Research Of Lisinopril And Losartan Potassium Process Impurities

This paper studied the process impurities which affected the quality of lisinopril and losartan potassium by using LC-MS and LC-PDA-QTOF.The chemical structures of the process impurities were finally confirmed by comparing the structural differences with the parent drugs and analyzing the characteristics of mass spectrometry.According to the chemical structures of the impurities,the way of the impurities formation was inferred and demonstrated based on the synthesis process and the processing controlling conditions.After that,by improving the process parameters and controlling the conditions,the impurities were reduced or removed;and the quality of the products was controlled.The main research contents are as follows.1、Study of Lisinopril Impurity1.1 Impurity Study of the ProductThere were two of abnormal impurity peaks founded in HPLC chromatogram which were confirmed to be unknown impurities by comparing with the relative retention time and mass spectrometry data of the known impurities listed in the ChP,USP and EP.By using low resolution LC-MS to make a analysis of the differential structure fragment of the process impurities in the product,impurities differences of molecular weight were compared with parent drug.The possible chemical structures were deduced.On this basis,the precise structures of impurities were confirmed by performing degradation experiments based on the product process using high-resolution mass spectrometry.These two impurities were identified as(S)-1-(S)-(2-(((S)-1-carboxyl-3-phenyl propyl))amino-6-(3-carboxyl propylene amide)f acyl)pyrrole-2-formic acidand(S)-1-(S)-(6-amino-2-(((S)-1-carboxyl-3-phenyl propyl)amino)amide)-2-(((S)-1-carboxyl-3-phenyl propyl)amino]pyrrole-2-formic acid acyl),respectively.1.2 Study of the Way of the Impurities Formation and the Quality ControlAccording to the process route of the product,we analyzed the synthetic route and possible mechanism of the target impurities.By changing reaction conditions and optimizing process parameters,the contents of the impurities can be reduced to an acceptable level,or even avoided and in such a way that the product quality was controlled effectively.In summary,based on the structural analysis of the unknown impurities in lisinopril and their generating mechanism,the contents of the impurities were significantly reduced by taking the corresponding workshop production control measures and the product quality was effectively ensured.2、Impurity Study of Losartan Potassium2.1 Impurity Study of the ProductUsing LC-PDA-QTOF,we analyzed and confirmed the chemical structure of the process impurity in losartan potassium.RRT1.12 impurity could affect the quality of the product and its structure was finally elucidated by comparing the MS,MS/MS and UV spectrum with its parent drug losartan.2.2 Study of the Way of the Impurity Formation and the Quality ControlBased on the structure of the impurity and the production process of the product,the carboxylic acid derivative(2-[4-(2-butyl-4-chloro-5-(hydroxymethyl)-imidazole]phenyl]benzoic acid)of losartan was proved to be the impurity that affected the quality of the product generated by the hydrolysis of chlorinated nitrile in the process of post-treatment processing.The chlorinated nitrile was employed as the key material in reaction process and it couldn’t react completely during the tetrazolium reaction.By adjusting the reaction parameters and extending the time of reaction,the impurity content was significantly decreased to below the limit of report(NMT0.02%)in the final product.Our studies have shown that the impurity could be detected quickly by using LC-PDA-QTOF.The impurity has been effectively controlled by adjusting the process control conditions,the quality of losartan potassium finished product was improved and also the yield of losartan potassium was increased simultaneously.