Equilibrium solubilities, model analysis, solvent effect, molecular dynamic simulation, and thermodynamic properties of itopride hydrochloride in eleven organic pure solvents at different temperatures

Itopride hydrochloride is a novel prokinetic drug used to relieve gastrointestinal diseases. In this paper, the equilibrium solubility of itopride hydrochloride in selected eleven pure solvents (methanol, ethanol, 1-propanol, 2-methoxyethanol, 2-ethoxyethanol, 2-propoxyethanol, acetonitrile, N-methyl-2-pyrrolidone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide) was determined by the laser monitoring technique at temperatures ranging from 278.15 K to 323.15 K and pressures of 101.3 kPa. The experimental results showed that the equilibrium solubility of itopride hydrochloride in the selected pure solvents were all positively correlated with temperature and the order of equilibrium solubility at 298.15 K was: dimethyl sulfoxide (28.06)＞methanol (16.63)＞2-methoxyethanol (12.04)＞N-methyl-2-pyrrolidone (8.020)＞N,N-dimethylformamide (5.117)＞N,N-dimethylacetamide(3.576)＞2-ethoxyethanol (1.463)＞ethanol (0.9341)＞2-propoxyethanol (0.4850)＞1-propanol (0.2504)＞acetonitrile (0.1887). In addition, we used the λh model, modified Apelblat model, NRTL model and van't Hoff model to correlate the experimental data of the equilibrium solubility of itopride hydrochloride. Comparing the ARD and RMSD fitted by the four models, it was found that the NRTL model fitted the best, with the 100ARD value less than 5, and the mean values of 100ARD and 10⁴RMSD were 2.15 and 1.61, respectively. Therefore, the NRTL model is more suitable for the correlation of equilibrium solubility data in this experiment. Furthermore, we analyzed the impact of different solvent properties on the equilibrium solubility of itopride hydrochloride, the molecular dynamics simulation was carried out and the interaction between solute and solvent molecules was analyzed by means of radial distribution functions (RDF). Finally, the apparent thermodynamic properties (Δ_disG°, Δ_disH°, Δ_disS°) of the phase equilibrium process of itopride hydrochloride in eleven organic pure solvents were analyzed by using the van't Hoff equation. The results of the analysis showed that it is entropically increasing and heat absorbing during the dissolution process of itopride hydrochloride.