Role of Molecular\nPacking in Solvent-Mediated Ellagic\nAcid·Phenazine Co-Crystals Toward Biological Activity Enhancement\nand Rational Drug Design

Ellagic\nacid (EA), a biologically active polyphenol abundant in\nvarious natural plants, has been widely applied in diverse pharmacological\nsystems. This study investigates cocrystals formed by EA with common\npharmaceutical intermediates, yielding crucial insights into their\natomic-level biological performance. Three novel cocrystals of EA·Phenazine\nwere synthesized in different solvents (cocrystal <b>1</b>:\nEA·Phenazine; cocrystal <b>2</b>: EA·Phenazine·2MeOH;\ncocrystal <b>3</b>: EA·Phenazine·2H<sub>2</sub>O).\nIn addition, their structures are characterized using single-crystal\nX-ray diffraction. Co-crystal <b>1</b> without lattice solvent\nand cocrystal <b>3</b> containing lattice H<sub>2</sub>O, exhibited\nintriguing EA–EA and phenazine–phenazine π–π\nstacking interactions. Conversely, cocrystal <b>2</b> bearing\nmethanol can illustrate robust interligand EA/phenazine π–π\nstacking interactions. Thus, cocrystal <b>2</b> displayed a\nwider absorption range and a more negative oxidation potential, indicative\nof enhanced functional performance. The superior properties of cocrystal <b>2</b> were attributed to the lower energy level of the lowest\nunoccupied molecular orbital, particularly the p−π* antibonding\norbitals of phenazine, owing to the potent π–π\ninteractions, as unveiled by theoretical calculations. In summary,\nthe presence of interligand interactions emerges as a pivotal factor\nin augmenting the biological activities of cocrystals, with the extent\nof enhancement contingent on specific packing modes. This structure–property\nrelationship allows a profound understanding of the polymorphism observed\nin drug molecules.