1.

1 Introduction :
Ibuprofen (from the now outdated nomenclature iso-butyl-propanoic-
phenolic acid) is a non-steroidal anti-inflammatory drug (NSAID). It is a colorless
crystalline solid widely used as an analgesic and anti-inflammatory medication. It is
most commonly known as ibuprofen, but is also known as α-methyl-4-(2-
methylpropyl) benzeneacetic acid and 4-isobutyl-@alpha;-methylphenylacetic acid.
Originally marketed as Nurofen, Advil and Motrin and since then under various other
trademarks, most notably Flamex, Profen, Inflam and Reumafen. It is also used for
relief of symptoms of arthritis, primary dysmenorrhea, fever, and as an especially
where there is an inflammatory component. Ibuprofen is known to have an
antiplatelet effect, though it is relatively mild and short-lived when compared to that
of aspirin or other more well-known antiplatelet drugs. Ibuprofen is a core medicine
in the World Health Organization's "Essential Drugs List", which is a list of minimum
medical needs for a basic health care system.

2-(4-isobutylphenyl)propionic Acid
(Ibuprofen)
Figure: Structure of Ibuprofen

Ibuprofen is a relatively safe drug. Because of its effectiveness and lack of side
effects, these are now frequently prescribed by the Doctors.

1.2. According to Conventional drug:

Ibuprofen is a widely used non-steroidal anti-inflammatory drug
(NSAID). It is also a conventional drug. So ibuprofen is used in conventional
treatment or therapy.

1.2.1.Conventional treatment:
A currently accepted and widely used treatment for a certain type of
disease, based on the results of past research. Also called conventional treatment.

1.2.2. Conventional medicine:

A system in which medical doctors and other healthcare professionals
(such as nurses, pharmacists, and therapists) treat symptoms and diseases using
drugs, radiation, or surgery. Also called Western medicine, mainstream medicine,
orthodox medicine, biomedicine, and allopathic medicine.
1.2.3. Conventional drug Therapy:
The short duration of activity is due to the inability of conventional
dosage forms to control temporal delivery. If any attempt is made to maintain drug
blood levels in the therapeutic range for longer periods by, for example increasing
the initial dose of an intravenous injection, as shown by the dotted line in the figure,
toxic level may be produce at early times. This approach is to administer the drug
repetitively with a constant-dosing interval as in multiple dose therapy, which is
shown below in figure for oral route;

In this case the drug blood level reached and the time required to
reach that level depend on the dose and the dosing interval. There are several
potential problems inherent in multiple dose therapy.

a) If the dosing interval is not appropriate for the biological half-life of the drug
large “peak” and “valley” in the drug blood level may result, e.g. drugs with
short half-lives require frequent dosing to maintain constant therapeutic
levels.
b) The drug blood level may not be within the therapeutic range at sufficiently
early times an important consideration for certain disease states.
c) Patients’ noncompliance with multiple dosing regimens can result in failure of
this approach.

In many instance, potential problem associated with conventional

drug therapy can be overcome. When this is the case, drugs given in conventional
dosage forms by multiple dosing can produce the desired drug blood level for
extended period of time. Frequently however these problems are significant enough
to make drug therapy with conventional dosage forms less desirable than sustained
drug therapy

1.2.4. Conventional NSAIDs:

It is extremely important to obtain an accurate diagnosis before trying
to find a cure. Many diseases and conditions share common symptoms: if you treat
yourself for the wrong illness or a specific symptom of a complex disease, you may
delay legitimate treatment of a serious underlying problem. In other words, the
greatest danger in self-treatment may be self-diagnosis.

In those patients with osteoarthritis whose symptoms are not relieved

by non-pharmacological therapy and ibuprofen and who have no gastrointestinal
risk factors, it is appropriate to use conventional NSAIDs, commencing at a low dose
and titrating against efficacy. Virtually all currently available conventional NSAIDs
have been tested in randomised, placebo-controlled trials in patients with
osteoarthritis and rheumatoid arthritis. In these studies, conventional NSAIDs have
been shown to be superior to placebo, but there has not been evidence suggesting
that one agent is more effective than another. There does, however, appear to be a
hierarchy of gastrointestinal risk, with agents such as paracetamol and diclofenac
being of the lowest risk and piroxicam and ketoprofen the highest.

Those with gastrointestinal risk factors who are unable to take CSIs,
NSAIDs could be prescribed, ideally with an agent to reduce the risk of
gastrointestinal bleeding. The prostaglandin analogue misoprostol or the proton-
pump inhibitor omeprazole have both been shown to reduce the risk of ulcer
complications in patients taking conventional NSAIDs. Unfortunately, the
Pharmaceutical Benefits Scheme in Australia does not currently support the
prophylactic co-prescribing of misoprostol or omeprazole. Conventional doses of H2-
receptor antagonists have not been found to protect patients from adverse
gastrointestinal events.

1.3.Ibuprofen and NSAIDs:

Ibuprofen is in a group of drugs called nonsteroidal anti-
inflammatory drugs (NSAIDs). The exact mechanism of action of
paracetamol/acetaminophen is uncertain, but it appears to be acting
centrally.Ibuprofen as NSAIDs inhibit cyclooxygenase, leading to a decrease in
prostaglandin production; this reduces pain and also inflammation (in contrast to
paracetamol and the opioids).Ibuprofen has few side effects.NSAIDs may predispose
to peptic ulcers, renal failure, allergic reactions, and hearing loss. They may also
increase the risk of hemorrhage by affecting platelet function. The use of certain
NSAIDs in children under 16 suffering from viral illness may contribute to Reye's
syndrome. Ibuprofen is used to reduce fever and treat pain or inflammation caused
by many conditions such as headache, toothache, back pain, arthritis, menstrual
cramps, or minor injury. Ibuprofen may also be used for other purposes not listed in
this medication guide

1.4.Comparison with other NSAIDs:

Ibuprofen unlike other common analgesic and antipyretic drug
such as aspirin and paracetamol, that is used for the relief of fever and other minor
aches and pains. Ibuprofen is also useful in managing more severe pain, allowing
lower dosages of additional non-steroidal anti-inflammatory drugs (NSAIDs) or
opioid analgesics to be used, thereby minimizing overall side-effects.

1.5. Historical Background of Ibuprofen:

When ibuprofen was placed on drugstore shelves in May, 1984, it was
the first new over-the-counter (OTC) pain-relief medication to enter the marketplace
in a generation. Prior to its introduction, nonprescription pain relief was mainly
provided by acetaminophen (introduced in 1955) and aspirin (marketed since 1899).
Ibuprofen was developed by the Boots Company, a British drug
manufacturer and retailer. Early in the 1960s, researchers at Boots identified
carboxylic acid as the agent that gave aspirin its anti-inflammatory property. The
Boots group investigated other carboxylic acids; when they found one that was
twice as strong as aspirin, they synthesized and tested more than 600 compounds
from these acids. The most effective and useful of these was ibuprofen, which Boots
began to sell in 1964 in the United Kingdom as the prescription medication Brufen.
(Ibuprofen became available OCT in the U.K. in 1983.) Ibuprofen appeared in
American pharmacies in 1974 when Boots granted a nonexclusive license to the
Upjohn Company, which marketed ibuprofen as the prescription arthritis-relief drug
Motrin. This drug soon became one of the most commonly prescribed drugs in the
United States. A few years later, Boots began selling its own prescription-form
ibuprofen, called Rufen, in the United States.
When the United States Food and Drug Administration approved OTC
sales of ibuprofen at a lower dosage than in prescription form, two major drug
companies immediately geared up for a product-introduction blitz. First, the
Whitehall Laboratories division of American Home Products came out with Advil.
This was soon followed by Nuprin, which was produced by Upjohn and marketed by
Bristol-Meyers. Both operated under licenses from Boots, which held the worldwide
patent for ibuprofen until May 1985 and exclusive marketing rights until September
1986. After that date, new manufacturers jumped into the lucrative market with
products of their own, including Johnson & Johnson's Medipren, Thompson's Ibuprin,
and a number of generic and private-label brands. Upjohn and AHP/Whitehall
countered with two new ibuprofen products, Haltran and Trendar, promoted as pain
relief for menstrual cramps. Sterling Drugs then introduced its own ibuprofen-based
menstrual cramps product, Midol 200.
Although ibuprofen, aspirin, and acetaminophen are chemically
different, all three give effective relief for minor aches and pains. Ibuprofen seems
to cause fewer stomach problems than aspirin. This drug is important because it
replaces its more dangerous relative, aspirin. Aspirin causes stomach distress in 2-
10% of users, as well as affecting the blood's ability to clot. Reye's syndrome,
another serious side effect of aspirin, affects children recovering from chicken pox
or flu, causing confusion, irritability, nausea, and sometimes death. So, Ibuprofen
acts like aspirin by blocking prostaglandins, which play a major role in sensing pain.
In addition, it controls inflammation and fever. It is more effective for many women
in relieving menstrual discomfort, and appears more effective for postsurgical
dental pain and soft-tissue injuries. Ibuprofen should not be taken by people with
certain medical conditions, including people allergic to aspirin and women in the
third trimester of pregnancy.
A 1997 study shows that the likelihood of developing Alzheimer's
disease may be reduced by up to 60 percent with frequent consumption of
ibuprofen over two or more years, and that use for an even shorter period may
reduce risk by 30 percent, according to Johns Hopkins University and the National
Institute on Aging. Researchers in that study caution, however, that consistent use
of ibuprofen can cause kidney failure. In a conflicting article published in the
American Journal of Medical Science in 1990, authors believe ibuprofen itself is not
an independent predictor of risk of kidney damage; however, when taken by
patients 65 years or older or who have coronary artery disease, the risk factor
increases.
1.6. Synthesis:
There have been many commercial and laboratory publications for
the synthesis of Ibuprofen. Two of the most popular ways to obtain Ibuprofen are the
Boot process and the Hoechst process. The Boot process is an older commercial
process developed by the Boot Pure Drug Company, and the Hoechst process is a
newer process developed by the Hoechst Company. Most of these routes to
Ibuprofen begin with isobutylbenzene and use Friedel-Crafts acylation. The Boot
process requires six steps, while the Hoechst process, with the assistance of
catalysts, is completed in only three steps.

