Beruflich Dokumente
Kultur Dokumente
*Arshi, Dr. Amresh Gupta, Dr. Satyawan Singh and Mr. Y. A. Vohra
conveniently. The formulation obtained is found well within the Indian Pharmacopoeia (IP)
acceptable limit.
I. INTRODUCTION
Paracetamol (also known as Acetaminophen) is an antipyretic, non-opioids analgesic, and
non-steroidal anti-inflammatory drug (NSAID), and is one of the most commonly used
medications worldwide. Paracetamol was first used clinically in 1893, then avoided for more
than 60 years due concerns about Paracetamol induced methaemoglobinaemia. Subsequently,
three separate research groups disproved the toxicity theory and Paracetamol was released in
the United States in 1950 as an oral formulation. It is now used ubiquitously in both
prescription and over-the-counter formulations with over 200 million prescriptions annually
and non-prescription sales exceeding 25 thousand million doses per year, making it the most
commonly dispensed pharmaceutical in India.
Paracetamol (acetaminophen) is a pain reliever and a fever reducer. It is used to treat many
conditions such as headache, muscle aches, arthritis, backache, toothaches, colds, and fevers.
It relieves pain in mild arthritis but has no effect on the underlying inflammation and swelling
of the joint. The various uses of Paraceatmol are as follows:-
1.1.1 Fever
The World Health Organization (WHO) recommends that paracetamol be used to treat fever
in children only if their temperature is higher than 38.5 °C (101.3 °F). The efficacy of
paracetamol by itself in children with fevers has been questioned and a meta-analysis showed
that it is less effective than ibuprofen. Paracetamol does not have significant anti-
inflammatory effects.
1.1.2 Pain
Paracetamol is used for the relief of mild to moderate pain. The use of the intravenous form
of paracetamol for short term pain in people in the emergency department is supported by
limited evidence.
1.1.3 Osteoarthritis
The American College of Rheumatology recommends paracetamol as one of several
treatment options for people with arthritis pain of the hip, hand, or knee that does not improve
with exercise and weight loss. A 2015 review, however, found it provided only a small
benefit in osteoarthritis.
Paracetamol has relatively little anti-inflammatory activity, unlike other common analgesics
such as the NSAIDs and ibuprofen but ibuprofen and paracetamol have similar effects in the
treatment of headache. Paracetamol can relieve pain in mild arthritis, but has no effect on the
underlying inflammation, redness, and swelling of the joint. It has analgesic properties
comparable to those of aspirin, while its anti-inflammatory effects are weaker. It is better
tolerated than aspirin due to concerns about bleeding with aspirin.
1.1.5 Headaches
A joint statement of the German, Austrian, and Swiss headache societies and the German
Society of Neurology recommends the use of paracetamol in combination with caffeine as
one of several first line therapies for treatment of tension or migraine headache. In the
treatment of acute migraine, it is superior to placebo, with 39% of people experiencing pain
relief at one hour compared with 20% in the control group.
dental treatment to help reduce pain after treatment for procedures under local anesthetic,
however the quality of evidence is low.
1.1 Other
The efficacy of Paracetamol when used in combination with weak opioids (such as codeine)
improved for approximately 50% of people but with increases in the number experiencing
side effects. Combination drugs of paracetamol and strong opioids like morphine improve
analgesic effect.
The combination of paracetamol with caffeine is superior to paracetamol alone for the
treatment of common pain conditions including dental pain, postpartum pain, and headache.
Paracetamol toxicity is the foremost cause of acute liver failure in the Western world and
accounts for most drug overdoses in the United States, the United Kingdom, Australia, and
New Zealand. According to the FDA, in the United States there were "56,000 emergency
room visits, 26,000 hospitalizations, and 458 deaths per year related to acetaminophen-
associated overdoses during the 1990s. Within these estimates, unintentional acetaminophen
overdose accounted for nearly 25% of the emergency department visits, 10% of the
hospitalizations, and 25% of the deaths.
