Insight into the phase equilibrium of mycophenolic acid-4,4′-bipyridine cocrystals with different stoichiometric ratios

Two distinctive mycophenolic acid(MPA)-4,4′-bipyridine(4,4′-BPY) cocrystals with different stoichiometric ratios, a 2:1 cocrystal,and a 1:1( Z' =2) cocrystal, were successfully prepared and thoroughly characterized by single crystal X ray diffraction, powder X ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopy. DSC analysis indicated that the 2:1 cocrystal exhibited a higher melting point (141.6 °C) in comparison to the 1:1( Z' =2) cocrystal(126.5 °C), indicating stronger intermolecular interactions (i.e., higher lattice energy) in the solid state. Both cocrystals exhibited good thermal stability, with onset decomposition temperatures (T d ) of 204 °C and 190 °C for the 2:1 and 1:1 (Z'=2) cocrystals, respectively, as confirmed by TG analysis. IGMH analysis indicated that both cocrystals exhibited analogous interaction patterns; however, the 1:1( Z' =2) cocrystal manifested more pronounced steric repulsion in the van der Waals region, which was deemed to be the underlying cause of its lower melting point. This hypothesis was further substantiated by binding energy calculations (E inter (2:1 fragment)>E inter (1:1( Z' =2) fragment). Consistent with the thermodynamic analysis, the 2:1 cocrystal, with its higher binding energy, exhibited both a higher melting point (141.6 °C), compared to the 1:1 (Z'=2) cocrystal(126.5 °C). Similary, the 2:1 cocrystal with its higher binding energy, was expected to have lower solubility than the 1:1 ( Z' =2) cocrystal in the same solvent, which was validated by the ternary phase diagram at 303.15 K, where the stable crystallisation zone of the 2:1 cocrystal is notably smaller than that of the 1:1( Z' =2) cocrystal. Solvation free energy calculations (ΔG solv (MPA-ACN)>ΔG solv (4,4′-BPY-ACN)) are consistent with the phase diagram skewed toward the 4,4′-BPY vertex. Furthermore, the interaction energy calculations further showed that E inter (2:1 fragment)>E inter (1:1( Z' =2) fragment)>MPA-ACN, and 4,4′-BPY-ACN, indicating that intrinsic cocrystal interactions dominated over solute-solvent interactions, thermodynamically favoring cocrystal precipitation. This work elucidated the structure-melting point-solubility relationships of MPA-4,4′-BPY cocrystals and provided a thermodynamic framework for cocrystal design.