Advantages and limitations of the inclusion of ascorbic acid on nitrosamine mitigation in pharmaceutical drug products-Pub

New Scientific Knowledge & Development
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Abstract

Nitrite scavenging is an effective strategy to control nitrosamine formation during the shelf-life of pharmaceutical drug products, particularly when other interventions are insufficient. Here, we showed that the addition of a specific nitrite scavenger, ascorbic acid, decreased nitrosamine formation in tablets. It was found that a homogeneous distribution of ascorbic acid in the excipient blend achieved through wet blending was critical to minimizing nitrosamine formation. As an antioxidant, the use of ascorbic acid requires a validated analytical method and established acceptance limits for regulatory compliance, which is complicated by our observation that ascorbic acid was unstable during routine tablet production and on stability. Additionally, new API related substances were seen and attributed to the reaction with ascorbic acid, which necessitates structure elucidation and toxicological qualification. With these limitations in mind, implementing a nitrite scavenging system for nitrosamine control requires well-defined workflows for the data package, analytical methods, and regulatory filing strategy throughout the product lifecycle.

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We saw this as well with a recent reformulation. While Ascorbic Acid worked really well to inhibit the nitrosation, we saw new impurities.

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Ascorbic acid demonstrates significant efficacy in mitigating nitrosamine formation; however, its broad application is constrained by incompatibility with a wide range of active constituents.

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I recalled Dr. Trampuž(@TrMa1990)'s excellent paper.

https://www.mdpi.com/2227-9717/10/11/2428

It should also be noted that there was a significant change in color observed after the stress test with some scavengers. This was most pronounced with scavengers 1 , 2 and 15 and is due to the chemical degradation of the scavenger. Ascorbic acid (1) is known to be unstable and discolors over time. Thus, including it as a scavenger would likely require strict storage conditions (e.g., protected from humidity, inert atmosphere).

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Thanks for sharing. It’s a topic that is talked about very often, especially in recent years, and it is always relevant.

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Dear Yosuke Mino, thanks for sharing, very interesting and helpful.

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