Discovery of Cocrystal Phase Diagrams: Precisely and Quickly Understanding Cocrystalline Region of Aminopyridine Cocrystal with 4‑Aminobenzoic Acid

• Published in: Crystal growth & design Vol. 24; no. 19; pp. 7948 - 7960
• Main Authors: Li, Huanxin, Ding, Xin, Sun, Kenan, Zhu, Bo, Zhao, Hongkun
• Format: Journal Article
• Language: English
• Published: American Chemical Society 02.10.2024
• ISSN: 1528-7483; 1528-7505
• DOI: 10.1021/acs.cgd.4c00860

Six cocrystal phase diagrams at 298.15 K for ternary systems consisting of 4-aminobenzoic acid (4-ABA) (1) + 2-/3-aminopyridine (2) + ethanol/ethyl acetate (3) and 4-aminobenzoic acid (1) + 4-aminopyridine (2) + ethanol/isopropanol (3) were constructed based on the mutual equilibrium solubilities, which were achieved using the isothermal saturation technique. Each ternary system yielded three distinct solids: aminopyridine, 4-ABA, and aminopyridine·4-ABA (1:1, mole ratio) cocrystal and included two cosaturation points, five crystalline regions, and three curves in a state of cosaturation. The size of the crystalline zone of the 2-/3-aminopyridine·4-ABA cocrystal is greater than that of the 4-aminopyridine·4-ABA cocrystal. All of the cocrystals exhibit stability in their solid form. Analysis of these diagrams elucidated the process of the cocrystal crystallization in solvent and determined the specific locations where each cocrystal remained stable in each solvent. The cocrystals of aminopyridine-4-ABA can be generated by favorable contacts, e.g., hydrogen bond force and van der Waals force. This outcome is obtained through the examination of an independent gradient model based on Hirshfeld partitions as well as the examination of the Hirshfeld surface, 2D fingerprint plot, and DFT analysis. Among the three cocrystals, 2-aminopyridine-4-ABA has the highest level of stability. The phase diagrams of cocrystals and the thermodynamic analysis can serve as a foundation for generating cocrystals of 2-/3-/4-aminopyridine·4-ABA.