Study On Phase Equilibrium Thermodynamics And Quantum Chemistry Of Phenylurea-Nitrobenzoic Acid Cocrystal Production

The organic cocrystal materials from urea as the main molecule with nitrobenzoic acid has been continuously studied and reported.However,most of the studies are focused on the design,synthesis,reaction mechanism and property characterization of the cocrystal molecules,which cannot provide systematic methods and theoretical guidance for the engineering expansion or high purity preparation of organic cocrystal materials.Therefore,this paper takes the phenylurea-nitrobenzoic acid cocrystal as the research object,explores its solubilityand crystallization related thermodynamic contents under different temperature and solvent conditions,draw the equilibrium phase diagram of the ternary system on this basis,and use the phase diagram to guide and improve the crystallization process operation of organic cocrystal.The details of the study are as follows:(1)The solubility of phenylurea in methanol,ethanol,n-propanol,n-butanol,isopropanol,isobutanol,ethyl acetate,1,4-dioxane,1,2-dichloroethane,acetonitrile,N,N-dimethylformamide(DMF),dimethyl sulfoxide(DMSO),N-methylpyrrolidone(NMP),ethylene glycol(EG)and water were determined using the isothermal dissolution equilibrium method within the temperature range of 283.15 K-323.15 K,The solubility of phenylurea in fifteen solvents increases with increasing temperature.The measured solubility data were correlated using four thermodynamic models with maximum average relative deviation(RAD)and root mean square deviation(RMSD)values of 69.47 × 10-4 and 5.61 × 10-2.In addition,the effect of solvent effect during the dissolution of phenylurea was discussed and the related dissolution properties such as entropy of dissolution,enthalpy of dissolution and Gibbs free energy of dissolution were calculated.The interaction parameters were obtained to provide basic data for the synthesis study of phenylurea-nitrobenzoic acid cocrystal.(2)The solubility data of the phase equilibrium of the ternary system of phenylurea-o(m)-nitrobenzoic acid solvent at 298.15 K and 313.15 K with ethanol,ethyl acetate and acetonitrile as solvents were determined by the wet slag method,and the corresponding ternary phase diagrams were plotted to determine the single-phase and cocrystal regions;Phenylurea-o(m)-nitrobenzoic acid cocrystal was characterized by X-ray diffraction analysis,infrared spectroscopy,differential scanning calorimetry and morphological analysis.The NRTL model was used to regress the solubility data to obtain the interaction parameters of phenylurea-o(m)-nitrobenzoic acid and the solubility product constants of the cocrystal,which provide methodological guidance and theoretical basis for the expanded preparation of the cocrystal.(3)Taking phenylurea-o(m)-nitrobenzoic acid cocrystal as the research object,the geometric structure was optimized through Gaussian 09 molecular simulation software,its surface electrostatic potential and weak intermolecular interaction were analyzed,and its binding energy in different solvents was calculated,so as to better understand cocrystal.