solid inclusion complexes were experimentally prepared by the kneading and spray-drying techniques. In order to confirm solid complex formation, X-ray diffractometry and differential scanning calorimetry were used. It was found that the spray-drying technique could be used to prepare the amorphous state of drug inclusion complexes. The dissolution rates of ketoconazole from the inclusion complex made by spray-drying were faster than the pure drug, kneading systems and the physical mixtures of drug and cyclodextrins. The enhanced dissolution rate of spray-dried products might be attributed to the decreased particle size, the high-energetic amorphous state and inclusion complex formation.