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

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Pooja S Dalvi

, Sharad S Sankhe

Ph.D. Scholar, Department of Chemistry, Patkar-Varde College, Goregaon West, Mumbai-61, India

Head of Department, Department of Chemistry, Patkar-Varde College, Goregaon West, Mumbai-61,

India







ABSTRACT

Nitrosamine impurities are chemical compounds that can unintentionally form in active pharmaceutical

ingredient during manufacturing or storage. Nitrosamine are carcinogenic and genotoxic. Nitrosamines are a

group of nitroso compounds that can be formed when secondary or tertiary amine from API like-Lansoprazole,

Dasatinib, Nilotinib or Oxybutynin react with nitrosating agents like NaNO

in acidic medium or Tert-butyl

nitrite etc. Validated analytical methods are used for identification and quantification these impurities. Highly

sensitive instruments like High performance liquid chromatography (HPLC) and Gas chromatography (GC)

required for quantification of these impurities and Mass Spectroscopy (MS) and Nuclear Magnetic Resonance

(NMR) are required for identification, these impurities have certain limit which can be detected on these

instruments.

Keywords: Nitrosamine impurities

, Drug substances

, Classifications

, Drug product

, Impurities

, Impurity

synthesis

INTRODUCTION

Nitrosamine impurities can be formed during formation and degradation of active pharmaceutical ingredients.

They can be formed by use of nitrosating agent, cross-contamination, solvent contamination, amines in raw

material and degradation. Nitrosamine has carcinogenic, genotoxic and mutagenic properties; very small

exposure to nitrosamines can lead to cancer. Regulatory agencies such as health Canada and FDA have

established acceptable intake limit for commonly identified nitrosamines in pharmaceuticals to minimize

potential carcinogenic risk shown in Table 2.

In July 2018 FDA (Food and Drug Administration) and EMA (European Medicines Agency) announced that N-

Nitroso dimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA) are carcinogenic impurities detected in

generic substances and drug product especially in Sartans class Angiotensin II receptor (AT

R) blockers like

Valsartan, losartan, Irbesartan, Candesartan, Azilsartan etc. which is used to treat Hypertension (High Blood

Pressure) and Heart failure in patients.

ICH M7 (Mutagenic impurity management expectations) classified nitrosamine impurities as Class 1 impurity

and known as carcinogenic and mutagenic based on their carcinogenicity and mutagenicity. Nitrosamines impact

the pharmaceutical material by mutation through rearrangement, chromosomal breaks or insertion into the DNA

during replication. Nitrosamine impurities even very low concentration in drug can cause cancer so identification

and quantification of these impurities is very important.

A Review On Synthesis And Biological Activities Of Nitrosamine Impurities

1. Sources of Nitrosamine Impurities

Impurities can be generated during formulation or degradation of active pharmaceutical ingredient. The possible

routes of nitrosamine formation in active pharmaceutical ingredients (APIs) shown in Fig.1. In process

nitrosamines can be generated due to impure starting material, residual solvents, reuse of catalyst, degradation

of active pharmaceutical ingredients at high temperature or due to moisture in storage. Nitrosamine can be

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formed during packaging when rubber stopper or nitrocellulose coating react with amine from active

pharmaceutical ingredients. Light exposure can lead to nitrosation in sensitive active pharmaceutical ingredients.

Figure 1 Sources of Nitrosamine Impurities

2. Formation of Nitrosamine impurities

When primary amine, secondary amine, tertiary amines or quaternary ammonium salts in acidic or thermal

condition react with nitrosating agents like Sodium nitrite or p-Toluene sulphonic acid are considered to be

precursors for the generation of Nitrosamine impurities as shown in Fig.2. During degradation of API in some

pharmaceutical ingredients containing diethyl amino, dimethyl amino, etc. can break down to free amine which

can react with nitrite during packaging.

Figure 2 General Reaction of Nitrosamine Formation

For example:

At room temperature when diethyl amine in acidic condition treated with sodium nitrite yields N-Nitroso diethyl

amine as shown below:

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Recovered solvents, raw materials and catalysts used in the synthesis may cause risk for Nitrosamine formation

during synthesis. Contaminated raw material or starting material may introduce the Nitrosamine impurities

formation in active pharmaceutical ingredients or drug product. In manufacturing process where nitrosating

agents are not intentionally used may be contaminated through nitrite present in the water used for process.

The U.S. FDA has recognized several common nitrosamines that have raised safety concerns in pharmaceuticals

due to their potential carcinogenicity. Impurities in Table 2 shows commonly detected in various drug classes

including Sartans, ranitidine, metformin, etc.

