Use of Additives in Oral Solid Dosage Forms to Inhibit Nitrosamine Formation

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Some nitrosamines (e.g. NDMA, NDEA) are classed as 'cohort of concern' genotoxic impurities and require control to extremely low limits in drug products. There has been a recent regulatory focus on nitrosamines due to detection of certain nitrosamines above the acceptable daily intake in several marketed drug products, leading to market-wide product recalls. Regulators require that novel nitrosamines, for which there is no or limited safety data, are regarded as mutagenic, and therefore controlled to very low acceptable daily intakes, which can be down to the order of nanograms. This can be challenging in drug products where the drug substance contains an amine functional group vulnerable to nitrosation. Nitrites are ubiquitous in excipients at trace levels and can act as nitrosating agents towards vulnerable amines (usually secondary or activated tertiary amines).There is a need for strategies to control the formation of nitrosamines in drug products such as the addition of a compound to act as a scavenging agent or oxidising agent towards nitrites (e.g. ascorbic acid/sodium ascorbate) or using an additive to control pH of the drug product, keeping the pH unfavourable for nitrosamine formation. However, there is very little industry experience with these approaches to inhibit nitrosamine formation in solid phase drug products. One of the most challenging aspects remains determining and ensuring sufficient distribution of the additive within each unit dose to prevent nitrosamine formation at levels above the permitted limit.This project will allow us to work with GSK (chemical industry) to investigate inhibition of nitrosamine formation using different possible additives within a research industry context. Other parameters could be investigated such as using pH to inhibit the formation of nitrosamine.In the first year, we would first conduct analysis of different nitrosamines and characterise them, in particular more complex structures of nitrosamines (not small structures such as NDMA as research shows that smaller nitrosamines are more likely to be carcinogenic). Then we would find any model amines that we can use to form nitrosamines through nitrosation. Then research would be conducted on finding possible additives that could be used to prevent nitrosation of the model amines. In the next year, formulation chemistry will then take place where these model amines and additives will be made into tablets and tested for nitrosamine formation both in the university labs as well as the GSK labs. In the third year, it the tablets results are positive, then the uniformity of the inhibitor (e.g. additives) will be investigated (including mechanism of inhibition) and control strategy would take place (to see how it would lead to a quality product).