Determination of valsartan solubility in supercritical carbon dioxide: Experimental measurement and molecular dynamics simulation

Abstract In this study, the solubility of valsartan in supercritical carbon dioxide (SC-CO2) was determined using a static method. The experimental data were measured under a limited range of pressures from 12 to 24MPa and at three different temperatures of 308.15, 318.15 and 328.15K. Furthermore, the effect of pressure and temperature on solute solubility was studied and discussed. Subsequently, the OPLS all-atom force field was applied to predict the free energy of solvation and solubility of valsartan in SC-CO2. To this purpose, the unknown parameters of the OPLS all-atom force field for valsartan were determined using quantum mechanics method and Nelder-Mead optimization algorithm. EPM2 model was used for CO2 molecules. In order to study the molecular interactions between the solute and the solvent, the contribution of electrostatic and Lennard-Jones interactions to the free energy of solvation was determined as a function of pressure at different temperatures. The results showed that, with increasing the pressure, the contribution of electrostatic interactions to the free energy of solvation decreased constantly close to linear shape. Moreover, with increasing the pressure, the contribution of Lennard-Jones interactions to the free energy of solvation decreased until reaching a minimum point; with a further increase in pressure, CO2 density increased and the contribution of repulsive part of Lennard-Jones potential becomes important, therefore, the continuation of the solvation process had become difficult. On the contrary, due to increase in the chemical potential of the solute, the solubility further increases. The calculated free energy of solvation was used for determining the solubility of valsartan over the studied range. The results of simulation were in a good agreement with the experimental data and the solubility behavior was well predicted at different temperatures and pressures. In this study, the value of 15.33% was obtained for Absolute Average Relative Deviation (AARD) between the experimental data and the simulation results.