Intake limit of nitrosamine varies depending on type of nitrosamine as shown in Table 2. Nitrosamine are class

of compounds and several of them are probable human carcinogens such as NDMD, NDEA, NMBA etc. so the

limit is extremely low based on lifetime cancer risk.

According to European Food Safety Authority (EFSA), exposure to nitrosamine poses significant health risk for

individual for all age group. Nitrosamine formation observed in food at certain condition such as high

temperature during cooking, flavouring agents, fermentation, etc. as shown in Table 1 which increased risk of

cancer and genotoxicity in human being and animals.

3. Comparative interpretation of commonly identified Nitrosamines

FDA had classified nitrosamine depending on its Carcinogenic Potency Categorization Approach (CPCA) into

following class:

a) Category 1 - Highest potency - Lowest acceptable limit (≈18 ng/day)

b) Category 2 & 3 - Intermediate potency - Moderate acceptable limit (≈ 36-100 ng/day)

c) Category 4 - Lower potency - Higher acceptable limit (≈ 500 ng/day)

d) Category 5 - Lowest potency - Highest acceptable limit (≈ 1500 ng/day)

Carcinogenic Potency Categorization Approach assigns nitrosamine to category based on their predicted

carcinogenic risk, which can be done by analysing α-Hydrogens, Activating features, Deactivating features.

a) α-Hydrogens

It is a Hydrogen atom which is directly bonded to the carbon atom adjacent to a carbonyl group (C=O)

b) Activating features

It increases the carcinogenic potential of nitrosamine by promoting metabolite activation especially by α-

Hydrogenation, Benzyl group, Electron-donating groups, Alkyl chains, etc.

c) Deactivating features

It reduces the carcinogenic potential of nitrosamine by hindering metabolite activation especially by

Carboxylic acid groups, Electron-withdrawing groups, Steric hindrance, etc.

These features are used in a scoring system called “CGPA” where:

Potency Score = α-Hydrogen Score + Activating feature Score + Deactivating feature Score

 Higher Potency Score indicates Lower carcinogenic potency

 Lower Potency Score indicates Higher carcinogenic potency

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Table 1 Common nitrosamines found in Food in certain condition are as follow

Table 2 Structure of commonly identified Nitrosamine impurities and its biological activities with Intake Limit

Amines

Corresponding

Nitrosamine Impurity

Name & Acronym

Stucture

Biological Activities on

Organ

Intake Limit

(in

nanograms)

Dimethyl amine

NDMA

(N-Nitroso

dimethylamine)

Liver, Lung, Kidney,

DNA

26.5 ng/day

Diethyl amine

NDEA

(N-Nitroso

diethylamine)

Liver, Oesophagus,

Respiratory track, DNA

damage,

26.5 ng/day

Diisopropylamine

NDIPA

(N-Nitroso

diisopropylamine)

Lung, Pancreas,

Enzyme, Respiratory

and Systemic toxicity

26.5 ng/day

Ethylisopropylami

NEIPA

(N-Nitroso

ethylisopropylamine)

Lungs, Urinary bladder,

Colon, Kidneys, Nasal

cavity, Pancreas,

Stomach and Central

nervous system

400 ng/day

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Dipropylamine

NDPA

(N-Nitroso

dipropylamine)

Liver, Oesophagus,

Nasal cavity, DNA

damage

26.5 ng/day

N-methylamino-

butyric acid

NMBA

(N-Nitroso-N-methyl

aminobutyric acid)

Oesophagus, Liver,

Lung, Kidney, Stomach

and intestine

1,500 ng/day

Morpholine

NMOR

(N-Nitroso morpholine)

Oesophagus, Nasal

cavity, Lungs

Not Available

Piperidone

NPYR

N-Nitroso Piperidone

Liver, Oesophagus,

Nasal cavity, Lungs

Not Available

DISCUSSION

In the article “Nitrosamine Impurities in Drug Substances and Drug Products’’[1] the researchers concentrated

how nitrosamine impurities get generated during formulation and degradation of any active pharmaceutical

ingredient (API), sources of nitrosamine impurities, regulatory perspective by Food and Drug Administration

(FDA) European Medicines Agency (EMA) and other regulatory agencies like Therapeutic Goods

Administration (TGA), and described acceptable intake limit of nitrosamine content containing drugs, and how

to avoid nitrosamine contamination.

