Analysis of Nitrosamines and Nitrosatable Compounds

Analysis of Nitrosamines and Nitrosatable Compounds in Pharmaceutical Active Ingredients using LCMSMS Nitrosamines are chemically highly active molecules with a structure generally expressed as «R2N-N=O». During the production process, due to high pH, temperature and the effects of chemicals used, they can form in many industrial products such as synthetic pharmaceuticals, chemical substances, tobacco, animal-derived foods, rubber and elastomeric products. Within this group, particularly NDEA and NDMA are classified as Group 2A carcinogenic substances by IARC due to their genotoxic carcinogenic effects. Following the detection of N-nitrosodimethylamine (NDMA) impurity in the valsartan pharmaceutical active ingredient, the European Medicines Agency (EMA) reported in its 5 July 2018 report that a decision was made to investigate whether this substance was present as an impurity in other valsartan-containing medicines. In the EMA's 21 August 2018 report, it was noted that another nitrosamine derivative, NDEA, was detected in trace amounts in some medicines containing losartan, and following this development, a decision was made to preventively examine other 'sartan' medicines with similar chemical structure in addition to valsartan. In this study, analysis of nitrosamines and nitrosatable compounds was conducted using a Shimadzu LCMS-8040 Triple Quadrupole LCMSMS system with a simple, rapid and reliable method.

Analytical Conditions:

MRM Transitions*

LC Conditions:

Results and Evaluation:

In this study, a calibration curve was drawn for NDMEA and NDEA compounds in the range of 0.5–20 µg/L (ppb).

Chromatograms

Chromatograms for the analytes evaluated quantitatively:

Calibration Curves NDMA, r²=0.9989

NDEA, r²=0.9996

Dr. Engin Bayram Chemist / MS Group Deputy Director Business Development & Application Ant Teknik Cihazlar  

References 1.EMA reviewing medicines containing valsartan from Zhejiang Huahai following detection of an impurity, EMA/459276/2018 5 July 2018. 2.EMA review update on review of valsartan medicines, EMA/585263/2018 13 September 2018. 3.EMA review of impurities in sartan medicines, EMA/643116/2018 21 September 2018. 4.European Standard; Safety Toys – Part 12: N-Nitrosamines and N-nitrosatable substances EN 71-12 June 2013.