Introduction to Nitrosamine and its control

1. Nitrosamine & NDSRI Learning and Challenges
By Nilesh Bonde

2. Nitrosamine History Perspective

3. Simple Nitrosamine:
NDMA and other related Nitrosamine Formation
Chlorination of Nitrite containing water
Presence of chloramine

4. N-Nitroso- CAS Number Acronym Structure
Dimethylamine 62-75-9 NDMA
Diethylamine 55-18-5 NDEA
Dibutylamine 924-16-3 NDBA
Diisopropylamine 601-77-4 DIPNA
Ethylisopropylamine 16339-04-1 EIPNA
Table 1. Chemical information for nitrosamines

5. N-Nitroso- CAS Number Acronym Structure
Methylpiperazine 16339-07-4 MeNP
Morpholine
59-89-2 NMOR
Methylphenylamine 614-00-6 NMPA
Methylaminobutyric Acid 61445-55-4 NMBA
Piperidine 100-75-4 NPIP
Piperazine 5632-47-3 NPIPZ

6. Nitrosamine Formation
Valsartan NDMA???
First discovered in batches that had been produced by the Chinese company Zhejiang Huahai Pharmaceutical, it turned
out in the following weeks that also batches from other manufacturers (e.g. Zhejiang Tianyu Pharmaceutical and Hetero
Labs, India) contained NDMA.
Sodium nitrite is a known impurity in sodium azide, which is often used for synthesizing tetrazoles.
An aqueous solution of sodium nitrite is used to quench residual azide

7. Nitrosamine Formation
Metformin  NDMA???
Ref: Org. Process Res. Dev. 2023, 27, 2123−2133
NDMA in Metformin has raise the alarm and many of manufacturer has
given root cause as due of formation due to either nitrite in excipients,nitrite
in water used in manufacturing,and nitrocellulose in packaging materials
may be nitrosating agents.
NDMA (AI) = 96ng/day; MDD = 2250mg; limit = 43ppb
Cited paper discloses, even after checking all identified sources one of the
Manufacturing site near metro city wherein air has more of NOx content, gives
NDMA more than permissible limit. This is due to use of fluidized bed granulation
Result shows 70ppb of NO2 in Air gives 43 ppb of NDMA in DS.

8. Ref: Org. Process Res. Dev. 2023, 27, 2123−2133
Metformin  NDMA???
Nitrosamine Formation

9. Nitrosamine Formation
Renitidine  NDMA???
Synthetic Pathway
Risk Identification
-Dimethyl amine has low B.P., maerial was distilled prior to expose to nitro olefin
-Sodium nitrite being nitrosating agent is absence as nitromethane is distilled prior to
use.
-Nitromethane in compound 7 is NMT 25ppm .
-Recovery of solvent was identified as not adding any Risk.
-All the eleven impurities were assessed as if dimethyl amine is generated as
degradation
-The long term degradation shows increase in the NDMA formation (0.04µg/g)/year.
- Labelled ranitidine sample of uncontrolled stability conditins shows intermoleculara
degradation pathway?

10. -Labelled sampled showing intermolecular degradation pathway, surface morphology and interaction with water leading for
NDMA formation.
-Columnar crystals are less responsive for NMDA formaton as compare to irregular crystals.

11. complex Nitrosamine
More recently an increasing number of larger nitrosamines derived from amine-containing API or API
impurities (NDSRIs) has been reported.
Nitrosamines are exceptionally potent genotoxic carcinogens, and hence the threshold of toxicological concern
(TTC) concept from ICH guideline M7 that limits exposure to mutagenic compounds to a maximum acceptable
intake (AI) of 1500 ng/day cannot be applied.

12. Calculation based on Current guidline

15. Ephedrine contains secondary Nitrosable nitrogen, which in susceptible for giving N-Nitrosoephedrine with structure as,
CH3
N
CH3
N
O
OH


Potency score = α Hydrogen score+ Deactivating Feature+ Activating Feature
Potency score (4) = 3 + 1 + 0
Limit = AI(in ng)/ MDD (in mg) = 1500/150 = 10ppm

17. Learning & Strategies to Avoid NDSRI
Nitrite Scavangers (Antioxidants, amino acids etc)
Use of suitable scavengers in drug product to mitigate NDSRI risk or reduce the level
pH modulators (inorganic bases)
Reduce the acidity of the formulation by using basic excipients (e.g. Na2CO3). The approach is generally effective, as the
Nitrosation rate decreases strongly at higher pH.
To control unit operations
e.g., Fluid-bed drying, wet granulation or adjusting manufacturing process parameters could also reduce the extent of
NDSRI formation during drug substance/ drug product formulation.

18. Role of Scavengers
There are two main type of scavangers,
(1) Nitrite scavenger (Anti-oxidant, Amino acids)
(2) pH modulators (inorganic bases)
-Natural anti-oxidants like ascorbic acid, polyphenols reduces nitrite (NO2-) to nitric oxide (NO)
- Amino acid are reactive towards nitrite therby forming diazonium salt and in presence of water forms hydroxyl acids.
- Inorganic bases used can also uphold NDSRI formation as are pH modulators.
- Catalytic hydrogenation condition can also uphold nitrite to nitroso compounds.