Study On The Pharmaceutical Salt Formation Of Dapsone And The Pharmaceutical Cocrystal Of Fluconazole

In recent years,with the development of crystal engineering strategy in the field of medicine,the method of forming pharmaceutical cocrystals or pharmaceutical salts to replace active pharmaceutical ingredients has been more and more applied in the field of scientific research and medicine,which can effectively improve the stability of pharmaceuticals,improve the solubility and dissolution rate of pharmaceuticals,and then improve the bioavailability.Based on the crystal engineering strategy,this paper selected dapsone(DDS)and fluconazole(FLZ)with poor solubility,camphor sulfonic acid(CAM),5-sulfosalicylic acid(SSA)and p-hydroxybenzoic acid(OHBA)as coformates,followed the concept of "green chemistry",using mechanical grinding method and solution evaporation method to synthesize a series of pharmaceutical salts or pharmaceutical cocrystals.The specific research content is as follows:1.Dapsone(DDS),camphor sulfonic acid(CAM),5-sulfosalicylic acid(SSA)with different stoichiometric ratios were selected by mechanical grinding method.Three pharmaceutical salts DDS-CAM,DDS-CAM-Et OH and DDS-SSA were prepared.The structure was characterized by X-ray powder diffraction,single crystal X-ray diffraction,proton nuclear magnetic resonance spectroscopy and infrared spectroscopy.Differential scanning calorimetry,thermogravimetric experiment explored the thermal stability of the three crystals,and the moisture absorption of DDS-CAM and DDS-SSA was tested by dynamic vapor adsorption experiment.The equilibrium solubility of DDS,DDS-CAM and DDS-SSA was tested.The results showed that the solubility of DDS and DDS-SSA in aqueous solution was 9.2 times and 13.1 times that of DDS,respectively.The solubility of DDS and DDS-SSA was also improved in three buffer solutions(pH = 1.2,4.5,6.8).In addition,the inherent dissolution rate test also showed that the pharmaceutical salt DDS-SSA had a good dissolution,indicating that dapsone effectively improved its poor solubility by forming pharmaceutical salts,and had an obvious effect on improving bioavailability.2.Fluconazole(FLZ)and para-hydroxybenzoic acid(OHBA)for pharmaceutical cocrystal FLZ-OHBA-Et OH were obtained by liquid-assisted grinding method and solution evaporation method.The structure was characterized by X-ray powder diffraction,single crystal X-ray diffraction and infrared spectroscopy.The thermal stability of its thermal stability was studied through thermogravimetric experiment and differential thermal experiment,and its equilibrium solubility in water,pH = 1.2,pH = 4.5,and pH = 6.8 three buffer solutions was tested,and the results showed that it exhibits improved solubility in a buffer solution with pH of 6.8,it is conducive to the absorption of drugs in the human intestinal tract.