Investigation on solubility behavior of 2-chloronicotinamide in ten mono-solvents: Measurement, correlation, molecular simulation and thermodynamic analysis

Solubility behavior as a significant molecular property should be known in the field of crystal form screening, dosage form along with separation and purification in the pharmaceutical industry. In this research work, solubility data of 2-chloronicotinamide (2-CNA) in ten pure solvents including methanol (MeOH), ethanol (EtOH), ethylene glycol (EG), 2-methoxyethanol (EGME), 2-ethoxyethanol (EGEE), methyl acetate (MeAc), water, 1,4-dioxane (Diox), N,N-dimethylformamide (DMF) and N,Ndimethylacetamide (DMAC) within the range of 278.15/288.15 K to 323.15 K was experimentally determined by laser monitoring method at 0.1 MPa. Solubility of 2-CNA presented a positive correlation with temperature, and increased with incremental temperature. The result was indicative of a common tendency: DMAC > DMF > EGME > EGEE > EG > MeOH > Diox > EtOH > MeAc > water. The solvation free energy, molecular electrostatic potential surface (MEPS) and Hirshfeld surface were used to study the intermolecular interactions. Moreover, six mathematical models namely Margules, UNIQUAC, NRTL, Wilson, NRTL-SAC and Jouyban model were utilized to correlate solubility data of 2-CNA in monosolvents. UNIQUAC model could provide maximum regression accuracy in correlation with solubility data among six models in terms of average relative deviation (ARD) and root mean square deviation (RMSD). Finally, thermodynamic parameters obtained from UNIQUAC equation indicated that all dissolution and mixing process were always entropy-increasing, endothermic and spontaneous. (c) 2022 Elsevier B.V. All rights reserved.

Automated summary

Solubility behavior is of significant importance in crystal form screening, dosage form preparation, and separation and purification in the pharmaceutical industry. This research work experimentally determined the solubility data of 2-chloronicotinamide (2-CNA) in ten pure solvents and found a positive correlation between solubility and temperature. Intermolecular interactions were studied using solvation free energy, molecular electrostatic potential surface, and Hirshfeld surface. Among six mathematical models, the UNIQUAC model provided the highest regression accuracy in correlating solubility data. Thermodynamic parameters from the UNIQUAC equation revealed that all dissolution and mixing processes were entropy-increasing, endothermic, and spontaneous.