✕
☰

Five benefits of using antioxidants in pharma formulations

by

Anne-Cecile Bayne, global science & innovation lead Pharma & Medical Nutrition, DSM discusses the benefits of using antioxidants to block nitrosamine development in drug products, and futureproof pharma formulations.

Key insights:

Nitrosamine contamination of drug products has emerged as a major regulatory issue for the global pharmaceutical industry in recent years – with upcoming legal deadlines requiring drug developers to take time-sensitive action.

Ever since the first discovery of N-nitrosamines in valsartan four years ago, nitrosamine mitigation has become a key focus for pharmaceutical manufacturers across the world. To protect patient health, drug developers now have a legal obligation to perform a thorough risk assessment for both new and existing products and, where necessary, implement an appropriate control strategy, which might include reformulation. The European Medicines Agency (EMA) and the Food and Drug Administration (FDA) have set stringent deadlines by which drug manufacturers are to present their risk mitigation plans for chemical medicines and biological medicines.

What is next for drug formulation?

With deadlines from the FDA and EMA fast approaching, drug developers are searching for solutions that will help overcome their formulation challenges in mitigating nitrosamine formation. Manufacturers can review and look to optimise the formulation process of drug products to limit nitrosamine formation and this, in turn, will support learnings for future drug development. However, optimisation of formulation processes may not prevent nitrosamine contamination entirely.

For these reasons, manufacturers may look to block nitrosamine formation in drug products. This is considered the best way to mitigate the risk and ensure that impurity levels are below allowable limits – which is an acceptable daily intake of 18 ng for newly emerging nitrosamine impurities according to current EU regulatory guidance and 26.5 ng/day in the US.

One possible strategy is that the formation of nitrosamines typically occurs under acidic conditions and the risk of contamination is much lower in neutral or basic environments. Formulations that incorporate excipients like sodium carbonate – which modify the microenvironment to a neutral or basic pH – should therefore, in principle, inhibit the development of nitrosamines. However, this strategy is not always suitable because some drug substances are not stable at higher pH levels. Another approach is blocking nitrosamines by including antioxidants, namely ascorbic acid (vitamin C) and α-tocopherol (vitamin E), in drug formulations.

1. Block nitrosamine formation

Nitrosamine impurities, like N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA), are formed when a nitrosating agent – like nitrous anhydride (N2O3) or nitrosonium ion (NO+) – reacts with a secondary or tertiary amine. Depending on the pH, these nitrosating agents will then react with secondary or tertiary amines to form a nitrosamine.

Any active substance or ingredient whose structure comprises secondary, tertiary amines or tertiary ammonium salts is therefore at risk of nitrosamine formation, as are drugs where the active is stabilised by buffers containing tertiary or quaternary amines. Drug formulations that include any excipient containing secondary or tertiary amines, or quaternary ammonium salts, are also likely to form nitrosamines.  

Known as a nitrosation inhibitor, ascorbic acid is a powerful reducing agent that can react with many nitrosating agents (like NO+ and N2O3), converting them into nitric oxide (NO) and effectively blocking nitrosamine formation. By reacting with nitrosating agents at a more rapid rate than nitrite does with secondary amines, the vitamin disarms nitrosating agents and ultimately prevents a reaction between nitrites and vulnerable amines. It has been demonstrated that ascorbic acid inhibits nitrosamine formation more effectively at pH 3-4 than other nitrite-reducing agents. Adequate quantities of α-tocopherol are also proven to be effective at reducing the precursor of nitrosating agents, NO2ˉ to NO.

By blocking the formation of nitrosamine impurities, both antioxidants can help to keep nitrosamine levels below the acceptable intake limits, making drug products safe for human use. Emerging research has found that ascorbic acid and α-tocopherol demonstrated greater than 80% inhibition when spiked at 1% levels in solid oral dosage forms.

2. Successfully used across the food industry

For the past 30 years, antioxidants have been used successfully by mitigating nitrosamine formation in foods. Nitrosamines first became a health concern in the 1980s when nitrites were typically added to processed meats to prevent the growth of bacteria. Amines are common chemicals in food products, therefore preserving foods with nitrites induced a reaction and nitrosamines became unintentional by-products of food preparation and processing. High concentrations of nitrosamine impurities were reported in bacon, sausages and hams at the time – leading to the development of the first mitigation strategies.

Take bacon as an example – when preserved with 150 ppm nitrite, high levels of N-nitrosopyrolidine (NPYR) are formed when the bacon is fried. Reducing the amount of nitrite to 120 ppm and adding 500 ppm ascorbic acid, lowered NPYR levels to 10 ppb. Today, manufacturers using nitrites to preserve food are required to add ascorbic acid to their products to inhibit nitrosamine formation.

3. FDA-recommended strategy

Adding ascorbic acid and α-tocopherol as antioxidants is one of the options recommended by the FDA as a mitigation strategy for pharmaceutical drug products. The inhibitory effect of ascorbic acid on nitrosamine formation was first noted in 1976 when investigators proposed that finished dosage forms of ‘easily and rapidly nitrosatable drugs’ should include the excipient. The most recent nitrosamine update from the FDA examined the effectiveness of antioxidants in oral dosage forms and concluded that ascorbic acid and α-tocopherol are suitable nitrosamine inhibitors in drug products.

4. Offer additional advantages

Next to their efficiency in blocking nitrosamine formation, in one study both ascorbic acid and α-tocopherol have been demonstrated to impact the carcinogenicity of preformed nitrosamines and other carcinogens directly – reducing tumour yields by up to 60%. When combined, they may also offer potent antioxidant activity, protecting against oxidative stress-induced damage. One study found that α-tocopherol (plus ferulic acid) increased the effectiveness of ascorbic acid eight-fold. Additionally, ascorbic acid regenerates α-tocopherol after it scavenges free radicals, further reducing oxidative stress in cells. Both excipients act as stabilisers in finished drug product formulations too – helping to protect the active ingredient from degrading and maintaining the efficacy of the drug.

5. Favourable safety profile

Ascorbic acid and α-tocopherol are already well-known excipients used across the pharmaceutical and dietary supplement industries. They can be used at high levels without any safety concerns. However, care should be taken to add only the necessary amounts to avoid Maillard reaction with reactive substances, which can cause undesirable colour changes or odours.

Reformulating with confidence

For drug developers to overcome critical drug formulation issues – like nitrosamine contamination – and develop safer therapies, they must adhere to the latest regulations and guidance. Ascorbic acid and α-tocopherol as antioxidants offer developers reliable opportunities to redesign their pharmaceuticals, or innovate new drugs, with reduced risk of nitrosamine formation. Drug developers can look to specialist industry partners, such as DSM, that can offer scientific and formulation support as well as regulatory expertise to overcome the nitrosamine challenge in the pharmaceutical space.

Back to topbutton