| Cocrystal has attracted widespread attention from pharmaceutical companies because it is a new type of solid form of drugs that can significantly improve some of the physicochemical properties of drugs.Here,metformin hydrochloride was used as the active pharmaceutical ingredient and the metformin hydrochloride cocrystal was screened out and its thermodynamic properties and cocrystal formation mechanism were studied.The specific work is as follows:(1)Based on the principles of crystal engineering,a variety of organic carboxylic acids were selected as the cocrystal formers.Metformin hydrochloride-citric acid cocrystal was screened out by gringding and solution crystallization methods.The structure of the cocrystal was characterized and verified by PXRD,DSC,TG,IR,Raman and SEM characterization methods.(2)The solubilities of metformin hydrochloride-citrate cocrystal and raw materials in different solvents at different temperatures was measured by equilibrium method.The solubility data was correlated with λh,Apelblat empirical equation,JA model,and Wilson equation.And the thermodynamic process of cocrystal dissolution was studied by van’t Hoff equation.(3)Based on the experimental basis of preparing cocrystal by grinding method,the ratio of cocrystal system was determined to be 1:1.The possibility of simple physical mixing of raw materials to form cocrystal under different conditions was studied.The results show that compared with anhydrous citric acid,metformin hydrochloride and citric acid monohydrate are easier to form cocrystal.The molecular diffusion mechanism of cocrystal formation was explored,and it was found that grinding and solvent can accelerate the molecular diffusion and promote the formation of cocrystal.(4)Using Materials Studio software as calculation tool,the mechanism of cocrystal formation was explored at the molecular level.By analyzing and refining the cocrystal structure,the hydrogen bonding position was analyzed.The binding energy between molecules was calculated by kinetic simulation with the Forcite module,and it was found that the binding energy between the metformin hydrochloride and citric acid monohydrate molecules is greater,which explains the easier formation of cocrystal between them.The solvation free energy of cocrystal and metformin hydrochloride in methanol and ethanol is calculated.The results show that the absolute value of the solvation free energy of the cocrystal in each solvent is greater,which explains that the solubility of the cocrystal is greater than the solubility of metformin. |
