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Paracetamol, Acetaminophen, N-Acetyl-4-aminophenol, APAP, 103-90-2

Paracetamol, Acetaminophen, N-Acetyl-4-aminophenol, APAP, 103-90-2

PARACETAMOL (ACETAMINOPHEN / APAP)

N-(4-hydroxyphenyl)acetamide / 4-Acetamidophenol

CAS Number: 103-90-2

EC Number: 203-157-5

1. IDENTIFICATION

Property Information
Chemical Name N-(4-hydroxyphenyl)acetamide
Synonyms Paracetamol, Acetaminophen, APAP, 4-Acetamidophenol, 4'-Hydroxyacetanilide, N-Acetyl-4-aminophenol
Chemical Formula C₈H₉NO₂
Molecular Weight 151.16 g/mol
CAS Number 103-90-2
EC Number (EINECS) 203-157-5
Appearance White, crystalline powder
Odor Odorless
Drug Class Analgesic, Antipyretic (Weak anti-inflammatory)

2. PHYSICAL PROPERTIES

Property Value
Physical State (20°C) Solid (crystalline powder)
Appearance White to off-white crystalline powder
Odor Odorless
Molecular Weight 151.16 g/mol
Melting Point 168 – 172 °C
Density ~1.26 g/cm³
Solubility in Water (20°C) Sparingly soluble (approx. 14 g/L)
Solubility in Ethanol Freely soluble (~750 g/L)
Solubility in Acetone Freely soluble
Solubility in Ether Practically insoluble
Log P (octanol/water) 0.46
pKa 9.5 (phenolic OH)
UV Absorption (λmax) 249 nm (in water)

3. CHEMICAL PROPERTIES

Property Information
Chemical Formula C₈H₉NO₂
Molecular Weight 151.16 g/mol
Chemical Class Para-aminophenol derivative
Structure Benzene ring with OH (para) and NHCOCH₃ (meta) substituents
IUPAC Name N-(4-hydroxyphenyl)acetamide
SMILES OC1=CC=C(NC(C)=O)C=C1
InChI Key RZVAJINKPMORJF-UHFFFAOYSA-N
Stability Stable under normal storage conditions; protect from light
Hygroscopicity Low (non-hygroscopic)
Incompatible Materials Strong oxidizing agents, strong bases

Chemical Structure:

HO-C₆H₄-NH-CO-CH₃

4. MECHANISM OF ACTION (THERAPEUTIC)

4.1. Analgesic & Antipyretic Effects

Parameter Description
Primary Mechanism Selective inhibition of cyclooxygenase-2 (COX-2) in the central nervous system (CNS)
COX-1 Inhibition (ex vivo) IC₅₀ ~113.7 μM (56% inhibition at 1000 mg dose)
COX-2 Inhibition (ex vivo) IC₅₀ ~25.8 μM (83% inhibition at 1000 mg dose)
Selectivity Approximately 4.4-fold selectivity for COX-2 over COX-1
Key Difference from NSAIDs Does not significantly inhibit COX-1 in peripheral tissues (minimal GI effects, no antiplatelet activity)

Key Points:

  • Unlike traditional NSAIDs (ibuprofen, naproxen), paracetamol has weak anti-inflammatory effects

  • Acts primarily centrally (CNS) rather than peripherally

  • Does not cause gastric irritation (minimal COX-1 inhibition in stomach)

  • Does not affect platelet function (no bleeding risk)

4.2. Hepatic Metabolism & Toxicity (At Overdose)

Parameter Description
Normal Metabolism Glucuronidation (~55%), sulfation (~30%), CYP450 oxidation (~10-15%)
Toxic Metabolite NAPQI (N-acetyl-p-benzoquinone imine) – produced via CYP2E1
Normal Disposition NAPQI is rapidly detoxified by hepatic glutathione
Overdose Mechanism Glutathione reserves are depleted; NAPQI accumulates causing hepatocyte necrosis
Antidote N-Acetylcysteine (NAC) – replenishes glutathione stores

5. PHARMACEUTICAL FORMS & STRENGTHS

Form Strength Route Notes
Immediate Release Tablet 500 mg Oral Most common form
Effervescent Tablet 500 mg + excipients Oral Faster absorption
Dispersible Tablet 500 mg Oral Dissolves in water
Suspension (Oral) 120 mg/5 mL, 160 mg/5 mL Oral For pediatrics
Suppository 60 mg, 125 mg, 250 mg, 500 mg Rectal When oral not possible
IV Injection 10 mg/mL Intravenous Hospital use

6. THERAPEUTIC APPLICATIONS

6.1. Primary Indications

Application Description Evidence Level
Acute Pain (Mild to Moderate) Headache, migraine, toothache, dysmenorrhea, musculoskeletal pain Strong
Fever (Pyrexia) Reduces elevated body temperature Strong
Post-operative Pain Mild to moderate post-surgical pain Strong
Osteoarthritis Chronic pain (though NSAIDs more effective) Moderate

