(218e) Improving Our Understanding of Nitrosamine Formation in Pharmaceutics: Computational and Experimental Approaches

With the pharmaceutical industry increasingly coming under scrutiny for the presence of nitrosamines in their products,¹ it is important for industry to create tools to better understand nitrosamine formation mechanisms, prevalence, and methods for prevention and removal.

Amines and nitrosating agents, the precursors of nitrosamines, are ubiquitous, with traces found in seemingly innocuous sources.² Given the prevalence of amines and nitrogen-containing compounds in various pharmaceutical processes, tools for conducting risk assessments, including kinetic models that describe the nitrosation reaction processes have been used by researchers for a while.^2–4 Leveraging these tools allows a quantitative evaluation of the risks associated with nitrosamine formation to be conducted and effective design of control measures implemented, as needed.

In this work, we investigate the opportunity to enhance existing kinetic models by incorporating additional phenomena, such as equilibrium equations, nitrosating agent decomposition reactions, along with the dissociation behavior or ions that facilitate nitrosation reactions.

Experiments were designed to evaluate nitrosation reactions in solution phase. In this work, we developed a comprehensive mathematical model to capture the behavior of typical pharmaceutical processes and to carry out a realistic risk assessment of nitrosamine formation. The model includes the dissociation equations of halides, the impact of solubility of amines, and other equilibria to enhance the already established solution-phase reaction model.² Our simulation results shine light on potential strategies that can be used to mitigate nitrosamine formation risk.

References:

(1) R. Nudelman, G. Kocks, B. Mouton, D.J. Ponting, J. Schlingemann, S. Simon, G.F. Smith, A. Teasdale, A.L. Werner, The Nitrosamine “Saga”: Lessons Learned from Five Years of Scrutiny, Org Process Res Dev 27 (2023) 1719–1735. https://doi.org/10.1021/acs.oprd.3c00100

(2) Ashworth, I. W.; Dirat, O.; Teasdale, A.; Whiting, M. Potential for the Formation of N-Nitrosamines during the Manufacture of Active Pharmaceutical Ingredients: An Assessment of the Risk Posed by Trace Nitrite in Water. Org Process Res Dev 2020, 24 (9), 1629–1646. https://doi.org/10.1021/acs.oprd.0c00224 .

(3) Rayson, M. S.; MacKie, J. C.; Kennedy, E. M.; Dlugogorski, B. Z. Accurate Rate Constants for Decomposition of Aqueous Nitrous Acid. Inorg Chem 2012, 51 (4), 2178–2185. https://doi.org/10.1021/ic202081z .

(4) Licht, W. R.; Deen, W. M. Theoretical Model for Predicting Rates of Nitrosamine and Nitrosamide Formation in the Human Stomach. Carclnogenesis 1988, 9 (12), 2227–2237. https://doi.org/https://doi.org/10.1093/carcin/9.12.2227 .