FORMULATION OF PARACETAMOL INFUSION · that it is less effective than ibuprofen. Paracetamol does not have significant anti-inflammatory effects. 1.1.2 Pain Paracetamol is used for

www.wjpps.com Vol 8, Issue 7, 2019.

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Arshi et al. World Journal of Pharmacy and Pharmaceutical Sciences

FORMULATION OF PARACETAMOL INFUSION

*Arshi, Dr. Amresh Gupta, Dr. Satyawan Singh and Mr. Y. A. Vohra

Goel Group of Sciences and Technology Lucknow, U.P.

ABSTRACT

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. Paracetamol is termed a simple analgesic and

an antipyretic. Despite enduring assertions that it acts by inhibition of

cyclooxygenase (COX)-mediated production of prostaglandins, unlike

non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol has been demonstrated not to

reduce tissue inflammation. The enzyme responsible for the metabolism of arachidonic acid

to the prostanoids (including prostaglandins and thromboxanes), commonly referred to as

cyclooxygenase, is also more appropriately called prostaglandin H2 synthetase (PGHS), and

possesses two active sites: the COX and the peroxidase (POX) sites. Ruggedness of the

current method was determined by analyzing six assay sample solutions of Paracetamol

formulation having concentration of 100μg/ml by two analysts in the same laboratory to

check the reproducibility of the test result. The % recovery and standard deviation were

calculated in both cases. Objective of the present study is to evaluate the oxidative potential

of available intravenous formulations in Indian market through selective stress degradation,

and to understand their potential for instability, if any, through presence/absence of anti-

oxidant Excipient. As paracetamol is known to be unstable in the presence of oxygen,

measurements and controls with respect to the minimize of oxygen in the solution with the

use of inert gas (Nitrogen) by purging Nitrogen gas throughout out the manufacturing and

filling process. The aqueous formulation of Paracetamol (Paracetamol Infusion) is found to

be stable as per stability has been performed at 40°C ± 2°C and 75% RH for 6 months. The

analytical method validation is performed to measure Paracetamol in aqueous formulation

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.421

Volume 8, Issue 7, 1568-1583 Research Article ISSN 2278 – 4357

Article Received on

20 May 2019,

Revised on 09 June 2019,

Accepted on 30 June 2019,

DOI: 10.20959/wjpps20197-14228

*Corresponding Author

Arshi

Goel Group of Sciences and

Technology Lucknow, U.P.


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conveniently. The formulation obtained is found well within the Indian Pharmacopoeia (IP)

acceptable limit.

KEYWORDS: Paracetamol, NSAID, formulation, Infusion.

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


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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.

1.1.4 Low back pain

Based on a systematic review, paracetamol is recommended by the American College of

Physician and the American Pain Society as a first-line treatment for low back pain. In

contrast, other systematic reviews have concluded that evidence for its efficacy is lacking.

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.

1.1.6 Postoperative pain

Paracetamol combined with NSAIDs may be more effective for treating postoperative pain

than either paracetamol alone or NSAIDs alone.

1.1.7 Dental use

NSAIDs such as ibuprofen, naproxen and diclofenac are more effective than paracetamol for

controlling dental pain or pain arising from dental procedures; combinations of NSAIDs and

paracetamol are more effective than either alone. Paracetamol is particularly useful

when NSAIDs are contraindicated due to hypersensitivity or history of gastrointestinal

ulceration or bleeding. It can also be used in combination with NSAIDs when these are

ineffective in controlling dental pain alone. The preoperative analgesics for additional pain

relief in children and adolescents shows no evidence of benefit in taking paracetamol before


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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.

1.2 DRUG INTERACTIONS

Interaction with a variety of other drugs may occur, and warrant caution in co-administration.

For example, concomitant intake of enzyme-inducing substances, such as carbamazepine,

phenytoin, or barbiturates, as well as chronic alcohol excess, may increase NAPQI

production and the risk of paracetamol toxicity. Concurrent use with isoniazid also increases

the risk of toxicity, though as an enzyme inhibitor, the mechanism is not entirely clear.

• Paracetamol absorption is increased by substances that increase gastric emptying (e.g.

metoclopramide)

• Paracetamol absorption is decreased by substances that decrease gastric emptying (e.g.

anticholinergic agents, and opioids)

• Cholestyramine (ion-exchange resin) reduces the absorption of paracetamol if given

within 1 h of paracetamol

• Caution with concomitant intake of enzyme-inducing substances, such as carbamazepine,

phenytoin, or barbiturates, or isoniazid, may increase the risk of paracetamol toxicity

• Probenecid causes an almost two-fold reduction in clearance of paracetamol by inhibiting

its conjugation with glucuronic acid. A reduction of the paracetamol dose should be

considered for concomitant treatment with Probenecid

• Salicylamide (analgesic and antipyretic) may prolong the elimination half-life of

paracetamol

• Subsequent use of paracetamol (4 g per day for at least 4 days) with oral anticoagulants

may lead to slight variations of International Normalized Ratio (INR) values

• Paracetamol may also increase chloramphenicol concentrations


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1.3 ADVERSE EFFECTS

Healthy adults taking regular doses of up to 4,000 mg a day show little evidence of toxicity

(although some researchers disagree). They are more likely to have abnormal liver function

tests, but the significance of this is uncertain.

