Study On Solid-liquid Equilibrium And Crystallization Process Of Salsalate

Salsalate is a widely used anti-inflammatory analgesic drug.Clinical studies in recent years have shown that the drug can be used for the prevention and treatment of type 2 diabetes.At present,the studies on salsalate mostly focus on the synthetic process and medicinal fields with lack of phase equilibrium and crystallization process research.In this paper,experimental analysis and theoretical study on the solid-liquid equilibrium and crystallization process of salsalate are carried out.The dissolution data in ten different pure solvents(methanol,ethanol,1-propanol,1-butanol,formic acid,acetonitrile,acetone,ethyl acetate and 1-butyl acetate)and two mixed solvents(ethanol+ acetonitrile,ethanol+ ethyl acetate)is determined by laser dynamics method.Whether in pure solvents or mixed solvents,the dissolution ability of salsalate is positively correlation with temperature.Among them,salsalate has strongest dissolving capacity in acetone and similar solubility in alcohol solvents.In ethanol + acetonitrile hybrid system,the solubility of salsalate increases firstly and then declines along with the increase of the proportion of ethanol.In ethyl acetate +acetonitrile mixed system,the solubility of salsalate increases with the increasing proportion of ethyl acetate.The measured solubility data in different solvents are regressed fitting the van't Hoff,Apelblat equation and modified J-A model,and calculated the thermodynamic functions of salsalate in different dissolution processes.To further explain the dissolution mechanism of salsalate in different solvents,the bond distance,bond angle,the electron density properties and interaction energy between salsalate and solvents are analyzed according to quantum chemical method.The results show that there are respectively two hydrogen bonding interactions between salsalate and methanol,ethanol and acetone,that interaction strength are different.The interaction energies of the three complexes indicate the differences of dissolving ability of salsalate in three solvents.Based on solubility data of salsalate in ethanol,the crystallization process parameters with ethanol as solvents and water as anti-solvent are optimized.The effects of crystal concentration,temperature,stirring rate,the flow rate of anti-solvent and the ratio between solvent and anti-solvent on crystal quality are respectively researched with crystal yield,particle size distribution and crystal habit,and then the better crystallization parameters are determined.Crystal concentration is 0.22 g/ml,temperature is 20 ?,-stirring rate is 150 rpm,the flow rate of anti-solvent is 1 ml/min and the ratio between solvent and anti-solvent is 1:3.