Paracetamol is metabolized by the liver and is hepatotoxic; side effects are multiplied when
combined with alcoholic drinks, and are very likely in chronic alcoholics or people with liver
damage. Some studies have suggested the possibility of a moderately increased risk of upper
gastrointestinal complications such as stomach bleeding when high doses are taken
chronically. Kidney damage is seen in rare cases, most commonly in overdose.
required to carry a warning label about skin reactions, and the FDA has urged manufacturers
to do the same with over-the-counter products.
1.3.3 Asthma
There is an association between paracetamol use and asthma, but whether this association is
causal is still debated as of 2017. Certain evidence suggests that this association likely
reflects confounders rather than being truly causal. A 2014 review found that among children
the association disappeared when respiratory infections were taken into account.
As of 2014, the American Academy of Pediatrics and the National Institute for Health Care
Excellence (NICE) continue to recommend paracetamol for pain and discomfort in
children, but some experts have recommended that paracetamol use by children with asthma
or at risk for asthma should be avoided.
1.3.4 Overdose
Untreated paracetamol overdose results in a lengthy, painful illness. Signs and symptoms of
paracetamol toxicity may initially be absent or non-specific symptoms. The first symptoms of
overdose usually begin several hours after ingestion, with nausea, vomiting, sweating, and
pain as acute liver failure starts. People who take overdoses of paracetamol do not fall asleep
or lose consciousness, although most people who attempt suicide with paracetamol wrongly
believe that they will be rendered unconscious by the drug. The process of dying from an
overdose takes from 3–5 days to 4–6 weeks.
Paracetamol hepatotoxicity is by far the most common cause of acute liver failure in both the
United States and the United Kingdom. Paracetamol overdose results in more calls to poison
control centers in the US than overdose of any other pharmacological substance. Toxicity of
paracetamol is believed to be due to its Quinine metabolite.
Untreated overdose can lead to liver failure and death within days. Treatment is aimed at
removing the paracetamol from the body and replenishing glutathione. Activated
Charcoal can be used to decrease absorption of paracetamol if the person comes to the
hospital soon after the overdose. While the antidote, acetyl cysteine (also called N-acetyl
cysteine or NAC), acts as a precursor for glutathione, helping the body regenerate enough to
prevent or at least decrease the possible damage to the liver, a liver transplant is often
required if damage to the liver becomes severe. NAC was usually given following a treatment
nomogram. (one for people with risk factors, and one for those without) but the use of the
nomogram is no longer recommended as evidence to support the use of risk factors was poor
and inconsistent, and many of the risk factors are imprecise and difficult to determine with
sufficient certainty in clinical practice. NAC also helps in neutralizing the imidoquinone
metabolite of paracetamol. Kidney failure is also a possible side effect.
Until 2004, tablets were available (brand-name in the UK Para dote) that combined
paracetamol with an antidote (methionine) to protect the liver in case of an overdose. One
theoretical, but rarely if ever used, option in the United States is to request a compounding
pharmacy to make a similar drug mix for people who are at risk.
In June 2009, a U.S. Food & Drug Administration (FDA) advisory committee recommended
that new restrictions be placed on paracetamol usage in the United States to help protect
people from the potential toxic effects. The maximum dosage at any given time would be
decreased from 1000 mg to 650 mg, while combinations of paracetamol and opioids
analgesics would be prohibited. Committee members were particularly concerned by the fact
that the then present maximum dosages of paracetamol had been shown to produce
alterations in hepatic function.
1.3.5 Pregnancy
Experimental studies in animals and cohort studies in humans indicate no detectable increase
in congenital malformations associated with paracetamol use during pregnancy. Additionally,
paracetamol does not affect the closure of the fatal ductus arteriosus as NSAIDs can.
1.3.6 Cancer
Some studies have found an association between paracetamol and a slight increase kidney
cancer but no effect on bladder cancer risk.
Filled water for injections IP (WFI) of NLT 800C temperature up to 800 litre in SS
Manufacturing tank.
Make up the volume up to 1000 litre and circulate the solution for 10 to 15 minutes.
After getting QC release (on the basis of PH and assay the solution is passed to filter press
arranged with 0.45 µ and 0.22 µ membrane filter and get filtered.
