Literature Review

Acetaminophen, also known as N-acetyl-para-aminophenol (APAP) or paracetamol shown in

(figure1.1) in many countries, is a non- opioid analgesic and antipyretic agent utilized for treating
pain and fever (Gerriets & Nappe, 2024). It is White odourless crystalline powder; large
monoclinic prisms from water having Melting-point of 169–170.5 °C. Soluble in water (1:70, 1:20
at 100°C), ethanol (1:7), acetone (1:13), chloroform (1:50), glycerol (1:40), methanol (1:10),
propylene glycol (1:9) and solutions of alkali hydroxides; insoluble in diethyl ether. A saturated
aqueous solution has a pH of ~6. Dry, pure paracetamol is stable to 45°C. Paracetamol may be
made by acetylation of para-aminophenol (obtained by reduction of para-nitrophenol) with acetic
acid or acetic anhydride. (Humans, 1990). Paracetamol clearance is lower in neonates than in
children and adults. is commonly administered orally, though it can also be given via intravenous
or rectal routes. It is absorbed rapidly from the gastrointestinal tract, primarily in the small
intestine. Peak plasma concentrations typically occur within 30 minutes to 2 hours after oral
administration. Bioavailability of oral paracetamol is about 60-90% due to first-pass metabolism
in the liver. This variability depends on individual factors and formulation differences. After
metabolic conversion, paracetamol is subsequently eliminated by the renal route. The main
metabolic conversions are conjugation with glucuronic acid and with sulphate. It has low plasma
protein binding (10-25%) at therapeutic doses, which means a significant portion remains free in
plasma for distribution. It has relatively low volume of distribution (Vd), around 0.9-1.0 L/kg,
indicating that it distributes primarily within body water. It can cross the blood-brain barrier and
reach the central nervous system (CNS), which is why it is effective as an antipyretic (fever
reducer) and analgesic (pain reliever). Metabolism occurs mainly in the liver By Glucuronidation
40-60% It is conjugated with glucuronic acid to form paracetamol-glucuronide , Sulfation (20-
40%), Oxidation (5-10%) a toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI) is formed
by oxidation of small amount of paracetamol. Most paracetamol and its metabolites are excreted
in the urine, with 85-95% eliminated within 24 hours. The half-life of paracetamol is generally 2-
3 hours in healthy individuals but can extend in cases of liver impairment or overdose (Forrest,
Clements, & Prescott, 2012).

Figure 1.1. Chemical Structure of Acetaminophen

Acetaminophen is widely used for mild to moderate pain (e.g., headaches, muscle
pain, dental pain) and fever reduction. The standard adult dose is 500 mg to 1,000 mg every
4–6 hours as needed, not exceeding 4,000 mg in 24 hours (Toms, McQuay, Derry, &
Moore, 2008). Paracetamol is commonly used for osteoarthritis, especially in patients
where NSAIDs are contraindicated. The typical recommended dose is 1,000 mg every 6-8
hours. Used as part of multimodal analgesia for postoperative pain management. A dose of
1,000 mg every 6 hours for adults, typically within the first 24-48 hours post-surgery
(Machado et al., 2015). Paracetamol is used to manage fever and mild to moderate pain in
pediatric populations. A dose of 10-15 mg/kg every 4-6 hours for children, not exceeding
60 mg/kg per day. (Moore & Moore, 2016).

Rajeev, R., et al. (2018) Developed Sustained Release Tablets of Paracetamol and
evaluated them for chronic pain management such as osteoarthritis, where prolonged
therapeutic levels are beneficial without frequent dosing. Sustained-release formulations
often use ingredients like hydroxypropyl methylcellulose (HPMC), ethylcellulose, or other
controlled-release polymers to extend the release of the drug over time. Additional
excipients like microcrystalline cellulose (as a filler), magnesium stearate (as a lubricant),
and lactose may also be used to improve tablet formation, stability, and patient
acceptability. Their research showed that sustained-release formulations successfully
maintained plasma drug concentrations over extended periods, minimizing the need for
frequent dosing ([Link], 2018). Boonkasidecha, S., et al. (2019) did comparison of
Paracetamol Suppositories and Oral Paracetamol for Pain Relief in Children. It is used in
pediatric patients who cannot take oral medication, for pain and fever reduction. In this
research for paracetamol suppositories, the formulation included lipid-based excipients
such as hard fat (e.g., hydrogenated vegetable oil) or cocoa butter to allow the drug to
solidify at room temperature and melt at body temperature for absorption. The study found
that suppository forms provide similar efficacy to oral forms but with a slower onset of
action. This formulation is effective for use in children or postoperative patients where oral
administration is challenging. Sinatra, R. S., et al. (2012), efficacy of Intravenous
Paracetamol in Postoperative Pain Management. Used for managing moderate to severe
pain post-surgery in patients who require rapid pain relief. IV paracetamol formulations
typically include paracetamol dissolved in a sterile aqueous solution to make it suitable for
intravenous administration. In addition to paracetamol, the formulation usually contains;
sodium citrate and citric acid as buffering agents to maintain pH stability, mannitol as a
stabilizer to help maintain the solution’s integrity, water for injection as the solvent. IV
paracetamol showed a significant reduction in pain intensity within minutes of
administration, making it suitable for acute pain management in clinical settings. The study
highlighted its role in reducing opioid requirements postoperatively. (sinatra, 2012).

