Simultaneous Determination and Quantification of NineNitrosamine Impurities in Semi-Solid Forms Using a GC–MS/MS Method
Abstract
:1. Introduction
2. Materials and Methods
2.1. Material and Reagents
2.2. Preparation of Standard Stock Solutions and Internal Standard Stock Solutions
2.3. Preparation of Sample Solutions
2.4. Operating Conditions of GC–MS/MS
2.5. Method Validation
3. Results
3.1. System Suitability and Selectivity
3.2. Linearity
3.3. Accuracy
3.4. Precision (Repeatability)
3.5. Limit of Quantification (LOQ) and Limit of Detection (LOD)
3.6. Robustness (Solution Stability)
4. Exploratory Evaluation of Method Applicability
5. Discussion
6. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
Abbreviations
NDMA | N-nitrosodimethylamine |
NDEA | N-nitrosodiethylamine |
NMEA | N-nitrosomethylethylamine |
NDPA | N-nitrosodipropylamine |
NDBA | N-nitrosodi-n-butylamine |
NPIP | N-nitrosopiperidine |
NMOR | N-nitrosomorpholine |
DIPNA | N-nitrosodiisopropylamine |
EIPNA | N-nitrosoethylisopropylamine |
PEG | Polyethyleneglycol |
ESI | Electronic Supporting Information (Supplementary Materials) |
FDA | Food and Drug Administration |
EMA | European Medicines Agency |
MFDS | Ministry of Food and Drug Safety |
RSD | Relative Standard Deviation |
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Name of Nitrosamines and Internal Standards | Retention Time (min) | Quantifier (MRM/Collision Energies (V)) | Qualifier (MRM/Collision Energies (V)) |
---|---|---|---|
NDMA | 17.2 | 74 → 44/4 | 74 → 42/22 |
NDMA-d6 | 17.2 | 80 → 50/6 | 80 → 46/20 |
NMEA | 18.9 | 88 → 71/5 | 88 → 42/20 |
NMEA-d3 | 18.9 | 91 → 74/3 | 91 → 46/5 |
NDEA | 19.9 | 102 → 85/5 | 102 → 56/20 |
NDEA-d10 | 19.8 | 112 → 94/5 | 112 → 50/10 |
EIPNA | 21.0 | 116 → 99/5 | 116 → 44/15 |
NDEA-d10 * | 19.8 | 112 → 94/5 | 112 → 50/10 |
DIPNA | 21.9 | 130 → 88/5 | 130 → 42/10 |
NDEA-d10 * | 19.8 | 112 → 94/5 | 112 → 50/10 |
NDPA | 24.3 | 130 → 43/10 | 130 → 71/10 |
NDPA-d14 | 24.0 | 144 → 50/20 | 144 → 126/10 |
NDBA | 29.2 | 158 → 99/5 | 158 → 84/20 |
NDBA-d18 | 28.9 | 94 → 62/20 | 94 → 46/20 |
NPIP | 29.9 | 114 → 84/10 | 114 → 97/5 |
NDPA-d14 * | 24.0 | 144 → 50/20 | 144 → 126/10 |
NMOR | 32.0 | 116 → 86/5 | 116 → 56/25 |
NMOR-d8 | 32.0 | 124 → 94/5 | 124 → 62/15 |
Test Solution | Specification | Name | Min. | Max. |
---|---|---|---|---|
2.0~50.0 ng/mL for nine impurity solutions | Coefficient of determination R2 ≥ 0.99 | NDMA | 0.99899 | 0.99936 |
NDEA | 0.99831 | 0.99959 | ||
NMEA | 0.99949 | 0.99981 | ||
NDPA | 0.99880 | 0.99939 | ||
NDBA | 0.99745 | 0.99812 | ||
NPIP | 0.99870 | 0.99894 | ||
NMOR | 0.99838 | 0.99874 | ||
DIPNA | 0.99845 | 0.99976 | ||
EIPNA | 0.99820 | 0.99955 |
Test Solution | Specification | Name | Average/RSD (%) |
---|---|---|---|
5, 10 and 50 ng/mL spiked sample | Recovery rate: 70.0~130.0% | NDMA | 114.23/5.27 |
NDEA | 110.75/4.98 | ||
NMEA | 110.47/4.09 | ||