The solution is filled in pre-washed Type II Glass 100 ml bottles with NLT the nominal
volume and NMT 5% of the nominal volume by filling machine
Sealed the bottles using bromo-butyl rubber stopper followed by Aluminium Flip- off seal via
sealing machine
Perform the sterilization process in Super heated water spray sterilizer at 1210 C for 15
minutes at pressure 2.2 bar.
2 Solubility: The solubility study was obtain as per table given below.
EVALUATION
I PH of the solution: The pH of different formulation were given below in Table 4.3.
II Assay: The drug percentage assay obtain is tabularized in Table 4.3.
III Method Validation: The method was validated in accordance with International
Conference on Harmonization guidelines (ICH2003) for validation of analytical procedures.
IV Linearity: The linearity was analyzed through the standard curves ranging from 80 to
120μg/ml and straight line is obtained on graph plotted between peak area and concentration.
V Accuracy: The results were expressed as percent recoveries of the Paracetamol in aqueous
formulation. The overall results of percent recoveries (mean ± %RSD) of Paracetamol in
aqueous formulation are given below in Table.4.4 indicating good accuracy of the HPLC
method.
IV. CONCLUSION
Paracetamol, an analgesic and an antipyretic drug has been widely used in the last four
decades by wide range of patients through different administration routes and via different
pharmaceutical formulations. The most widely used oral solid formulations are considered
chemically stable, as paracetamol in solid state is non-hygroscopic and well tolerated against
hydrolysis and oxidation. However, intravenous formulations are absolutely necessary in case
of post-surgery pain treatment or acute hyperthermia or inaccessible oral route of
administration. Instability of paracetamol in aqueous medium is well known. Hydrolysis and
oxidation are the primary mechanisms of drug degradation.
V. REFERENCES
1. “Indian Pharmacopoeia”, Ministry of Health and Family Welfare, Governmnent of India,
The Indian Pharmacopoeia Commission, Ghaziabad, 2018 edition; vol. III, Page 2853-
2855.
2. Mattia C, Coluzzi F. What anesthesiologists should know about paracetamol
(acetaminophen), Minerva Anestesiol, 2009; 75: 644-53.
3. Jahr JS, Filocamo P, Singh S. Intravenous acetaminophen: a review of
pharmacoeconomic science for perioperative use, Am J Ther, 2013; 20: 189-99.
4. Moller PL, Sindet-Pedersen S, Petersen CT, Juhl GI, Dillenschneider A, Skoglund LA.
Onset of acetaminophen analgesia: comparison of oral and intravenous routes after third
molar surgery, Br J Anaesth, 2005; 94: 642-8.
5. Smith HS. Potential analgesic mechanism of acetaminophen, Pain Physician, 2009; 12:
269-20.
6. Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S. Paracetamol: new vistas
of an old drug, CNS Drug Rev, 2006; 12: 250-75.
7. Fenlon S, Collyer J, Giles J, et al. Oral vs intravenous paracetamol for lower third molar
extractions under general anaesthesia: is oral administration inferior?, Br J Anaesth, 2013;
110: 432-7.
8. Boyle M, Nicholson L, O'Brien M, et al. Paracetamol induced skin blood flow and blood
pressure changes in febrile intensive care patients: an observational study, Aust Crit Care,
2010; 23: 208-14.
9. Ishida T, Sato T, Irifune M, Tanaka K, Nakamura N, Nishikawa T. Effect of
acetaminophen, a cyclooxygenase inhibitor, on Morris water maze task performance in
mice, J Psychopharmacol, 2007; 21: 757-67.
10. Yalcin N, Uzun ST, Reisli R, Borazan H, Otelcioglu S. A comparison of ketamine and
paracetamol for preventing remifentanil induced hyperalgesia in patients undergoing total
abdominal hysterectomy, Int J Med Sci, 2012; 9: 327-33.
11. Sen H, Kulahci Y, Bicerer E, Ozkan S, Dagli G, Turan A. The analgesic effect of
paracetamol when added to lidocaine for intravenous regional anesthesia, Anesth Analg,
2009; 109: 1327-30.
12. Eneli I, Sadri K, Camargo CJr, Barr RG. Acetaminophen and the risk of asthma: the
epidemiologic and pathophysiologic evidence, Chest, 2005; 127: 604-12.