Enhancement of the Dissolution Rate of Ketoconazole Through a Novel Complexation with Fulvic Acid Extracted from Shilajit

Abstract

The objective of the current research work was to investigate the potential of fulvic acid, extracted from shilajit, as a bioavailability enhancer. Ketoconazole was selected as a model drug because of its insolubility in water except at low pH, leading to poor bioavailability. Complexes of fulvic acid with ketoconazole were prepared in a molar ratio of 1:0.5 and 1:1 by solvent evaporation, spray drying and physical mixing methods. The prepared complexes were characterized by differential scanning calorimetry (DSC) and X-ray diffractometry (XRD). Phase solubility and intrinsic dissolution rate study of ketoconazole with fulvic acid were carried out in phosphate buffer of pH 5 and 6 to study the interaction between ketoconazole with fulvic acid. Phase solubility study indicates that solubility of ketoconazole was significantly increased at fulvic acid concentration greater than 0.3 % w/v due to micellization of fulvic acid. DSC and XRD studies showed differences between ketoconazole and ketoconazolefulvic acid complexes prepared by various methods. Solvent evaporated and spray dried complexes showed significant improvement in dissolution rate as compared to ketoconazole or ketoconazole-fulvic acid physical mixture. Further, spraydried complexes showed better dissolution rate than solvent evaporated complexes. The results indicate that the fulvic acid extracted from shilajit could be used to increase the dissolution rate and hence the bioavailability of poorly water-soluble drugs.