6.2. Combination Products

Combination Typical Strengths Purpose Reference
Paracetamol + Codeine 500 mg + 8 mg / 300 mg + 15 mg / 400 mg + 20 mg Enhanced analgesia (opioid + non-opioid) WHO, eMC, Canada DPD
Paracetamol + Caffeine 400 mg + 50 mg / 500 mg + 30 mg Adjuvant for headache; may enhance absorption VIDAL, eMC
Paracetamol + Caffeine + Codeine 400 mg + 50 mg + 20 mg Moderate-severe pain VIDAL

7. DOSAGE GUIDELINES (THERAPEUTIC)

Population Route Single Dose Maximum Daily Dose Frequency
Adults (≥50 kg) Oral 500 – 1000 mg 4000 mg Every 4-6 hours
Adults (<50 kg) Oral 500 mg 3000 mg Every 4-6 hours
Children (6-12 years) Oral 250 – 500 mg 1500 – 2000 mg Every 4-6 hours
Children (2-6 years) Oral 120 – 250 mg 1000 – 1200 mg Every 4-6 hours
Infants (3-24 months) Oral 60 – 120 mg 400 – 600 mg Every 4-6 hours
Adults (IV) IV 500 – 1000 mg 4000 mg Every 4-6 hours

Important Safety Limits:

  • Maximum single dose: 1000 mg

  • Maximum daily dose: 4000 mg (adults with normal liver function)

  • Minimum dosing interval: 4 hours

  • Chronic use limit: Consult physician for use beyond 3-5 days

8. QUALITY SPECIFICATIONS (PHARMACEUTICAL GRADE)

Parameter Specification (USP / Ph. Eur.)
Appearance White crystalline powder
Assay (dried basis) 98.5 – 101.0%
Identification Positive (IR, HPLC, Chemical tests)
Melting Point 168 – 172 °C
pH (saturated solution) 5.5 – 6.5
Loss on Drying ≤ 0.5%
Residue on Ignition ≤ 0.1%
Heavy Metals (as Pb) ≤ 10 ppm
Chloride (Cl) ≤ 0.01%
Sulfate (SO₄) ≤ 0.02%
Related Substances (Impurities) ≤ 0.5% total
4-Aminophenol (toxic impurity) ≤ 50 ppm (critical limit)
Residual Solvents Meets ICH Q3C requirements
Microbial Limits TAMC ≤ 1000 CFU/g, TYMC ≤ 100 CFU/g, Absence of E. coli, Salmonella

9. STORAGE & HANDLING

Parameter Information
Storage Conditions Cool, dry, well-ventilated area; 15-25°C recommended
Container Requirements Tightly closed, light-resistant containers (amber glass or opaque HDPE)
Protect From Light, moisture, strong oxidizing agents, strong bases
Shelf Life (Pharmaceutical grade) 36-60 months (when stored properly in unopened packaging)
Stability Stable under normal storage; may discolor if exposed to light/moisture
Packaging Options 25 kg fiber drums with polyethylene liner, 50 kg drums, 500 kg/1000 kg FIBC

Storage Note: Protect from light to prevent discoloration. Store in original containers with tight closures.

10. SAFETY & HEALTH INFORMATION

GHS Classification (for bulk powder)

Hazard Class Category
Acute Toxicity (Oral) Category 4 (H302)
Skin Irritation Category 2 (H315)
Eye Irritation Category 2A (H319)
Specific Target Organ Toxicity (Repeated exposure) Category 2 (H373) – liver

Hazard Statements (H-Codes)

Code Statement
H302 Harmful if swallowed (at very high doses)
H315 Causes skin irritation
H319 Causes serious eye irritation
H373 May cause damage to organs (liver) through prolonged or repeated exposure (overdose)

Precautionary Statements (P-Codes)

Code Statement
P261 Avoid breathing dust
P264 Wash thoroughly after handling
P280 Wear protective gloves and eye protection
P301+P312 IF SWALLOWED: Call a POISON CENTER if you feel unwell
P305+P351+P338 IF IN EYES: Rinse cautiously with water for several minutes

Adverse Effects (Therapeutic Use)

Type Effects
Common Generally well-tolerated at therapeutic doses
Less Common Nausea, vomiting, allergic reactions (rash, urticaria)
Serious (Overdose) Hepatotoxicity (liver damage) – potentially fatal; requires immediate medical attention
Very Rare Stevens-Johnson syndrome, toxic epidermal necrolysis, agranulocytosis

Contraindications

Condition Status
Severe hepatic impairment Absolute contraindication
Hypersensitivity to paracetamol Absolute contraindication
Chronic alcoholism (with malnutrition) Relative contraindication (increased hepatotoxicity risk)
G6PD deficiency Caution (rare hemolytic anemia)

First Aid Measures

Exposure Route Action
Inhalation Remove to fresh air. Seek medical attention if respiratory irritation occurs.
Skin Contact Wash with plenty of water and soap.
Eye Contact Rinse immediately with plenty of water for at least 15 minutes. Seek medical attention.
Ingestion (Therapeutic use) Unlikely to cause harm at therapeutic doses.
Ingestion (Overdose) Seek immediate medical attention. NAC (N-acetylcysteine) is antidote. Do not delay.

