Nitrosamines are chemically highly active molecules generally expressed structurally as "R2N-N=O".
During the production process, due to high pH, temperature and the effects of chemical substances used, they can form in many industrial products such as synthetic pharmaceuticals, chemical substances, tobacco, animal-based 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.
In a report dated 05.07.2018 from the European Medicines Agency (EMA), it is stated that following the detection of N-nitrosodimethylamine (NDMA) impurity in the valsartan active pharmaceutical ingredient, a decision was made to investigate whether this substance was present as an impurity in other medicines containing valsartan.
In the EMA report dated 21.08.2018, it is stated that another nitrosamine derivative, NDEA, was detected in trace amounts in some medicines containing losartan, and following this development, a decision was made to provisionally examine other 'sartan' medicines with similar chemical structure in addition to valsartan.
Analytical Conditions:
MS Conditions;
| Instrument
Model
Interface Temperature
Heat Block Temperature
DL Temperature
Nebulizing Gas
Drying Gas
Source/Polarity |
: Shimadzu
: LCMS-8040 (TQ)
: 350°C
: 200°C
: 200°C
: 3.0 L/min
: 5 L/min
: APCI/(+) |
MRM Transitions*
| ID# |
Name |
m/z |
Ref. Ions |
| 1 |
NDMA |
74.90>43.10 |
74.90>58.00 |
| 2 |
NDEA |
102.90>75.00 |
102.90>47.00 |
LC Conditions;
| Instrument
Model
Column
Mobile Phase A
Mobile Phase B
Flow Rate |
: Shimadzu
: Nexera-i (LC-2040 Plus)
: ARC18 (2.7um, 100x2.1mm)
: Water (0.1% Formic Acid)
: Methanol (0.1% Formic Acid)
: 0.3 mL/min (Gradient Program) |
Results and Evaluation:
In this study, a calibration curve was plotted for NDMEA and NDEA compounds in the range of 0.5-20 μg/L (ppb).
Chromatograms
Chromatograms of Quantitatively Evaluated Analytes
Calibration Curves
References:
-
EMA reviewing medicines containing valsartan from Zhejiang Huahai following detection of an impurity, EMA/459276/2018 5 July 2018.
-
EMA review update on review of valsartan medicines, EMA/585263/2018 13 September 2018.
-
EMA review of impurities in sartan medicines, EMA/643116/2018 21 September 2018.
-
European Standard; Safety Toys – Part12: N-Nitrosamines and N-nitrosatable substances EN 71-12 June 2013.
