Solubility enhancement, solvent effect and thermodynamic analysis of pazopanib in co-solvent mixtures

Highlights: • Research on equilibrium of pazopanib in two solvent mixtures. • Discuss the solvent effect on solubility in mixtures by KAT-LSER method. • Correlate the experimental solubility values with different thermodynamic models. • Evaluate the apparent dissolution properties in dissolution process. • Obtain the suitable cosolvent concentrations to maximize the pazopanib solubility. As is known to all, co-solvency or solvent mixing is the most common and easy-to-use method in the pharmaceutical industry for the improvement of solubility of poorly soluble drugs. The aim of this investigation was to determine the solubility data of pazopanib in (ethyl acetate + ethanol) and (ethyl acetate + 2-propanol) binary mixture solvents at various temperatures ranging from 288.15 K to 328.15 K, and correlated by Jouyban-acree model and Apelblat-Jouyban-Acree model. The results showed that solubility of pazopanib increased with the increasing temperature, and the co-solvency phenomenon was occurred in the dissolution process of pazopanib in two mixed solvents. The maximum solubility value appeared at w = 0.60 (the mass fraction of ethyl acetate in mixed solvents systems). At 288.15 K, solubility was increased by 4.37 and 3.94 times. The correlation results show that the maximum values of RAD and RMSD are no more than 5.13% and 3.37 × 10⁻⁶, respectively. The thermodynamic models can all correlate the solubility behaviour of pazopanib in pure and mixed solvents mixtures well. In addition, from the solvent effect results, nonspecific dipolarity/polarizability interactions are favorable to dissolution, and the nonspecific dipolarity/polarizability interactions had a great contribution to dissolution. Moreover, apparent thermodynamic quantities of pazopanib dissolution process in the ethyl acetate + ethanol/2-propanol mixtures, including entropy, enthalpy and Gibbs energy were computed using van't Hoff and Gibbs equations. The results of apparent dissolution properties are all positive which indicate the dissolution of pazopanib in two mixed solvents is an endothermic and entropy-increasing process and the enthalpy is the main contributor to standard Gibbs energy of solution process in all compositions. The discovery of co-solvency phenomenon is important to optimize the purification and improve bioavailability of pazopanib, and the solvent mixing is a common, easy-to-use and effective method to improve the solubility of pazopanib.