Nitrosamine Reactivity: A Survey of Reactions and Purge Processes

Borths, Christopher J.; Burns, Michael J.; Curran, Timothy T.; Ide, Nathan D.

doi:10.1021/acs.oprd.1c00162

Cited by 19 publications

(11 citation statements)

References 94 publications

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“…The finding that certain members of the sartan family of active substances contained levels of N -nitrosamines and subsequent findings of N -nitrosamines in other medicinal products have led to efforts to better understand the formation of N -nitrosamines during the manufacture of active pharmaceutical ingredients (APIs) and drug products (DPs). , Recent publications − have focused on the formation of N -nitrosamines, including from trace nitrite in water, nitrosamine reactivity, and behavior in aqueous extractions . This scientific understanding may be used to support manufacturers in undertaking risk assessments to determine whether a risk of nitrosamine presence or formation exists in APIs or DPs. − …”

Section: Introductionmentioning

confidence: 99%

Formation of Dialkyl-N-nitrosamines in Aqueous Solution: An Experimental Validation of a Conservative Predictive Model and a Comparison of the Rates of Dialkyl and Trialkylamine Nitrosation

Ashworth

Dey

Dirat

et al. 2023

Org. Process Res. Dev.

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The potential for active pharmaceutical intermediates and active ingredients to contain low levels of N-nitrosamines is a topic of continued interest from industry and regulatory authorities, which has led us to generate experimental data demonstrating that the published kinetic model of dialkylamine nitrosation is conservative and may overpredict the level of N-nitrosamine formation that will actually occur. Additionally, studies comparing the nitrosation of simple trialkylamines to that of the relevant dialkylamines have demonstrated that trialkylamines do indeed undergo nitrosative dealkylation to form N-nitrosamines but at a rate that is at least 500 times lower than for the related dialkylamines.

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Section: Introductionmentioning

confidence: 99%

Formation of Dialkyl-N-nitrosamines in Aqueous Solution: An Experimental Validation of a Conservative Predictive Model and a Comparison of the Rates of Dialkyl and Trialkylamine Nitrosation

Ashworth

Dey

Dirat

et al. 2023

Org. Process Res. Dev.

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“…In the cosmetics industry, nitrosamines were reported in hair dyes, nail polish, and other personal care products. Nitrosamines have also been reported in pharmaceuticals, particularly in products that contain nitrosatable compounds [2,[7][8][9]. Recent reports have shown that…”

Section: Introductionmentioning

confidence: 99%

Nitrosamine Impurities in Herbal Formulations: A Review of Risks and Mitigation Strategies

et al. 2023

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Nitrosamines are a class of chemical compounds that have been found to be impurities in a variety of pharmaceutical products. These impurities have raised concerns due to their potential carcinogenic effects. Recent studies have identified nitrosamines as impurities in a number of pharmaceutical products including angiotensin II receptor blockers (ARBs) and proton pump inhibitors (PPIs). The presence of nitrosamines in these products has led to recalls and market withdrawals. In addition to pharmaceuticals, nitrosamines have also been found in some herbal medicines particularly those containing traditional Chinese medicinal ingredients. The presence of nitrosamines in herbal formulations poses a significant risk to public health and highlights the need for quality control and regulations in the herbal drug industry. The present review article aims to discuss nitrosamine impurities (NMI) prominent causes, risks and scientific strategies for preventing NMI in herbal formulations. The primary objective of this study is to examine the origins of nitrosamine contamination in herbal formulations, the risks associated with these contaminants, and the methods for reducing them. The significance of thorough testing and examination before releasing herbal products to the public is also emphasized. In conclusion, the presence of nitrosamines is not limited to pharmaceutical products and poses a significant threat to the safety of herbal drugs as well. Adequate testing and extensive research are crucial for producing and distributing herbal medicines to the general population.

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“…Residual nitrite, however, can come from various sources such as not only API but also excipients, process water, etc . Therefore, control and measurement of residual nitrite becomes a critical part of N -nitrosamine control strategy in the pharmaceutical industry. − …”

Section: Introductionmentioning

confidence: 99%

Rapid-Response Nitrite Probes: Intramolecular Griess Reaction for Nitrite Detection at Picogram Level

2023

Org. Process Res. Dev.

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Nitrite is abundantly used not only in the food industry but also in various chemical reactions such as diazotization to furnish azo-dye compounds and the Sandmeyer reaction. When a secondary amine is in the presence of nitrite, residual levels of nitrite ions can potentially form corresponding N-nitrosamines, many of which are known to be carcinogenic. The carcinogenicity concerns with N-nitrosamines resulted in worldwide recalls of numerous marketed pharmaceutical products since 2018. Therefore, the residual nitrite assay is a critical part of N-nitrosamine risk assessment, as many components present in drug products including not only the drug substance but also excipients can be a potential source of nitrite ions. While ion chromatography serves as a primary analytical tool for the nitrite ion assay, leveraging the Griess reaction shows several benefits over ion chromatography, which includes rapid and visible responses as well as flexibility of sample preparations in organic solvent. In order to simplify the Griess reaction method and enhance reactivity toward the nitrite ion, a series of probe molecules was designed and synthesized. Upon exposure to the nitrite ion, molecular probes undergo diazotization followed by intramolecular cyclization to form benzo[c]cinnoline, which elicits dramatic absorption and emission changes as a signal readout for the nitrite assay. The reactivity toward the nitrite ion depends on nucleophilicity as well as electron-withdrawing/donating properties of substituents on probe molecules. Among a series of probe molecules, comparative kinetic studies revealed that the para-sulfonamide-substituted molecule (probe 1) has the highest reactivity with no-detectable side reaction. With probe 1, method validation was performed with two representative excipients, microcrystalline cellulose and dicalcium phosphate dihydrate, which demonstrated excellent accuracy, linearity, precision, and multilevel spike/recovery as well as very low detection limit (sub-parts-per-billion level) when coupled with a fluorescence detector. This new probe molecule offers low detection limits and wide flexibility in terms of sample preparation in a higher composition of organic solvent. Such flexibility of solvent choice enables a broader application of the method to any components in drug products including API, process intermediates, and excipients.

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Nitrosamine Reactivity: A Survey of Reactions and Purge Processes

Cited by 19 publications

References 94 publications

Formation of Dialkyl-N-nitrosamines in Aqueous Solution: An Experimental Validation of a Conservative Predictive Model and a Comparison of the Rates of Dialkyl and Trialkylamine Nitrosation

Formation of Dialkyl-N-nitrosamines in Aqueous Solution: An Experimental Validation of a Conservative Predictive Model and a Comparison of the Rates of Dialkyl and Trialkylamine Nitrosation

Nitrosamine Impurities in Herbal Formulations: A Review of Risks and Mitigation Strategies

Rapid-Response Nitrite Probes: Intramolecular Griess Reaction for Nitrite Detection at Picogram Level

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