Articles

The Nitrosamines Challenge

Since 2018, the issue of nitrosamines has been a significant concern for pharmaceutical companies, becoming a routine part of their processes. This includes planning projects, assessing risks, planning the Route of Synthesis (RoS), assessing the RoS, evaluating the risk of nitrosamine formation, and purchasing standards.

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Secondary Amine and the Beauty of Chemistry

A common assumption is that if an Active Pharmaceutical Ingredient (API) is a secondary amine, there is a risk of nitroso-API formation. Additionally, if nitroso-API standards are readily available, it seems straightforward to order them. However, this approach can be misleading. Chemistry, with its myriad possibilities for rearrangements and side reactions, often defies expectations. At Polpharma, we continually challenge the status quo to remain competitive.

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A Case Study: Nitroso-Ticagrelor

Polpharma’s API is renowned for its exceptional know-how and expertise. Our team of specialists is dedicated to pushing the boundaries of pharmaceutical science, ensuring that we stay ahead of industry challenges. A notable case involved nitroso-Ticagrelor, an API with a secondary amine group, posing a high risk of nitrosamine formation due to commonly used reagents. Initially, it seemed like a standard procedure: obtain the standard, develop the analytical method, and analyze the API for impurities. However, analyses revealed the absence of the nitroso group in the structure, prompting further investigation.

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The Investigation

Our dedicated team of chemists launched an investigation, meticulously monitoring the transformations during Ticagrelor’s nitrosation. Despite the expected molecular mass, the product did not exhibit the anticipated structure.Leveraging our extensive knowledge and innovative problem-solving approaches, we proposed multiple synthesis routes to explore alternative mechanisms. Through targeted experiments and comprehensive analyses, including UHPLC, IR,and NMR, we identified the issue.

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The investigation revealed that the cyclopropyl ring near the nitrosated amine undergoes rearrangement, forming an oxazole ring—a non-toxic, stable derivative unlike the expected compound. This discovery underscored the importance of verifying assumptions and not blindly trusting impurity standards. Despite the availability of nitroso-Ticagrelor standards, our findings highlighted the need for critical evaluation and continuous questioning of popular beliefs.

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Questioning the Status Quo

Inconclusion, the pharmaceutical industry must remain vigilant and skeptical ofwidely accepted standards. The case of nitroso-Ticagrelor serves as a reminderthat thorough investigation and innovative thinking are crucial in ensuringproduct safety and efficacy. Polpharma API’s commitment to excellence and ourteam’s expertise play a pivotal role in navigating these complex challenges,reinforcing our position as industry leaders.

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