Polymorphism Of Febuxostat

Febuxostat,as an anti-gout drug,has been studied systematically,including the preparation of crystals,characterization,solubility and dissolution,the transformation of Form A and Form C in heating process,the stability of crystal state,and the establishment of effective crystal quality control methods.In order to ensure the effectiveness,safety and quality control of the drug,the research on febuxostat's polymorphs provides the basis for the selection of dominant crystal,the detection and control of effective crystal,the optimization of production process,the determination of storage and transportation conditions,and the formulation of quality standards.The contents are as follows:(1)Four typical crystal forms(Form A,Form C,Form G and amorphous)of febuxostat were prepared and characterized by PXRD,DSC,TGA,FT-IR,Raman,PLM,DVS and melting point instrument.An effective qualitative analysis method was established for the identification of four polymorphic forms of febuxostat,which provided basic data for the quality control of the crystal forms of API;(2)The solubilities and dissolution rates of four febuxostat polymorphs in vitro were evaluated by equilibrium solubility experiment and inherent dissolution rate experiment.It was found that febuxostat was a p H-dependent product.In different p H buffers,the higher the p H value,the higher the solubility is in the buffer with p H value of 1.2,4.5,5.0 and 6.8,respectively.The equilibrium solubilities and intrinsic dissolution rates of the four polymorphs were listed in this order from high to low: amorphous,Form C,Form A and Form G;(3)The single crystals of Form A and Form C were cultured.The results of the hot stage microscope,DSC and PXRD experiments showed that there was a melting transition phenomenon of Form A and Form C in the heating process.It could be inferred that the double peaks in DSC spectrum should be caused by crystalinter conversion rather than mixed crystal when PXRD spectra and other characterization results were normal.In addition,the effects of different heating rate and sample particle size on DSC patterns were also investigated,which provided a reasonable explanation for the phenomenon that some DSC patterns of the same drug substance with the same crystal type showed double peaks and some showed single peaks.More information was provided for the quality control of API through the study of thermal transformation of Form A and Form C.(4)Taking Form A as the research object,the stability of Form A under the experimental conditions of influencing factors and of wet granulation process on the polymorphic state was investigated.The results showed that Form A was relatively stable under the conditions of high temperature,high humidity,light and pressure,and easy to store;under the wet granulation process,crushing and pressure had no effect on Form A,crushing and the platen would not change the crystal form.However,it was easy to re-crystallize in contact with water under high temperature and agitation conditions.In the preparation process,the risks of crystal izing caused by using water as solvent under high temperature and agitation conditions should be ful y considered.(5)A quantitative analysis method of Form G in the binary mixed crystal system of febuxostat tablet was established based on PXRD technology.The verification data showed that the method had good accuracy,precision and sensitivity.It could be used for the quantitative analysis of the polymorph of the drug substance in febuxostat tablet,so as to monitor the effective crystal form of the drug substance in the preparation.