| Objective In order to explore the effect of pharmaceutical cocrystals of enoxacin on the physicochemical properties and antibacterial activity of enoxacin,pharmaceutical cocrystals of enoxacin have been designed and synthesized based on pharmaceutical cocrystal technology to analyze the relationship between structure and properties;meanwhile,explore the synthetic conditions and rules of pharmaceutical cocrystals of enoxacin,which may provide theoretical base and evidence for design and synthesis of ideal enoxacin clinical solid drugs forms.Methods The pharmaceutical cocrystals of enoxacin（EX）with oxalic acid（OXA）,malonic acid（MLO）,fumaric acid（FUM）,phthalic acid（PHA）,m-hydroxybenzoic acid（3HBA）,protocatechuic acid（PCA）and gallic acid（GLA）were designed and synthesized by solvent evaporation.The structure were characterized by single-crystal X-ray diffraction,powder X-ray diffraction analysis（XRD）,infrared spectroscopy（IR）,1H-NMR and thermogravimetric analysis（TGA）.Hirshfeld surface maps of these pharmaceutical cocrystals were analysed by Crystal Explorer software to explore the intermolecular hydrogen bonding and other forces.The solubilities of EX pharmaceutical cocrystals were tested by basket method.The oil-water distribution coefficients of EX pharmaceutical cocrystals were determined by UV spectrophotometry.The permeability of EX pharmaceutical cocrystals was tested by Franz diffusion cells.The hygroscopicity of EX pharmaceutical cocrystals was investigated under gradient humidity condition.Kirby-Bauer agar diffusion methods were detected the antibacterial activity in vitro of EX pharmaceutical cocrystals.Results Designed and synthesized by solvent volatilization reported for the 3 categories of8 kinds of pharmaceutical cocrystals of enoxacin:the pharmaceutical cocrystals of enoxacin and dicarboxylic acids,enoxacin-oxalic acid(C15H17FN4O3·0.5（C2H2O4）·2（H2O）,EX-OXA),enoxacin-malonic acid(C15H18FN4O3·C3H3O4,EX-MLO)and enoxacin-fumaric acid(C15H18FN4O3·C4H3O4,EX-FUM);pharmaceutical cocrystals of enoxacin with phthalic acid,enoxacin-phthalic acid(C15H18FN4O3·C8H4O4,EX-PHA)and enoxacin-phthalic acid-Et OH(C15H18FN4O3·C8H5O4·C2H6O,EX-PHA-Et OH),pharmaceutical cocrystals of enoxacin with hydroxybenzoic acids,enoxacin-3-hydroxybenzoic acid(C15H18FN4O3·C7H5O3·H2O,EX-3HBA),enoxacin-protocatechuic acid(C15H18FN4O3·C7H5O3·H2O,EX-PCA)and enoxacin-gallic acid(C15H18FN4O3·C7H5O5·0.5（CH4O）,EX-GLA).The structure analysis on the single crystal X-ray diffraction and Hirshfeld surface showed that the structure of EX,phthalic acid and hydroxy benzoic acid have an aromatic ring which is easy to formπ-πstackingand and other interactions to form supermolecule syntheses.In addition,the hydrogen bonds/CAHBs formed by the N atom in the piperazine ring from EX molecule with the carboxylic acid group from dicarboxylic acids,phthalic acid and hydroxybenzoic acid to link adjacent supermolecule synthesis to form stable two-dimensional layered structures.The solubility experiments showed that the water solubilities of the 8 pharmaceutical cocrystals of EX are significantly improved compared to EX.The oil-water distribution coefficients experiment showed that the lipid solubility of EX-FUM is lower than EX,the EX-OXA and EX-3HBA are close to EX,and others pharmaceutical cocrystals are better EX.The permeability of EX-OXA,EX-MLO and EX-FUM is significantly improved compared with EX.Hygroscopicity experiments showed that the 8 EX pharmaceutical cocrystals are lower than EX,among which the EX-OXA and EX-FUM is significantly lower than EX.The antibacterial experiments show that 8 EX pharmaceutical cocrystals have excellent antibacterial activity in vitro against E.coli,S.aureus,and S.albus,among which the antibacterial activity of pharmaceutical cocrystals of enoxacin with dicarboxylic acids and phthalic acid against E.coli,S.aureus,and S.albus is significantly higher than EX.Conclusions Pharmaceutical cocrystals of EX have been synthesized by the solvent evaporation method.The structural analysis shows that choice of compounds with good hydrogen bond donor and hydrogen proton as coformers will be more conducive to forming stable crystal structure with EX.The property test and activity study show that the water solubilities of pharmaceutical cocrystals of EX are higher than enoxacin due to the influence of the water solubilities of coformers and/or formation of CAHB between EX and coformers;the lipid solubility of some pharmaceutical cocrystals of EX is correspondingly improved;the permeability of pharmaceutical cocrystals of EX is influenced by its water solubility and lipid solubility to improve their antibacterial activity in vitro.In addition,the hygroscopicity of pharmaceutical cocrystals of EX are lower than enoxacin. |
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