N-Nitrosodimethylamine Contamination in the Metformin Finished Products
Abstract
:1. Introduction
2. Results
2.1. Validation Results
2.2. Artifact Formation
2.3. Results of the Assay of NDMA Concentration
2.4. Study of Possible Formation Routes of NDMA
3. Discussion
4. Materials and Methods
4.1. Materials
4.2. GC-MS Method of Nitrosamine Determination
4.3. Standard Solution Preparation
4.4. Sample and Spiked Sample Preparation
4.4.1. Active Pharmaceutical Ingredient (API)
4.4.2. Finished Product
4.4.3. Prolonged Dosage Finished Product
4.4.4. Excipient Samples
4.4.5. Sample Blank Solution Preparation
4.5. Validation of the GC-MS/MS Method
4.5.1. Specificity
4.5.2. Linearity, Precision and Accuracy, Limits of Detection (LOD) and Limits of Quantification (LOQ)
4.5.3. Recovery
4.5.4. System Suitability Test
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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NA | Linearity Range | Equation | R2 (n = 8) | LOD | LOQ | Final Concentration after NA Addition | Accuracy | Precision |
---|---|---|---|---|---|---|---|---|
[ng/mL] | [ng/mL] | |||||||
N-nitrosodimethylamine NDMA | 0.5–9.5 ng/mL | y = 0.216x − 0.001 | 0.9990 | 0.33 | 1.00 | 1.5 ng/mL | 99.60% | 6.01% |
2.0 ng/mL | 99.52% | 3.42% | ||||||
2.5 ng/mL | 100.21% | 4.85% | ||||||
N-nitrosomethylethylamine NMEA | y = 0.301x − 0.068 | 0.9997 | 0.16 | 0.49 | 1.5 ng/mL | 105.03% | 4.76% | |
2.0 ng/mL | 104.08% | 5.21% | ||||||
2.5 ng/mL | 100.03% | 5.48% | ||||||
N-nitrosodiethylamine NDEA | y = 0.203x − 0.023 | 0.9970 | 0.32 | 0.97 | 1.5 ng/mL | 104.11% | 6.27% | |
2.0 ng/mL | 106.13% | 3.17% | ||||||
2.5 ng/mL | 103.69% | 5.58% | ||||||
N-nitrosodi-n-propylamine NDPA | y = 0.145x − 0.014 | 0.9992 | 0.26 | 0.79 | 1.5 ng/mL | 98.99% | 6.91% | |
2.0 ng/mL | 101.88% | 3.23% | ||||||
2.5 ng/mL | 103.09% | 5.92% | ||||||
N-nitrosodi-n-butylamine NDBA | y = 0.257x − 0.040 | 0.9960 | 0.48 | 1.46 | 1.5 ng/mL | 92.61% | 8.10% | |
2.0 ng/mL | 96.31% | 6.79% | ||||||
2.5 ng/mL | 95.17% | 2.50% | ||||||
N-nitrosopiperidine NPip | y = 0.172x + 0.002 | 0.9976 | 0.45 | 1.36 | 1.5 ng/mL | 98.39% | 6.79% | |
2.0 ng/mL | 102.99% | 8.89% | ||||||
2.5 ng/mL | 99.04% | 4.73% | ||||||
N-nitrosopyrrolidine NPyr | y = 0.124x − 0.013 | 0.9958 | 0.49 | 1.48 | 1.5 ng/mL | 97.53% | 7.56% | |
2.0 ng/mL | 103.05% | 5.53% | ||||||
2.5 ng/mL | 103.22% | 5.94% | ||||||
N-nitrosomorpholine NMor | y = 0.247x − 0.023 | 0.9981 | 0.39 | 1.20 | 1.5 ng/mL | 101.76% | 10.55% | |
2.0 ng/mL | 100.18% | 8.07% | ||||||
2.5 ng/mL | 98.96% | 5.78% |
GC-Parameters | |
Column | TG-WAXMS 30 m × 0.25 mm; 0.5 µm |
Carrier gas | Helium |
Flow rate | 36.2 cm/s (1 mL/min) |
Injector port temp. | 250 °C |
Injection volume | 2 µL |
Injection mode | Splitless, high-pressure injection 300 kPa |
Oven program | 45 °C hold time 3 min 130 °C rate 25 °C hold time 0 min 200 °C rate 12 °C hold time 0 min 250 °C rate 20 °C hold time 3 min |
MS-Parameters | |
Ion Source Temperature | 250 °C |
Interface Temperature | 250 °C |
Fixed Electron Energy | 70 eV |
Acquisition Type | MRM |
Solvent Delay | 5 min |
Collision Gas | argon 200 kPa |
Component | Quantitative Transition | Qualitative Transition | ||||
---|---|---|---|---|---|---|
Precursor Ion (m/z) | Product Ion (m/z) | CE (V) | Precursor Ion (m/z) | Product Ion (m/z) | CE (V) | |
NDMA | 74 | 44.10 | 5 | 74 | 42.10 | 14 |
d6-NDMA | 80 | 50.10 | 5 | 80 | 46.10 | 14 |
NMEA | 88 | 71.10 | 5 | 88 | 73.10 | 7 |
NDEA | 102 | 85.10 | 5 | 102 | 56.10 | 14 |
NDPA | 130 | 113.20 | 5 | 130 | 88.10 | 9 |
NDBA | 116 | 99.10 | 5 | 158.15 | 99.10 | 7 |
Npip | 114 | 84.10 | 8 | 114 | 97.10 | 8 |
Npyr | 100 | 55.10 | 7 | 100 | 68.10 | 15 |
Nmor | 116 | 86.10 | 3 | 116 | 56.10 | 23 |
Sample Availability: Samples of the compounds are not available from the authors. |
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Zmysłowski, A.; Książek, I.; Szterk, A. N-Nitrosodimethylamine Contamination in the Metformin Finished Products. Molecules 2020, 25, 5304. https://doi.org/10.3390/molecules25225304
Zmysłowski A, Książek I, Szterk A. N-Nitrosodimethylamine Contamination in the Metformin Finished Products. Molecules. 2020; 25(22):5304. https://doi.org/10.3390/molecules25225304
Chicago/Turabian StyleZmysłowski, Adam, Iza Książek, and Arkadiusz Szterk. 2020. "N-Nitrosodimethylamine Contamination in the Metformin Finished Products" Molecules 25, no. 22: 5304. https://doi.org/10.3390/molecules25225304