Study on solubility of ketoconazole in binary mixtures of water and cosolvents of N-methyl-2-pyrrolidone and 1-propanol at various temperatures

Abstract

Solubility is one of the important thermodynamic properties in drug discovery. Various methods such as cosolvency have been developed to increase the aqueous solubility of poorly soluble drugs that is the most common method in the pharmaceutical industry. A number of mathematical models have been developed which are good alternatives to the experimental determinations, for finding suitable cosolvent concentrations to increase the drug solubility. Objectives The objectives of the current study were to determine the solubility and density of saturated solutions of ketoconazole in the binary solvent mixtures of cosolvents (i.e. N-methyl-2-pyrrolidone (NMP) and 1-propanol) with water at five different temperatures (i.e. 293.2–313.2 K) and correlate the experimental density data with computational models. Methods and Materials The shake-flask method was used in this project in that the excess amount of drug was added to the vials of mixtures in the specific mass fractions. It was shaken 48 hours till the equilibrium point. Then they were centrifuged and aliquots were recorded at 291 nm after proper dilution. The concentration of saturated solutions was calculated using the calibration curve. Results According to the solubility data, the highest solubility value for the studied mixed solvents is obtained in pure l-propanol and NMP at 313.2 K, whereas the lowest solubility is observed in pure water at 293.2 K in both experiments. Moreover, it can be observed that the ketoconazole solubility enhanced by the increase of temperature in all solvent mixtures. Conclusion This study reports the measured solubility data for ketoconazole in the mixtures of 1-propanol and NMP with water at five different temperatures. Some cosolvency models are employed to mathematically representation of the solubility data. Apparent thermodynamic parameters for ketoconazole dissolving process are also studied and its details are discussed.