Nitrite Scavengers in Solution and Solid State

A fantastic study by Miha Homšak et al. Assessment of a Diverse Array of Nitrite Scavengers in Solution and Solid State: A Study of Inhibitory Effect on the Formation of Alkyl-Aryl and Dialkyl N-Nitrosamine Derivatives

Thanks for sharing @TrMa1990

Open access: Processes | Free Full-Text | Assessment of a Diverse Array of Nitrite Scavengers in Solution and Solid State: A Study of Inhibitory Effect on the Formation of Alkyl-Aryl and Dialkyl N-Nitrosamine Derivatives

Abstract

The ubiquitous presence of mutagenic and potentially carcinogenic N-nitrosamine impurities in medicines has become a major issue in the pharmaceutical industry in recent years. Rigorous mitigation strategies to limit their amount in drug products are, therefore, needed. The removal of nitrite, which is a prerequisite reagent for the N-nitrosation of amines, has been acknowledged as one of the most promising strategies. We have conducted an extensive literature search to identify nineteen structurally diverse nitrite scavengers and screened their activity experimentally under pharmaceutically relevant conditions. In the screening phase, we have identified six compounds that proved to have the best nitrite scavenging properties: ascorbic acid (vitamin C), sodium ascorbate, maltol, propyl gallate, para-aminobenzoic acid (PABA), and l-cysteine. These were selected for investigation as inhibitors of the formation of N-methyl-N-nitrosoaniline (NMA) from N-methylaniline and N-nitroso-N’-phenylpiperazine (NPP) from N-phenylpiperazine in both solution and model tablets. Much faster kinetics of NMA formation compared to NPP was observed, but the former was less stable at high temperatures. Vitamin C, PABA, and l-cysteine were recognized as the most effective inhibitors under most studied conditions. The nitrite scavenging activity does not directly translate into N-nitrosation inhibitory effectiveness, indicating other reaction pathways may take place. The study presents an important contribution to identifying physiologically acceptable chemicals that could be added to drugs to prevent N-nitrosation during manufacture and storage.

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Just to add this to your radar: @Yosukemino @ASrinivasan

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Thanks, Naiffer, a good paper. I think that the nitrite scavengers will be the answer to this problem, at the end of the day. It is just that a lot of work is needed.

Aloka

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Thank you, @Naiffer_Host.
It’s a great investigation. When applying this approach, we can select the best scavenger for our own products by case by case basis. Pre-mixed excipients may be convenient for formulation, if available.

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Thanks for sharing. This could be adapted into a bolt on to a standard excipient compatibility study early in formulation as well.

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Thanks for sharing @Naiffer_Host . This is a great publication.

It would be great to see direct application of a nitrosamine scavenger as a control strategy in a real case commercial APIs. I wonder what the solution Merck will apply to Januavia is.

Is anybody already aware of any real case when scavengers have been used and accepted by regulators?

Thanks again
Hugo

Feel free to engage with @TrMa1990, who shared the paper with us, and @ASrinivasan, who lead many discussions around scavenger agents.

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Hi,
I just joined this community but currently supporting a technology that adsorbs molecules which can be precursors or actual LMW nitrosamines. We have commercial platform technology for blisters which this technology can be implemented. There have been various actives used based on different reaction situations and drug moiety.

@Naiffer_Host @Hugo @ASrinivasan @Yosukemino

I am happy to discuss more offline

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