Measurement of Solubility and Molecular Simulation of Dissolution Behavior of Isonicotinamide in 15 Pure Solvents

The solubility of isonicotinamide(INA) in 15 pure solvents (including N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, n-propanol, iso-propanol, n-butanol, n-pentanol, tetrahydrofuran, ethyl acetate, methyl acetate, acetonitrile, n-propyl acetate, iso-propyl acetate, acetone) has been measured (P = 0.1 MPa, T = (278.15-323.15 K)) by the gravimetric method. At 323.15 K, the order of solubility of INA(P21/c) in 15 mono-solvents was N,N-dimethylacetamide > N,N-dimethylformamide > methanol > ethanol > n-propanol > iso-propanol > n-butanol > n-pentanol > tetrahydrofuran > ethyl acetate > methyl acetate > acetonitrile > n-propyl acetate > iso-propyl acetate > acetone. Five thermodynamic models (modified Apelblat, Yaws, Wilson, NRTL, and two-suffix Margules models) were used to fit the solubility data, and the highest accuracy was obtained by fitting the modified Apelblat model. Furthermore, the Hansen solubility parameters (HSPs) were used to further examine the miscibility of INA in the investigated solvents. The intermolecular interaction between solutes and solvents was investigated using molecular dynamics simulation (Hirshfeld surface (HS), molecular electrostatic potential surface (MEPs), and crystal electrostatic potential distribution (CEPD)). The essence of the dissolution of INA is that the "N--H" and "O--H" forces in the crystal are disrupted, and the INA molecule breaks away from the crystal and enters the solvent.