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.

Formation of N-Nitrosamine Drug Substance Related Impurities in Medicines: A Regulatory Perspective on Risk Factors and Mitigation Strategies

“…Current understanding is that nitrite is the limiting reagent in the formation of NDSRIs and thus its concentration determines the maximum amount of N -nitrosamine that can form in the drug product . It is important to note however that only a fraction of the total nitrite effectively leads to N -nitrosamine impurities under usual formulation and storage conditions, with the levels depending on the reactivity of the vulnerable secondary amine: typically a few percent for aliphatic amines, whereas the extent of nitrosation of aromatic derivatives can be much higher (e.g., 25% nitrosation of N -methyl phenylamine) …”

“…It is plausible that this is due to the restricted mobility of the two reacting species (i.e., nitrite and vulnerable amine) in the solid phase and the heterogeneous nature of the system where reactants may be immobilized in highly crystalline phases or in the core of large particles. Other factors that may play a role here are the limited stability of nitrite and/or some N -nitrosamines. , Data in this area are scarce, and more research is necessary to clarify these aspects.…”

“…Scheme 5. Model Studies for the Inhibition of NDSRI Generation in Drug Products by the Use of Nitrite Scavengers70,82 …”

Regulatory Highlights

“…So, if we cannot control via reduction/elimination of nitrite in excipients, what other options exist? Tantalizingly, research showed that nitrosamine formation could be inhibited by the use a scavenger, , but to date there is not one example of an approved product where such an approach has been utilized. Thus, the idea that tens of thousands of products could be reformulated to include a scavenger is impossible, especially when other considerations relating to studies needed to support such a process change are taken into consideration.…”

Stability and Degradation Pathways of N-Nitroso-Hydrochlorothiazide and the Corresponding Aryl Diazonium Ion

“…Subsequent investigations revealed that APIs, which possess vulnerable secondary or tertiary amine moieties, can also be susceptible to N -nitrosation, forming nitroso-API impurities ( N -nitrosamine drug substance-related impurities, NDSRIs) . In the case of formation in the drug product itself, there is limited opportunity to mitigate the risk of NDSRI formation due to the lack of opportunity for purging . Such cases have already triggered recalls of drugs from the market…”