Novel Lithium Ionic Cocrystal Hydrates of Phenolic Acids and l -Proline: Structures and Properties

In this work, we report the design and characterization of two novel lithium ionic cocrystal (ICC) hydrates, formulated with p-coumaric acid (p-CA) or vanillic acid (VA) and l-proline (LPCA and LPVA). Single-crystal X-ray diffraction revealed distinct hydration modes: in LPCA, water molecules were incorporated into the lattice, whereas in LPVA, water directly coordinated with lithium cations. Complementary analyses, including FT-IR spectroscopy, Hirshfeld surface analysis, differential scanning calorimetry, thermogravimetric analysis, and powder X-ray diffraction, confirmed that water molecules played a critical role in stabilizing the crystal frameworks and modulating intermolecular interactions. Both ICCs exhibited remarkable solubility enhancements compared with their parent phenolic acids, with 448-fold and 88-fold increases for p-CA and VA, respectively. Furthermore, LPCA and LPVA demonstrated significantly improved antioxidant activities in DPPH, ABTS, and FRAP assays, consistent with synergistic effects arising from ionic assembly and hydrogen-bonding networks. These findings highlight the potential of lithium ICC hydrates as promising solid forms that combine structural novelty with enhanced physicochemical and functional properties, offering prospects for safer and more effective lithium-based therapeutics.