Molecular Self-assembly in Solution and the Nucleation Pathway: the Case of p-Nitrobenzoic Acid

The homogeneous nucleation during fast cooling crystallization and the heterogeneous nucleation during the solution-mediated polymorphic transformation (SMPT) of p-nitrobenzoic acid (PNBA) were investigated to elucidate the connection between the molecular self-assembly and the nucleation process. Process analytical technology (PAT) tools, such as attenuated total reflection-Fourier-transform infrared (ATR-FTIR) spectroscopy were successfully applied to highlight the existence of solution-phase dimers and monomers. The combination of solubility measurements, measured nucleation induction time, polymorphic outcome and transformation, and computational chemistry was used to demonstrate the connection among solvation, molecular self-assembly in solution, and the nucleation pathway of PNBA. The orders of solubility and nucleation rates in different solvents were found to be consistent with those of solute–solvent binding energies. The dimerization of PNBA molecules in hydrogen-bonded dimers and stacked dimers through π–π interactions seem similar in all four solvents investigated in this study, which indicates that the desolvation of PNBA is the key step during the overall nucleation pathway.