1.3.1 Liver damage

Acute overdoses of paracetamol can cause potentially fatal liver damage. In 2011 the U.S.

Food & Drug Administration launched a public education program to help consumers avoid

overdose, warning: "Acetaminophen can cause serious liver damage if more than directed is

used. In a 2011 Safety Warning the FDA immediately required manufacturers to update

labels of all prescription combination acetaminophen products to warn of the potential risk

for severe liver injury and required that such combinations contain no more than 325 mg of

acetaminophen. Overdoses are frequently related to high-dose recreational use of

prescription opioids, as these opioids are most often combined with acetaminophen. The

overdose risk may be heightened by frequent consumption of alcohol.

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.

1.3.2 Skin reactions

On August 2, 2013, the U.S. Food & Drug Administration (FDA) issued a new warning about

paracetamol. It stated that the drug could cause rare and possibly fatal skin reactions such as

Johnson Syndrome and toxic epidermal necrolysis. Prescription-strength products will be


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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


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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.

In January 2011, the FDA asked manufacturers of prescription combination products

containing paracetamol to limit the amount of paracetamol to no more than 325 mg per tablet

or capsule and began requiring manufacturers to update the labels of all prescription

combination paracetamol products to warn of the potential risk of severe liver

damage. Manufacturers had three years to limit the amount of paracetamol in their

prescription drug products to 325 mg per dosage unit.

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.


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1.4 PARACETAMOL INFUSION

The pharmacological importance of paracetamol has been established by the vast number of

non-prescription and prescription formulations available. While the oral route of paracetamol

administration is common in the hospital setting, its clinical application is limited to

subgroups such as critically ill, heavily sedated, anaesthetised or postoperative patients. The

rectal route may be used in this setting, however rectal suppositories have an unpredictable

bioavailability of 24-98%, similar to that of the oral formulation bioavailability of 63-89%.

Secondly, the placement of the rectal suppository has been implicated as a mechanism for its

variable absorption and metabolism due to the different drainage pathways of the rectum.

Drugs placed in the distal portion of the rectum drain into the general circulation, while drugs

are subjected to the hepatic first-pass effect if placed in the proximal rectum. Importantly,

accurate dosing adjustments in the event of early expulsion of the suppository are

complicated by the potential for uneven distribution of the active drug throughout the

suppository and its availability only in fixed doses. Finally, rectal administration can be

considered unpleasant, inconvenient and intrusive. As a result of these limitations, a major

advancement in the clinical use of paracetamol has been the introduction of the IV

formulations, all of which have a bioavailability of 100%.

1.5 PREPARATION OF PARACETAMOL INFUSION IN OTHER COUNTRIES

Paracetamol is one of the most commonly used drugs worldwide with non-prescription sales.

The haemodynamic effects of the intravenous paracetamol formulations are largely

understudied. There is an emerging body of evidence suggesting that intravenous paracetamol

may cause iatrogenic hypotension. Little is known as to the mechanisms of this phenomenon

or if intravenous paracetamol indeed does cause hypotension. As paracetamol has negligible

solubility in aqueous solutions, many of the commercially available intravenous formulations

contain mannitol (up to 3.91 g/100 mL paracetamol) as a stabilising ingredient. It is unknown

if mannitol is a contributing factor in the observed hypotension. In this review, we outline the

development of paracetamol’s current intravenous formulations, describe the composition of

these formulations, and overview the literature pertaining to the proposed phenomenon of

paracetamol-induced altered hypotension. Understanding the pharmacokinetic and

pharmacodynamics properties of intravenous paracetamol may have important clinical

implications for vulnerable patients in subgroups where haemodynamic stability is at risk

such as those undergoing elective and emergency surgery.


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During degradation, paracetamol is converted to 4-aminophenol, which is rapidly converted

to the hepatotoxic substance N-acetyl-p-benzoquinoneimine (NAPQI). Paracetamol must be

synthesized within an optimum pH range of 5-6 to avoid a hydrolysis reaction and thus

conversion to 4-aminophenol. Secondly, chemical oxidation reactions must be avoided. This

is managed by bubbling nitrogen into the IV formulations to reduce the amount of oxygen

present and by the strict adoption of hermetically sealed oxygen-impermeable glass bottles

filled with a ready-to-use formulation that does not require reconstitution from an external

ampoule.

1.5. Paracetamol vs. oral and rectal formulations

A comparative study between the three common modes of administration found the IV

formulation carries a faster time to peak plasma-drug concentrations (15 minutes after

initiation of infusion) and a significantly higher peak plasma-paracetamol level. In contrast,

oral paracetamol requires approximately 2 hours and rectal paracetamol at least 3 hours,

depending on the placement of the suppository, to reach their respective peak plasma

concentrations. These results correlate with the faster time to antipyretic in IV paracetamol

compared to the oral formulation. Similarly, Levy proposed that the faster the time to

complete absorption of an analgesic, the longer-lasting the analgesic effect. This theory,

however, has not been confirmed due to contradictory evidence from two other studies.