Figure: Two synthetic routes to ibuprofen.

Cheminor Drugs have developed a process for an improved version
of ibuprofen based on chiral synthesis. The move is significant given that pure S-
Ibuprofen (the active form of ibuprofen) could near halve the regular ibuprofen
dosage, besides improving the side-effect profile.
However the human body can convert the inactive (R) form into
the (S) form, so eventually 100% of the ibuprofen taken becomes active. The
process discovered by Cheminor is therefore unlikely to have commercial
significance.
1.7. Mechanism of action:
buprofen is an NSAID which is believed to work through inhibition
of cyclooxygenase (COX), thus inhibiting prostaglandin synthesis. There are at least
2 variants of cyclooxygenase (COX-1 and COX-2). Ibuprofen inhibits both COX-1 and
COX-2. It appears that its analgesic, antipyretic, and anti-inflammatory activity are
achieved principally through COX-2 inhibition; whereas COX-1 inhibition is
responsible for its unwanted effects on platelet aggregation and the GI mucosa. The
role of the individual COX isoforms in the analgesic, anti-inflammatory and gastric
damage effects of NSAIDs is uncertain and different compounds cause different
degrees of analgesia and gastric damage.[10]
In 2002 it was reported that ibuprofen selectively blocks a
variant of the COX enzyme that was different from the then known variants COX-1
and COX-2. This isoenzyme, which is only expressed in the brain and the spinal cord,
is now referred to as COX-3. Its exact mechanism of action is still poorly understood,
but future research may provide further insight into how it works. a single study has
shown that administration of ibuprofen increases the bioavailability of serotonin (5-
HT) in rats, with some early evidence for a similar mechanism in humans. Down
regulation of central 5-HT2A receptors and an increase in the number of serotonin
transporter proteins have also been observed with chronic ibuprofen treatment in
rats.
In 2006, it was shown that ibuprofen is converted to N-
arachidonoylphenolamine, or AM404, a compound known as an endogenous
cannabinoid reuptake inhibitor. As such, it indirectly activates the CB1 cannabinoid
receptor, resulting in analgesia. This activity was proven through the induction of a
CB (1) receptor antagonist which resulted in the reversal of the analgesic action of
ibuprofen.

1.8.Pharmacological Activity:
Ibuprofen have the following pharmacological activity on biological
system. They are:
1. Analgesic
 2. Antipyretic
3. Anti-inflammatory effect

1.8.1.Analgesic Activity:
Analgesics are drugs used to control pain without producing loss of
consciousness. Unlike anesthetics, which block all sensation, analgesics do not
affect sensations other than pain. Mild analgesics, such as (Advil), acetaminophen
(Tylenol), and aspirin (e.g., Bayer, Bufferin), work throughout the body at the source
of pain. Researchers think acetaminophen may work at the nerve endings, dulling
the sensation of pain. Ibuprofen and other non-steroidal anti-inflammatory agents
interfere with the production of pain-causing chemicals. Opiate analgesics, such as
codeine and morphine, work within the central nervous system (the brain and spinal
cord). Opiateswork not by relieving the underlying reason for pain, but by changing
the way the individual perceives pain. People who take opiates can become
addicted to them, so these drugs require a doctor's prescription.

Ibuprofen is a widely used non-steroidal anti-inflammatory drug

(NSAID). Inhibition of prostaglandin biosynthesis is considered to be the main
mechanism of action of this substance. Recently, a central analgesic activity was
described in an experimental study. In order to explore the possibility that ibuprofen
induces analgesia at central level in humans, we investigated, in a double-blind
design, the effects of orally-given 600 mg granular ibuprofen or placebo on
nociceptive flexion reflex in normal volunteers. Ibuprofen produced a significant
increase, as compared to placebo, in the threshold of the nociceptive reflex. The
ratio between subjective pain threshold (Tp) and reflex threshold (Tr) was
unchanged after either ibuprofen or placebo administration, indicating that
Tpstrictly paralleled Tr. These results indicate that ibuprofen
displays a central antalgic activity in humans. Different supraspinal structures are
probably involved, but the exact mechanisms are still to be clarified.

1.8.2.Antipyretic Action:
lowering of a raised temperature via decrease in a mediator
prostaglandin which is responsible for elevating the hypothalamic temperature
control.
Antipyretic drug often used to treat malarial fever in endemic areas
is the non-steroidal anti-inflammatory agent ibuprofen. In various studies, ibuprofen
has been shown to be more efficacious than acetaminophen (paracetamol) in
lowering febrile temperatures of infectious origin in children.
Fever represents the most apparent clinical manifestation of
Plasmodium falciparum malaria. The role of fever in defence against malaria or in
other infectious diseases remains a matter of debate. However, it has been shown
that febrile temperatures inhibit the growth of P. falciparum in vitro.
To control fever, the World Health Organization recommends
mechanical measures such as fanning, tepid spoging, and cooling blankets .
However, antipyretic drugs are commonly and widely used to treat malarial fever in
endemic areas, though there is a controversy about the benefit of reducing fever in
children with malaria . Data from Gabon have revealed that neither paracetamol,
nor naproxen or metamizol – antipyretics often used in this area – had an effect on
fever clearance time. Naproxen showed a weak effect in reducing fever peaks and in
reducing the time spent with fever. Worryingly, paracetamol increased parasite-
clearance times (i.e. inhibited clearance of parasites) and significantly decreased
the production of oxygen radicals and tumor necrosis factor, mechanisms of the
innate immune response pivotal to combat infections.
Another antipyretic drug often used to treat malarial fever in
endemic areas is the non-steroidal anti-inflammatory agent ibuprofen. In various
studies, ibuprofen has been shown to be more efficacious than acetaminophen
(paracetamol) in lowering febrile temperatures of infectious origin in children. But
the rationale of its use and its capacity of reducing fever due to P. falciparum
malaria has never been proven in a double blind, placebo controlled trial. In a
randomized, double-blind study in Thai adults, comparing a single dose of ibuprofen
with paracetamol for the treatment of fever due to uncomplicated falciparum
malaria, ibuprofen was significantly more effective than paracetamol in lowering
temperatures throughout the first 4.5 h after dosing, whereas in Malawian children
aged less than five years both drugs were equally effective in reducing fever.
In this double-blind randomized controlled trial, the effect of
ibuprofen on fever compared to placebo in children with uncomplicated P.
falciparum malaria in Gabon was investigated.