NDPA | 108.35/5.73 | ||
NDBA | 111.62/9.34 | ||
NPIP | 113.34/5.10 | ||
NMOR | 99.15/6.28 | ||
DIPNA | 112.16/4.95 | ||
EIPNA | 114.68/4.76 |
Test Solution | Specification | Name | RSD (%) |
---|---|---|---|
Six replicates (20 ng/mL) | RSD ≤ 20.0% | NDMA | 4.7 |
NDEA | 3.8 | ||
NMEA | 5.1 | ||
NDPA | 3.8 | ||
NDBA | 5.0 | ||
NPIP | 5.6 | ||
NMOR | 4.9 | ||
DIPNA | 4.3 | ||
EIPNA | 3.6 |
Test Solution | Specification | Name | RSD (%) | S/N Min, Max |
---|---|---|---|---|
2 ng/mL solution | RSD ≤ 20.0% Signal-to-noise (S/N) ≥ 10 | NDMA | 2.222 | 26.1, 36.3 |
NDEA | 2.505 | 19.3, 25.2 | ||
NMEA | 4.366 | 23.6, 38.6 | ||
NDPA | 2.968 | 28.8, 54.2 | ||
NDBA | 7.889 | 28.2, 56.7 | ||
NPIP | 0.712 | 11.6, 17.1 | ||
NMOR | 1.493 | 17.0, 30.9 | ||
DIPNA | 1.444 | 29.3, 40.0 | ||
EIPNA | 1.605 | 20.0, 27.4 |
Test Solution | Specification | Name | RSD (%) | S/N Min, Max |
---|---|---|---|---|
1 ng/mL solution | Signal-to-noise (S/N) ≥ 3 | NDMA | 2.040 | 16.3, 27.0 |
NDEA | 5.542 | 10.1, 13.5 | ||
NMEA | 2.156 | 17.5, 25.6 | ||
NDPA | 0.778 | 17.0, 43.8 | ||
NDBA | 6.230 | 15.8, 19.4 | ||
NPIP | 4.277 | 7.5, 11.1 | ||
NMOR | 1.695 | 10.9, 16.1 | ||
DIPNA | 0.741 | 16.5, 20.4 | ||
EIPNA | 1.465 | 13.1, 18.1 |
Test Solution | Specification | Name | Change Rate (24 h, 48 h (%)) |
---|---|---|---|
50 ng/mL spiked sample | Change rate after 24 and 48 h (%) ≤ 20.0% | NDMA | 0.75, 0.26 |
NDEA | 0.61, 3.07 | ||
NMEA | 0.55, 2.18 | ||
NDPA | 1.72, 3.19 | ||
NDBA | 0.93, 1.32 | ||
NPIP | 4.01, 6.38 | ||
NMOR | 2.39, 0.82 | ||
DIPNA | 4.14, 5.95 | ||
EIPNA | 2.21, 4.13 |
No. | NDMA | NDEA | NMEA | NDPA | NDBA | NPIP | NMOR | DIPNA | EIPNA |
---|---|---|---|---|---|---|---|---|---|
1 | 81.7 | 90.7 | 89.6 | 86.3 | 93.4 | 89.0 | 88.7 | 84.9 | 80.0 |
2 | 87.1 | 83.9 | 83.3 | 77.2 | 85.3 | 80.5 | 82.9 | 83.6 | 82.4 |
3 | 94.8 | 85.8 | 82.3 | 89.0 | 88.3 | 82.6 | 85.5 | 79.6 | 78.5 |
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Lee, N.; Go, H.; Park, Y.-j. Simultaneous Determination and Quantification of NineNitrosamine Impurities in Semi-Solid Forms Using a GC–MS/MS Method. Separations 2025, 12, 120. https://doi.org/10.3390/separations12050120
Lee N, Go H, Park Y-j. Simultaneous Determination and Quantification of NineNitrosamine Impurities in Semi-Solid Forms Using a GC–MS/MS Method. Separations. 2025; 12(5):120. https://doi.org/10.3390/separations12050120
Chicago/Turabian StyleLee, Namjin, Hyejin Go, and Young-joon Park. 2025. "Simultaneous Determination and Quantification of NineNitrosamine Impurities in Semi-Solid Forms Using a GC–MS/MS Method" Separations 12, no. 5: 120. https://doi.org/10.3390/separations12050120
APA StyleLee, N., Go, H., & Park, Y.-j. (2025). Simultaneous Determination and Quantification of NineNitrosamine Impurities in Semi-Solid Forms Using a GC–MS/MS Method. Separations, 12(5), 120. https://doi.org/10.3390/separations12050120