Research Of Analytical Methods For Nitrosamine Genotoxic Impurities And Their Precursors Nitrite In Irbesartan

Genotoxic impurities refer to some exogenous substances that can damage genetic materials(DNA,chromosome),also known as genotoxic impurities.The purpose of genotoxic impurities research is to identify genotoxic hazards,to investigate whether the target impurities will cause damage to genetic material,and then reduce the exposure risk.In July 2018,the "valsartan incident" caused by Zhejiang Huahai pharmaceutical Co.,Ltd.caused a sensation in the entire pharmaceutical industry,which revealed that there are many major flaws in the assessment strategy of genotoxic impurities of relevant domestic pharmaceutical R&D and production enterprises.The scourge is not alone,and then more types of genotoxic impurities have been detected in more drugs internationally.National regulatory authorities have proposed that relevant companies and R&D units have the responsibility to develop and use appropriate methods to detect genotoxic impurities.As the main research object of this event,nitrosamines genotoxic impurities are defined as substances with high carcinogenicity.Therefore,such impurities in drugs should be strictly controlled.However,nitrosamines rarely exist in nature,and their prerequisites nitrite and amines are very common.Under certain conditions,the two react to form nitrosamines,so nitrite should also be studied and controlled.In this thesis,the morden chromatographic and mass spectrometry analysis techniques HPLC-MS/MS(high performance liquid chromatography tandem mass spectrometry)and IC(ion chromatography)method are used to analysis 6 kinds of nitrosamine genotoxic impurities such as NDMA,NMBA,NDEA,NEIPA,NDIPA,NDBA and their precursor-nitrite.The detection methods are developed respectively to ensure the safety and reliability of drugs.The first part of this thesis uses ion chromatography to analyze the nitrite in irbesartan.The specific of inorganic anions in ion chromatography was used to analyze the nitrite.The sample was pretreated by extraction separation method,and the suitable extraction solvent and diluent were selected.After selecting Dionex IonPac AS18 ion chromatographic column,the chromatographic conditions such as column temperature,flow rate and eluent concentration were optimized to ensure the sensitivity and analytical efficiency of detection.Then the methodology validation was established.The method is proved to be sensitive,accurate and specific.The second part of this thesis uses high performance liquid chromatography tandem mass spectrometry to analyze six nitrosamine genotoxic impurities in Irbesartan.The experiment was conducted using an atmospheric pressure chemical ionization source(APCI)in positive ion mode.Use needle pump injection to confirm the qualitative and quantitative ion pairs of 6 impurities,and select the optimal mass spectrometry parameters such as declustering voltage(DP),collision voltage(CE),atomizing gas(GS1),collision gas(CAD),and Chromatographic parameters such as column temperature,flow rate,mobile phase and gradient conditions ensure the sensitivity and specificity of the detection.Finally,the method is proved to be specific,accurate and reliable,and can meet the detection requirements.