Thermodynamics And Polymorphic Transformation Mechanism Of Probenecid-4,4’-Azobispyridine Cocrystal

Cocrystals are a new type of solid with improved physical and chemical properties compared with the original material.The physical and chemical properties of cocrystals with different polymorphs differ greatly.Researches on the thermodynamics and polymorphic transformation behavior of cocrystals can provide important theoretical basis for cocrystal preparation,polymorphic screening and industrial scale-up.The cocrystal probenecid-4,4’-azopyridine is the first case of multiple-stimuli-responded crystal material so far,which can twist and bend as an elastically flexible crystal in responds to external stimuli.In this paper,probenecid-4,4’-azopyridine cocrystal was selected as the model system,and its thermodynamics of crystallization process and polymorphic transformation process were studied.Probenecid-4,4’-azopyridine cocrystal form I and form III was prepared by solution cocrystallization in bulk amount for the first time.The new method can save a lot of time and help scale up in industrial production.The ternary phase diagrams of probenecid-4,4’-azopyridine cocrystal form I at298.15 K in three pure solvents acetonitrile,ethanol and ethyl acetate and that in acetonitrile at 308.15 K were determined.The effects of different solvents and temperatures on the ternary phase diagram of probenecid-4,4’-azopyridine cocrystal were investigated.The operating area and the optimal solvents and temperatures of the subsequent cocrystallization process were determined.Furthermore,the second form of the 1:1 + 2:1 complexation model was used to fit the experimental data and the functional relationship of the cocrystal solubility and the concentration of the coformer4,4’-azopyridine was obtained.The solubility of probenecid-4,4’-azopyridine cocrystal form I from 273.15 K to313.15 K in six pure solvents and two binary solvents was measured.As the temperature increases,the solubility of cocrystals increases.Five models were used to correlate the solubility data,providing great correlation and accuracy.Besides,apparent dissolution thermodynamic properties were obtained the result of which shows that the process of dissolution of form I of probenecid-4,4’-azopyridine cocrystals is spontaneous,endothermic and driven by entropy.The solvent-mediated phase transformation processes of probenecid-4,4’-azopyridine cocrystal form I and form III were studied.The two polymorphs were determined to be interconversion systems in solution.The temperature of phase transformation and controlling steps of processes were also determined.The effects of temperature,solid phase loading and seed addition on transformation processes were investigated.In addition,Avrami-Erofeev model was used to fit the experimental data with dynamics of phase transformation,the result of which showed well.