Development of GC-MS/MS Method for Simultaneous Estimation of Four Nitrosoamine Genotoxic Impurities in Valsartan.

Objectives: Recently, N-nitrosamines were unexpectedly detected in valsartan and other generic sartan products. Taking into this account, we developed a sensitive and stable multiple reaction monitoring mode-based "gas chromatography-tandem mass spectrometry (GC-MS/MS)" approach for the quantification of "four N-nitrosamines" in valsartan, especially, N-nitrosodiisopropylamine, N-nitroso ethyl isopropylamine, N-nitrosodiethylamine, and N-nitrosodimethylamine.

Materials and methods: GC and MS conditions were optimized with specificity, sensitivity, linearity, precision, and accuracy of the parameters. The approach was validated as per the "International Council for Harmonization" recommendations.

Results: The identification limits and limits of quantification of N-nitrosamines in valsartan varied between 0.02 and 0.03 ppm, and 0.06-0.09 ppm, respectively. The obtained values were satisfactory with limits established by the United States Food and Drug Administration for sensitivity requirements. The regression coefficients greater than 0.999 for four N-nitrosamines in the calibration curve demonstrated the strong linearity of the process. The retrievals of "N-nitrosamines" in valsartan between 91.9-122.7%. For the intra-day and inter-day accuracy studies, the (relative standard deviation) was less than 9.15%.

Conclusion: The proposed approach has rapid analysis capability, high precision, accuracy, and good sensitivity, which give a reliable approach for N-nitrosamines quality control in valsartan.