Physicochemical characterization and dissolution study of solid dispersions of ketoconazole with nicotinamide

The aim of the present study was to improve the solubility and dissolution rate of a poorly water-soluble drug ketoconazole using solid dispersion technique.

Solid dispersions of ketoconazole were prepared in ratios of 90 : 10, 70 : 30, 50 : 50, 30 : 70 and 10 : 90 by the melting method using nicotinamide as carrier. These solid dispersions were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (XRD) and Fourier transform infrared (FT-IR) spectroscopy to ascertain if there were any physicochemical interactions between drug and carrier that could affect dissolution. Solubility and dissolution studies were conducted with pure ketoconazole, physical mixtures and solid dispersions.

Solubility studies indicated that nicotinamide increased significantly the solubility of ketoconazole in water. The Gibbs free energy (ΔG°(tr)) values were negative indicating the spontaneous nature of ketoconazole solubilization, and it decreased with increase in concentration of the carrier, demonstrating that the reaction became more favorable as the concentration of the carrier increased. The cumulative release of ketoconazole within 120 min from solid dispersion at a drug-to-nicotinamide ratio of 10 : 90 (w/w) was 6 times higher than the pure drug in phosphate buffer of pH 6.8.

Solid state characterization indicated that there is no interaction between ketoconazole and nicotinamide in the solid state. In contrast to the very slow dissolution rate of pure ketoconazole, the dispersion of the drug in nicotinamide considerably enhanced the dissolution rate. The drug dissolution rate was highest at a drug-to-nicotinamide ratio of 10 : 90 (w/w).