1.8.3.Anti-inflammatory effect:
There exists in medical practice at the close of the 20th century
two basic categories of anti-inflammatory drugs: steroidal (from steroid compounds)
and non-steroidal. Steroids are given their own section in this volume. They are
potent inhibitors of inflammation and the immune system, but also have a host of
serious, even deadly, side-effects. The non-steroidal agents are in general less
potent but also have fewer side-effects and will be the subject of this section.

Chemically there are at least eight classes of NSAIDs but only

those in common use are described here. Salicylic acid derivatives include aspirin;
Para-aminophenol derivatives are not used in 1999 except for acetaminophen
(Tylenol, etc.) which is like aspirin in its fever and pain reducing properties but has
no COX-2 enzyme anti- inflammatory effect (or COX-1 side-effects). For a time in the
early 1990s one Heteroaryl acetic acid, ketorolac (Toradol) was used primarily for
post-operative pain, however it has fallen into some disfavor due to the amount of
side-effects. In 1999 the Propionic acid derivatives such as ibuprofen (Motrin, Advil,
etc.), naproxen (Naprosyn, Alleve, etc.), and ketoprofen (Orudis, etc.) have become
the mainstays of NSAIDs used in the United States. Many are available without
prescription, and sometimes one may be much more effective, varying from patient
to patient.

1.9.Metabolism:
Ibuprofen is a non-steroidal anti-inflammatory agent belonging
to a group of propionic acid derivatives. It has three major types of effect which are
all linked to its primary action, the inhibition of an enzyme known as arachidonate
cyclooxygenase or COX of which there are two types COX-1 and COX-2.
The cyclooxygenase pathway:-
 Figure: cyclooxygenase pathway
Ibuprofen is metabolized primarily in the liver, where most of it
(60–90% of a therapeutic dose) is converted to inactive compounds by conjugation
with sulfate and glucuronide, and then excreted by the kidneys. Only a small portion
(5–10% of a therapeutic dose) is metabolized via the hepatic cytochrome P450
enzyme system (specifically CYP2E1 and CYP1A2); the toxic effects of ibuprofen are
due to a minor alkylating metabolite (N-acetyl-p-benzo-quinone imine, abbreviated
as NAPQI) that is produced through this enzyme, not ibuprofen itself or any of the
major metabolites. It must be understood however, that there is a great deal of
polymorphism in the P450 gene. Genetic polymorphisms in CYP2D6 have been
studied extensively. The population can be divided into "extensive metabolizes" and
"poor metabolizes" depending on their levels of CYP2D6 expression. Depending on
the drug effects this could be an area of interest for the patient. If the compound
produces a toxic metabolite when metabolized by the P450 system, being an
"extensive metabolize" could lead to adverse effects, whereas being a "poor
metabolize" of a compound whose clearance depends mainly of the P450 system
could as well produce adverse effects. NAPQI is a highly reactive compound that can
lead to formation of protein adducts oxidative stress, and toxicity. Ibuprofen
overdose results in more calls to poison control centers in the US than any other
pharmacological substance. In addition, 35% of cases involving liver failure are
caused by ibuprofen poisoning, according to the American Liver Foundation. The
metabolism of ibuprofen is an excellent example of toxication, because the
metabolite NAPQI is primarily responsible for toxicity rather than ibuprofen itself.

1.10.Dose of Ibuprofen:
Low doses of ibuprofen (200 mg, and sometimes 400 mg) are
available over the counter (OTC) in most countries. Ibuprofen has a dose-dependent
duration of action of approximately 4–8 hours, which is longer than suggested by its
short half-life. The recommended dose varies with body mass and indication.
Generally, the oral dose is 200–400 mg (5–10 mg/kg in children) every 4–6 hours,
adding up to a usual daily dose of 800–1200 mg. 1200 mg is considered the
maximum daily dose for over-the-counter use, though under medical direction, a
maximum daily dose of 3200 mg may sometimes be used in increments of 600–800
mg.
Ibuprofen is also available in topical form, which is absorbed
through the skin, and can be used for sports injuries, with less risk of
gastrointestinal problems.

1.11.Use of Ibuprofen:
• As with other NSAIDs, ibuprofen may be useful in the treatment of severe
orthostatic hypotension.[4]
• In some studies, ibuprofen showed superior results compared to placebo in
the prophylaxis of Alzheimer's disease, when given in low doses over a long
time.[5] Further studies are needed to confirm the results before ibuprofen can
be recommended for this indication.
Ibuprofen has been associated with a lower risk of Parkinson's disease, and may
delay or prevent Parkinson's disease. Aspirin, other NSAIDs, and paracetamol had
no effect on the risk for Parkinson's.[6] Further research is warranted before
recommending ibuprofen for this use.

1.12.Side Effect:
Upset stomach, nausea, vomiting, heartburn, headache,
diarrhea, constipation, drowsiness, and dizziness may occur. If any of these effects
persist or worsen, notify your doctor or pharmacist promptly. Tell your doctor
immediately if any of these serious side effects occur: stomach pain, swelling of the
hands or feet, sudden or unexplained weight gain, ringing in the ears (tinnitus). Tell
your doctor immediately if any of these unlikely but serious side effects occur:
vision changes, rapid or pounding heartbeat, easy bruising or bleeding. Tell your
doctor immediately if any of these highly unlikely but very serious side effects
occur: change in amount of urine, severe headache, very stiff neck, mental/mood
changes, persistent sore throat or fever. This drug may infrequently cause serious
(rarely fatal) bleeding from the stomach or intestines. If you notice any of the
following unlikely but very serious side effects, stop taking ibuprofen and consult
your doctor or pharmacist immediately: black stools, persistent stomach/abdominal
pain, vomit that looks like coffee grounds. This drug may rarely cause serious
(possibly fatal) liver disease. If you notice any of the following highly unlikely but
very serious side effects, stop taking ibuprofen and consult your doctor or
pharmacist immediately: yellowing eyes and skin, dark urine, unusual/extreme
tiredness. An allergic reaction to this drug is unlikely, but seek immediate medical
attention if it occurs. Symptoms of an allergic reaction include: rash, itching,
swelling, severe dizziness, trouble breathing. If you notice other effects not listed
above, contact your doctor or pharmacist.

1.13.Adverse effects:
Ibuprofen appears to have the lowest incidence of
gastrointestinal adverse drug reactions (ADRs) of all the non-selective NSAIDs.
However, this only holds true at lower doses of ibuprofen, so over-the-counter
preparations of ibuprofen are generally labeled to advise a maximum daily dose of
1,200 mg.
Common adverse effects include: nausea, dyspepsia,
gastrointestinal ulceration/bleeding, raised liver enzymes, diarrhea, epistaxis,
headache, dizziness, unexplained rash, salt and fluid retention, and hypertension.[11]
Infrequent adverse effects include: oesophageal ulceration,
heart failure, hyperkalaemia, renal impairment, confusion, bronchospasm, and
rash.[11]

1.14.Drug Interaction:
Before using this medication, tell your doctor or pharmacist
of all prescription and nonprescription products you may use, especially of: oral
bisphosphonates (e.g., alendronate), other medications for arthritis (e.g., aspirin,
methotrexate), "blood thinners" (e.g., warfarin), corticosteroids (e.g., prednisone),
cyclosporine, high blood pressure drugs (including ACE inhibitors such as captopril,
angiotensin II receptor antagonists such as losartan, and beta-blockers such as
metoprolol), lithium, "water pills" (diuretics such as furosemide, hydrochlorothiazide,
triamterene). Check all prescription and nonprescription medicine labels carefully
since many contain pain relievers/fever reducers (NSAIDs such as aspirin, celecoxib,
naproxen) which are similar to this drug and if taken together may increase your
risk for side effects. Low-dose aspirin, as prescribed by your doctor for specific
medical reasons such as heart attack or stroke prevention (usually these dosages
are 81-325 mg per day), should be continued. Consult your doctor or pharmacist for
more details. Do not start or stop any medicine without doctor or pharmacist
approval.

