SAGAR Email: [email protected] ABSTRACT: Ibuprofen is a non-steroidal anti-inflammatory

SAGAR
BASHYAL*

Department of
Biotechnology, IILM College of Engineering and Technology,

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                                               Greater
Noida- 201 306, U.P, India

Email:
[email protected]

 

 

ABSTRACT:

Ibuprofen is a non-steroidal
anti-inflammatory drug (NSAID) and its similar class includes aspirin,
indomethacin (Indocin), naproxen (Aleve), nabumetone (Relafen) and many others.
This drug is used in moderate pain, fever, and inflammation which is promoted
by the release in the body of chemicals called prostaglandins. According to
IUPAC, it is (RS)-2-(4-(2-Methylpropyl) phenyl) propanoic acid. The original
synthesis of ibuprofen by the Boots Group started with the compound
2-methylpropylbenzene. Ibuprofen blocks the enzyme that makes prostaglandins
(cyclooxygenase), resulting in lower levels of prostaglandins that helps in
reducing inflammation, pain, and fever. Employing various scientific techniques,
Ibuprofen can be synthesized chemically at industrial scale. Various methods
like potentiometric, UV spectrophotometric, Gas chromatography, High-Performance
Liquid Chromatography(HPLC), Reverse-HPLC etc. can be used for the detection,
extraction, quantification and quality analysis of Ibuprofen.

Keywords:
Ibuprofen,
Anti-inflammatory, Prostaglandins, Analytical methods

INTRODUCTION:

 Ibuprofen is a medication
in the non-steroidal anti-inflammatory drug (NSAID) class that is used for
treating pain, fever. 1
It is used for the treatment of mild to moderate pain, inflammation and fever
caused by many and diverse diseases. It is used for treating menstrual cramps
(dysmenorrhea), osteoarthritis, rheumatoid arthritis, and juvenile idiopathic
arthritis. It increases the risk of heart failure, kidney failure, and liver
failure. 1 At low
doses, it does not appear to increase the risk of heart attack; however, at
higher doses it may. 2
It is on the World Health Organization’s List of Essential Medicines, the
most effective and safe medicines needed in a health system. 3

Structural
formula 4

 

 

 

Molecular
Formula: C13H18O2

Molecular
Weight: 206.29 g/mole

IUPAC
name: (RS)-2-(4-(2-Methylpropyl) phenyl) propanoic acid

Density:
1.03 g/ml g/cm3

Melting
Point: 75 to 78 °C (167 to 172 °F)

Boiling
Point: 157 °C (315 °F)

Odor:
Characteristic order

Color:
Colorless, crystalline stable solid

 

Synonyms 5

1.      Alpha-Methyl-4-(2-methylpropyl)
benzene acetic Acid

2.      Aluminum
Salt Ibuprofen

3.      Brufen

4.      Calcium
Salt Ibuprofen

5.      I.V.
Solution, Ibuprofen

6.      Ibumetin

7.      Ibuprofen

8.      Ibuprofen
I.V. Solution

9.      Ibuprofen
Zinc

10.  Ibuprofen,
(+-)-Isomer

11.  Ibuprofen,
(R)-Isomer

12.  Ibuprofen,
(S)-Isomer

13.  Ibuprofen,
Aluminum Salt

14.  Ibuprofen,
Calcium Salt

15.  Ibuprofen,
Copper (2+) Salt

16.  Ibuprofen,
Magnesium Salt

17.  Ibuprofen,
Potassium Salt

18.  Ibuprofen,
Sodium Salt

19.  Ibuprofen,
Zinc Salt

20.  Ibuprofen-Zinc

21.  IP
82

22.  IP-82

23.  IP82

24.  Magnesium
Salt Ibuprofen

25.  Motrin

26.  Nuprin

27.  Potassium
Salt Ibuprofen

28.  Rufen

29.  Salprofen

30.  Salt
Ibuprofen, Magnesium

31.  Salt
Ibuprofen, Sodium

32.  Salt
Ibuprofen, Zinc

33.  Sodium
Salt Ibuprofen

34.  Trauma
Dolgit Gel

35.  Trauma-Dolgit
Gel

36.  TraumaDolgit
Gel

37.  Zinc
Salt Ibuprofen

 

