Thermodynamic Research On The Dissolution Process Of Pyrimidines And Molecular Dynamics Simulation

Pyrimidine drugs are widely used in many medical fields,such as anti-inflammatory,antipyretic,antifungal,antiviral and so on,among which the most popular is the research on the application of anti-cancer drugs.But whether in the actual production,storage or clinical use,poor solubility will affect and limit the application and clinical effect of pyrimidine drugs.Therefore,it is of great significance to study the solid-liquid equilibria of pyrimidine compounds in different kinds of pure solvents and mixed solvents,which can not only provide basic solubility data,but also provide reference for industrial production separation and purification,and help to screen crystal forms and dosage forms in drug application.In the temperature range of 283.15 K-318.15 K,the equilibrium solubility of thymine in DMF,2-butanone,methanol,ethanol,1,4-dioxane,1-butanol,acetone,1-propanol,2-propanol,acetonitrile and 5-fluorocytosine in ethyl acetate,DMSO,DMF,n-butanol,acetonitrile,1-propanol,2-propanol,2-propanol,butanone was measured by isothermal dissolution equilibrium method.The solvent effect was studied in single solvent.Hydrogen bond interaction and non-specific dipole/polarization rate interaction were beneficial to the dissolution of thymine and 5-fluorocytosine,while solvent-solvent interaction was not conducive to dissolution.The dissolution model of thymine and 5-fluorocytosine was established by molecular dynamics simulation.RDF analysis showed that the solute-solvent interaction had a strong correlation with solute solubility,and hydrogen bond interaction was the dominant factor,which promoted the dissolution of solute.The Modified Apelblat model and Wilson model were used to correlate the solubility data of thymine.The solubility of 5-fluorocytosine was correlated by Modified Apelblat model andλh model.The results showed that the solubility of two solutes in single solvent could be well correlated.In addition,the thermodynamic properties of the dissolution of thymine and 5-fluorocytosine are calculated.The results show that the dissolution of thymine and 5-fluorocytosine is an endothermic and entropy driven process.The equilibrium solubility data of thymine in DMF+methanol/ethanol mixed solvent system and 5-fluorocytosine in DMSO/DMF+2-propanol mixed solvent system at 283.15 K-318.15 K were measured by isothermal dissolution equilibrium method.The solubility of two solutes increased with the increase of temperature,and the solubility of thymine increased with the increase of DMF content.and the solubility of 5-fluorocytosine increased with the increase of DMF/DMSO content.Both thymine and 5-fluorocytosine showed preferential solvation,for thymine,DMF preferentially dissolved thymine.For 5-fluorocytosine,DMSO/DMF preferentially dissolved 5-fluorocytosine,and the preferential solvation was discussed by K_ps.In addition,Jouyban-Acree model and CNIBS/R-K model are used to correlate the solubility data of thymine and 5-fluorocytosine in mixed solvents.These two models can well correlate the solubility data of thymine and 5-fluorocytosine in mixed solvents,and show good correlation.Based on Van’t-Hoff equation and Gibbs equation,the thermodynamic properties of thymine dissolution process were calculated.The results show that the dissolution of two solutes in mixed solvents is an endothermic and entropy-driven process.The phase equilibria of the ternary system of 5-fluorocytosine+salicylic acid+methanol:water（2:1,v:v）at 308.15 K,318.15 K and 328.15 K were determined by wet residue method.With the decrease of temperature,the crystallization area of cocrystal gradually increases,which means that the lower the temperature is,the more conducive to the cultivation of cocrystal.The complexing mechanism and complexing form of 5-fluorocytosine and salicylic acid in solvent were discussed.The phase equilibrium data of 5-fluorocytosine and salicylic acid were fitted by nonlinear method,and the complexing model of solution was obtained.The cocrystal of 5-fluorocytosine and salicylic acid was obtained by solvent evaporation method.Through single crystal analysis,it is monoclinic system,space group of its monoclinic system is P2₁/n,a=8.1038（10）（?）,b=10.5008（11）（?）,c=13.5034（15）（?）,α=γ=90°,β=101.521°,V=1125.9（2）（?）³,and the hydrogen bond interaction is also studied by the Hirshfeld Surface method.