Solubility determination and thermodynamic model analysis of nefopam hydrochloride in eight plain solvents and three binary solvents from 273.15 K to 323.15 K

Nefopam hydrochloride (NPH) is a non-narcotic analgesic with antipyretic, analgesic, and muscle relaxant effects. Solubility is an important molecular property that can inform the crystallization and purification of drugs. In the present study, NPH solubility was measured in eight plain solvents and three binary solvents at 273.15 K-323.15 K. Results showed that in the plain solvents, NPH had the greatest solubility in methanol and the least in acetone. The solubility in the solvent system of methanol + acetone and ethanol + acetone becomes greater with the increase of the molar fraction of the positive solvent, while it becomes greatest in the system of water + acetone when the molar fraction of the positive solvent is 0.8 and at molar fractions>0.8 the solubility begins to decrease, which may be owing to the existence of the phenomenon of co-solubility. NPH solubility in plain solvents and binary solvents is positively correlated with temperature. By XRD and TG-DSC, the crystal structure of NPH in solvent did not change and the weight loss and melting temperatures were 500.49 K and 518.34 K respectively, which were much higher than the experimental temperatures. Selection of Hansen solubility parameter to predict the solubility effect of NPH in different solvents. The analysis was carried out using five thermodynamic models, ranging from Modified Apelblat model, Buchowski-Ksiazaczak λh model, CNIBS/R-K model, Jouyban-Acree model and SUN model, to fit the solubility data, out of which Modified Apelblat model and CNIBS/R-K model had more accurate prediction results.