Solubility:

·        
Readily sol in most org solvents 6

·        
Very soluble in alcohol 7

·        
21 mg/L (at 25 °C) 8

 

Vapor
Pressure:

·        
4.74X10-5
mm Hg @ 25 deg. C 9

Pharmacology:

This drug has the
analgesic and antipyretic properties. Pharmacologically, it has similar action
to those of other prototypical NSAIAs. Ibuprofen is a propionic acid derivate
and nonsteroidal anti-inflammatory drug (NSAID) with anti-inflammatory,
analgesic, and antipyretic effects.

Ibuprofen inhibits the
activity of cyclo-oxygenase I and II, resulting in a decreased formation of
precursors of prostaglandins and thromboxane’s. This leads to decreased
prostaglandin synthesis, by prostaglandin synthase, the main physiologic effect
of ibuprofen. Ibuprofen also causes a decrease in the formation of thromboxane
A2 synthesis, by thromboxane synthase, thereby inhibiting platelet aggregation 10

The absorption of
ibuprofen is rapid and complete when given orally. Ibuprofen is eliminated
following biotransformation to glucuronide conjugate metabolites that are
excreted in urine, with little of the drug being eliminated unchanged. 11 The excretion of
conjugates may be tied to renal function and the accumulation of conjugates
occurs in end-stage renal disease. Hepatic disease and cystic fibrosis can
alter the disposition kinetics of ibuprofen. Ibuprofen is not excreted in
substantial concentrations into breast milk. Significant drug interactions have
been demonstrated for aspirin (acetylsalicylic acid), cholestyramine and
methotrexate. 12

Mechanism
of action:

Cyclooxygenase (COX),
which is required for the synthesis of prostaglandins via the arachidonic acid
pathway is needed to convert the arachidonic acid to prostaglandin H2 (PGH2) in
the body. Anticoagulant effects are also mediated through inhibition of COX,
which converts arachidonic acid into thromboxane A2, a vital component in
platelet aggregation that leads to the formation of blood clots. Thus, it
reduces the pain inhibiting the synthesis of cyclooxygenase the long-term
blockage of COX-1 with chronic use of NSAID, however, may cause gastric
toxicity, as COX-1 usually maintains the gastric mucosa.

Uses:

Ibuprofen is used
primarily for

·        
Headache

·        
Back pain

·        
Menstruation pain

·        
Pain in teeth

·        
Symptoms of cold and influenza

·        
Pain in body

·        
Analgesic

·        
Muscles pain

·        
Joints pain

·        
Pain in nerves

Contraindications:

Hypersensitivity
to Ibuprofen is a contraindication. In addition, Ibuprofen should not be used
in the following conditions.

·        
Active peptic ulcer

·        
Aspirin

·        
Breastfeeding

·        
Gastrointestinal bleeding

·        
Hypersensitivity

·        
Neonates with congenital heart disease

·        
A study of pregnant women suggests those
taking any type or amount of NSAIDs (including ibuprofen, diclofenac and
naproxen) were 2.4 times more likely to miscarry than those not taking the
drugs. 13

 

Side
effects 14,15

·        
Abdominal pain

·        
Allergic reactions

·        
Kidney problems

·        
Hepatic problems

·        
Abnormal blood counts

·        
Severe skin reactions

·        
Feeling sick

·        
Loose motions

·        
High blood pressure

·        
Skin rash

·        
Liver problems

·        
Itching

·        
Bleeding from the skin or nose

·        
Severe skin allergies

·        
Heartburn

·        
Constipation

·        
Gas

·        
Headache

 

Safety
methods:

·        
Consult with doctor before taking the
Ibuprofen.