11. OVERDOSE MANAGEMENT

Parameter Information
Toxic Dose > 150 mg/kg (or > 10 g total in adults)
Mechanism Glutathione depletion; accumulation of NAPQI
Symptoms Nausea, vomiting, anorexia (first 24h); then right upper quadrant pain, jaundice, liver failure
Treatment N-Acetylcysteine (NAC) IV or oral
Time Window Most effective within 8-10 hours of ingestion
Prognosis Excellent with early treatment; may require liver transplant in severe cases

12. ENVIRONMENTAL INFORMATION

Parameter Information
Biodegradability Readily biodegradable (inherently)
Aquatic Toxicity Low to moderate toxicity
Bioaccumulation Not expected
Waste Disposal Dispose according to local regulations (pharmaceutical waste)

13. TRANSPORT INFORMATION

Parameter Information
UN Number Not regulated (non-hazardous)
Hazard Class None
Packing Group Not applicable

14. REGULATORY INFORMATION

Region Status
EU Approved medicinal substance; OTC availability
USA (FDA) Approved OTC (over-the-counter) drug
Turkey Approved OTC and prescription drug
UK (MHRA) Approved OTC and POM for combination products
Canada (Health Canada) Approved OTC drug
WHO Included in WHO Essential Medicines List

Prescription Status:

  • OTC: Single ingredient (500 mg)

  • Prescription: Some high-strength or combination products (with codeine)

15. SYNONYMS & OTHER NAMES

Turkish Name English Name
Parasetamol Paracetamol
Asetaminofen Acetaminophen
APAP APAP
N-(4-hidroksifenil)asetamid N-(4-hydroxyphenyl)acetamide
4-Asetamidofenol 4-Acetamidophenol

Trade Names (Partial List):

  • Tylenol® (USA)

  • Panadol® (Global)

  • Calpol® (Pediatric)

  • Ultramol (UK)

  • Various generics

16. SUMMARY

Paracetamol (Acetaminophen / APAP, CAS 103-90-2) is the most widely used analgesic (pain reliever) and antipyretic (fever reducer) medication worldwide. It is a para-aminophenol derivative that acts primarily as a selective COX-2 inhibitor in the central nervous system.

Key Features:

Feature Description
Appearance White crystalline powder
Molecular Weight 151.16 g/mol
Melting Point 168-172 °C
Solubility Sparingly soluble in water; freely soluble in ethanol

Main Therapeutic Applications:

Use Indication
Analgesic Mild to moderate acute pain (headache, toothache, dysmenorrhea, post-operative)
Antipyretic Fever reduction
Combination Products With codeine, caffeine for enhanced effect

Key Safety Points:

  • WELL-TOLERATED – Minimal GI effects, no antiplatelet activity

  • HEPATOTOXICITY RISK – Overdose can cause severe liver damage

  • MAXIMUM DAILY DOSE – 4000 mg (adults)

  • ANTIDOTE – N-Acetylcysteine (NAC) for overdose

  • WIDELY AVAILABLE – OTC in most countries

17. IMPORTANT NOTES

  1. Mechanism Clarification: Unlike traditional NSAIDs, paracetamol has minimal peripheral anti-inflammatory effects. Its primary action is central (CNS) COX-2 inhibition.

  2. Overdose Danger: Paracetamol overdose is a leading cause of acute liver failure. The maximum daily adult dose is 4000 mg. Never exceed recommended doses.

  3. Hepatotoxicity Mechanism: At therapeutic doses, the toxic metabolite NAPQI is detoxified by glutathione. Overdose depletes glutathione, causing NAPQI accumulation and hepatocyte necrosis.

  4. Combination Products: Many OTC cold/flu and prescription pain medications contain paracetamol. Patients must avoid double-dosing from multiple products.

  5. Purity Critical Parameter: 4-Aminophenol is a toxic impurity and degradation product. Pharmacopeial limits require ≤ 50 ppm. High-quality pharmaceutical grade is essential.

  6. Stability: Protect from light to prevent discoloration (oxidation). Discolored product should not be used.

  7. Codeine Combinations: Paracetamol + codeine combinations are controlled substances in many countries (opioid component).

  8. Pediatric Dosing: Dosing is weight-based (10-15 mg/kg). Infant formulations (suspension) are available. Never exceed recommended pediatric doses.

  9. Alcohol Interaction: Chronic alcohol use may increase hepatotoxicity risk at therapeutic doses due to glutathione depletion.

  10. Regulatory Status: While single-ingredient paracetamol is OTC worldwide, some combination products require prescription (e.g., with codeine).

Important Disclaimer: This Technical Data Sheet (TDS) is for informational purposes only. For complete safety, handling, storage, and regulatory compliance information, always refer to the official Safety Data Sheet (SDS) and product information provided by the manufacturer/supplier. This document is not a substitute for medical advice. Paracetamol should be used according to medical guidance. Overdose is a medical emergency.

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