Research on solubility behavior of iminostilbene in twelve mono-solvents: Measurement, modeling, molecular simulation and thermodynamic properties

Abstract

Iminostilbene (IMB) is an important pharmaceutical intermediate that can be used to prepare the antiepileptic drug omazepine. The measurement of solid–liquid equilibrium solubility parameters in various solvents can be employed for crystallization and separation processes of IMB. In this research, mole-fraction solubility of IMB in twelve individual organic solvents namely: “methyl acetate (MeAC), ethyl acetate (EtAC), n-propyl acetate (NPAC), isopropyl acetate (IPAC), n-butyl acetate (NBAC), isobutyl acetate (IBAC), N-methylpyrrolidone (NMP), acetone (DMK), N,N-dimethylformamide (DMF), acetonitrile (MeCN), N,N- dimethylacetamide (DMAC) and 1,4-dioxane (Diox)” was critically evaluated ranged from 278.15/288.15 K to 323.15 K at 0.1 MPa using laser monitoring method. Experimental solubility data had a general uptrend with the incremental temperature. Simultaneously, IMB solubility in selected mono-solvents showed an obvious order from high to low of: NMP > DMAC > DMF > Diox > DMK > NBAC > NPAC > EtAC > IBAC > IPAC > MeAC > MeCN. In order to explore dissolution behavior, Hirshfeld surface as well as molecular electrostatic potential surface (MEPs) were employed to analyze intermolecular interaction, and result indicated hydrogen bonding was easily formed on >NH group and its opposite position CHCH group. Meanwhile, Hansen solubility parameters (HSPs) were used to investigate solubility order, the result of which suggested that dispersion interaction could be the main factor influenced on solubility order in homologous solvents. Moreover, four activity coefficient models (Margules, UNIQUAC, NRTL, NRTL-SAC model) as well as a combined equation (Jouyban model) were applied for correlation of solubility data with twelve solvents. UNIQUAC model provided the highest regression accuracy among five models in terms of average relative deviation (ARD) lower than 1.178 % and root mean square deviation (RMSD) not higher than 1.176 ‰. Furthermore, based on UNIQUAC equation, thermodynamic properties including dissolution and mixing process were strictly evaluated for further research on solubility behavior. The results demonstrated that both of mixing and dissolution behaviors were spontaneous and entropically driven.