Non-covalent binding of non-steroidal anti-inflammatory drugs to antibiotics: preparation, characterization, physicochemical properties and study of single crystals of tolfenamic acid-enrofloxacin drug-drug salt and their antibacterial and anti-inflammatory activities

To improve the physicochemical properties and biological activities of the nonsteroidal anti-inflammatory drug tolfenamic acid (TA) and the fluoroquinolone enrofloxacin (ENR). Based on the previous experience of our group in designing and synthesizing quinolone pharmaceutical co-crystals/salts single crystals by non-covalent bonding to improve their physicochemical properties, a drug-drug salt single crystal of tolfenamic acid-enrofloxacin was prepared for the first time using TA and ENR(TA-ENR, C 19 H 23 FN 3 O 3 ·C 14 H 11 ClNO 2 ·C 2 H 3 N). Single-crystal X-ray diffraction (SCXRD) analysis indicated that TA and ENR interacted predominantly through charge-assisted hydrogen bonds (CAHBs) within non-covalent bonds to form asymmetric units. Subsequently, the formation of dimers between ENR + cations in adjacent asymmetric units was promoted, leading to the formation of a stable crystalline structure through C6-H6···O2 and π···π stacking. Solubility experiments demonstrated that the solubility of TA-ENR was notably increased compared to TA. This can be ascribed to the CAHBs formed between TA and ENR, which facilitated the dissociation of TA in the dissolution medium, thereby enhancing TA’s affinity for the dissolution medium. Permeability experiments also revealed that the permeability of TA-ENR was significantly improved compared to both TA and ENR. The in vitro antimicrobial activity and anti-inflammatory activity of TA-ENR were also somewhat improved compared to TA and ENR. The success of this work implies that we may provide new ideas for designing and synthesizing solid drugs with better physicochemical properties and bioactivity, as well as for the treatment of septic arthritis, through the formation of drug-drug co-crystals/salts.