Preparation Of Theophylline Cocrystal In Water/Ethanol Mixed Solvents And Thermodynamic Analysis Of Its Binding With BSA

Cocrystal is a new type of supramolecular compound which is formed by the binding of a small drug with a cocrystal former through hydrogen bond,Van der Waals forces,etal.It can significantly change physical property of drug molecular(However,which has no effect on the efficacy of the original drug).And it has been one of the most important means to improve the storage and absorption of drugs.In order to investigate the advantages of mixed solvent in the preparation of cocrystal.In this paper,XPRD,DSC and other methods was used to measure the grinding conditions of cocrystal(theophylline–phthalate).The solubility of drugs in mixed solvents of water/ethanol was measured by static method.Under the same environment,the thermodynamic constants were determined by phase solubility method.Selecting the appropriate proportion of mixed solvent according to the solubility of drugs has a significantly influence on the cocrystal production.The three–phase diagram of the mixed solvent was plotted.Base on the three–phase diagram and the calculation thermodynamic date,it's found that 94% ethanol system is the most suitable for the production of theophylline cocrystal.The effect of temperature inside the process by calculation have been concluded that the temperature had a negative effect on the complexation process.The interaction of between cocrystal components and bovine serum albumin(BSA)was investigated by fluorescence,ultraviolet spectrum.It found that the hydrophobic force played mainly role of both combinations.The experiment of identification of the binding sites of two drugs on BSA by labeled drugs shown that the binding site of both drugs is site?and the number of binding site is 1.The result also showed that the competition binding of drugs to BSA displayed that THEO lead the reduction of the combination force between phthalate and BSA,vice versa.In this paper,the pharmacokinetics of cocrystal in vivo was explored,the advantages of cocrystal were further discussed from the pharmacological point.