Design,Synthesis And Properties Of Pharmaceutical Cocrystals Of Gatifloxacin

Objective Gatifloxacin（GAT）,as one of the fourth-generation quinolones,due to its poor solubility and easy to develop drug resistance,it is difficult to give full play to its clinical effects.In order to improve the physiochemical properties of gatifloxacin,pharmaceutical cocrystals of gatifloxacin were designed and synthesized by pharmaceutical cocrystal technology,and the internal relationship between its structure and properties was studied.On this basis,the synthetic law of pharmaceutical cocrystals of gatifloxacin was systematically explored.It provides theoretical guidance and basis for the manual and controllable design and synthesis of pharmaceutical cocrystals of gatifloxacin with ideal physiochemical properties.Methods Based on the theoretical analysis of the reported pharmaceutical cocrystals of quinolones,pharmaceutical cocrystals of gatifloxacin were synthesized by the method of evaporation of the solvent;The structures of pharmaceutical cocrystals of gatifloxacin were characterized by single crystal X-ray diffraction,XRD and IR;The crystal structures were analyzed by Hirshfeld surface with Crystal Explorer software to explore various intermolecular forces in pharmaceutical cocrystals of gatifloxacin;The solubility of gatifloxacin and its cocrystals in pure water were investigated by cradle method;Franz diffusion cell was used to test the permeability of gatifloxacin and its pharmaceutical cocrystals;The hygroscopic stability of gatifloxacin and its pharmaceutical cocrystal were investigated by relative humidity method;SD rats were used as animal models to investigate the plasma drug concentration of pharmaceutical cocrystals of gatifloxacin pharmaceutical cocrystals;Kirby-Bauer agar diffusion method was used to detect the antibacterial activity of pharmaceutical cocrystals of gatifloxacin and their parent compound in vitro;Using the gradient concentration increasing method and gatifloxacin as the test drug,the drug resistance of Escherichia coli was induced,so as to obtain stable gatifloxacin-resistant E.coli,and the in vitro antibacterial activity of pharmaceutical cocrystals of gatifloxacin against artificially induced gatifloxacin-resistant E.coli were tested.Results（1）Three types of six kinds of pharmaceutical cocrystals of gatifloxacin were designed and synthesized by solvent evaporation method:gatifloxacin-2,3-dihydroxybenzoic acid（C19H23FN3O4·C7H5O4,GAT-2,3-HBA）;gatifloxacin-sulfosalicylic acid(C₇H₅O₆S·C₁₉H₁₉FN₃O₄·3（H₂O）,GAT-SSA);gatifloxacin-terephthalicacid(C₈H₅O₄·C₁₉H₂₃FN₃O₄,GAT-PTA);gatifloxacin-p-nitrobenzoicacid（C19H23FN3O4·C7H4NO4,GAT-PNA）and gatifloxacin p-methylbenzoic acid(C₁₉H₂₃FN₃O₄·C₈H₇O₂·2（H₂O）·C₂H₆O,GAT-PIA);（2）The solubility study showed that the maximum solubilities of GAT,GAT-2,3-HBA,GAT-SSA,GAT-PTA,GAT-IPA,GAT-PNA and GAT-PIA in water were 0.21 mg·m L^-1,0.63 mg·m L^-1,1.64 mg·m L^-1,0.24 mg·m L^-1,1.89 mg·m L^-1,0.64 mg·m L^-1and 0.67 mg·m L^-1,respectively;（3）The permeability study showed that the cumulative permeabilities of GAT,GAT-2,3-HBA,GAT-SSA,GAT-PTA,GAT-IPA,GAT-PNA and GAT-PIA within 500 min were 12.53 mg·cm^-2,8.54 mg·cm^-2,20.38mg·cm^-2,6.09 mg·cm^-2,15.50 mg·cm^-2,13.36 mg·cm^-2and 17.24 mg·cm^-2,respectively;（4）Hygroscopic study shows that the hygroscopicity of GAT,GAT-2,3-HBA,GAT-SSA,GAT-PTA,GAT-IPA,GAT-PNA and GAT-PIA at 75%RH were 11.57%,2.45%,13.68%,1.87%,2.84%,9.09%and 14.03%,respectively.The hygroscopicity of GAT,GAT-2,3-HBA,GAT-SSA,GAT-PTA,GAT-IPA,GAT-PNA and GAT-PIA at 80%RH were 9.87%,9.33%,3.55%,5.88%,8.02%,7.76%and 12.19%,respectively.The hygroscopicity of GAT,GAT-2,3-HBA,GAT-SSA,GAT-PTA,GAT-IPA,GAT-PNA and GAT-PIA at 98%RH were 43.36%,3.20%,14.29%,6.88%,30.73%,8.82%and 20.59%,respectively;（5）Plasma drug concentration study shows that the AUC_0-24 of GAT,GAT-2,3-HBA,GAT-SSA,GAT-PTA,GAT-IPA,GAT-PNA and GAT-PIA were 23.51μg·m L^-1、23.55μg·m L^-1、27.36μg·m L^-1、18.06μg·m L^-1、25.73μg·m L^-1、25.67μg·m L^-1and 28.75μg·m L^-1,respectively;（6）Antibacterial experiments showed that the antibacterial activities of six pharmaceutical cocrystals of GAT against E.coli,S.aureus and S.typhi in vitro were higher than those of gatifloxacin.The antibacterial experiment in vitro of six gatifloxacin pharmaceutical cocrystals against artificially induced gatifloxacin-resistant E.coli showed that when the drug pharmaceutical concentration was 0.1 mmol·L^-1,only GAT-SSA and GAT-IPA had antibacterial activity against artificially induced gatifloxacin-resistant E.coli.When the drug concentrations were 0.2 mmol·L^-1 and 0.3 mmol·L^-1,the in vitro antibacterial activity of six gatifloxacin pharmaceutical cocrystals against artificially induced gatifloxacin-resistant E.coli were higher than that of the parent compound gatifloxacin.Conclusions Three types of six kinds of pharmaceutical cocrystals of gatifloxacin were designed and synthesized by pharmaceutical cocrystal technology.Structural analysis shows that cocrystal formers with polar groups are easy to promote the crystal accumulation by forming charge assisted hydrogen bonds in the process of forming pharmaceutical cocrystals with gatifloxacin,so as to form a stable crystal structure.It is speculated that CAHBs are formed in the process of the formation pharmaceutical cocrystals between cocrystal formers and gatifloxacin,which improves the solubility of pharmaceutical cocrystals compared with gatifloxacin,and then affects its permeability,bioavailability and antibacterial activity.This work shows that CAHBs plays a major role in the synthesis of pharmaceutical cocrystals and the improvement of physiochemical properties of gatifloxacin.It shows that the new solid form of gatifloxacin with target structure and required physiochemical properties can be designed based on CAHBs interaction.