Solubility behavior and prediction for antihelmintics at several temperatures in aqueous and nonaqueous mixtures.

A model based on solubility parameters is proposed to predict the solubility curves of antihelmintic drugs at several temperatures, including aqueous and non-aqueous mixtures. The solubility of the drugs was measured in ethanol-water and ethanol-ethyl acetate mixtures at 15-35 degrees C (mebendazole) and at 25 degrees C (thiabendazole and metronidazole). The solid phases were analyzed by differential scanning calorimerty. The polymorphic form A of mebendazole was also characterized from infrared spectroscopy. Markedly different solubility profile shapes were obtained against the solubility parameter of the mixtures: two symmetrical peaks (metronidazole), two maxima of different height (mebendazole) and a single peak (thiabendazole). The solubility parameter of the drugs was related to the co-solvent action of both mixtures and to the solubility peaks. The single equation proposed was able to predict solubility profiles of different shape, including both mixtures and all temperatures, providing reasonable physical meaning for the regression coefficients. The model was successfully tested for its predictive capability using a limited number of experimental data. More than 100 solubilities were predicted at several temperatures using 20 data point for each drug.

Influence of temperature on the solubilization of thiabendazole by combined action of solid dispersions and co-solvents.

Co-solvents and solid dispersions with polyvinyl pyrrolidone were tested to increase solubility of thiabendazole. Solid dispersions were prepared by the solvent method and analyzed by differential scanning calorimetry. The solubility was measured at 15-35 degrees C in aqueous (ethanol-water) and non-aqueous (ethanol-ethyl acetate) mixtures. Combination of solid dispersions with cosolvents increased the water solubility of thiabendazole in a larger extent that each method separately. The effect of the solid dispersions is greatest in water and it decreases nonlinearly as the volume fraction of ethanol-in water increases. The solubility enhancement is smaller in ethanol-ethyl acetate and is uncorrelated with co-solvent concentration. Solubility parameters delta were used to predict drug/carrier compatibility and related to solubility profiles. Thiabendazole shows an intermediate behaviour between solubility curves with two peaks (more polar drugs with larger delta values) and a single peak (less polar drugs with lower delta values). The solid dispersions increase the solubility parameter of thiabendazole from delta=24 to delta=25.7 MPa(1/2). The model of Bustamante et al. allowed solubility prediction including jointly both mixtures whereas the equation of Jouyban et al. was able to predict the solubility at several temperatures in each binary mixture separately, using a few experiments.