·        
Avoid taking alcohol or salicylates to
prevent bleeding.

·        
Consult your doctor if you develop blurred
vision, ringing or roaring in ears

·        
Consult your doctor if you have systemic
lupus erythematosus.

·        
Inform your doctor if you have bruising or
bleeding.

·        
Take the drug with a meal or snack to
prevent upset stomach.

·        
Keep away from heat, hot surface, sparks,
open flames and other ignition sources. – No smoking.

 

Dosage:

Ibuprofen can be found at
various form like tablets, inhalation etc. The various dosages according to the
type of diseases and age of person can be as follows.

·        
Adult people who are suffering from minor
aches, mild to moderate pain, menstrual cramps, and fever, dose is 200 or 400
mg every 4 to 6 hours.

·        
Person with arthritis is treated with 300
to 800 mg 3 or 4 times daily. 20

·        
Individuals should not use ibuprofen for
more than 10 days for the treatment of pain or more than 3 days for the
treatment of a fever unless directed by a physician.

·         
Children 6 months to 12 years of age
usually are given 5-10 mg/kg of ibuprofen every 6-8 hours for the treatment of
fever and pain. The maximum dose is 40 mg/kg daily. 20

·        
Person suffering from Juvenile arthritis
is treated with 20 to 40 mg/kg/day in 3-4 divided doses.

 

Studies
& specifications:

Each drug after a design requires the clinical trials
process where several types of animals are used. After successful trials on
animals, human trials are performed. Some of the animals trialed during the
testing of Ibuprofen and their effects towards the given drug is given in Table
1.

Table
1: Experimental Studies of Ibuprofen

Organism

Route

Reported Dose

Effect

Holstein
calves 

Intraperitoneal

 10mg/kg 

Ibuprofen
decreased PGE2, modulated the immune response, lung histopathology was not
affected and viral shedding was increased. 16

Rat

Intravenous

20
mg/kg body wt./day

Rats
injected with ibuprofen significantly worsened compared to non-treated
injured animals. 17

Sprague-Dawley
rats

oral

15
mg/kg

Fracture
histology and serum osteocalcin levels were no different in treated animals
than control animals. 18

Infants

oral

2.2
mg/kg/day

Prophylactic
ibuprofen reduces the need for surgical ligation of patent ductus arteriosus,
but does not reduce mortality or morbidity. 19

 

 

 

 

 

 

 

 

Trade
Names:

Ibuprofen is available in
different trade name by different companies as shown. (Table 2)

 

Table
2: Trade name and respective companies of Ibuprofen.

 

 

Brand Name

Dosage Forms

Company

 

Motrin

Tablets, Suspension

Sigma Aldrich

 

Brufen

Tablets

Wyeth pharmaceuticals Inc.

 

Nurofen

Tablets

Reckitt Benckiser Pharmaceuticals

 

Advil

Tablets

Pfizer

 

Dolgit

Tablets

Dolorgiet, Budapharma

 

Liptan

Tablets

Wyeth pharmaceuticals Inc.

 

Anflagen

Tablets

Adare pharmaceuticals Inc

 

Apsifen

Tablets

TEVA UK Limited

 

Trendar

Tablets

Zibo Xinhua Perrigo Pharmaceutical Co
Ltd

 

Buburone

Tablets

BCM

 

 

 

 

 

 

METHODS
OF MANUFACTURING:

Various methods can be
employed to manufacture the Ibuprofen and its common constituents. Industrially,
Ibuprofen can be produced by biological transformation process but due to some
costlier process easy methods are being used where chemical synthesis process
is the most prominent one.

 

 

 

 

 

Table3:
Chemical and processes for Ibuprofen manufacturing.

 

S.N.

                         Chemicals

Process

 

1.

Isobutyl benzene +
acetyl chloride + triethylaluminum + potassium cyanide.

