Study On Solid-liquid Phase Equilibrium Of Probenecid Based On Molecular Simulation

In this paper,our experiments combined with software simulation could explain the microscopic mechanism,the liquid-solid equilibrium of probenecid was systematically studied.The laser dynamic method was used to determine the solubility of probenecid in eleven single solvents and two mixed solvents.The solubility of probenecid was found to increase with increasing temperature.The order of solubility in the single solvent is:DMF>acetone>ethyl acetate(alcohols)>chloroform>acetonitrile.In the mixed solvent of acetone and ethanol,the solubility increased first and then decreased with the increase of the mole fraction of acetone.The maximum value could be detected when the molar fraction was 0.60.In the mixed solvent of acetone and acetonitrile,the solubility increased with the increase of acetone mole fraction.The thermodynamic model Apelblat equation,Van't Hoff equation,?h equation,and J-A model were used to fit data,and thermodynamic functions were further solved.Molecular simulations of solid-liquid phase equilibrium of probenecid using Materials Studio(MS)software:The learning table of Blends module was used to calculate the thermodynamic mixing variables of probenecid in different solvent molecules and different temperatures.The results showed that the order of the compatibility of probenecid and solvent was DMF>acetone>ethyl acetate>ethanol>acetonitrile at 293 K.The compatibility was improved with the increase of temperature,which was consistent with the experimental results.In the DMol3 module,the generalized gradient approximation method in density functional theory was used to optimize the molecules under the appropriate functional,basis set,and parameters.The Forcite and DMol3 modules were used in turn to optimize the combination and to accurately calculate.As a result,the absolute value order of the interaction energy of probenecid and solvent molecules was as follows:DMF>acetone>ethyl acetate>ethanol>chloroform>acetonitrile.Except for chloroform,hydrogen bonds were formed with the other five kinds of solvent molecules.The larger the binding energy is,the smaller the hydrogen bond distance is.The Amorphous Cell module was used to create a true ratio solution box.Optimize the box,followed by NPT and NVE ensemble for molecular dynamics calculations,calculate the radial distribution function(RDF).Result indicates that the first RDF peak of probenecid in acetone,ethanol,and acetonitrile was sharper,respectively at 1.3 A,2.1 A,and 2.2 A.It was proved that the binding strength was greater,so the order was acetone>ethanol>acetonitrile.Probenecid and acetone not only form Hydrogen bonding but also may be present in the form of covalent bonds.Because the peak was at 1.7 A,and the interaction was strong and the hydrogen bonding was dominant in the mixed solvent.And according to the peak changes can explain the "solubilization" phenomenon.Explore the crystallization process of probenecid in ethanol solvent,The best crystallization conditions were as follows:stirring speed 250 rpm,anti-solvent dropping rate 2.0 mL/min,crystallization temperature 25 ?,and crystal growth time 30 min.