The research was based on Preparation of Orodispersible Films (ODFs) of

acetaminophen, a fast-dissolving dosage form designed to provide immediate release of the
active ingredient. The casting solution was prepared by dissolving 2g of Hydroxypropyl
Methylcellulose (HPMC) in 20mL of water and 10mL of ethanol under stirring, then 0.5g
of glycerin and 0.2g of sucralose were added and stirred until dissolved. Next, 500mg of
acetaminophen was dissolved in the casting solution under stirring. The solution was
poured onto a glass plate or silicone surface and spread evenly to achieve a uniform
thickness of 50-200μm. The film was allowed to dry at room temperature (25°C) for 2
hours or using infrared drying (30°C, 30 minutes). Once dry, the film was cut into desired
sizes (e.g., 2x2 cm). Finally, the orodispersible films were packaged in airtight containers
or pouches and stored in a controlled environment (25°C, 50% humidity).These ODFs were
indicated to treat fever, providing rapid relief and convenience for patients.

The aim of this study is to formulate acetaminophen loaded orodispersible

film to improve patient compliance in childern and elders.

References
1. Forrest, J. A., Clements, J. A., & Prescott, L. F. (2012). Clinical pharmacokinetics of
paracetamol. Clinical Pharmacokinetics, 7(2), 93–107. [Link]
198207020-00001
2. Gerriets, V., & Nappe, T. M. (2024). Acetaminophen. Retrieved from National Library of
Medicine website: [Link]
3. Humans, I. W. G. on the E. of C. R. to. (1990). Paracetamol (Acetaminophen). Retrieved
from [Link] website: [Link]
4. Machado, G. C., Maher, C. G., Ferreira, P. H., Pinheiro, M. B., Lin, C.-W. . C., Day, R.
O., … Ferreira, M. L. (2015). Efficacy and safety of paracetamol for spinal pain and
osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials.
BMJ, 350(mar31 2), h1225–h1225. [Link]
5. Moore, R. A., & Moore, N. (2016). Paracetamol and pain: the kiloton problem. European
Journal of Hospital Pharmacy, 23(4), 187–188. [Link]
000952
6. [Link]. (2018). Developed and Evaluated Sustained Release Tablets of Paracetamol.
7. sinatra. (2012). efficacy of Intravenous Paracetamol in Postoperative Pain Management.
Retrieved from google scholar website: [Link]
8. Toms, L., McQuay, H. J., Derry, S., & Moore, R. A. (2008). Single dose oral paracetamol
(acetaminophen) for postoperative pain in adults. Cochrane Database of Systematic
Reviews, 1(1). [Link]
 WORK PLAN

1. PRE FORMULATION Test

1.1 Solubility test
1.2 Melting point test
1.3 Potentiometric titration method to determine pKa
1.4 Organoleptic Properties
1.5 Angle of repose
1.6 Bulk density

2. Development Of Orodispersable Films

2.1 Master Formula

2.2 Methodology

[Link] formulation Test

3.1 Disintegration Time

3.2 Dissolution Testing:

3.3 Friability

3.4 Uniformity of Dosage Units

[Link] and labelling

A. Packaging
4A.1 Blister Packaging
4A.2 Unit-Dose Packaging
 4A.3 Foil Laminate Packaging

4A.4 Moisture-Absorbing Inserts

4A.5 High Barrier Films or Foils

B. Labelling
4B.1. Product Name
4B.2. Formulation Type
4B.3. Active Ingredients

4B.4. Dosage Form and Strength

4B.5. Directions for Use
4B.6. Storage Instructions
4B.7. Expiry Date

4B.8. Batch Number

4B.9. Manufacturer Information
4B.10. Safety and Precautionary Statements
PREFORMULATION STUDIES
 1. Solubility Test For Acetaminophen

Aim of this study is to identify best solvent for solubilizing drug.