1.15.Over Dose:
If overdose is suspected, contact your local poison control
center or emergency room immediately. Symptoms of overdose may include:
severe stomach pain, coffee ground-like vomit, unusually fast or slow heartbeat,
trouble breathing, extreme drowsiness, loss of consciousness, or seizures.
Ibuprofen overdose has become common since it was licensed for
over-the-counter use. There are many overdose experiences reported in the medical
literature, although the frequency of life-threatening complications from ibuprofen
overdose is low.[19] Human response in cases of overdose ranges from absence of
symptoms to fatal outcome in spite of intensive care treatment. Most symptoms are
an excess of the pharmacological action of ibuprofen and include abdominal pain,
nausea, vomiting, drowsiness, dizziness, headache, tinnitus, and nystagmus. Rarely
more severe symptoms such as gastrointestinal bleeding, seizures, metabolic
acidosis, hyperkalaemia, hypotension, bradycardia, tachycardia, atrial fibrillation,
coma, hepatic dysfunction, acute renal failure, cyanosis, respiratory depression, and
cardiac arrest have been reported.[20] The severity of symptoms varies with the
ingested dose and the time elapsed, however, individual sensitivity also plays an
important role. Generally, the symptoms observed with an overdose of ibuprofen
are similar to the symptoms caused by overdoses of other NSAIDs.

1.16.Photosensitivity:
As with other NSAIDs, ibuprofen has been reported to be a
photosensitising agent.[12][13] However, this only rarely occurs with ibuprofen and it is
considered to be a very weak photosensitising agent when compared with other
members of the 2-arylpropionic acid class. This is because the ibuprofen molecule
contains only a single phenyl moiety and no bond conjugation, resulting in a very
weak chromophore system and a very weak absorption spectrum which does not
reach into the solar spectrum.

1.17.Cardiovascular risk:
Along with several other NSAIDs, ibuprofen has been
implicated in elevating the risk of myocardial infarction, particularly among those
chronically using high doses.[14]

1.18.Risks in pregnancy:
Two studies have found an increased risk of miscarriage with
the use of NSAIDs such as ibuprofen early in pregnancy; however, several other
studies did not find this association. There are also concerns that drugs such as
ibuprofen may interfere with implantation of the early fetus, although a clear risk
has not been established.
When ibuprofen is used as directed in the first and second
trimester of pregnancy, it is not associated with an increased risk for birth defects.
However, ibuprofen is generally not the pain reliever of choice during pregnancy
because there are concerns with the use of ibuprofen during the third trimester.

1.19.Risks in Inflammatory Bowel Disease (IBD):

Ibuprofen should not be used regularly in individuals with
Inflammatory Bowel Disease (IBD-Crohn's Disease and Ulcerative Colitis) due to its
ability to cause gastric bleeding and form ulceration in the gastric lining. Drugs such
as Advil should be avoided in persons afflicted with IBD. Pain relievers such as
Tylenol (containing acetaminophen) or drugs containing Codeine (which slows down
bowel activity) are safer methods than Ibuprofen for pain relief in IBD. Ibuprofen is
also known to cause worsening of IBD during times of a flare-up, thus should be
avoided completely.

1.20.Stereochemistry:
Ibuprofen, like other 2-arylpropionate derivatives (including
ketoprofen, flurbiprofen, naproxen, etc), contains a chiral carbon in the α-position of
the propionate moiety. As such, there are two possible enantiomers of ibuprofen,
with the potential for different biological effects and metabolism for each
enantiomer.
Indeed it was found that (S)-(+)-ibuprofen (dexibuprofen) was
the active form both in vitro and in vivo.It was logical, then, that there was the
potential for improving the selectivity and potency of ibuprofen formulations by
marketing ibuprofen as a single-enantiomer product (as occurs with naproxen,
another NSAID).

Further in vivo testing, however, revealed the existence of an

isomerase (2-arylpropionyl-CoA epimerase) which converted (R)-ibuprofen to the
active (S)-enantiomer.[15][16][17] Thus, due to the expense and futility that might be
involved in making a pure enantiomer, most ibuprofen formulations currently
marketed are racemic mixtures.

(R)-ibuprofen (S)-ibuprofen

Figture: Stereochemistry of Ibuprofen

1.21.Water Solubility:
Ibuprofen is only very slightly soluble in water, less than 1mg of
Ibuprofen dissolves in 1ml water (< 1 mg/mL).[18]
2.Method of study:
2.1.Dissolution:
 The time is takes for the drug to dissolve from the dosage form.
Numerous factors affect dissolution. Thus the dissolution medium, agitation,
temperature are carefully controlled. The dissolution medium may be water,
simulated gastric juice, or 0.1M HCL. The temperature is usually 37 degree C. The
apparatus and specifications may be found in the U.S.P. The U.S.P. methods are
official however there is a wide variety of methods based on other apparatus. These
are used because they may be faster, cheaper, easier, sensitive to a particular
problem for a particular drug, or developed by a particular investigator.
Dissolution tests are used as quality control to measure variability
between batches which maybe be reflected by in vivo performance. Thus the in
vitro test may be a quick method of ensuring in vivo performance. Thus there has
been considerable work aimed at defining the in vitro/in vivo correlation.

2.2 Drug Dissolution:

So far we have looked at the transfer of drugs in solution in the G-I
tract, through a membrane, into solution in the blood. However, many drugs are
given in solid dosage forms, and therefore must dissolve before absorption can take
place.

Figure: Dissolution and Absorption

If absorption is slow relative to dissolution then all we are
concerned with is absorption. However, if dissolution is the slow, rate-determining
step (the step controlling the overall rate) then factors affecting dissolution will
control the overall process. This is a more common problem with drugs which have
a low solubility (below 1 g/100 ml) or which are given at a high dose, e.g.
griseofulvin.

2.3. Single dose Review:

Oral (Extra vascular)
 Figure. A Diagram Illustrating a One-Compartment Model - Oral
This model can be defined using both differential and integrated equations.

Equation. Differential Equation describing a One Compartment Model - Oral

Equation. Integrated Equation describing a One Compartment Model - Oral

2.4.Dissolution of Tablets:
Dissolution can be defined as the process by which a drug particle
dissolves and it is important for solid dosage form for absorption.

The dissolution phenomenon of drugs can be described by the

“Noyes and witneys” equation. When the dissolution process is diffusion controlled
and involves no chemical reaction, the equation can be written as;
 dm/dt=DA/h (CS-C)

dm/dt= the rate of dissolution of drug particles.

D=the diffusion co efficient of the drug is solution in GI fluid.

A= thickness of the diffusion layer around tech particle.

Cs=the saturation of the drug in the diffusion layer.

C=the concentration of drug in solution of the GI fluid.

Cs-C=the concentration gradient.

2.5.Rate of Dissolution:
Dissolution is not always an instantaneous process. It is fast when salt
and sugar dissolve in water but much slower for a tablet of aspirin or a large crystal
of hydrated copper (II) sulfate. The speed at which a solid dissolves may depend on
its crystalline properties (crystalline vs. amorphous, crystal size) and the presence
of polymorphism. This is important in many practical systems, for example in
designing methods for controlled drug delivery. Critically, the dissolution rate
depends on the presence of mixing and other factors that determine the degree of
under saturation in the liquid solvent film immediately adjacent to the solid solute
crystal. In some cases, solubility equilibrium can take a long time to establish
(hours, days, months, or many years; depending on the nature of the solute and
other factors). In practice, it means that the amount of solute in a solution is not
always determined by its thermodynamic solubility, but may depend on kinetics of
dissolution (or precipitation).
The rate of dissolution and solubility should not be confused--they are different
concepts (kinetic and thermodynamic, respectively).

2.6.Measurement of Dissolution Rate:

Many methods have been described in the literature, particularly
in Relation to the determination of the rate of release of drugs into solution from
tablet and capsule formulations, because such release may have an important
effect on the therapeutic efficiency of these dosage forms.
The followings are the more commonly used methods:

1) Beaker method
2) Flask-stirrer method
3) Rotating basket method
4) Paddle method.

2.7. Importance of dissolution of drugs from tablet:

A drug must be dissolved first in the fluid at the absorption side
for absorption for instance an orally administered tablet or capsule form cannot be
absorbed until the fluids dissolve drug particles and some point within the GIT. For
this reason, dissolution is process that can affect the absorption of the drugs
particles as well as bioavailability and also pharmacological response of the drug.
In, in vitro testing procedures, dissolution is the only test that can more or less
indirectly correlate the in vivo bioavailability. Other than bioavailability two objects
can be fulfilled through dissolution testing which are;

1) That the release of the drug from the tablet is as close as possible to100%
and

2) That the rate of drug release is uniform from batch proven to be bioavilable
and clinically effective.
In case of enteric-coated tablet, the dissolution process gets special importance.
Because in such case, the drug cannot be dissolved in gastric and pH have to be
dissolved within specified time in intestinal fluid.

