Predicting Nucleation of Isonicotinamide from the Solvent-Solute Interactions of Isonicotinamide in Common Organic Solvents

The interactions of isonicotinamide (INA) with seven common solvents (acetic acid, acetonitrile, acetone, chloroform, ethyl acetate, and methanol) have been studied to examine solute-solvent effects on the nucleation of INA from these solvents. In a simple model of 1:1 solute-solvent interactions, the strongest INA-solvent interaction is with acetic acid (binding energy, ΔE_bind = -64.05 kJ mol^-1) and the weakest is with chloroform (ΔE_bind = -24.85 kJ mol^-1). This arises since acetic acid and INA form a hydrogen-bonding motif containing two moderate strength N-H···O hydrogen bonds, while chloroform and INA have a single weak C-H···O hydrogen bond. Taking acetic acid, chloroform, and methanol, the solvents with the strongest, the weakest, and an intermediate strength INA-solvent binding energy, the solvation of INA was studied to compare it with the 1:1 model. Acetic acid has the strongest binding energy (-872.24 kJ mol^-1) and solvation energy (-341.20 kJ mol^-1) with chloroform binding energy (-517.72 kJ mol^-1) and solvation energy (-199.05 kJ mol^-1). Methanol has intermediate binding energy (-814.19 kJ mol^-1) and solvation energies (-320.81 kJ mol^-1). These results further confirm the recent the findings which indicate that the key trends in solvent-solute interactions can be determined from a simple and efficient 1:1 dimer model and can be used to predict ease of nucleation with stronger binding energies correlating to slower, more difficult nucleation. A limit of this model is revealed by considering alcohol and acid solvents with longer alkyl chains.