Quantitation of Reactive Nitrosating Agents in Pharmaceutical Excipients for N‑Nitrosamine Risk Assessments

Risk Assessment Strategy / Tools & Technology
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Dear all,

I am very happy to notice you Dr. Yamamoto et.al has published an article referring “Reactive NOx Content in Excipients”. https://pubs.acs.org/doi/epdf/10.1021/acs.oprd.2c00402
Simply mixing the amine with each excipient and storing them at an elevated temperature is a facile way to obtain the reactive NOx content, which can be used to predict the maximum amount of nitrosamine that can be formed. Furthermore, this method can be applied to various nitrosamine precursors other than just dimethylamine.

Maximum Values of Reactive NOx Content after 2−3 Days or 1−4 Weeks under Stress Condition are as follows;

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Hi @Yosukemino,

Thanks for this info, I really second this kind of studies that in summary are compatiblity studies. With this binary mixtures being stressed pretty useful data could be generated and the methodology of course can be modified with your amine of interest.

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@Yosukemino, the presented discussion offers valuable insights for streamlining pharmaceutical product development. I’d like to address the role of temperature.

It’s crucial to carefully select temperature ranges (Approaches and Considerations for the Investigation and Synthesis of N-Nitrosamine Drug Substance-Related Impurities (NDSRIs)) to prevent nitrite decomposition at higher temperatures. These temperature-related factors are particularly important in the context of N-nitrosamine formation in drug manufacturing processes.

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I had considered doing something very similar to this, as the methods for the detection of nitrosamines are far more sensitive than those generally utilized for the detection of nitrite etc. - especially for excipients where the level of NOx is very low.
There are some results in here that I think are showing something different to values that have been published elsewhere using different techniques - one that especially stands out is the value for talc (much higher in this paper), but also the value for povidone, which is lower.
It is important to remember when seeing these values that they are for one particular batch from one supplier. The level of variability from batch to batch and supplier to supplier has been shown to be pretty significant, and decisions shouldn’t be made on individual reported values. Is the methodology used in this paper robust enough to generate consistent results between labs, so that a larger data set can be generated?

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@Yosukemino
Thank you for introducing our paper.

@MarkS
Thanks for your interest in our research.
We also find it very interesting that the values are different from, for example, nitrite ion levels evaluated by other methods. This may suggest that factors other than nitrite ions that contribute to nitrosation also need to be considered.
Our method is very simple. Although there is a need to ensure that photolysis does not occur, there is no problem with inter-room reproducibility as long as the environment is such that nitrosamines can be measured with high accuracy.

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