In the article by Antonis Manolis (April 26, 2019), “Carcinogenic Impurities in Generic Sartans: An Issue of

Authorities’ Control or a Problem with Generics”,[2] researchers recalled Sartans generics like Valsartan,

Irbesartan, Losartan in which nitrosamine impurities generated and companies involved. Studies have shown

that NMBA is known to be a co-carcinogen in animal which can cause bladder cancer in rats which renders its

potential in human carcinogen.

Jennifer L. Caulfield's 1997 doctoral dissertation, titled ‘‘The chemistry of nitric oxide-induced deamination and

cross-linking of DNA’’,[3] explores the chemical reactions between nitric oxide and DNA resulting structural

and functional consequences for DNA, specifically focusing on how nitric oxide can cause deamination and

cross-linking of DNA. In the context of DNA deamination can alter the pairing properties of nucleotides which

potentially leading to mutation.

The article, ‘‘The molecular basis for induction of human cancers by tobacco specific nitrosamine’ by R. Nilsson

(July, 2011)’’,[4] explores the link between cancer development and tobacco-specific nitrosamines (TSNAs),

specifically focusing on how nitrosamine compounds damage DNA. Cellular DNA damage if not repaired, it

can lead to cancer development. An exposure level of TSNA does not increase the baseline levels of DNA

damage which can be considered as virtually safe.

In the paper, by Lijinsky William & Andrews A. W. October 1983, “The superiority of hamster liver microsomal

fraction for activating nitrosamines to mutagens in Salmonella typhimurium”,[5] investigated the mutagenic

activation of nitrosamine nitrosamines by hamster liver microsomal fractions in Salmonella typhimurium, the

study also noted that nitrosamines activated by hamster liver microsomes showed a tendency to be more

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carcinogenic in hamsters than in rats. Some nitrosamine impurities were found to be very potent mutagens when

activated by hamster liver.

In the article, ‘‘U. S. Food and Drug Administration update (Jan 25, 2019), “Statement on the FDA’s ongoing

investigation into valsartan and ARB class impurities and the agency’s steps to address the root causes of the

safety issues”,[6] The FDA was actively investigated the presence of nitrosamine impurities in valsartan and

other ARB medications The agency was working to understand how these impurities were forming during the

manufacturing process. The FDA also reported recalls of certain valsartan, losartan, and irbesartan products due

to the presence of impurities.

In the article, by G. Subba Rao (1980), “N-Nitrosamines from drugs and nitrite: potential source of chemical

carcinogens in humans”, Pharmacy International, Volume 1’’,[7] drug-drug interactions may lead to nitrosamine

formation thus organic ester vasodilator drugs when ingested with propranolol a secondary amino anti-

arrhythmic drug yields as N-Nitroso propranolol, a tertiary amino tranquilizer drug, form the N-nitroso

piperazine.

In the article, “U.S. Food & Drug Administration. 2019. FDA provides update on its ongoing investigation into

ARB drug products; reports on finding of a new nitrosamine impurity in certain lots of losartan and product

recall”, [17] research concentrated on nitrosamine impurities formed during synthesis Afatinib at laboratory

scale, and MRM transitions used for quantification and identification of N-Nitrosodimethylamine (NDMA)and

internal standard NDMA-d6, standard process for analysis of traces of NDMA in tablet.

In the paper, “Genotoxicity of glycidamide in comparison to (l)-anti-benzo[a]pyrene-7,8-dihydrodiol-9,10

epoxide and a-acetoxy-N-nitroso-diethanolamine in human blood and in mammalian V79-cell”, [21] the

researcher concentrated on genotoxic and neurotoxic activity of glycidamide in comparison to known

carcinogens (l)-anti-benzo[a]pyrene-7,8-dihydrodiol-9,10 epoxide and a-acetoxy-N-nitroso-diethanolamine. GA

induced DNA damage in human blood in concentration dependent manner.

In the paper, “Nitrosamine Contamination in Pharmaceuticals: A Comprehensive Review on Nitrosation

Pathways, Potential Root Cause, Detection, Risk Assessment, and Mitigation Strategies”,[22] the researchers

concentrated on formation of nitrosamine in active pharmaceuticals like - ARBs, Anti-diabetic, Histamine-2

receptor, Anti- microbial and other during process and contamination. Nitrosamine formation pathway between

nitrosating agent and primary, secondary, tertiary and quaternary ammonium amines under certain conditions.

