Synthesis Of XTandi And Preparation Of Solid Dispersion

XTandi(enzalutamide),joinly developed by Medivation company of the US and Astellas of the Japan,is a drug for the treatment of castration resistant prostate cancer.XTandi is almost insoluble in water,and its bioavailability is low.In this paper,XTandi was be prepared into solid dispersion to improve the solubility of drugs in water and improve the oral absorption rate of drugs.The research contents of this paper were as follows:1.The Synthesis of XTandi:In this paper,we synthesised XTandi's two intermediates: N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methyl-alanine methyl ester and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile.Finally,the two intermediates occured ring closure reaction to give the desired product XTandi.the product was white powder in a yield of 70%.The structure of XTandi was confirmed by infrared absorption spectrum,nuclear magnetic resonance spectroscopy,mass spectrometry;The purity of XTandi was determined by HPLC.2.The preformulation study of XTandi solid dispersion:The physical and chemical properties of Xtandi raw materials were studied,including the dissolution of drugs in different solvents,and the changes of the properties and absorbance with time under the condition of high temperature or high humidity.UV-Vis analysis In vitro was established for XTandi,and the method for solid dispersion's determination of the content and dissolution were Determined.3.The preparation study of XTandi solid dispersion: In this paper,CoPVP,PEG6000,PEG4000 and PVPk30 were used as carriers to prepare XTandi solid dispesion by solvent method,melting method and solvent melting method.Based on the dissolution of SD in dissolution medium,This paper studied influence of the carrier types,preparation methods,drug-carrier ratio,experimental time,experimental temperature and solvent dosaget on the solid dispersions of dissolution and determines the best preparation technology.Final formulation: the solvent method was chosen as the preparation method,methanol as solvent,CoPVP as carrier,drug-carrier=1: 5(1 g: 5 g),the experimental time was 30 min,the experimental temperature was 50 ?.The raw materials were almost insolubled in 45 min,and the dissolution of the solid dispersion reached 76.8%.4.The quality standard study of XTandi solid dispersion:In this paper,differential scanning calorimeter,X-ray powder diffraction,infrared absorption spectroscopy and scanning electron microscopy were used to identify XTandi raw materials,CoPVP,solid dispersion and physical mixture.The results showed that the XTandi in the physical mixture existed in the form of crystallization,and the appearance of XTandi in the solid dispersion had changed obviously,and no crystal exists.In addition,this paper studied the influence of high temperature,high humidity,strong illumination,accelerated test,long-term test on characters,content,dissolution of solid dispersion,which showed that XTandi solid dispersion should be stored under low temperature,dry,sealed conditions.