Solubility determination, model correlation, solvent effect, molecular simulation and thermodynamic properties of flutamide in eleven pure solvents at different temperatures

Abstract

The equilibrium solubility and thermodynamic properties of flutamide in eleven organic mono-solvents were reported. Solubility determinations were performed through the laser monitoring method at T = (278.15–323.15) K and p = 101.3 kPa (except DMSO at 293.15–323.15 K and dichloromethane at 278.15–308.15 K). It is found that the mole fraction solubility of flutamide increases apparently with the augmented experimental temperature. The solubility of flutamide in mono-solvents exhibits the following order from minimal to maximum: ethanediol < dichloromethane < methanol < ethanol < methyl acetate < ethyl acetate < 2-methoxyethanol < 2-ethoxyethanol < acetone < DMF < DMSO. The highest value in flutamide solubility profile is related to DMSO at 323.15 K (x1 = 5.120*10−3) and the lowest one is obtained for ethanediol (8.900*10−6, T = 278.15 K). The results of using the KAT-LSER model to study the solvent effect of flutamide solubility show that the solute-solvent interactions are principally attributed to the hydrogen bonding basicity and solvent's self-cohesiveness. Then, the analysis of solute-solvent interactions using MD simulation shows that the interactions between solute and solvent molecules have an important influence on the solubility of flutamide in selected solvents. In addition, all recorded solubility of flutamide was regressed by λh model, modified Apleblat model, Two-Suffix Margules model, NRTL model and UNIQUAC model. The deviation analysis proves that the λh model obtains the best agreement between the measured data and calculated values, with the minimum mean values of 100ARD (0.275) and RMSD (3.703*10−4). Moreover, apparent thermodynamic properties of flutamide in all mono-solvents studied were also calculated and investigated according to Van't Hoff equation, and it turns out that the dissolution process is an endothermic, non-spontaneous process driven by entropy.