In the paper, “An update on the current status and prospects of nitrosation pathways and possible root causes of

nitrosamine formation in various pharmaceuticals”, [23] researchers concentrated on classification of

nitrosamine based on their carcinogenic potential and possible roots causes contamination in active

pharmaceutical ingredients like Sartans, Histamine-2 (H

) receptor antagonists, Antidiabetic agents, Anti-

microbial agents, etc., and have explained Acceptable Limit of commonly identified nitrosamines.

In a paper, “Analytical Methodologies to Detect N‑Nitrosamine Impurities in Active Pharmaceutical Ingredients,

Drug Products and Other Matrices’’,[25] researcher concentrated on Availability of analytical methods,

toxicological data, list of nitrosamines and their limits, and explained main sources of nitrosamine through

which human is exposed to these impurities which include food such as cooked/fried meat, vegetable, spiced

food, cocoa, beer, fats, oils, treated water, tobacco, pharmaceutical products, air pollution, personal care products

and cosmetic, etc.

CONCLUSION

The synthesis of nitrosamine impurities plays an important role in modern research. Nitrosamine impurities are

highly mutagenic and carcinogenic need acceptable limit in drugs and drug products. Potential sources of

nitrosamine impurities such as raw material, reagents, solvents, catalysts, cross-contamination, degradation

product, etc. Nitrosamine impurities need to be identified to control it in drug product and drug substance.

Impurity synthesis can be avoided by selecting pure and proper reagents, solvents and catalysis during synthesis

of drug substances. The analytical methods such as HPLC, Mass, NMR, GC are used for identification and

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quantification of impurities. The available research data point out possibility of carcinogenic nitrosamine

formation in humans from drug-nitrite interactions.

Sartans recall due to carcinogenic impurities, detected in large numbers, continue to raise concerns about the

reliability of the generic drug industry. However, there is still problem with these generic, two of these are pseudo

generics and carcinogenic impurities (NDMA) were detected and recall, NDMA contaminated generic is

valsartan.

The chemical interactions between nitric oxide and DNA can cause deamination and cross-linkage of DNA. A

chemical reaction where an amine group (-NH

) is removed from a molecule, the context of DNA determination

alters the base pairing properties.

The study link between tobacco-specific nitrosamines (TSNAs) and cancer development, specifically focusing

on how these compounds damage DNA, TSNA forms adduct with DNA it means they attach to DNA strands,

potentially disrupting normal function of DNA. If DNA damage is not repaired in time, it can initiate cancer.

Further study found that the level of TSNA inducted DNA damage in individuals using low nitrosamine oral

snuff product indicating low risk of cancer from these products.

The study focused on the role of liver microsomal fractions in the metabolic activation of nitrosamines.

Microsomes, derived from the endoplasmic reticulum, contain enzymes like cytochrome P450s that can

metabolize xenobiotics, including nitrosamines. The research indicated that hamster liver microsomes were

particularly efficient in activating a range of nitrosamines to mutagens compared to other liver preparations. The

metabolic activation of nitrosamines, particularly by hamster liver, plays a crucial role in their mutagenic and

potentially carcinogenic effects.

Nitrosamines are a class of compounds that are considered probable human carcinogens. Their presence in

medications has raised significant concerns, leading to recalls and regulatory action. The FDA has been working

with manufacturers to identify and address the sources of these impurities and to implement preventative

measures. The FDA was taking steps to mitigate the risks associated with these impurities and ensure the safety

of medications for patients. The agency was working to understand how these impurities were forming during

the manufacturing process.

The organic nitrate drugs generate nitrite ions under acidic condition found in the human stomach which then

react with secondary or tertiary amino drugs to yield nitrosamines. All new drugs containing secondary and

tertiary amino groups should be evaluated for nitrosative toxification by nitrite. Nitrate and nitrite are extensively

used as fertilizers in agriculture, colour and flavour enhancer in processed food.

Nitrosamine represent a significant class of pharmaceutical and environmental contaminants with well-

established carcinogenic properties. Their synthesis occurs through multiple pathways. The recent detection of

nitrosamine impurities in pharmaceuticals has highlighted the need for comprehensive understanding of their

formation, detection, and control. Future research should focus on developing more sensitive analytical methods,

better understanding tissue-specific effects, and implementing effective prevention strategies.

Supplier qualification and Row material testing can reduce nitrosamine formation possibility during process.

Nitrite scavengers such as Ascorbic acid, alpha-tocopherol and amino acids can be used to prevents nitrosamine

formation. Nitroso reactions are pH dependent so adjusting pH of final product to basic or neutral can prevent

degradation of API to Nitroso compound. Avoid use of recycled solvents or by testing make sure that recycled

solvents are nitrosamine free.

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