Solubility determination, model correlation, thermodynamic analysis, molecular dynamic simulation of Favipiravir in twelve pure solvents

Abstract

The solubility of Favipiravir in twelve pure solvents, including methanol (MeOH), ethanol (EtOH), n-propanol (NPOH), isopropanol (IPOH), n-butanol (NBOH), acetone (DMK), acetonitrile (MeCN), dichloromethane (DCM), N, N-Dimethylformamide (DMF), methyl acetate (MtAC), ethyl acetate (EtAC), butyl acetate (NBAC) was measured by gravimetric method at a temperature range of 293.15 to 333.15 K at 0.1 MPa. The maximum and minimum of Favipiravir solubility were obtained in DMF at 333.15 K (0.02599 mol·mol−1) and MeOH at 293.15 K (0.00147 mol·mol−1), respectively. At 298.15 K, the order of solubility in different solvents is: DMF > NBAC > DMK > MtAC > EtAC > NBOH > DCM > EtOH > NPOH > IPOH > MeCN > MeOH. The Hansen solubility parameter (HSP) was used to analyze the miscibility of Favipiravir in selected solvents. In addition, the solvent effect was studied by analyzing solvent properties, which indicate that the solubility of Favipiravir in selected solvents is influenced by the synergistic effect of multiple factors. The Modified Apelblat model, λh model, NRTL model, and Wilson model were employed to correlate the solubility data, indicating the Apelblat model provides the highest regression accuracy corresponding to the lowest average value of average relative deviation (ARD, 0.017459) and root mean square deviation (RMSD, 0.00012). In order to explain the dissolution behavior of Favipiravir in different solvents, the intermolecular interactions were analyzed by using Hirshfeld surface (HS), Molecular electrostatic potential surface (MEPS), and solvation free energy. The thermodynamic parameters derived from van’t Hoff equation including ΔdisG0 (10.71–16.57 kJ·mol−1), ΔdisH0 (6.33–18.67 kJ·mol−1), and ΔdisS0 (−32.77–25.47 J·mol−1·K−1) indicate that the dissolution of Favipiravir is endothermic, entropy-driven or has no driving force, and non-spontaneous.