Study On The Quality Standard And Stability Of Ambrisentan API And Ambrisentan Tablets

Ambrisentan,a non-peptide,is an orally active and highly selective endothelin-1 type endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension(PHA),developed by Myogen Inc.It’s described chemically as(2S)-2-[(4,6-dimethyl-pyrimidin-2-yl)oxy]3-methoxy-3,3-diphenylpropanoic acid.It blocks the effects of endothelin-1 which can constrict the arteries in lungs.Ambrisentan is approved by the US Food and Drug Administration in 2007.Ambrisentan was synthesized from 2-Hydroxy-3-methoxy-3,3-diphenylpropanoic acid methyl ester.By condensation with 4,6-Dimethyl-2-methylsulfonylpyrimidine,after basic hydrolysis,racemic ambrisentan was obtained.At last,ambrisentan was gain by resolving with L-1-Phenylethylamine.To the best of our knowledge,the quality standard of Ambrisentan is not official in pharmacopoeias.In this paper,according to related drug development guidelines from Chinese Food and Drug Administration,it is a systematic study of ambrisentan quality which contains character,physic-chemical characteristics,impurity profile,assay of API,and degradation product analysis,dissolution,content uniformity.The quality standard was drafted by then.And this paper compares the consistency of product quality with the original product in vitro.The QS limit value is formulated by the stress testing,long-term studies,and accelerated studies.This study is consisted of the following four parts:PART I The quality standard and stability of Ambrisentan API1、The study of the impurity profile and the quality standard for Ambrisentan API The main impurity contains organic impurities(related substance generateddur in the synthesis manufacturing and the shelf life)、organic volatile compound and inorganic impurities.There are 5 potential impurities((S)-1-phenylethanamine,4,6-dimethyl-2-(methtylsulfony)pyrimidine,Methyl 2-hydroxy-3-methoxy-3,3-diphenypropanoate,Methyl 2-(4,6-dimethylpyrimidin-2-yl)oxy-3-methoxy-3,3-diphenylpropanoate,and 2-((2,2-diphenylvinyl)oxy)-4,6-dimethylpyrimidine)which is determined by HPLC with the correction factor,and other unknown impurities.The R isomer in ambrisentan is separable by chiral column.By the GC with headspace sampler,the residual solvents(methanol,ethanol,methyl-butyl ether,ethyl acetate,dioxane and N,N-Dimethylformamide)in ambrisentan can be determined accurately.2、The determination of the assay for ambrisentan in API.Benzene ring and carboxyl group conjugated structures exit in the API’s chemical structure.HPLC and neutralization titration validating is used to control the content of ambrisentan.3、The stability of Ambrisentan API During the stress testing for high temperature、high humility and photo stability testing,and after accelerated stability testing for 6 months and long term stability for 24 months,the description,water,related substance,isomer,and assay shows insignificant change.Ambrisentan API is stability.PART Ⅱ The quality standard and stability of Ambrisentan tablets1、The study of impurity profile in Ambrisentan tablets.The related substance was determined by HPLC with the correction factor.The R isomer in ambrisentan tablets is separable by chiral column.Comparing with the original product in impurity profile and assay,the general drug is the same as the original product in preclinical.2、The study of dissolution.Comparing 4 dissolution curves to evaluate Dissolution behavior in vitro consistency with original products,the most discriminatory method was selected for the dissolution standard.It is reached that the dissolution behavior in 4 different mediums(water,pH 1.0,pH 5.0 and pH 6.8 buffered salt solutions)among 3 bathes of samples manufacturing for their uniformity in the intra-assay and the inter-assay.3、The study of assay.A specific,sensitive and accuracy HPLC method was established.4、The study of content uniformity.A RP-HPLC method was developed for the content uniformity test,which is specific,simple,rapid and accuracy.5、The stability of Ambrisentan tablets.During the stress testing for high temperature、high humility and photo stability testing,and after accelerated stability test for 6 months and 18 months long term stability,the description,related substance,isomer,dissolution and assay show insignificant change.Ambrisentan tablets are stability.