While there is not enough evidence to suggest superiority in terms of prolonged analgesia,

several studies have questioned the ability of oral and rectal formulations to produce the

desired plasma-paracetamol concentrations for effective analgesia. Sub-therapeutic plasma-

drug concentrations with use of oral and rectal paracetamol, even at the recommended

dosages, have been observed. For this reason, IV paracetamol is also an attractive choice for

postoperative analgesia. Despite the ab over considerations, a clear disadvantage regarding

the use of the IV formulation is the noticeable cost difference when compared to other

methods of administration.


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II. MATERIALS AND METHOD

Method of Preparation of Paraceamol Infusion

Manufacturing process (Batch Size 1000 Litre)

The manufacturing process consists of dissolving and mixing the various components,

followed by filtration, filling into the final containers and sterilization.

The formulation of Paracetamol Infusion 10mg/ml is manufactured by using Paracetamol IP

(Parenteral Grade) as API & excipients Mannitol IP which act as stabilizing agent due to poor

aqueous stability of Paracetamol and Water for Injections, where PH (4.5 to 6.5) is maintained

by Hydrochloric acid. The solution is filtered by using filter paper 0.45µ & 0.22µ and filled

in pre-washed Type II glass bottles sealed with bromo butyl rubber stopper followed by

Aluminium Flip-off seal. The process of manufacturing and filling is performed by purging

nitrogen gas throughout the preparation and filling.

The manufacturing process is as given below in flowchart.

Filled water for injections IP (WFI) of NLT 800C temperature up to 800 litre in SS

Manufacturing tank.


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Added Mannitol IP 50 kg in the above tank with continue stirring

Added Paracetamol IP 10kg

Adjusted the PH

with Hydrochloric Acid (Dilute)

Make up the volume up to 1000 litre and circulate the solution for 10 to 15 minutes.

Send the approx. 500ml of solution for analysis to Q.C.

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.


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The solution is then transfer to holding tank after filtration.

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.

III. RESULT AND DISCUSSION

1 Description: The physical parameters of Paracetamol were found to be as white, odourless

and crystalline solid.

Table. 1: Physical appearance of Paracetamol.

Physical parameters Observation

Color White

Odor Odorless

Physical form Crystalline solid


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2 Solubility: The solubility study was obtain as per table given below.

Table 2: Solubility study of different solvents.

Solvent Solubility

Dichloromethane Very slightly soluble

Ether Very slightly soluble

Water Sparingly soluble

Ethanol (95%) Freely soluble

3 Determination of λmax by UV Spectroscopy

The absorbance obtain is 0.47 at 249nm.

4 Color test: Complies

5 Test for Acetyl Groups: Complies

6 Heavy metals: Found to be less than 10 ppm

7 Sulphated Ash: 0.07%

8 Loss on Drying: 0.16%

9 Assay (on dried basis) 99.70%

10 Related substances (BY HPLC)

• 4-Chloroacetanilide: Below detection limit <5ppm

• 4-Aminophenol: 3.1ppm

• 4-Nitrophenol: Below detection limit <0.0009%

• Any other impurities: 0.01%

• Total of other impurities: 0.01%

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.

Table 3: pH and Assay (%).

Formulation code pH of Solution Assay (%)

P1 6.80

P2 6.72 99.80

P3 6.58 99.94

P4 6.20 102.20

P5 6.10 98.76

P6 5.99 98.68


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Fig. 1: Comparison of PH of solution of Formulation P1 to P6.

Fig 2: Comparison of Assay (%) of solution of Formulation P1 to P6.

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.

Fig.3: Linearity showing straight line.


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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.

Table 4 Accuracy Studies of Paracetamol in aqueous solution.

Standard

Solution

Amount added

(μg/ml) Peak area

Amount

recovered (μg/ml) % Recovery

Recovery

(Mean ± %RSD)

50 5280275 49.99 99.98

99.99 ± 0.017 50 5282196 50.01 100.02

50 5280629 49.99 99.99

100 10514207 99.90 99.90

99.99 ± 0.066 100 10528725 100.04 100.04

100 10528617 100.04 100.04

150 15652717 150.07 100.05

99.99 ± 0.039 150 15638662 149.94 99.96

150 15641363 149.97 99.98

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.

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3. Jahr JS, Filocamo P, Singh S. Intravenous acetaminophen: a review of

pharmacoeconomic science for perioperative use, Am J Ther, 2013; 20: 189-99.


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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

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Documents

FORMULATION OF PARACETAMOL INFUSION · that it is less effective than ibuprofen. Paracetamol does not have significant anti-inflammatory effects. 1.1.2 Pain Paracetamol is used for