Development and Validation of four Nitrosamine Impurities Determination Method in Medicines of Valsartan, Losartan, and Irbesartan with HPLC-MS/MS (APCI).

Abstract

Since 2018, regulation and control of genotoxic nitrosamine impurities levels have been a mandatory quality and safety characteristic for various drugs. The main issue of nitrosamine determination in drugs is a low sensitivity of the existing methods and a continuously extending list of controlled compounds. The reason is the low safe daily dose of these impurities and chromophores’ absence within their structure. Development and validation of a method for nitrosamine impurities (regulated by the regulatory authorities) determination in Valsartan, Losartan, and Irbesartan using high-performance liquid chromatography with mass spectrometry detection. An Agilent Infinity II chromatographic system with a mass spectrometric detector (MSD 6460 Triple Quad) and atmospheric pressure chemical ionization was used in this study. During the development of a method, the optimal conditions for chromatographic separation (composition of mobile phases, gradient parameters) were selected, as well as the parameters of mass spectrometric detection were optimized. The usage of chemical ionization made it possible to achieve the method’s maximum sensitivity concerning the studied nitrosamines, and the optimized parameters of mass spectrometric detection made it possible to get rid of the matrix effect. The absence of additional stages of purification and concentration can significantly reduce the total time of the analysis, which is a significant advantage of nitrosamine’s advanced determination method. The resulting method was validated for specificity, linearity, LOQ, LOD, accuracy, and precision. Resulting method met all acceptance criteria and can be used for routine quality control of Valsartan, Losartan, and Irbesartan pharmaceutical substances.