2.8. Factors affecting dissolution:

Physiochemical properties of drugs; Dissolution of tablets is
greatly influenced by size, shape and surface area of the drug particles. Noyes and
Whiteyes equation shows that the rate of dissolution is directly related to the
surface area i.e. if the surface is increased, the dissolution rate would also be
increased.

The solid phase characteristics of drugs, such as amorphicity,

crystallininty, state of hydration and polymorphic structure have been shown to
have a significant influence of the dissolution rate. For example, the amorphous
form of novobiocin has a greater solubility and higher dissolution rate than the
crystalline form.

2.8.1. Formulation factors:

Various excipients such as diluents, binders, lubricants,
disintegrate and granulating agent is used with the formulation to satisfy certain
pharmaceutical function. Usually drug dissolution rate is increased when hydrophilic
excipients are used.

2.8.2 Effects of processing factors:

many processing factors used in tablet manufacturing such as
method of granulation and compression force etc. have great influence on the
dissolution rates of the active ingredients.

2.8.3 Effects of dissolution medium:

increased temperature and agitation rage of dissolution medium
also increase the rate of dissolution. Other characteristics of dissolution medium
affecting the dissolution rate include pH, viscosity and surface tension of the
medium.

2.9 Preparation of Standard Solution:

Preparation of stock Solution:

0.033 gm active ibuprofen

Dissolve

1000 ml water

Stock solution

Concentration of the stock solution=330μg/ml

Table 2.9: Preparation of standard curve of Ibuprofen.

 Concentration Absorbance
(µg/mL)
0 0
1 0.0458
2 0.0917

4 0.1791

6 0.2738

8 0.3661

10 0.458

12 0.5401

14 0.64512
16 0.7321

Standard Curve of Ibuprofen

0.8
y = 0.0458x - 0.0009
0.7 2
R = 0.9998
0.6
0.5
Absorbance

0.4
Abs
0.3
Linear (Abs)
0.2
0.1
0
-0.1 0 5 10 15 20
Concentration

Figure: Standard Curve of Ibuprofen

2.10 In-vitro studies:

Drug dissolution studies may under certain conditions give an
indication of drug bioavailability. Ideally, the in-vitro drug dissolution rate should
correlate with in-vivo drug bioavailability. Dissolution studies are often performed on
several test formulations of the same drug. The test formulation that demonstrates
the most rapid rate of drug dissolution in vitro will generally have the most rapid
rate of drug bioavailability in vivo.

2.11 In-vitro dissolution testing:

Dissolution tests in vitro measure the rate and extent of dissolution of
the drug in an aqueous medium in the presence of one or more excipients
contained in the drug product.

During drug dissolution the following factors must be considered-

1. Temperature (370c usually)

2. Size and shape of the dissolution vessel
3. Nature of stirrer (paddle, basket/others)
4. Agitation
5. Nature of dissolution medium (volume and composition)
6. The design of dissolution apparatus
7. Duration/ the time interval after which the sample are withdrawn

2.12 Dissolution Study:

2.12.1 Dissolution Setup:
The USP basket system contains six cylinder vessels with the spherical
bottom, which contain dissolution medium. There are six paddles for agitating which
rotate at a predetermined rpm. A temperature of 37°C was used for dissolution
study. Here water was used for all dissolution study.10 ml of dissolution fluid was
withdrawn at a predetermined time interval and water was added after the
dissolution fluid withdrawn. The total duration of dissolution study was 60 mins.

2.12.2 Dissolution Test Procedure:

At first the water bath was filled with tap water. Then six washed vessels
were in the dissolution tester. The vessel remained immersed in water.900ml of
water was kept at each glass vessels. The temperature of water bath is set at 37
degree C and paddle rotation was set at 50 rpm. Time was recorded as soon as the
tablet were into the dissolution vessels.10 ml of sample solution from dissolution
medium was withdrawn time to time, for 60 mins, the time interval was 30,45 and
60 minutes.

2.13 Disintegration:
For immediate release, solid dosage forms, the drug product must
disintegrate into small particles and release the drug. To monitor uniform tablet
disintegration, the united state pharmacopoeia (USP) has established an official
disintegration test. Solid drug products exempted from disintegration tests include
troches, tablets that are intended to be chewed and drug products intended for
sustained released or prolonged or repeat action.

The process of disintegration does not imply complete dissolution of the tablet
and/or the drug. Complete disintegration is define by the USP as “that state in which
any residue of the tablet, expect fragments of insoluble coating, remaining on the
screen of the tablet, except fragments of insoluble coating, remaining on the screen
of the test apparatus in the soft mass have no palpably firm core”. The official
apparatus for the disintegration test and procedure is described in the USP separate
specifications are given for drug products that are designed not to disintegrate.
These products include troches, chewable tablets, and modified released drug
products.

Although disintegration test allow for precise measurement of the formation of

fragments, granules, or aggregates from solid dosage forms, no information as
obtained from these tests on the rate of dissolution of the active drug. However,
there has been some interest in using only the disintegration test and no dissolution
test for drug products that meet the biopharmaceutical classification system (BCS)
for highly soluble and highly permeable drugs. In general, the disintegration test
serves as a component in the overall quality control of tablet manufacture.

According to BP-2004:
Apparatus-A (for smaller tablet/capsule (18 mm long)

Apparatus-B (for longer)

Composition: a rigid Basket-rack assembly supporting-

 1. 6 cylindrical transparent tubes (vertical) II
2. 6 cylindrical transparent plastic disc ( one for each tube)
3. 1000 ml beaker
4. A suitable device maintain temperature 37±20C

According to USP:
Composition:
1. Basket rack assembly
2. 1000 ml beaker
3. Temperature 37±20 c
4. RPM: 29-32 cycles/min
5. Time: time required for upward stroke≈ downward strok
6. 6 tubes and disc

Uncoated tablets (USP)

No. of tablets: 6 tablets/6 tubes

Media: water, temp: 37±20C rpm: 29-32

Time: specific monograph

2.13.1. Result:
After specific time, all tablets have disintegrated completely. If 1-2 tabs fail
to disintegrated, repeat the test on 12 additional tabs. Not less than 16 of the total
18 tablets tested disintegrated completely.

This test also for-

1. Coated tablets
2. Buccal tablets
3. Sublingual tablets
4. Hard gelatin capsules
5. .Soft gelatin capsule
2.14. Evaluation of Tablets:
Evaluation or stability test of tablets or suspension is one of the key
factors for determining the quality of drug substance or drug product. Evaluation of
tablets provides evidence on how the quality of a drug substance or drug product
will maintain within specific time under the influence of a variety of environmental
factors such as temperature, humidity etc and measures and documents the ability
of a product to retain its potency prior to its predicted expectation. These data are
used to determine acceptable shelf life, proper storage conditions. These data also
play a key role in determining labeling instruction as well as determining the
monitoring process. These are also a requirement for manufacturing of regulatory
approved drug.

2.14.1. Diameter Size and Shape:

The size and shape of the tablet can be dimensionally described,
monitored and controlled. A compressed tablets shape and dimensions are
determined by the tooling during the compression process. The diameter size and
shape of the tablets depends n the die and punch selected for making the tablets.
The tablets of various sizes and shapes are prepared but generally they are circular
with either flat or biconvex faces.

2.14.2. Uniformity of Weight:

With a tablet designed to contain a specific amount of drug in a
specific amount of tablet formula, the weight of the tablet being made is routinely
measured to help ensure that a tablet contains the proper amount of drug. It is
desirable that all the tablets of a particular batch should be uniform in weight. If any
weight variation is there, that should fall within the prescribed limits.

Table 4.2: Weight variation Tolerance for uncoated tablets.

