Curcumin Cocrystals with Bipyridyl-like Coformers: Crystal Structures, Characterization, and Enhanced Dissolution

Curcumin (Cur) exhibits broad pharmacological activities, but its clinical application is limited by the extremely low solubility. Cocrystallization has emerged as an effective approach to improve physicochemical properties of drugs without altering their chemical structure and intrinsic bioactivity. The Cur cocrystal with 4,4′-bipyridine (Bpy) has demonstrated enhanced solubility facilitated by weaker O–H···N hydrogen bonds, in contrast to the O–H···O bonds formed with hydroxyl coformers (CCFs). Herein, three Bpy-analogous CCFs, 1,2-bis(4-pyridyl)ethane (Bpa), 1,2-bis(4-pyridyl)ethylene (Bpe), and 1-(4-pyridyl)piperazine (Pyp), were selected to construct novel cocrystals with Cur, which were successfully synthesized and thoroughly characterized by single-crystal X-ray diffraction and complementary analytical techniques. Structural analysis revealed that all three cocrystals form similar 1D chains via O–H···N hydrogen bonds between Cur and the CCFs. Powder dissolution studies revealed that all cocrystals present “spring-and-parachute” profiles, with Cur–Bpa and Cur–Pyp exhibiting enhanced solubility, whereas Cur–Bpe showed unexpectedly reduced equilibrium solubility. Their different dissolution behaviors are rationalized by lattice energy (as reflected in melting point) and CCF basicity.