The recent years have witnessed the emergence of nitrosamines as a serious contaminant group in APIs from the sartan family. In this article, from Issue 11 of the Analytix Reporter, produced by Merck, a GC-MS method to determine nitrosamines in Valsartan tablets according to US FDA guidelines is described.

Nitrosamines_AR11The active pharmaceutical ingredient (API) valsartan is an angiotensin-Il- receptor blocker. It is used to treat hypertension, heart failure, and heart attack in patients intolerant to ACE inhibitor therapy. Valsartan belongs to a group of structurally related compounds known as sartans, having a tetrazole group (a ring with four nitrogen and one carbon) in common. Later, other nitrosamine impurities such as N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (NDIPA), N-nitrosoethylisopropylamine (NEIPA), and N-nitrosodibutylamine (NDBA) were found to be present in other medicines belonging to the sartan family, and in ranitidine drugs. The subsequent issue of a worldwide recall on pharmaceutical products using bulk valsartan drug substances lead to an interim shortage of valsartan-based drugs in the market.

This work presents a procedure for the determination of 5 nitrosamine impurities (NDMA, NDEA, NEIPA, NDIPA, and NDBA) in a valsartan drug product at trace levels by GC-MS/MS in EI MRM mode, according to US FDA guidelines. One of the FDA’s Office of Testing and Research (OTR) published methods was used as a base for method development. Method validation was conducted according to the requirements of USP.

The GC-MS/MS method used liquid injection to cover a broad range of nitrosamines. Contrary to the OTR method, a wax column with a thinner film thickness (0.5 µm instead of 1 µm) was chosen. This complied with the USP general chapter <621> on chromatography. The chromatographic conditions, as well as the MS/MS conditions are given in the full article.

The determination of nitrosamine impurities can be easily achieved by GC-MS/MS in MRM mode using the SUPELCOWAX® column based on the suggested method by FDA-OTR. All nitrosamines were well separated from each other as well as from the solvent and matrix peaks, meeting the system suitability requirements. The method was successfully applied for the analysis of a valsartan drug product spiked with nitrosamine impurities.

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Published  Feb 10, 2022

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