Average Weight of Maximum Percentage

Tablets (mg) Difference
Allowed
130 or less 10
 130-324 7.5
More than 324 5

Ref: USP XX---NF XV, 1980

The weight variation test would be a satisfactory method of determining the drug
content uniformity of tablets if the tablets were all or essentially all active ingredient
or if the uniformity of the drug distribution in the granulation or powder from which
the tablets were made perfect. The test is considered correct if not more than two
tablets fall outside the range if tablets are taken for the test and not more than one
tablet falls outside this range if only ten tablets are taken for the test. The
difference of weight variation in tablets can lead to variation in doses. Therefore all
the tablets of a batch must conform to this test. The test is repeated after short
intervals of time to ensure that tablets of required weight are produced.

2.14.3. Calculation of Weight Variation:

To calculate the weight variation of tablets in a batch, it is required to determined
the following data,

• Weight of taken tablets of in that batch (W)

• Average weight of tablets in that batch (W1)
• Highest weight of tablet in that batch (WH)
• Lowest weight of tablet in that batch (WL)

So, % of error for highest weight ofWtablet

1
= ×100

W1—WL

And, % of error for highest weight of tablet = ×100

2.14.4. Thickness:
The thickness of a tablet can vary without any change in weights. This is
generally due to the difference of density of granules, pressure applied for
compression and the speed of compression. The thickeness should be controlled
within ±5 of standard value. In addition, thickness must be controlled to facilitate
packaging. The PTB 311E (511E) Table Testing Instrument is used to determine the
thickness of the individual tablets of each batch.

2.14.5. Hardness:
Tablet requires a certain amount of strength or hardness to withstand
mechanical shocks of handling in manufacture, packaging and shipping. In addition,
tablet should be able to withstand reasonable abuse when in the hands of
consumer. Adequate tablet hardness and resistance to powdering are requisite for
customer acceptance. More recently, the relationship of hardness of tablet
disintegration and perhaps more significantly, to drug dissolution release rate, has
become apparent. The monitoring of tablet hardness is especially important for drug
products that posse’s real or potential bioavailability problems or those are sensitive
to altered dissolution release profiles as a function of the compressive force.
Therefore, It is very necessary to check the hardness of tablets when they are being
compressed and pressure adjusted accordingly on the tablet machine.

There are no specification of hardness of the tablet described on BP or USP. The PTB
311E (511E) Table Testing Instrument is used to determine the hardness of the
individual tablets of each batch.

Range: Not given

Reference: A344 Appendix XVIIG, BP 2003, Vol 4

2.14.6. Friability:
Friability test is performed to valuate the ability of the tablets to
withstand abrasion in packing, handling and transporting .The instrument used for
this test is known as Friabilator.

2.14.6.1 Specification:
• Rotation: 100 times
• Number of Tablets: 20 tablets
• Range: Should be less than < 1 %
• Reference: BP 2003, Volume 4
2.14.7. Disintegration time:
The disintegration test is performed to find out that within how much
time the tablet disintegrates. The test is very important and necessary for all the
tablets, coated or uncoated to be swallowed because the dissolution rate depends
upon the time of disintegration which ultimately affects the rate of absorption of
drugs.
Specification:
• For Uncoated Tablet: 15 Min
• For Coated Tab: 60 Min or 1 Hour.

2.15.Materials:
2.15.1 Apparatus:
Apparatus is the equipment designed to serve a specific function. Apparatus

Used here are:

1. Volumetric Flasks (100 ml)

2. Funnel
3. Beaker
4. Pipette
5. Filter Paper

2.15.2 Funnel:
Funnel is a laboratory apparatus which is used in dispensing a liquid in
a controlled and substantially way to prevent the loss of the sample or substance.
Here, filtration process is facilitate.

2.15.3 Beaker:
A beaker is a simple container for stirring, mixing and heating liquids,
they are commonly used in any laboratory. Beakers are generally cylindrical in
shape, with a flat bottom. Beakers are available in a wide range of sizes, from 1 mL
up to several liters. Beakers are often graduated, marked on the side with lines
indicating the volume contained. For instance, a 250 mL beaker might be marked
with lines to indicate 50, 100, 150, 200, and 250 mL of volume. The accuracy of
these marks can vary from one beaker to another. They may be made of glass or of
plastic.
They may be made of glass (very often Pyrex) or of plastic. Beakers used for holding
solutions of corrosive chemicals, such as acids, should be made of Teflon or other
materials resistant to corrosion, e.g., borosilicate glass.

2.15.4 Pipette:
Pipette is a laboratory instrument used to transport a measured
volume of liquid. Pipettes come in several designs for various purposes with
differing levels of accuracy and precision, from single piece glass pipettes to more
complex adjustable or electronic d by the laboratory funnel

Pipettes. A pipette works by creating a vacuum above the liquid-

holding chamber and selectively releasing this vacuum to draw up and dispense
liquid. Various types of pipettes are available in the market. Volumetric pipettes
were used in this case, as it is a quantitative analysis. Pipette fillers are used to fill
the pipette easily, avoiding the need for mouth pipetting. Certain considerations
should be observed to ensure maximum accuracy and repeatability such as
calibration, heat, dispensing angle, operator’s skill etc.

2.15.5 Filter Paper:

Filter paper is a semi-permeable paper barrier placed perpendicular
to a liquid flow and is used to separate fine solids from liquids. In laboratories, filter
paper is usually used with a filter funnel. Choice of filter paper for a given task
depends on four parameters: strength, compatibility, efficiency and capacity. The
main purpose of the filter paper in this quantitative analysis is to remove the
excipients of the paracetamol and other unwanted particles from the mother
solution.

2.16. Instrumentation:
Sophisticated instruments that are used here:
1. Electrobalance
2. The PTB 311(511E) Tablet Testing Instrument
3. Friabilator (Roche)
4. The PTZ Tablet Disintegration Time Testing Instrument.
 5. UV-VIS spectrophotometer (DRU-400)
6. The PT-DT (70) Dissolution tester.
7. Tablet compression.

2.16.1 Electro balance:

An electro balance is also a microbalance in that it is used to weigh
microquantities of material. In principle, it is similar to the balance described above
except that the balance beam is lined up controlling current through a coil with a
potentiometer. Since the beam is always returned to the same position, torque is
proportional to current. In this quantitative analysis following instruments were used
for accurate weighing.

Figure: electro balance

Accurate weighing is one of the most important factors in any

quantitative analysis because the results are totally dependent on it. Any variation
during weighing will not give accurate results. Weighing can be done by several
methods. Here, direct weighing method has been applied.

The electro balance provide with the most accurate results. However, errors
do occur when weighing an object on an analytical balance such as:

2.16.2 The Table Testing Instrument:

 The PTB 311E (511E) Table Testing Instrument is a sophisticated
instrument to test the individual thickness, diameter and hardness of solid samples
like tablets, capsules etc.

Figure: The PTB 311(511E) Tablet Testing Instrument.

The measurement for thickness and diameter can either be expressed in

mm (millimeters) or in (inch), hardness results can b expressed in either N
(Newton), Sc (strong Cobb) or Kp (kilopond).
In order to calibrate the individual testing stations of the instrument calibrated
standard s are used. A 10 kg reference weigh handle is required to calibrate the
hardness test station. Which is equipped with a electronically operated load cell
(stain gauge), a 10mm reference block is used to calibrate both thickness and
diameter testing stain.
The hardness test is performed in compliance to the European Pharmacopoeia (EP)
and the German Pharmacopoeia (DAB). The force rate can be adjusted to either
linear force increase (N/sec) or linear speed increase (mm/min) with variable range
adjustments. It is recommended to use the linear force increase setting (20N/sec) as
this can be easily be validated using just a stop watch. Also setting copies more
close the breaking of the sample when manually done.

Diameter (length): min.2.0 mm max: 50.0mm

Thickness (length): min 3.0 mm max: 26.0mm
Hardness: 300N DMS min. 5.0 N max: 300N
500N DMS min. 10N max: 500N
2.16.3 Friabilator:
The laboratory friabilator tester is also known as Roche Tester. This Device
subjects a number of tablets to the combined effects of abrasion and shock by
utilizing a number of tablets to the combined effects of abrasion and shock by
utilization in plastic chambers that revolves at 25 rpm, dropping the tablets a
distance of 6 inches with each revolution.

Figure: Friabilator

Normally, a preweighted tablets sample is placed in the friabilator, which is then

operated for 100 revolutions. The tablets are dusted and reweighed again.
Conventional compressed tablets that loss than 0.5 to 1.0 % of their weight
generally considered acceptable.

