(665b) Determining Nitrosation Kinetics in Organic Solvents and the Impact of Process Parameters on Nitrite Levels

Nitrosamines have been identified as a cohort of concern (CoC).^1-3 Understanding their formation rate and the impact of process parameters can aid the design engineering controls to mitigate nitrosamine risk of formation.

In a recent work, we showed that dialkylamine molecular descriptors (e.g., bulkiness, aqueous solubility, and sterics) plays an important role in the aqueous nitrosation rate of the amines in the liquid phase.⁴ Kinetic data for different types of amines were collected at different temperatures and pH and a process model was developed for both homogeneous and heterogeneous reactions. The results were compared to the most common surrogate, dimethylamine. It was found that bulkier amines undergo nitrosation at much slower rates than dimethylamine.

In this work we are focusing on two main topics: 1) understanding the reaction kinetics of the nitrosation reactions in organic solvents to investigate the formation rates, and 2) how process parameters could impact nitrite levels and thus nitrosation rates. Two questions this work answers are: 1) is the nitrosation rate in organic solvents comparable to the nitrosation rate in water? and 2) what process parameters impact nitrite levels? The answers to these questions can help answer other questions related to nitrosamine formation risk assessment of key pharmaceutical processes, including purification, isolations, as well as spray drying processes.

References:

¹ Nudelman, R. et al. The Nitrosamine “Saga”: Lessons Learned from Five Years of Scrutiny. Org. Process Res. Dev. 27, 1719–1735 (2023).

² 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

³ U.S. Department of Health and Human Services Food and Drug Administration. Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) Guidance for Industry; 2023. https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs

⁴ Eren, A., & Luciani, C. (2024, October). Improving Our Understanding of Nitrosamine Formation in Pharmaceutics: Computational and Experimental Approaches. In 2024 AIChE Annual Meeting. AIChE.