Unpacking Drug Degradation : Hydrolysis and Oxidation

Drug substances, the active chemical entities in pharmaceuticals, are constantly susceptible to chemical degradation over their shelf life. These molecular changes, driven by inherent functional groups and environmental factors like temperature, moisture, and pressure, are the primary reasons drugs lose their potency and stability.

While degradation can follow several minor pathways (such as Decarboxylation, Isomerisation, and Elimination), the two most common and critical reactions promoting drug degradation are Hydrolysis and Oxidation. Understanding these pathways is essential for formulating stable and effective pharmaceutical products.

💧 Hydrolysis: The Water Reaction

Hydrolysis is a degradation reaction that involves the chemical compound reacting with water ( $H_2O$ ), which results in the cleavage of a chemical bond and the formation of two or more products. It is the most common degradation pathway in aqueous solutions and liquid dosage forms.

Susceptible Functional Groups

Compounds containing the following functional groups are highly susceptible to hydrolytic cleavage:

Esters
Amides
Imides
Carbamates
Lactones
Nitriles
Carbohydrates

The pH of the medium plays a critical role, as drugs can be prone to either acidic or alkaline hydrolysis.

Key Examples of Hydrolysis

1. Hydrolysis of Esters

This reaction is a second-order reaction and is accelerated by temperature.

Acidic Hydrolysis: Yields carboxylic acid and alcohol.
Basic Hydrolysis: Yields carboxylate salt and alcohol.
Aspirin (Acetylsalicylic acid): Hydrolyzes to produce salicylic acid and acetic acid.
Procaine: Primarily controlled by this reaction, forming 4-aminobenzoic acid and dimethylaminoethanol.

2. Hydrolysis of Amides

Amide bonds are generally less susceptible to hydrolysis than ester bonds because the carbonyl carbon has lower electrophilicity. When it does occur, the carbon-nitrogen bond breaks down, yielding carboxylic acid ( $\text{COOH}$ ), ammonia ( $\text{NH}_3$ ), or an amine.

Paracetamol: Hydrolyzes to form 4-aminophenol and acetic acid.
Sulfacetamide: Hydrolyzes to produce acetic acid and sulphanilamide.

3. Hydrolysis by Ring Opening

Riboflavin (Vitamin B12): Hydrolyzes in a basic medium, converting into two complex compounds, a reaction that is enhanced by increasing the temperature and is detectable by a reduction in absorption at 445 nm.
Norfloxacin: This fluoroquinolone antibiotic undergoes cleavage of the piperazine ring in an alkaline medium, forming desethylene norfloxacin.

🌬️ Oxidation: The Electron and Oxygen Exchange

Oxidation is the process where an element or compound gains oxygen or loses an electron from its outermost shell. The process is initiated by an oxidizing agent or simple atmospheric oxygen during manufacturing, packing, or storage.

Key Factors and Susceptible Compounds

pH: The pH of the medium significantly affects the rate of oxidation by influencing the compound's ionization and redox potential.
Susceptible Compounds: Drugs containing functional groups like phenols, aldehydes, and certain amines are easily oxidized. Examples include ascorbic acid, morphine, and phenols.

Key Examples of Oxidation

1. Oxidation of Ascorbic Acid (Vitamin C)

A highly complex, water-soluble molecule, Ascorbic acid ( $H_2A$ ) is readily oxidized, undergoing a change in its chemical structure and property.

\text{H}_2\text{A} \rightarrow \text{DHA} + 2e^- + 2\text{H}^+

Ascorbic acid is converted to dehydroascorbic acid (DHA). In an alkaline solution, DHA further degrades into diketogulonic acid via hydrolysis.

2. Oxidation of Morphine

Morphine, a natural tranquilizer, is oxidized in an aqueous solution by air and light. This reaction converts it into two primary degradation products:

Pseudomorphine (dextrorotatory form, also marketed as noxydimorphine).
Morphine-N-Oxide (levorotatory form).

3. Oxidation of Phenols

Phenols are easily oxidized because the hydroxyl group ( $\text{OH}$ ) is capable of donating an electron and initiating the process.

Mechanism: The removal of a proton yields a radical. At higher $\text{pH}$ levels, deprotonation occurs, forming the highly nucleophilic phenolate anion ( $\text{PhO}^-$ ), which significantly catalyzes the auto-oxidation process.
Product: The resulting dicarbonyl compound from certain oxidation reactions is para-benzoquinone.