Friedel-Crafts acylation/cyanohydrin
formation/hydrogenation/nitrile hydrolysis 21

 

2.

isobutyl benzene +
propionyl chloride
+ methanol.

Friedel-Crafts
acylation/ketal formation/alpha Bromination /rearrangement 21

 

3.

Isobutyl benzene +
acetyl chloride + carbon monoxide.

Friedel-Crafts
acylation/carbonyl reduction/carbonylation 21

 

4

Isobutyl benzene +
acetyl chloride + methyl chloroacetate.

Friedel-Crafts
acylation/Darzens reaction/hydrolysis/decarboxylation/carbonyl oxidation 21

 

5

Ethyl
4-isobutylphenylacetate and diethyl carbonate with sodium ethoxide gas+
methyl iodide and sodium ethoxide.

Methylation,
saponification, Decarboxylation 22

 

ANALYTICAL
METHODS:

Various analytical
methods can be used to determine Ibuprofen. The methods are:

1.     
Potentiometry:

 

Potentiometry
is a technique based on a measurement of the potential difference

between
an indicator electrode and a reference electrode in solution, while the current
is

held
at zero. 23

For
the potentiometric determination of ibuprofen sodium hydroxide and
triethanolamine can be used as titrants.

The
influence of different solvents, such as water, methanol, acetonitrile,
dimethyl sulfoxide and N, N-dimethylformamide, on the conductometric titrations
can be investigated.

The
same titrants as in the potentiometric titrations can be used.

The
methods are accurate and results are reproducible in quantities ranging from 1
to 10 mg of ibuprofen in analyzed pharmaceutical dosage forms.

 

2.     
Chromatographic
and UV spectrophotometric methods:

 

 

 

 

 

 

Table
4: Chromatographic & UV spectrophotometric methods for various experiments:

 

S. N.

Title

Method

Mobile phase

Column

Wavelength(nm)

 

1

Ethambutol
hydrogen chloride and ibuprofen determination in tablets. 24

Reversed-phase
HPLC

Methanol-H2O
(70:30)

Bonda
Pak C18 column packed with octadecylsilane bonded to porous silica

254

 

2

Ibuprofen
in acidified plasma extraction with hexane-isopropanol (9:1). 25

HPLC

Methanol-water-0.05
molar trisodium phosphate buffer (220:100:10)

Gel
beads

214

 

3

Determination
of ibuprofen in different ointment bases. 26

Reversed-phase
HPLC

Aqueous
tetrahydrofuran buffered by phosphate.

Octadecyl
silica column protected by a precolumn

219

 

4

Chromatographic
and electrochemical methods for biological material analyses. 27

Capillary
Column Cas chromatography

500
mg lithium perchlorate trihydrate, 110 ml water, and methanol up to 1 l.

Hypersil
APS column

219

 

5

Detection
of ibuprofen in human plasma and urine. 28

Gas
chromatography

Helium

Fused
silica capillary column wall-coated with carbowax.

219

 

6

Screening
of plasma samples for the presence of sixteen non-steroidal anti-inflammatory
drugs. 29

Isocratic
 HPLC

acetonitrile-0.3%
acetic acid-tetrahydrofuran (36:63.1:0.9, vol/vol)

Octadecyl
reversed-phase column

254
and 370

 

 

CONCLUSION:

The study revealed that Ibuprofen is a popular drug popular for it
medicinal features in the pharmaceutical sector that can be used for the
treatment of pain, fever and inflammation. Though, there are a lot of
advantages one should use the right amount of drug with consultation by doctor.
Ibuprofen has been discussed in all its aspects in this review. HPLC-UV methods
were found to be the most widely used. Furthermore, the analytical mentioned
are time saving, simple and do not require elaborate treatments associated with
chromatographic methods. With any no doubt, future will be gifted by newer
types of Ibuprofen formulation techniques.

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