EPR in Pharma

Detecting and evaluating degradation

Therapeutic drugs require a well characterized shelf-life to ensure correct dosage and patient safety. Degradation processes quite often involve free radicals and transition metals that are responsible for the majority of the damage that occurs in drug products. By analyzing an EPR signal, one can identify, quantify and monitor temporal behavior of the free radicals involved in product degradation.

Photodegradation of Nifedipine after exposure to light shows the formation of N-based free radicals. The amount of free radicals corresponds to the level of degradation
EPR spectrum of Nifedipine before and after light degradation

Optimizing stability and shelf-life

Forced oxidation, also known as “stress testing,” is routinely used in pharmaceutical development to predict the stability of drug products that affects purity, effectiveness, and safety. In stress testing, the drug product is often exposed to heat, light or chemical agents with the goals being to understand degradation pathways, determine intrinsic stability and shelf-life, develop stable formulations, and evaluate antioxidant efficiency.

EPR shows that antioxidant A is more effective than antioxidant B at quenching the free radicals in the drug formulation

Reaction monitoring

Pharmaceutical regulations require more fundamental understanding of the chemistry involved in API production, including reactive intermediate identification. The surge of new molecules that exhibits specific properties is vital to pharmaceutical development, and EPR reaction monitoring is a critical step in optimizing the synthesis of new drugs.

Additionally, understanding reaction mechanism can lead to cost savings and high-quality final products. Chemistry involving radicals and transition metals is an integral component of maximizing product yield and minimizing environmental footprint. 

Simplified proposed mechanism of indoline oxidation
Peng F. et. al. (Merck), A mild Cu(I)-catalyzed oxidative aromatization of indolines to indoles, J. Org. Chem. (2016) 81 10009

Sterilization processes

Proper sterilization of surfaces is important in pharmaceutical manufacturing, equipment and packaging, as well as the pharmaceuticals themselves. The most commonly used sterilization processes are gamma or electron beam irradiation, dry heat, and pressure. These processes generate free radicals that are responsible for degradation of the irradiated materials, and cause alteration of the physicochemical properties of the sterilized product. This can also decrease drug potency by partial decomposition during sterilization and may be a toxicological hazard.

Examples:

 

  • Gamma-irradiation of drugs in the solid-state (Captopril, Selegiline, Pentoxifylline) induces S-or C-centered free radicals
  • Identifying the structure of radicals provides a better understanding of the mechanism of radiolysis
  • Quantification of radical amount enables one to establish a threshold for the radiosterilization of these drugs

 

Paramagnetic impurity profiling

All drugs contain impurities that can arise from APIs, excipients, or both. They can also be introduced into the drug during formulation, packaging, and storage. Impurities have many unwanted effects, including decreasing the therapeutic effect, lowering the product shelf life and inducing toxicity. Organic impurities are often free radicals from byproducts, intermediates, or degradation processes, while inorganic impurities are frequently transition metals. EPR spectroscopy with its high sensitivity can detect traces of impurities down to parts-per-billion levels.

Metal concentration correlates with the EPR signal