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Nitrosamines
Nitrosamines are mutagenic substances that can cause cancer. Since the discovery of N-nitrosodimethylamine in the drug valsartan in 2018, their analysis has become increasingly important. This is also reflected by the discovery of nitrosamines in other drugs such as ranitidine, amitriptyline, metformin, candesartan, irbesartan, losartan and nizatidine, to name but a few. In addition, limits have been set for nitrosamines and these must be strictly controlled. Revised sartan monographs have been in force in this regard since April 2021.
Nitrosamines can be formed during the reaction of secondary amines with nitrites (Figure 1). Possible sources in pharmaceutical production can be the recycling of DMF, catalysts or other materials.
Technical Data
The following nitrosamines are of particular concern:
| N-nitrosamines | Abbreviation | N-nitrosamines | Abbreviation |
| N-nitrosodimethylamine | NDMA | N-nitroso-N-methyl-4-aminobutyric acid | NMBA |
| N-nitrosodiethylamine | NDEA | 1-Nitroso-4-methylpiperazine | MeNP |
| N-Nitrosoethylisopropylamine | NEIPA | N-nitrosodibutylamine | NDBA |
| N-nitrosodiisopropylamine | NDIPA | N-nitrosomethylphenylamine | NMPA |
The various nitrosamines can be separated by reversed-phase or gas-phase chromatography. Below are some applications from various manufacturers.
Applications
Reversed Phase Separation of Nitrosamines according to EPA 8270 with Macherey-Nagel Nucleodur C18 HTec
Peak identities
1. n-nitrosodimethylamines 2. n-nitrosomorpholines 3. n-nitrosomethylethylamines 4. n-nitrosopyrrolidines 5. n-nitrosodiethylamines 6. n-nitrosopiperidines 7. n-nitrosodipropylamines 8. n-nitrosodibutylamines 9. n-nitrosodiphenylamines
Test conditions
Column: Nucleodur C18 HTec 150x4.6mm, 3µm
Mobile phase A: Acetonitrile
Mobile phase B: Water
Gradient: 97%B for 5min, 97-45%B in 10min, 45-10%B in 10min
Flow rate: 1 mL/min
Temperature: 20 °C
Injection volume: 1 µL
Detection: UV, 230 nm
Gas Chromatography of Nitrosamines in Drinking Water according to EPA 521 with Rxi-624Sil MS
Peak identities
1. n-nitrosodimethylamine-d6 2. n-nitrosodimethylamine 3. n-nitrosomethylethylamine 4. n-nitrosodiethylamine 5. N-nitrosodipropylamine-d14 6. N-nitrosodipropylamine 7. N-nitrosopyrrolidine 8. N-nitrosopiperidine 9. N-nitrosodibutylamine
Test conditions
Column: Rxi-624Sil MS 30m x 0.25mm, 1.4µm (RT13868)
Temperature: 38 °C (hold 1min) to 160 °C at 12 °C/min to 200 °C at 5 °C/min (hold 1min)
Carrier gas: Helium
Flow rate: 1.4 mL/min
Injection volume: 10 µL splitless (hold 1min)
Injection temperature: 250 °C
Sample: 10 ng/mL
Downloads
Manufacturer overview
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Avantor ACE
UHPLC - Reversed Phase:
- Avantor ACE Excel 2 C18-PFP, 2µm
HPLC - Reversed Phase:
- Avantor ACE UltraCore C18, 3.5µm
GL Sciences
HPLC - Reversed Phase:
- Intersil ODS-2, 5µm
- InertSustain PFP, 3µm
Macherey-Nagel
HPLC - Reversed Phase:
- Nucleodur C18 HTec, 3µm (EPA 8270)
- Nucleodur π2, 3µm
- Nucleosil 100-5 C18, 5µm
- Nucleodur C18 Gravity-SB, 3µm
- Nucleodur PFP, 5µm (EPA 8270)
- Nucleodur PolarTec, 3µm (EPA 8270)
Gas chromatography:
- Optima XLB
- Macherey-Nagel Analysis of nitrosamines by LC-MS/MS
- Macherey-Nagel Luminarin-9 Fluorescent reagent for the precolumn derivatization of main volatile-non-volatile N-nitros