2.16.4 The Tablet Disintegration Time Testing Instrument:

Several international pharmacopeias ep/dab/bp describe a tablet
disintegration time testing instrument.

6 samples are placed into a testing basket assembly, which is introduced

into a special holder and placed into a water bath. The water inside the water bath
is heated to 30-45°C.the disintegration baskets is moved smoothly up and down for
28-32 stokes per minute and for a distance of 55mm.The samples are disintegrated
if no solid rest is left within the basket.
 Figure: Tablet disintegrationApparatus.

The PTZ allows the test of 6 tablets/capsules at the same time within
absolutely identical conditions., as all samples are introduced into the same bath,
the moving arm is driven by a micro processor controlled electronics to allow exact
30 strokes/minute oeration with automated re-adjustment at each stroke, while the
moving distance is pre-adjusted by means of an eccentric drive arm. A suitable
thermostat is used to program the testing temperature usually 36 to 38.0 C. A
digital timer can be programmed for the total testing time within a range of 10
seconds to 9 hours, 59 minutes and 59 seconds.

2.16.5 Spectrophotometry:
Spectrophotometry is the quantitative study of electromagnetic spectra. It
is more specific than the general term electromagnetic spectroscopy in that
spectrophotometry (DRU-400) deals with visible light, near ultraviolet, and near
infrared. Spectrophotometry involves the use of a spectrophotometer. A
spectrophotometer is a photometer (a device for measuring light intensity) that can
measure intensity as a function of the color, or more specifically, the wavelength of
light.

Here are two major classes of spectrophotometers; single beam and double
beam. A double beam spectrophotometer measures the ratio of the light intensity
on two different light paths, and a single beam spectrophotometer measures the
absolute light intensity. Although ratio measurements are easier, and generally
stabler, single beam instruments have advantages; for instance, they can have a
larger dynamic range, and they can be more compact.

Figure: Spectrophotometer

Spectrophotometers use a monochromator to analyze the spectrum. The

spectrophotometer measures quantitatively the fraction of light that passes through
a given solution. In a spectrophotometer, a light from the lamp is guided through a
monochromator, which picks light of one particular wavelength out of the
continuous spectrum. This light passes through the sample that is being measured.
After the sample, the intensity of the remaining light is measured with a photodiode
or other light sensor, and the transmittance for this wavelength is then calculated.

In short, the sequence of events in a spectrophotometer is as follows:

• The light source shines through the sample.
• The sample absorbs light.
• The detector detects how much light the sample has absorbed.
• The detector then converts how much light the sample absorbed into
a number.
 • The numbers are either plotted straight away, or are transmitted to a
computer to be further manipulated (e.g. curve smoothing, baseline
correction)

2.16.5.1. Function of Different parts of Spectrophotometer

• Hollow cathode lamp:
*Provide the analytical light line for the element of interest
*Provide a constant yet intense beam of that analytical line

• Nebulizer:
*Acquire liquid sample at a controlled rate
*Create a fine aerosol for introduction into the flame
*Mix the aerosol and fuel and oxidant thoroughly for introduction
into the flame

• Flame:
*Destroy any analyte ions and breakdown complexes
*Create atoms (the elemental form) of the element of interest Fe0,
Cu0, Zn0, etc.

• Monochromator:
*Isolate analytical lines' photons passing through the flame
*Remove scattered light of other wavelengths from the flame .In
doing this, only a narrow spectral line impinges on the PMT.

• Photomultiplier Tube (PMT):

As the detector the PMT determines the intensity of photons of the analytical line
exiting the monochromator.

2.16.6.The PT-DT (70) Dissolution tester:

The USP basket system contains six cylinder vessels with the spherical
bottom, which contain dissolution medium. 900ml of water was contain at each
glass vessels. There are six paddles for agitating which rotate at a predetermined
rpm. A temperature of 37°C was used for dissolution study.

Figure: The PT-DT (70) Dissolution tester

Here water was used for all dissolution study.10 ml of dissolution fluid was
withdrawn at a predetermined time interval and water was added after the
dissolution fluid withdrawn. The total duration of dissolution study was 60 mins.

2.18 Reagents:
A reagent is a substance consumed during a chemical reaction. Although
they are involved in the reaction, are usually not referred to as reactants. Reagent is
often used in a more specialized sense as "a test substance that is added to a
system in order to bring about a reaction or to see whether a reaction occurs"

In another use of the term, when purchasing or preparing chemicals,

"reagent-grade" describes chemical substances of sufficient purity for use in
chemical analysis, chemical reactions or physical testing. Purity standards for
reagents are set by organizations such as ASTM International.

Reagents that are used in this assay:

-Water.
-Ibuprofen tablet
3.1. Results of Physical Tests of Tablets:
Table: 3.1.General Appearance:

Brand Shape Coating Color

Code
A Round and Flat Yes white
Shape
B-1 Round and Flat Yes Pink
Shape
B-2 Round and Flat Yes Pink
Shape
B-3 Round and Flat Yes Pink
Shape
B-5 Round and Flat Yes Pink
Shape
 B-5 Round and Flat Yes Pink
Shape

3.2 Diameter Size and Shape:

Diameter of the tablets was measured by using “THE PTB 311
(511E)” Tablet testing instrument. Twenty tablets were taken from each batch to
carry out the test. The average value and standard deviation were then calculated
and was expressed in millimeter (mm) the results of the diameter size test for all
the samples are summarized in Table
TABLE 3.2: DIAMETER VALUES OF DIFFERENT BATCHES UNDER
INVESTIGATION

BRAND CODE *DIAMETER ± STANDARD

DEVIATION
A 9.95±0.01269
B-1 9.25±0.00489
B-2 10.01±0.008
B-3 12.74±0.02
B-4 9.60±0.01414
B-5 10.37±0.004899

*Each value is the average of ten tablets ± standard

deviation

3.3 Uniformity of Weight:

The Results for weight variation for all the samples are summarized below in Table

TABLE 3.2: UNIFORMITY OF WEIGHT OF DIFFERENT BATCHES UNDER

INVESTIGATION

Bran Average Weight of Range of Weight Remar

d Tablet Of each Variation Of Each ks

Code batch (gm) Batch

A 608 -1.9 % to +2.9% Passed

B-1 614 -4.4 % to +2.2 % Passed

B-2 647.5 -3.5 % to +2.7 % Passed
 B-3 643 -4.1 % to +5.1 % Passed

B-4 603 -2.8 % to +3.8 % Passed

B-5 597 -3.8 % to +2.8 % Passed

3.4 Thickness Test:

The average value and standard deviation were calculated and was
expressed in millimeter (mm). The Results for thickness for all the samples are
summarized below:

TABLE 3.3: THICKNESS VALUES OF DIFFERENT BATCHES UNDER

INVESTIGATION

BRAND *THICKNESS± STANDARD

CODE DEVIATION

A 3.26±0.013
B-1 3.57±0.020
B-2 3.37±0.026
B-3 4.39±0.045
B-4 3.41±0.007
B-5 2.91±0.011

*Each value is the average of ten tablets ± standard dev

3.5 HARDNESS TEST:

The average value and standard deviation were calculated and was
expressed in kilopond (kp). The Results for thickness for all the samples are
summarized below:

TABLE 3.4: HARDNESS VALUES OF DIFFERENT BATCHES UNDER

INVESTIGATIO

BRAND *HARDNESS± STANDARD

CODE DEVIATION

A 97.4±4.193
B-1 83.2±3.493
B-2 116.4±8.645
 B-3 90.4±2.148
B-4 70.5±0.492
B-5 55.2±4.258

3.6 Friability Test:

The Results for friability test for all the samples are summarized below:
TABLE 3.5: RESULTS OF FRIABILTY TEST OF DIFFERENT BATCHES UNDER
INVESTIGATION

B PERCENATGE OF REMARKS
RAN FRIABILITY OF EACH
D BRAND

A 0.1 % Passed
B-1 0.4 % Passed
B-2 0.4 % Passed
B-3 0.6 % Passed
B-4 0.3 % Passed
B-5 0.3 % Passed

3.7 Disintegration Test:

3.7.1 Disintegrates:
Disintegrates are required to break up capsules, tablets and granules
into primary powder particles in order to increase the surface area of the drug
exposed to the gastrointestinal fluids. A tablet that fails to disintegrate or
disintegrates slowly may result in incomplete absorption or a delay in the onset of
action of the drug. The compaction force used in tablet manufacture can affect
disintegration: in general, the higher the force the slower the disintegration time.
Even small changes in formulation may result in significant effects on dissolution
and bioavailability

