Polymorphism,Cocrystal And Salt Of Febuxostat:Preparation,Characterization And Properties

Febuxostat?2-[3-cyano-4-isobutoxyphenyl]-4-methylthiazole-5-carboxylc acid,FEB in short?is a non-purine selective inhibitor of xanthine oxidase which is used for lowering the level of serum uric acid?sUA?in vivo.FEB has become the most regularly and widely applied drug for the treatment of hyperuricemia in patients with gout.In this thesis,the main research was on polymorphism,cocrystal and salt of febuxostat.The solvent induced effect on the formation polymorphism and the pharmacokinetics of febuxostat polymorphism have been studied.What's more,several new cocrystals and salts of febuxotat have been prepared and characterized.This paper provides valuable basic data for screening out the advantageous solid form of FEB.This article includes the following content:?1?The ¹⁵N-labeled febuxostat was successfully prepared and added to acetonitrile,methanol,ethyl acetate and mixed solvents in different proportions.A significant shift in the¹⁵N peak in the ¹⁵N-NMR spectrum was found,indicating that the solvent induced effect can cause changes in the febuxostat configuration.Based on the theoretical calculation of CAM-B3LYP/6-311++G?d,p?/SMD,the cis conformer is dominant in methanol solution,the trans conformer turns to be dominant in acetonitrile,while the febuxostat exists as a mixture of cis and trans conformer in ethylethanoate.Therefore,the solvent is an important factor in inducing the configuration change of febuxostat,and the configuration of febuxostat is easily changed under the induction of the solvent.?2?This paper prepared febuxostat A,W,Z three crystal forms through methanol,ethyl acetate and acetonitrile solvents and characterized A,W,Z three crystal forms by powder X-ray diffraction?PXRD?,thermogravimetry?TG?,differential scanning calorimetry?DSC?,infrared spectroscopy?IR?,Raman and variable temperature powder X-ray diffraction?VT-PXRD?.The order of crystal thermal stability was found to be FEB-A>FEB-Z>FEB-W.?3?Study on the pharmacokinetics of three types of febuxostat:there was no significant difference in plasma concentration,peak time,and bioavailability of SD rats after oral administration of the three crystalline forms of FEB-A,FEB-W,and FEB-Z?P>0.05?;after oral administration of three crystalline forms of FEB-A,FEB-W and FEB-Z,the bioavailability of FEB-Z beagles was significantly greater than that of FEB-A and FEB-W?P<0.05?.These results show that after the crystalline drug was dissolved,the difference in polymorphism among the crystalline forms was lost,and the relative bioavailability in the three forms of rats was not significantly different.However,the bioavailability of FEB-Z crystals in beagles is higher than those of FEB-A and FEB-W crystals.The relative bioavailability of the FEB-Z crystal form is better than that of the marketed FEB-A crystal form.?4?Two cocrystals?namely FEB-BIP and FEB-TET?,two salts?namely FEB-AHP and FEB-DMAP·H₂O?and three salt solvates?namely FEB-MIN·ACE?FEB-MIN·THF and FEB-MIN·IPA?of febuxostat have been manufactured.The cocrystal,salts and salt solvates were characterized and thermodynamically analyzed by PXRD,SXRD,IR and TG-DSC.It was found that the obtained 7 solid forms could increase solubilities apparently.The stability of solvents in the salt solvates was involved in both steric hinerance and hydrogen bonds.This research work revealed that salt solvate was an important strategy to produce the solvent-free form and to improve the solubility.Considering the predominant configuration,safety and solubility of febuxostat,the FEB-TET cocrystal was finally selected as the optimal solid form.