Study on Thermodynamics, Crystallization Kinetics, and Molecular Simulation of Cocrystals: The Case of 4‑Nitropyridine N‑Oxide/p‑Aminobenzoic Acid

• Published in: Crystal growth & design Vol. 22; no. 5; pp. 2925 - 2934
• Main Authors: Zhang, Xirui, Xu, Yunfei, Yang, Denghui, Gong, Yue, Du, Wei, Tang, Na, Jiang, Jianwei
• Format: Journal Article
• Language: English
• Published: American Chemical Society 04.05.2022
• ISSN: 1528-7483; 1528-7505
• DOI: 10.1021/acs.cgd.1c01336

Dry grinding and solvent-drop grinding to prepare the cocrystals of 4-nitropyridine N-oxide (NPNO) and p-aminobenzoic acid (PABA) were investigated in this study. Seven solvents were used during the solvent-drop grinding to accelerate the formation of the cocrystal, and the corresponding implicit solvent models were applied to compute the binding energy between NPNO and PABA via Gaussian 09 to determine the effect of the solvent on solvent-drop grinding. With a combination of Raman spectroscopy and powder X-ray diffraction (PXRD), the ternary phase diagrams of the NPNO–PABA–acetonitrile system at different temperatures were experimentally determined. It was found that the formation of the cocrystal is mainly due to the involvement of an O···H–O hydrogen bond between the −NO group of NPNO and the −OH group of PABA, and the stronger the binding energy of O···H–O in solvents, the faster the formation of the cocrystal. The crystallization region of the cocrystal of NPNO and PABA becomes larger with an increase in temperature. From an analysis of Ksp and K 11, the equation K SP K 11≪ [B] T is satisfied when the experimental temperature is 308.15 K, and a 1:1 complex solution model was used to describe the NPNO–PABA–acetonitrile system at 308.15 K. While the equation was not satisfied at 298.15 K, a solution-free complexation model was applied to describe the system at 298.15 K. The solution crystallization of the cocrystal of NPNO and PABA was successfully monitored by in situ Raman, PXRD, and a polarizing microscope, which collaboratively indicate that the nucleation of the cocrystal occurred almost immediately as soon as the two components were mixed in acetonitrile, and the dissolution processes of NPNO and PABA are the rate-determining steps during the solution crystallization of the cocrystals of NPNO and PABA.