Many nitrosamines are regarded as potential mutagens and have recently been found to contaminate commonly used drugs, such as those prescribed for high blood pressure (valsartan), type 2 diabetes (metformin) and heartburn (ranitidine). Approximately 85% of the 137 nitrosamines listed in the Lhasa Limited Carcinogenicity Database (LCBD) are considered carcinogenic by the study authors (Thresher 2020), indicating a high likelihood of any nitrosamine being a possible carcinogen. It is estimated that more than 90% of nitrosamines are possible carcinogens as they have a volatile structure that can react with DNA to potentially cause cancerous mutations.1,2 As such, the discovery of nitrosamines in pharmaceuticals in 2018 sent shockwaves throughout the pharmaceutical industry and put the development of nitrosamine mitigating strategies at the forefront of manufacturers’ minds. Since then, researchers have delved deeper into nitrosamine formation and possible mitigating strategies for the pharmaceutical industry, building on the body of work produced in the 1970-1980s on removing nitrosamines from food products.3,4 Below, we roundup the latest findings and how you can use these insights to produce safer pharmaceuticals.
We know nitrosamine formation is a risk in many drug products – but is the industry really aware of the extent? A new study conducted by Schlingemann et al., applied a novel method to landscape the potential risk of nitrosamine contamination in pharmaceuticals.5 The study analyzed over 12,000 small drug molecules and drug impurities from a publicly available registration system and identified any structure that could potentially form nitrosamines under relevant conditions. Alarmingly, results indicated that the risk of nitrosamine contamination in regularly prescribed drug products was more common than previously thought, with 40.4% of active pharmaceutical ingredients (API) and 29.6% of API impurities being classified as potential nitrosamine precursors.
Furthermore, Schlingemann and his team revealed that whole drug classes could have an inherent nitrosamine formation risk due to similar structures. Drug classes most at risk include beta blockers and angiotensin-converting enzyme (ACE) inhibitors, amongst many more. The authors shared their insights on ways to mitigate nitrosamine formation, including reformulation with low-nitrite excipients and/or addition of a scavenger to the formulation.
DSM’s senior scientist, René Stemmler, provides expert insight on why nitrosamine contamination is such a common challenge in pharma: “Many drugs are at risk of contamination because API’s frequently contain amine and amide functionalities, which are well suited to interact with the drug’s target protein, but are also vulnerable to nitrosation.6 Also, in some cases a nitrosating agent or a secondary amine is even used as a reagent in the manufacture of the API; as a result, it is often almost impossible to completely remove such nitrosamine precursors from the API (and consequently from the final drug product). This stresses the need for effective solutions to help reduce the development of nitrosamines given that their formation is difficult to avoid otherwise.”
In 2021, Nanda et al., published important findings on the use of certain antioxidants for nitrosamine mitigation.7 The study investigated the efficiency of five antioxidants, including ascorbic acid, in inhibiting the formation of nitrosamines in oral solid dosage forms using a model API. Results indicated that all antioxidants employed in this study, when spiked at 1.0-2.4 wt% in solid drugs, could inhibit nitrosamine formation by >80%. Therefore, in this proof-of-concept study the scientists demonstrated the potential of incorporating scavengers into drug products as a powerful and effective mitigation strategy.
Building on these findings, Homšak et al., published a study taking the principle proposed by Nanda to the next stage.8 The researchers conducted a comprehensive screening of many known nitrite scavengers and 19 compounds were selected for further investigation, all of which were either acceptable for use in medicinal products, commonly present in food or known human metabolites. Experiments identified that ascorbic acid was the most effective nitrosamine inhibitor under the majority of conditions studied. Most strikingly, ascorbic acid was able to completely remove all nitrite after 1-2 hours in aqueous solutions kept at pH 3 and 20°C and significantly decreased the level of N-nitroso-N’ – phenylpiperazine (NPP) in tablets.
DSM’s Principal Scientist and formulation expert, Zdravka Misic, comments on the feasibility of reformulating with ascorbic acid: “To protect against the formation of nitrosamines, ascorbic acid removes nitrosating agents before they have the chance to react with vulnerable amines.9 Ascorbic acid can be easily incorporated into most drugs as it is water soluble and is available in different forms, from fine powder to coarser particles10, which means it can be added to liquid formulations or to granulation solutions for solid dosage forms.” Misic continues to shed light on the benefits of using antioxidants over other mitigating strategies: “Adding antioxidants to formulations that are at risk of oxidation can also improve the stability of drug products in addition to blocking nitrosamine formation.”
Further evidence suggests additional nutrient-derived antioxidants, other than ascorbic acid, could be considered for nitrosamine mitigation, such as alpha-tocopherol. Supplementing alpha-tocopherol has been shown to effectively reduce nitrosamine formation and also precursors to nitrosating agents.11
It may also be a beneficial strategy to add multiple antioxidants, such as ascorbic acid and alpha-tocopherol, to the drug formulation as they can have cooperative and synergistic effects.12
For manufacturers looking to implement a nitrosamine mitigation strategy, Anne-Cécile Bayne, DSM’s Global Science Innovation Lead Pharma & Medical Nutrition, reveals the company’s safe and effective solution: “As a purpose-led innovation partner in the pharmaceutical industry, DSM can help you implement a proven mitigation strategy by providing the technical guidance you need to reformulate existing products or develop new, risk-free pharmaceuticals. As well as offering customers with several grades of high-quality ascorbic acid and alpha-tocopherol excipients, plus the knowledge to formulate with these ingredients, our broad experience in nitrosamine assessment is supported by strong expertise in chemistry and toxicology.”
Ready to mitigate nitrosamines with confidence? Download our whitepaper to find out how.
10 February 2023
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