 50-100mg/10ml acetaminophen is used

 10ml of ethanol is taken
 The mixture is stirred for 24 hours at a constant temperature, usually 25°C.
 The solution is filtered to remove excess paracetamol.
 The concentration of paracetamol in the solution is measured using techniques like UV-
Vis spectroscopy or High-Performance Liquid Chromatography (HPLC). And the
solubility of paracetamol is calculated.

(Bellucci, 2019)

Standard result:
Paracetamol has a relatively high solubility in
ethanol

 Weigh 50-100mg Acetaminophen.

 Add APAP to 10 mL distilled water.
 Stir until dissolution or precipitation occurs.
 Stir mixture for 24 hours at 25°C.
 Filter solution through 0.45 μm filter paper.
 Measure paracetamol concentration using UV-Vis spectroscopy or HPLC.
(a, 2018)

Solubility of paracetamol in water: 14.2

mg/mL (25°C)

 Weigh 1-2 g paracetamol.

 Add paracetamol to 10 mL propylene glycol.
 Stir until dissolution or precipitation occurs.
 Stir mixture for 24 hours at 25°C.
 Filter solution through 0.45 μm filter paper.
 Measure paracetamol concentration using UV-Vis spectroscopy or HPLC.
(Jouyba, 2008)

The solubility of paracetamol in propylene

glycol increases with temperature and reaches
 a maximum at 70% propylene glycol at 25°C,
the solubility is approximately 50-70 mg/mL

APAP solubility increases with temperature arising and also with the cosolvents-proportion in
the mixtures. It is soluble in polar solvents mainly alcohols.
 2. Melting Point Test For Acetaminophen:

The aim of performing a melting point study of acetaminophen is to confirm its purity and
thermal stability .

 Fill a capillary tube with paracetamol powder.

 Seal one end of the tube.
 Suspend the tube in a heating device.
 Initial temperature is set 10-15℃ below the expected melting point.
 Heat at 1-2°C/min.
 Observe and record the temperature when paracetamol melts.

Standard result:
Initial melting temperature: 168°C
Peak melting temperature: 170.5°C
Final melting temperature: 171.5°C

(I Jendrzejewska T Goryczka, 2018)

The melting point is reported a 169-170℃.

 3. Determination of the pKa of acetaminophen

The aim is to understand its acid-base dissociation properties which are crucial for optimizing its
solubility and stability.

Preparation of the Acetaminophen Solution

 Dissolve a known amount of acetaminophen (approximately 0.1 g) in a suitable solvent
(e.g., 50 mL of distilled water or a non-aqueous solvent like ethanol or
dimethylformamide).
 Calibrate the pH meter using standard buffer solutions (e.g., pH 4.0 and pH 7.0).
 Set up a burette with the standardized NaOH solution.
 Begin with the acetaminophen solution in a beaker, and place it on a magnetic stirrer if
available.
 Slowly add the NaOH solution from the burette to the acetaminophen solution while
continuously stirring.
 Measure the pH after each addition of the base. It is important to record the volume of
NaOH added and the corresponding pH value.
 After completing the titration, plot a graph of pH against the volume of NaOH added. The
curve typically shows a gradual increase in pH, followed by a steep rise near the
equivalence point.
 Determining the pKa:
Identify the inflection point on the titration curve, which corresponds to the pKa. The pKa
value can be determined at the midpoint of the buffer region where the concentration of the
acid and its conjugate base are equal.

Reference:
Gupta, S. R. N. (2016). Potentiometric and pHmetric Studies of Paracetamol. Med Chem, 6(1),
047-052. Link to Article HILARIS PUBLISHING SRL
 Development Of Orodispersible Films

1) Master formula

Formulation of 50mg orodispersible film

Ingredient For 1 Film (in mg) For 20 Films (in mg)

Acetaminophen 12.5 250

Polymer (HPMC) 7.5 150

Plasticizer (Glycerin) 10 200

Citric Acid 0.5 10

Sweetner(Sucrose) 1.5 30

Solvent (Ethanol) 15.5 350

Flavouring agent 1.5 20

2) Methodology

 Solvent Casting Method