Determination of N-nitrosodimethyl amine impurity in valsartan by HPLC and LC-MS/MS methods

Abstract

In this study, two novel, rapid, sensitive, and specific chromatographic methods were developed and validated for the determination of N -nitrosodimethylamine (NDMA) impurity in the valsartan drug substance. The first method is a high-performance liquid chromatography method with a diode array detector (HPLC-DAD). The method was validated according to ICH Q2 (R1) guidelines and was used for the determination of NDMA in valsartan drug substances from different suppliers. Satisfactory validation results were obtained in terms of linearity with a range from 9.10 to 29.5 µg L −1 and R 2 = 0.994, precisions with a coefficient of variation of 1.2%, accuracy with recovery between 94.5% and 103.1%, limit of detection (LOD) and limit of quantitation (LOQ) were 0.0027 and 0.0091 mg kg −1 , respectively. Assay of NDMA in valsartan drug substances using the developed HPLC-DAD method showed that samples from Zhejiang Huahai supplier, obtained between 2012 and 2017, contained high levels of NDMA that exceed the acceptable limits with an average concentration of 59.3 mg kg −1 . On the other hand, the new Zhejiang Huahai samples, obtained after November 2018, did not show significant contamination with NDMA. For confirmation of our results, a second method was developed which is the liquid chromatography method with tandem mass spectrometry detection (LC-MS/MS). The new LC-MS/MS method was developed and validated for confirmation of the results of the NDMA assay in the new valsartan samples obtained from Zhejiang Huahai after November 2018. The new LC-MS/MS method has been more selective than the HPLC-DAD method with LOD and LOQ values of 0.0021 and 0.0070 mg kg −1 , respectively. The results of LC-MS/MS show good agreement with those obtained with the HPLC-DAD method.