C₈H₉NO₂ — Paracetamol

Paracetamol, chemically known as N-(4-hydroxyphenyl)acetamide, and internationally referred to as acetaminophen, is one of the most widely used medicines for relieving pain and reducing fever. Its molecular formula is \(C_8H_9NO_2\). Paracetamol acts as an analgesic (pain-reliever) and antipyretic (fever-reducer), commonly prescribed for headaches, toothaches, muscle pain, arthritis, and common colds. Unlike many NSAIDs such as aspirin or ibuprofen, paracetamol is gentle on the stomach and does not cause gastric irritation or bleeding.

First synthesized in the late 19th century, paracetamol is now considered one of the safest and most essential drugs worldwide. It is listed in the World Health Organization’s Model List of Essential Medicines and available under various brand names such as Tylenol, Panadol, and Calpol.

Paracetamol consists of a benzene ring with two substituents:

• A hydroxyl group (–OH) in the para position.
• An amide group (–NHCOCH₃) derived from acetic acid.

This structure makes paracetamol both a phenol and an amide. The molecule exhibits hydrogen bonding due to the presence of the hydroxyl and amide groups, contributing to its moderate solubility in water and stability at room temperature. Its resonance structure allows electron delocalization between the aromatic ring and the amide group, enhancing molecular stability and biological activity.

The origins of paracetamol date back to the 19th century when researchers were exploring derivatives of coal tar compounds. It was first discovered in 1877 by Harmon Northrop Morse, who synthesized it by reducing p-nitrophenol with tin in glacial acetic acid. However, its medicinal properties were not widely recognized until the mid-20th century.

In 1948, Bernard Brodie and Julius Axelrod rediscovered paracetamol and demonstrated its safety and effectiveness compared to acetanilide, which caused toxic side effects. By the 1950s, paracetamol was introduced commercially and quickly became a staple medication for pain and fever management across the world.

1. From p-Aminophenol:

The most common method for synthesizing paracetamol is by acetylation of p-aminophenol using acetic anhydride. The reaction proceeds as follows:

In this reaction, p-aminophenol acts as the nucleophile, reacting with acetic anhydride to form paracetamol and acetic acid as a by-product. The product is purified by recrystallization from hot water or ethanol.

2. Industrial Synthesis:

Industrial-scale production involves similar acetylation reactions but under optimized conditions for yield and purity. Catalysts like sulfuric acid or acetic acid are sometimes used to enhance the reaction rate. Modern pharmaceutical manufacturing ensures high-quality control to produce medical-grade paracetamol free from impurities.

Physical Properties:

• Appearance: White crystalline powder.
• Solubility: Slightly soluble in cold water but more soluble in hot water, ethanol, and acetone.
• Stability: Stable under dry conditions but decomposes in moist air or light.
• Crystallinity: Orthorhombic crystals.

Chemical Properties:

• Acid-Base Behavior: Paracetamol is weakly acidic due to the phenolic –OH group and the amide hydrogen.
• Hydrolysis: Under alkaline conditions, paracetamol hydrolyzes into p-aminophenol and acetic acid.

\(HOC_6H_4NHCOCH_3 + H_2O \rightarrow H_2NC_6H_4OH + CH_3COOH\)

• Reaction with Iron(III) Chloride: Paracetamol gives a violet coloration with FeCl₃ due to the presence of a phenolic group.
• Thermal Decomposition: On heating above 170°C, paracetamol decomposes into various by-products, including p-aminophenol and acetic acid vapors.

Paracetamol exerts its effects primarily in the central nervous system (CNS) by inhibiting the enzyme cyclooxygenase (COX), particularly the COX-3 variant. This reduces the synthesis of prostaglandins, which are responsible for pain and fever.

Unlike NSAIDs, paracetamol has minimal effect on peripheral inflammation because it is inactivated by high concentrations of peroxides in inflamed tissues. Hence, it is effective as an analgesic and antipyretic but not as an anti-inflammatory agent. Additionally, paracetamol affects the hypothalamic heat-regulating center, promoting vasodilation and sweating to reduce fever.

• Medical Uses:
• Relieves mild to moderate pain such as headaches, dental pain, back pain, and arthritis.
• Reduces fever caused by infections or illnesses like flu and cold.
• Safe for children and adults when taken in recommended doses.
• Combination Drugs: Paracetamol is often combined with caffeine, codeine, or ibuprofen for enhanced pain relief in severe conditions.
• Veterinary Use: Occasionally used under veterinary supervision for treating pain and fever in animals.
• Pharmaceutical Industry: Used as a model compound in drug solubility and release studies.

Paracetamol is safe when taken within therapeutic limits, but overdose can cause severe hepatotoxicity (liver damage) due to the accumulation of the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). Normally, NAPQI is detoxified by glutathione in the liver. However, in overdose conditions, glutathione stores become depleted, leading to cellular injury.

Symptoms of overdose include nausea, vomiting, abdominal pain, and jaundice. Immediate treatment involves administering N-acetylcysteine (NAC), which replenishes glutathione levels and neutralizes NAPQI. Therefore, it is crucial to adhere to the recommended dosage limits: generally, not exceeding 4 grams per day for adults.

Paracetamol is generally well-tolerated and biodegradable. It is considered environmentally safe at low concentrations, though its overuse or improper disposal can lead to pharmaceutical residues in water bodies. Medical professionals recommend responsible usage, avoiding self-medication or combining multiple paracetamol-containing products unknowingly.

Due to its effectiveness and safety profile, paracetamol remains one of the world’s most indispensable over-the-counter medications for pain and fever management.