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

OBJECTIVES

Recently, -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 -nitrosamines" in valsartan, especially, -nitrosodiisopropylamine, -nitroso ethyl isopropylamine, -nitrosodiethylamine, and -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 the "International Council for Harmonization" recommendations.

RESULTS

The identification limits and limits of quantification of -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 -nitrosamines in the calibration curve demonstrated the strong linearity of the process. The retrievals of "-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 -nitrosamines quality control in valsartan.