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
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.
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.
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.
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?
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.
hallo to everyone,
coming back to the case of the scavengers, i would like your feedback regarding the permitable quantity of ascorbic acid which could be used from regulatory perspective.
Furthermore, is there any defined quantity which could be add in the formulation, in order not to resulted to the repeat of the bioequivalenve study, in case of re-formulation?
kind regards
From experience with other products in a previous role this could well depend on the market in which your product will be sold. Different markets have different acceptable levels of Ascorbic acid before the amount has to be declared as an active in that market. Active levels will cause many more problems in terms of declaring a level and ensuring you stay within that level throughout the shelf-life.
It will also depend on your product and the number of doses a day.
Recommended levels and accepted safe levels can vary wildly, from less than 100mg a day, all the way through to 2g a day (though these high levels are controversial and probably far exceed anything that would be needed from a scavenger perspective).
From a bioequivalence perspective, this isn’t something that I have seen a definitive answer on to date. It may require individual conversations with the appropriate regulatory authorities.
@chrischar I suggest reviewing both FDA presentations on both: Using scavenger in a model compound (Dr. Shakleya) and Bioequivalence assessment (Dr. Dongmei) during the CRCG workshop last year.
Dr. Shakleya et al. published the work and I am aware of additional publication coming on that area from his group.
The link to the CRGC workshop does not work. The new link is as follows;
Recordings and slides are available there. Please check these slides.
Session 1
Effectiveness of Antioxidants in Selected Model Drugs: Mitigation Strategy and Impact of Reformulation in Their Stability (Dr. Shakleya)
Session3
Use of a Novel Technology, the In Vitro Dissolution Absorption System, to Investigate the Effects of Antioxidants on the Intestinal Permeation of BCS Class III Drugs (Dr. Bode)
Physiologically Based Pharmacokinetic (PBPK) Absorption Modeling to Evaluate the Impact of Excipients on Bioequivalence of BCS Class III Drug Products (Dr. Wu)
good morning or evening,
thanks a lot to all of you for your input and ideas.
The story behind my questions is that, before some months we proceeded with a small DoE with several concentrations of ascorbic acid in a product in which the API is a secondary amine and presented relatively high levels of the corresponding nitrosamine (near to 50% of the specification limit). The stability results at 6 months in accelerated conditions were very impressive, as even 0.1% (or approximately 0.15mg/tablet) resulted to approximately 50% decrease of the level of the nitrosamine.
have a nice day ahead
