Forced Degradation Study and Challenges in Analytical Method Development and Validation | Part II

Oxidation Degradation

Oxidation is the second most common degradation pathway for pharmaceuticals, after hydrolysis. Oxidation degradation studies are conducted in the pharmaceutical industry to determine the stability of drugs under conditions that may induce oxidation, such as exposure to light, heat, or oxygen.

The goal of these studies is to identify the degradation products that are formed and to assess their potential toxicity.

Hydrogen peroxide is widely used for oxidation of drugs in forced degradation studies but other oxidizing agents such as metal ions, oxygen, and radical initiators (e.g.,AIBN (azobisisobutyronitrile) can also be used.

Selection of an oxidizing agent, its concentration, and conditions depends on the drug substance. It is reported that subjecting the solutions to 0.1–3% hydrogen peroxide at neutral pH and room temperature three or five or seven days or up to 5- 20% degradation could potentially generate relevant degradation products.

The oxidative degradation of drug substance involves an electron transfer mechanism to form reactive anions and cations. Amines, sulphides, and phenols are susceptible to electron transfer oxidation to give N-oxides, hydroxylamine, sulfones, and sulfoxide.

The functional group with labile hydrogen like benzylic carbon, allylic carbon, and tertiary carbon or α-positions with respect to hetero atom is susceptible to oxidation to form hydro peroxides, hydroxide, or ketone.

Examples of oxidation degradation of drugs

Penicillin is an antibiotic drug that is also susceptible to oxidation. When exposed to oxygen, penicillin can form a degradation product called penicillenic acid. Penicillinic acid is inactive and can cause allergic reactions in some people.

Aspirin is an anti-inflammatory drug that can be oxidized to form a degradation product called salicylic acid. Salicylic acid is a known irritant and can cause stomach upset and other side effects.

The results of oxidation degradation studies are used to design formulations and packaging that will protect drugs from oxidation and to establish stability intervals for drugs. Stability intervals are the ranges of temperatures and humidity at which a drug can be stored without significant degradation.

Oxidation degradation studies are an important part of the drug development process. By understanding the mechanisms of oxidation degradation, pharmaceutical scientists can develop drugs that are more stable and safer for patients.

Hydrolytic Degradation

Hydrolytic stress test is a common chemical degradation reaction of the analyte with water. Apart from water, hydrolysis reactions are normally performed over a wide range of pH by exposure of the sample to acidic or basic catalysed stress conditions.

The selection of the type for the stress testing - acid or base- depends on the stability of the sample. The stability of the analyte also defines the concentration. Hydrochloric acid (0.1–1 M) for acid hydrolysis and sodium hydroxide or potassium hydroxide (0.1–1 M) for base hydrolysis are the most common and suggested as suitable reagents for hydrolysis.

The hydrolytic stress testing normally is conducted at room temperature with or without co-solvent and if no degradation appears, continues under higher temperature of 50°C to 70°C.

Stress testing generally not exceed more than 7 days. The degraded sample is then neutralized before injection using suitable acid, base, or buffer, to avoid further decomposition.

Acidic conditions: Hydrolysis is catalysed by acids, so exposing a drug to an acidic solution will speed up the degradation process. The type and concentration of acid used will depend on the stability of the drug molecule.

Basic conditions: Bases can also catalyse hydrolysis, so exposing a drug to a basic solution will also speed up the degradation process. The type and concentration of base used will depend on the stability of the drug molecule.

Drugs contain functional groups that are susceptible to hydrolysis, such as esters, amides, and carboxylic acids. When these drugs are exposed to water, the functional groups can be broken down, resulting in the formation of smaller molecules. In some cases, these smaller molecules may be more active or less active than the original drug molecule.

Hydrolytic degradation can also occur in the body. When drugs are ingested or injected, they are exposed to the water in the digestive tract or bloodstream. This can lead to the degradation of the drug, which may affect its safety and efficacy.

For this reason, it is important to understand the hydrolytic stability of drugs before they are marketed. Hydrolytic degradation studies can help to identify drugs that are susceptible to degradation and to develop strategies by formulation scientists to minimize this degradation.

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Resource Person: Vadivelan Elangovan

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