Directional Self-Assembly of Ofloxacin and Syringic Acid: The First Salt Cocrystal of Ofloxacin with Phenolic Acid Displays Superior <i>In <i>V</i>itro/Vivo</i> Biopharmaceutical Property and Enhanced Antibacterial Activity

A cocrystallization tactic of double optimization and synergistic enhancement efficacy has been proposed, aiming at maximizing the benefits of phenolic acid nutriment syringic acid (HSA) to perfect biopharmaceutical features of antibacterial drug ofloxacin (OA). This strategy utilizes the salt-forming function and cocrystallization ability of HSA interplaying with OA to assemble into a salt cocrystal, thus ameliorating OA’s physicochemical properties in vitro, which, in turn, can optimize its pharmacokinetic characteristics in vivo, making OA’s pharmaceutical peculiarities be doubly optimized on both in vivo and in vitro levels. Ulteriorly, the antibacterial potency of OA is heightened by stimulating the auxiliary antibacterial ability of HSA, fulfilling the cooperativeness of OA and HSA in antibacterial efficacy. Taking this tactic as orientation, the first OA– nutriment salt cocrystal, viz., [HOA+-SA–]-HSA-H2O, is directionally synthesized and structurally identified. Single-crystal X-ray diffraction substantiates that the salt cocrystal has a bilayer hole structure, wherein, a hexahelical hydrogen-bonding motif of [HOA+-SA–] salts situates outside with a double spiral of neutral HSA and H2O molecules inside, thus endowing the salt cocrystal with the capacity to simultaneously enhance solubility and permeability compared with OA itself, which achieves positive correlations with theoretical investigations. Intriguingly, the strengthened in vitro properties of the salt cocrystal have been effectually turned into in vivo pharmacokinetic advantages, displaying an advanced peak plasma concentration and protracted half-life along with raised relative bioavailability. More meaningfully, the antibacterial capacity of the salt cocrystal has also attained significant enhancement owing to the congenerous antibacterial action of OA and HSA. Therefore, this investigation not only offers a novice strategy for optimizing in vitro/vivo pharmaceutical characteristics and concurrently elevating antibacterial efficacy of OA through formation of the salt cocrystal but also fulfills a breakthrough in developing new salt cocrystal systems of antibacterial drugs.