Study On Crystal Form Of The Hypotensive Drug Azilsartan

Azilsartan is an angiotensin Ⅱ receptor antagonist drug used to treat hypertension.It is currently the only angiotensin Ⅱ receptor antagonist（Sartan）drug used in end-stage clinical trials.This article studies the polymorphic phenomenon of Azilsartan.The content includes preparation of Azilsartan single crystal and analysis of its structure,developing a new simple and efficient process for the preparation of amorphous Azilsartan and studying the effect of amorphization on the dissolution performance of Azilsartan.The details are as follows:（1）Azilsartan crystal form I single crystal was prepared by slow solvent evaporation method.Single crystal X-ray diffraction analysis was performed on Azilsartan single crystal with suitable crystal grain size,and its crystal structure was analyzed.After analysis,it can be seen that the obtained crystal is Azilsartan crystal type I single crystal,which belongs to the monoclinic crystal system,and its unit cell parameters are as follows:a=9.7094（7）（?）,b=11.2885（7）（?）,c=19.5538（14）（?）;α=90°,β=91.729（3）°,γ=90°,V=2142.2（3）（?）3,Z=4,and the space group is P21/c.A single unit cell is composed of four Azilsartan molecules connected by hydrogen bonds-NH...N,-CH...O and-OH...O.In addition,the preparation process of the crystal form I Azilsartan was optimized,and the polymorphic crystal form I was obtained by the crystallization process of low-temperature crystallization.The physical and chemical properties of Azilsartan of crystal formⅠsingle crystal and polycrystalline Azilsartan were compared.（2）A mixed solvent of ethyl acetate and ethanol is selected,and the solvent is quickly removed by rotary evaporation technology to obtain amorphous Azilsartan.The amorphous and crystalline form I Azilsartan were characterized by powder X-ray diffraction,infrared spectroscopy,thermogravimetric analysis,scanning electron microscopy and high performance liquid chromatography.It is determined that the Form I has better thermal stability,and the prepared amorphous Azilsartan does not contain crystal impurities and is completely amorphous.The results show that the obtained amorphous azilsartan completely amorphous type.Compared with the crystal form I,the amorphous form has a sheet-like structure,has a larger specific surface area,and exhibits a good apparent solubility(2.26×10^-3 mg/m L)（3）The dissolution properties of Azilsartan crystal form I and amorphous form were studied.Comparing the hardness and disintegration time limit of the amorphous and crystal form I Azilsartan tablets,it can be seen that the amorphous Azilsartan tablets have high hardness and short disintegration time.Observing the dissolution curve,it can be concluded that the complete dissolution time of crystal form I is 55 min,and the cumulative dissolution rate is86%;the complete dissolution time of amorphous form is 40 min,and the cumulative dissolution rate is 94%.It can be seen that the dissolution rate and dissolution rate of the amorphous form are better than those of the crystal form I.Amorphous form is significantly better than medicinal crystal formⅠdue to its particle size,fluidity,dissolution rate and solubility.Therefore,the amorphization of Azilsartan can improve the dissolution performance of the bulk drug formulation and is expected to be used in formulations.