- Macherey-Nagel Rapid extraction method for volatile N-nitrosamines in meat products
- Macherey-Nagel Separation of Nitrosamines EPA 8270 on Nucleodur C18 HTec
- Macherey-Nagel Separation of Nitrosamines EPA 8270 on Nucleodur PFP
- Macherey-Nagel Separation of nitrosamines EPA Mix 8270 on Nucleodur PolarTec
- Macherey-Nagel Separation of Nitrosamines EPA 8270 on Nucleodur C18 Gravity-SB
Restek
Gas chromatography:
- Rxi-5Sil MS (EPA 521, 522)
- Rxi-624Sil MS (EPA 521)
- Stabilwax-DB
- Rtx-5 (EPA 607)
- Restek 10 μL CSR-LVSI with 5 ng Nitrosamines, THF, and 1,4-Dioxane On-Column
- Restek 50 µL CSR-LVSI with 5 ng Nitrosamines, THF, and 1,4-Dioxane On-Column
- Restek U.S. EPA Methods 521 & 522, Nitrosamines & 1,4-Dioxane, on Rxi®-5Sil-MS by CSR-LVSI
- Restek Nitrosamines in Drinking Water on Rxi®-624Sil MS (Modified EPA Method 521)
- Restek Nitrosamines on Rxi-624Sil MS
- Restek Nitrosamines Stabilwax®-DB
- Restek Nitrosamines US EPA Method 607 Rtx®-5
Shimdazu
HPLC - Reversed Phase:
- Shim-pack Solar C18, 5µm
- Shim-pack GIST C18-AQ, 3µm
UHPLC - Reversed Phase
- Shim-pack Scepter C18-120, 1.9µm
Gas chromatography:
- SH-Rxi-624Sil MS
- SH-Stabilwax DA
- SH-Stabilwax
- Shimadzu Detection and Quantitation of Nitrosamine Impurities in Drug Substances by LC-HRMS on LCMS-9030
- Shimadzu Determination of Nitrosamines Impurities in Sartan Drug Products
- Shimadzu High-Sensitivity Quantitative Analysis of Nitrosamines on Shim-pack Scepter C18-120
- Shimadzu Quantitation of 5 Nitrosamines5 in Metformin API & Formulation by HS-GCMS
- Shimadzu Quantitation of 7 Nitrosamines in API by HSGC-MS/MS
- shimadzu_analysis-of-pharmaceuticals-impurity.pdf
- Shimadzu Quantitation of 8 Nitrosamnes on Shim-pack GIST C18-AQ
Sielc
HPLC - Mixed Mode:
- Newcrom R1, 5µm
Thermo Fisher
UHPLC - Reversed Phase:
- Hypersil GOLD C18, 1.9µm
HPLC - Reversed Phase:
- Acclaim PolarAdvantage, 5µm (EPA 8270)
Gas chromatography:
- TG-1701MS
- TG-WAX MS
- Thermo Analysis of Nine N-Nitrosamines Using Liquid Chromatography on Hypersil GOLD
- Thermo Determination of nitrosamines in drinking water on TG-1701MS
- Thermo Determining Nitrosamines Using GC-MS_MS with Electron Ionization on TG-WAX MS
- Thermo High resolution analysis of nitrosamines in EPA 8270 on Acclaim PolarAdvantage
Waters
UHPLC - Reversed Phase:
- ACQUITY UPLC HSS T3, 1.7µm
- ACQUITY UPLC BEH C18, 1.7µm
- ACQUITY UPLC HSS T3, 1.8µm
HPLC - Reversed Phase:
- XSelect HSS T3, 3.5µm
- Waters Fast Efficient Method to Determine the Presence of Nitrosamines in Cosmetics
- Waters Method Development for the Analysis of Valsartan and Nitrosamines Impurities
- Waters Dilute and Shoot Method for the Determination of Tobacco Specific Nitrosamines
- Waters Highly Sensitive UPLC MS Quantification of Nitrosamine Impurities in Sartan & Ranitidine Drug Substances
- Waters HPLC/UV Quantification of Nitrosamine Impurities in Valsartan & Ranitidine Drug Substances
- Waters Sensitive HR Mass Spectrometry Method for Quantitation of N-Nitrosamines
- Waters Use of a Proprietary Polar Column Chemistry for the Separation of Nitrosamines
- Waters Quick Analysis of N-Nitrosodimethylamine in Ranitidine Drug Substances
ZirChrom
HPLC - Reversed Phase:
- DiamondBond-C18, 5µm
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