Study On Crystal Form Of The Antihypertensive Drug Irbesartan

Irbesartan,white or analogous white power,chemical name 2-butyl-3-[4-[2-?1H-tetrazole-5-radical?phenyl]benzyl]-1,3-diazaspiro-[4.4]nonyl-1-alkene-4-ketone,the molecular formula C₂₅H₂₈N₆O with molecular weight 428.5,is known as an angiotensin II receptor blocker.Irbesartan showes very good therapeutic effect on treatment of hypertension or blood diseases such as left ventricular hypertrophy,diabetic nephropathy and heart failure.It belongs to polycrystalline drug,the patent CN1061656C published crstal forms A and B and relevant preparation methods.In fact,during the production,form A is used for drug preparation because of its good stability and high bioavailability.The paper is devoted in study on the crystal forms of Irbesartan.The spherical granule products of Irbesartan form A without static electricity was first prepared successfully.Secondly,a single crystal of form B was obtained by recrystllization from different solvents,and its crystal structure was solved.The influence of the preferential orientation of polymorphic form B on its physicochemical properties was preliminarily studied.Finally,the amorphous product of Irbesartan was successfully obtained using rotary evaporative technology,and its physicochemical properties were also analyzed by various test techniques.The specific contents are as follows:?1?The method to prepare spherical granule products of form A was developed by rapid cooling technology and it can successfully eliminated static electricity resulted in the troditional preparation process.The properties of form A spherical granule product of Irbesartan were then analyzed by XRD,SEM,DSC and TSM.The above results indicate this technology can not only eliminate static electricity phnomenism,but also increased product size and yield.Meanwhile this product shows better stability at the 40±3?,60±5%RH conditions.Furthermore,the spherical granule product of have better mobility and apparent solubility compared with the product prepared by traditional technology.?2?Perfect single crystals of Irbesartan form B were cultivated by accurately controling the experiment conditoins.A single crystal was selected for X-ray single crystal diffraction testing and the relevant crystal structure data of form B were calculated to be a triclinic,P-1?2?space groups with cell parameters:a=9.3445?7??,b=11.1434?9??,c=12.1603?8??,?=112.910?7?°,?=90.739?6?°and?=105.208?7?°.Its unit cell volume is estimated as V=1116.05?17??³ and Z=2.The melting point of form B single crystals was mesured to be188.82?,and apparent solubility is 6.26 mg/m L.?3?Finally,a new Irbesartan polymorphic form,amorphous form,was prepared by rotary evaporation technology.The preparation method as follows:a certain of Irbesartan was first dissolved in a mixture of alcohol and water under stirring,and then heated up to 70?until compeletly clear.Above solution was evaporated under a vacuum degree 0.09⁰.1 MPa and rotate speed?200 r/min?for 1 hour.The amorphous solid powder will graduallly precipitate with the solvents gone.PXRD pattern of the amorphous product shows two very broad diffraction peaks at12.86°and 19.58°,respectively.DSC results indicate that a solid-solid irreversible phase transformation,from the amorphous into form A,occurs in the temperature range of 125¹65?.In addition,the amorphous form exhibits best apparent solubility with 10.52 mg/m L compared with the other two forms.Owning to microstructure of slice layer with size of 5²0?m,it has good fluidity and is potential as API for drugpreparation production.The study on crystal form of Irbesartan first solved the serious static electricity problem of form A.Single crystals of form B were then cultivated and its crystal structure was solved.Furthermore,amorphous form was prepared by rotary evaporation technology,which shows good physical and chemical properties and is suitble to be API for drug preparation.