Design,Synthesis And Properties Of Pharmaceutical Cocrystals Of Sparfloxacin

Objective Sparfloxacin（SPX）,as a BCS class II drug,is difficult to give full play to its clinical medicinal effect due to its poor solubility.To improve the physicochemical properties of sparfloxacin such as solubility or stability,the pharmaceutical cocrystals of sparfloxacin were designed and synthesized by using the pharmaceutical cocrystal technology,deeply study the internal relationship between its structure and properties,and systematically explore its synthesis law on this basis,so as to provide preliminary experimental basis and theoretical guidance for the artificial controlled synthesis of new solid state forms sparfloxacin drug with the desired physicochemical properties.Methods The unreported pharmaceutical cocrystals of sparfloxacin have been synthesized by solvent evaporation method.The structure characterization and analysis of the synthesized pharmaceutical cocrystals of sparfloxacin were carried out by single crystal X-ray diffraction,X-ray powder diffraction,infrared spectrum,proton nuclear magnetic resonance and Hirshfeld surface methods.The solubilities of pharmaceutical cocrystals of sparfloxacin were tested by basket method in phosphate buffered saline.The permeability of pharmaceutical cocrystals of sparfloxacin was tested by Franz diffusion cells.The hygroscopic stability of pharmaceutical cocrystals of sparfloxacin was investigated under gradient relative humidity condition.The plasma drug concentration of pharmaceutical cocrystals of sparfloxacin was determined by HPLC.The antibacterial activities in vitro of pharmaceutical cocrystals of sparfloxacin were determined by the K-B paper agar diffusion method.Results Synthesized by solvent evaporation method unreported for the 3 types of 7 kinds of pharmaceutical cocrystals of sparfloxacin:pharmaceutical cocrystals of sparfloxacin and hydroxybenzoic acids,sparfloxacin-pyrocatechuic acid-methanol(C₁₉H₂₃F₂N₄O₃·C₇H₅O₄·CH₄O·H₂O,SPX-PCA-Me OH)and sparfloxacin-pyrocatechuic acid(C₁₉H₂₃F₂N₄O₃·C₇H₅O₄,SPX-PCA);pharmaceutical cocrystals of sparfloxacin with salicylic acids,sparfloxacin-salicylic acid(C₁₉H₂₃F₂N₄O₃·C₇H₅O₃,SPX-SCA)and sparfloxacin-5-sulfosalicylic acid(C₁₉H₂₃F₂N₄O₃·C₇H₆O₆S,SPX-SSA);pharmaceutical cocrystals of sparfloxacin with benzoic acids,sparfloxacin-benzoic acid(C₁₉H₂₃F₂N₄O₃C₇H₅O₂·3H₂O,SPX-BZA),sparfloxacin-p-toluylic acid(C₁₉H₂₃F₂N₄O₃·C₈H₇O₂,SPX-PTA)and sparfloxacin-4-nitrobenzoic acid(C₁₉H₂₄F₂N₄O₃·C₇H₄NO₄·H₂O,SPX-NBA).The solubility results showed that the solubility of the 7 sparfloxacin pharmaceutical cocrystals was 10.35,13.72,13.22,11.27,7.44,8.35 and 9.13 times higher compared to sparfloxacin under the same conditions.The permeability results showed that the permeability of the 7 sparfloxacin pharmaceutical cocrystals was 1.77,2.16,2.49,1.87,2.21,1.39 and 2.98 times higher compared to sparfloxacin under the same conditions.The results of hygroscopic stability showed that under the conditions of 75%,80%and 98%RH,the maximum hygroscopicity of sparfloxacin and 7 sparfloxacin pharmaceutical cocrystals was 18.87%,14.42%,9.88%,9.28%,10.52%,10.65%,9.01%and14.54%respectively.The plasma drug concentration results showed that the plasma drug concentration of the 7 sparfloxacin pharmaceutical cocrystals was 1.30,1.45,1.34,1.05,1.11,1.44 and 1.41 times higher compared to sparfloxacin under the same conditions.The antibacterial activities in vitro studies showed that 7 pharmaceutical cocrystals of sparfloxacin have excellent antibacterial activities in vitro against S.aureus,S.typhi and E.coli.Among them,it is worth noting that the inhibition zones of SPX-PCA,SPX-PCA-Me OH,SPX-PTA and SPX-NBA against S.aureus,S.typhi and E.coli are larger than the corresponding parent compounds（SPX）.Conclusions In this paper,7 pharmaceutical cocrystals of sparfloxacin with excellent physicochemical properties were designed and synthesized by the solvent evaporation method.Structural analysis indicates that the hybridization state of N atom on piperazine ring of sparfloxacin and the number of polar groups in coformers are the key factors affecting the design and synthesis of sparfloxacin pharmaceutical cocrystals.Studies on properties and activities showed that the solubility and permeability of sparfloxacin could be effectively improved by forming pharmaceutical cocrystals to enhance its plasma drug concentration,while its hygroscopic stability and in vitro antibacterial activities were also improved.It is further confirmed that the pharmaceutical cocrystals technology can effectively improve many physicochemical properties of sparfloxacin without changing the structure of sparfloxacin by introducing appropriate coformers,which provides a preliminary experimental basis and theoretical basis for the design and synthesis of new solid state forms of sparfloxacin drugs.