for Pharmaceutical Analysis, Food Analysis, and Water Environment Analysis

Nitrosamines Analysis

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Nitrosamines are compounds of the chemical structure where hydrogen of the amine nitrogen is substituted with a nitroso group. These compounds are widely used industrially in plasticizers, additives, etc., but at least some of them are known to be carcinogenic.
Nitrosamine are also formed by reaction of secondary amine and nitrous acid. Therefore, they are often detected as impurities during the manufacturing process of a drug product. Recently, nitrosamines were detected in some sartan and ranitidine products, and these products were recalled. In response to this event, in September 2019, the EMA (European Medicines Agency) requested the marketing authorization holders to evaluate the risk of the presence of nitrosamine impurities in their drugs and take appropriate risk mitigation measures. FUJIFILM Wako offers a wide range of analytical standards of nitrosamines.

10 Nitrosamines Mixture Standard Solution

Feature

Mixture standard solution of 10 nitrosamines regulated by USP, Ph. Eur., And EMA!

LC/MS Chromatogram (Positive Mode)

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Peak No. Nitrosamine Monitoring ion (m/z) Mode Peak No. Nitrosamine Monitoring ion (m/z) Mode
1 MeNP 130 + 6 NIPEA 117 +
2 NDMA 75 + 7 NDIPA 131 +
3 NMOR 117 + 8 NMPA 137 +
4 NMBA 147 + 9 NDPA 131 +
5 NDEA 103 + 10 NDBA 159 +

Analysis conditions

[ Internal Standard ]

N-Nitrosomethylethylamine Standard

[HPLC]
Column
Wakopakr® Ultra C18-3 4.6 × 150 mm
Column temperature
40℃
Eluent
A) 0.1 vol% HCOOH in H2O,  B) 0.1 vol% HCOOH in CH3OH
Gradient
Time (min.) B conc. (%)
0-30 10-95
30-40 95
Flow rate
0.5 mL/min.
[MS]
Ionization
ESI
Mode
SIM

GC/MS Chromatogram (Positive Mode)

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Analysis conditions

[ Internal Standard ]

N-Nitrosomethylethylamine Standard

[GC]
Column
DB-624UI 0.14 μm, 0.25 mm × 30 m
Column temperature
40℃ (5 min.)→5℃/min.→260℃ (11 min.)
Injection temperature
260℃
Carrier gas
He 1.3 mL/min.
Splitless
1 min.
[MS]
Ionization
EI
Interface temperature
250℃

* Since NMPA is easily decomposed under thermal conditions1), it is detected as a decomposition peak under this conditions.
1) Mutsuga, M. et al.: Am. J. Anal. Chem., 4, 277 (2013).
* NMBA is rarely detected in GC/MS.

CAS RN® and Abbreviation

Structural
formula
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Chemical name N-Nitrosodimethylamine N-Nitrosomethylethylamine N-Nitrosodiethylamine
Abbreviation NDMA NEMA, NMEA NDEA
CAS RN® 62-75-9 10595-95-6 55-18-5
Structural
formula
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Chemical name N-Nitrosoethylisopropylamine N-Nitrosodi-n-propylamine N-Nitrosodiisopropylamine
Abbreviation EIPNA, NEIPA NDPA DIPNA, NDIPA
CAS RN® 16339-04-1 621-64-7 601-77-4
Structural
formula
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Chemical name N-Nitrosodi-n-butylamine N-Nitrosomethylaminobutyric Acid N-Nitrosomethylphenylamine
Abbreviation NDBA NMBA NMPA
CAS RN® 924-16-3 61445-55-4 614-00-6
Structure
formula
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Chemical name N-Nitrosomorpholine N-Nitroso-N'-methylpiperazine
Abbreviation NMOR MeNP
CAS RN® 59-89-2 16339-07-4

USP, EP and Other Compendial Regulations and Analytical Methods

Regulatory Trends in Each Country

Chemical name Abbreviation FDA USP EMA Ph. Eur.
N-Nitrosodi-n-butylamine NDBA
N-Nitrosodiethylamine NDEA
N-Nitrosodiisopropylamine DIPNA, NDIPA
N-Nitrosodimethylamine NDMA
N-Nitrosodi-n-propylamine NDPA
N-Nitrosoethylisopropylamine EIPNA, NEIPA
N-Nitrosomethylaminobutyric Acid NMBA
N-Nitrosomethylphenylamine NMPA
N-Nitroso-N'-methylpiperazine MeNP
N-Nitrosomorpholine NMOR

Analytical Methods of USP and EP

■Ph. Eur. 10.6 2.5.42 N-Nitrosamines in active substances (As of February 2022)

Analytical method Target nitrosamines Internal standard
Procedure A LC/MS/MS NDMA, NDEA, NMBA, NDIPA, NEIPA NDEA-d10
Procedure B GC/MS NDMA, NDEA NEMA
Procedure C GC/MS/MS NDMA, NDBA, NDIPA, NEIPA, NDPA, NDEA NEMA

■USP <1469> N-Nitrosamine impurities (As of February 2022)

Analytical method Target nitrosamines Internal standard
Procedure 1 LC/HRMS NDMA, NDEA, NDIPA, NEIPA, NMBA, NDBA, NMPA
Procedure 2 GC/MS NDMA, NDIPA, NEIPA, NDEA NDMA-d6
Procedure 3 LC/MS/MS NDMA, NDEA, NDIPA, NEIPA, NMBA, NDBA NDMA-d6, NMBA-d3, NDEA-d10, NDBA-d18
Procedure 4 GC/MS/MS NDMA, NDEA, NDIPA, NEIPA, NDBA, NMPA NDMA-13C2-d6

*The regulated components and analytical methods are based on the information available as of February 2022. For details, see the website of each pharmacopoeia.

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Mixture Standard Solution

Standard

Stable isotopes

For research use or further manufacturing use only. Not for use in diagnostic procedures.

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