Assembly of two pharmaceutical salts of sparfloxacin with pyrocatechuic acid: Enhancing in vitro antibacterial activity of sparfloxacin by improving the solubility and permeability

• Designing and synthesizing two pharmaceutical salts of sparfloxacin (SPX). • Cocrystallization of SPX with pyrocatechuic acid by CAHBs interactions. • Improving the solubility and permeability of SPX by forming pharmaceutical salts. • Enhancing antibacterial activity of SPX by improving the solubility and permeability. With the purpose of improving the solubility and permeability of sparfloxacin (SPX) to enhance the antibacterial activity in vitro , two unreported pharmaceutical salts including a salt with pyrocatechuic acid (PCA) containing methanol, and another salt with PCA without methanol, namely, SPX-PCA-MeOH (C 19 H 23 F 2 N 4 O 3 ·C 7 H 5 O 4 ·CH 4 O·H 2 O) and SPX-PCA (C 19 H 23 F 2 N 4 O 3 ·C 7 H 5 O 4 ), were synthesized and structure characterized. Comprehensive crystal structures, molecular electrostatic potential and Hirshfeld surface analysis reveal that in the two pharmaceutical salts of SPX prepared, the protons of carboxylic moiety groups on the coformer were transferred to the nitrogen atom of the SPX piperazine ring, and the SPX was ionized from neutral to form charge assisted hydrogen bonds (+) CAHBs (N + -H···O) to construct a stable crystal structure. By forming pharmaceutical salts, the equilibrium solubility order of two pharmaceutical salts of SPX and pure SPX is SPX-PCA>SPX-PCA-MeOH>SPX, and the order of permeability is SPX-PCA>SPX-PCA-MeOH>SPX. Preliminary structure-activity relationships speculate that the SPX and PCA rely on CAHBs to form pharmaceutical salts, which makes SPX change from neutral to ionized, resulting in the increase of the solubility of SPX. The increased permeability of the two pharmaceutical salts of SPX may be attributed to the combination of the N atom of the piperazine ring of SPX and the hydroxyl group of the PCA molecule by CAHBs, which reduces the number of polar sites in the system and thus reduces the hydrophilicity and increases hydrophobicity of the pharmaceutical salt of SPX, therefore creating condition for the transmembrane transport. Meanwhile, the antibacterial activities in vitro of two pharmaceutical salts of SPX are improved, when compared with the corresponding parent compound (SPX), which change the order is consistent with the solubility and permeability. This implies that the introduction of solvent molecules may play a minimal role in improving the physicochemical properties of the active pharmaceutical ingredients. Further to this, it is surprising that the hygroscopic stabilities of two pharmaceutical salts of SPX were significantly improved compared with that of pure SPX.