Study On Phase Equilibrium And Dilution Crystallization Process Of Istradefylline

Istradefylline is the first adenosine A_2Areceptor inhibitor listed in the world.As a new generation of anti-Parkinson drugs,its research is mainly focused on pharmacology,toxicology,and chemical synthesis.There were few literature reports on its solid-liquid phase equilibrium and crystallization.Solubility data is an essential parameter in solid-liquid equilibrium and the basis of the crystallization process.The determination of solid-liquid equilibrium and the study of crystallization technology of istradefylline are of great value for the production and purification of istradefylline.In this paper,the solid-liquid phase equilibrium and crystallization process of istradefylline in different solvents were systematically studied,mainly from four aspects.（1）The solid-liquid equilibria of istradefylline in selected solvents were studied.The solubility of istradefylline in twelve single pure solvents（2-butanone,ethanol,methyl acetate,acetonitrile,ethyl acetate,n-propanol,n-Propyl Acetate,methyl propionate,butyl acetate,n-butanol,amyl acetate,DMF）and mixed solvents with different molar concentrations（ethanol+ethyl acetate,ethanol+2-butanone）were determined by the dynamic method.（2）This paper uses the Apelblat model,λh model,van’t Hoff model,and polynomial empirical model to correlate the solubility data of istradefylline in twelve pure solvents.The Apelblat model,λh model,was used to fit the solubility data of istradefylline in binary mixed solvents.Relative deviation（RD）,relative average deviation（ARD）,and root mean square deviation（RMSE）were used to evaluate the relevant results of the model.The fitting effects of each model are excellent.The fitting effect of the polynomial empirical model was the best in the pure solvent system,and the correlation degree of the Apelblat model was higher in the mixed solvent system.（3）Based on the measured solubility data of istradefylline,the thermodynamic properties of istradefylline in pure solvent and mixed solvent were calculated by van’t Hoff equation,namely the enthalpy of dissolution（ΔH_d）,dissolution entropy（ΔS_d）,and the Gibbs free energy of dissolution（ΔG_d）.The contribution value of relative enthalpy was calculated（ξ_H/%）and relative entropy contribution(ξ_TS/%)to judge the driving force of the dissolution process.The results show that the dissolution process of istradefylline in pure and mixed solvents was endothermic and entropy increases The enthalpy of dissolution was the main contributor to the Gibbs free energy of dissolution.（4）The crystallization process of istradefylline in DMF was studied by dilution crystallization and cooling crystallization.The yield,crystal morphology,and particle size distribution of the products of the two crystallization methods were analyzed and compared.It was determined that the dilution crystallization process of istradefylline was mainly studied.The effects of different crystallization conditions（initial concentration of crystallization solution,volume fraction ratio of solvent and dissolving agent,drop acceleration rate of the dissolving agent,crystallization temperature,and aging time）on the dilution crystallization process of istradefylline were studied by controlling a single variable method.The crystal yield,particle size distribution,and crystal morphology were used as evaluation criteria.By analyzing various influencing factors,better crystallization conditions of istradefylline were obtained:the initial concentration of crystallization solution was 12 mg/ml,the volume fraction ratio of water and DMF was 3:1,the drop acceleration rate was 2 ml/min,the crystallization temperature was 20℃and the aging time was 60 min.The short needle shape of istradefylline crystal was obtained through this scheme,and the yield,average particle size（MS）,and coefficient of variation（CV）were93.7%,12.6%,4.25μm.It provides the fundamental basis and reference for the industrial preparation of high-quality istradefylline products.Through the determination of solid-liquid phase equilibrium data and the study of the crystallization process of istradefylline,this subject provides a certain theoretical basis for the separation,purification,and industrial production of istradefylline.