The disintegration time of each sample from each brand was expressed in
minutes (min). The Results for disintegration test for all the samples are
summarized below:
 TABLE 3.6: RESUTLS OF DISINTEGRATION TEST DIFFERENT BATCHES
UNDER INVESTIGATION

B DISINTEGRATION TEST REMARKS

RAN (MIN.)
D
A 1 Min. and 40 sec. Passed
B-1 0 Min. and 41 sec. Passed
B-2 3 Min. and 14 sec. Passed
B-3 8 Min. and 08 sec. Passed
B-4 1 Min. and 10 sec. Passed
B-5 4 Min. and 10 sec. Passed

3.8 Dissolution Profile:

Table 3.8.1. Sample A:

in 900
Time(min) absorbance Conc.(µg/mL) conc. in 10 mL mL %release

30 0.474 413.07189 0.413072 4.130718954 371.7647 74.35294

45 0.557 485.40305 0.485403 4.854030501 436.8627 87.37255

60 0.581 506.31808 0.506318 5.063180828 455.6862 91.13725

Table 3.8.2. Dissolution profile of sample A.

Time(min) % release
0 0
30 74.35
45 87.37
 60 91.14

Graphical representation of time vs. % release of: A

Sample A

100

80
%release

60
%release
40

20

0
0 20 40 60 80
Time

Figure: Time Versus % release of Sample A

The above chart and figure gives the idea about the sequential release of the drug
at those withdrawal times. The release of Ibuprofen at 60 minutes maintains the
specification according to British Pharmacopoeia.

Table3.9.1. Sample B-1:

Time absorban Conc.(µ in 10 in 900
(min) ce g/mL) Conc. mL mL %release

30 0.47 409.586 0.409586 4.09586 368.6274 73.72549

45 0.486 423.529 0.423529 4.23529 381.1764 76.23529

60 0.499 434.858 0.434858 4.34858 391.3725 78.27451

Table3.9.2. Dissolution profile of Sample B-1

Time(min) %release
0 0
30 73.73
45 76.26
60 78.27
Graphical representation of time vs. % release of: B-1

Sample B-1

90
80
70
60
%release

50
%release
40
30
20
10
0
0 20 40 60 80
time

Figure: Time Versus % release of Sample B-1

The above chart and figure gives the idea about the sequential release of the drug
at those withdrawal times. The release of Ibuprofen at 60 minutes maintains the
specification according to British Pharmacopoeia.

Table 3.10.1. Sample B-2:

in 900 %releas
Time(min) absorbance Conc.(µg/mL) conc. in 10 mL mL e

30 0.466 406.1002 0.4061 4.061002 365.4901 73.0980

45 0.485 422.6579 0.4226 4.226579 380.3921 76.0784

60 0.511 445.3159 0.445 4.453159 400.7843 80.1568

Table 3.10.2. Dissolution profile of Sample B-2

Time(min) %release
0 0
30 73.09
 45 76.07
60 80.16

Graphical representation of time vs. % release of: B-2

Sample B-2

90
80
70
60
%release

50
%release
40
30
20
10
0
0 20 40 60 80
time

Figure: Time Versus % release of Sample B-2.

The above chart and figure gives the idea about the sequential release of the drug
at those withdrawal times. The release of Ibuprofen at 60 minutes maintains the
specification according to British Pharmacopoeia.

Table:3.11.1. Sample B-3:

Time Conc.(µg/
(min) absorbance mL) conc. in 10 mL in 900 mL %release

30 0.503 438.3442 0.43834 4.38344 394.509 78.901

45 0.528 460.130 0.4601 4.6013 414.117 82.823

60 0.549 478.4313 0.4784 4.7843 430.588 86.117

Table:3.11.2. Dissolution profile of Sample B-3.

Time(min) %release
0 0
 30 78.9
45 82.82
60 86.12

Graphical representation of time vs. % release of: B-3

Sample B-3

100

80
%release

60
%release
40

20

0
0 20 40 60 80
Time

Figure: Time Versus % release of Sample B-3.

The above chart and figure gives the idea about the sequential release of the drug
at those withdrawal times. The release of Ibuprofen at 60 minutes maintains the
specification according to British Pharmacopoeia.

Table: 3.12.1. Sample B-4

Time(min absorbanc Conc.(µg/m in 10 in 900 %releas
) e L) conc. mL mL e
0.422 4.22657 380.39
30 0.485 422.6579 6 9 2 76.078
0.438 394.50
45 0.503 438.3442 3 4.38344 9 78.901
5.13289 461.96
60 0.589 513.2897 0.513 7 0 92.392

Table: 3.12.2. Dissolution profile of Sample B-4.

Time(min) %release
0 0
30 76.07
 45 78.9
60 92.39

Graphical representation of time vs. % release of: B-4

Sample B-4

100

80
%release

60
%release
40

20

0
0 20 40 60 80
time

Figure: Time Versus % release of Sample B-4.

The above chart and figure gives the idea about the sequential release of the drug
at those withdrawal times. The release of Ibuprofen at 60 minutes maintains the
specification according to British Pharmacopoeia.

Table: 3.13.1. Sample B-5:

in 900
Time(min) absorbance Conc.(µg/m) Conc. in 10 mL mL %release
30 0.474 413.07189 0.41307 4.130718 371.764 74.352
45 0.557 485.40305 0.48540 4.854030 436.862 87.372
60 0.581 506.31808 0.50631 5.063180 455.68 91.137

Table:3.13.2. Dissolution profile of Sample B-5.

Time(min) %release
0 0
30 74.35
45 87.37
 60 91.14

Graphical representation of time vs. % release of: B-5

Sample B-5

100

80
%release

60
%release
40

20

0
0 20 40 60 80
time

Figure: Time Versus % release of Brand B-5.

The above chart and figure gives the idea about the sequential release of the drug
at those withdrawal times. The release of Ibuprofen at 60 minutes maintains the
specification according to British Pharmacopoeia.

Table: 3.14: Comparison of time (minutes) for releasing of drug from

various Sample.

B- B- B-
A %of B -1% B-2%of 3%of 4%of 5%of
releas of releas releas releas releas
Time(min) e release e e e e

0 0 0 0 0 0 0

30 74.35 73.73 73.09 78.90 76.07 74.35

45 87.37 76.26 76.07 82.82 78.90 87.37

60 91.14 78.27 80.16 86.12 92.39 91.14

Graphical Comparison representation of time vs. % release of: A, B-1, B-2,
B-3, B-4, B-5.

COM PERATATIVE POLOT

100
90
80 A%of release
70 B-1% of release
%release

60
B-2 %of release
50
B-3% of release
40
30 B-4% of release
20 B-5% of release
10
0
0 20 40 60 80
Time

Figure: Time Versus % release of A, B-1, B-2, B-3, B-4, B-5.

From the above table and the graphical representation it can be concluded that
the release profile of almost all the samples were complied with the specification.
No major difference between their release properties.

3.15.Assay Of The Tablets:

Assay of Ibuprofen in Tablets:
1. 5 tablets were weighted and average weight of 1 tablet was calculated.
2. The tablets were powdered in a mortar and taken a quantity of powder
equivalent to 0.26 gm of Ibuprofen in 25 ml ethanol and filter the solution.
3. The filter was titrated with 0.1N NaOH using Phenolphthalein as indicator
until Red color is obtained.

Titration Table for: A

Observati Ibuprofe Initial Final Volume Average Amount
on n Burette Burette Require Volume of
d NaOH of Ibuprofe
No Solution Reading Reading
(ml) n in the
 (ml) (ml) (ml) NaOH sample
(ml)
01 25 0 10.5 10.5

02 25 10.5 20.8 10.3

10.27 91.85%
03 25 20.8 30.8 10

The amount of Ibuprofen in the sample was 91.85%

Titration Table for: B -1

Observati Ibuprofe Initial Final Volume Average Amount
on n Burette Burette Require Volume of
d NaOH of Ibuprofe
No Solution Reading Reading
(ml) n in the
(ml) (ml) (ml) NaOH
sample
(ml)
01 25 0 9.6 9.6

02 25 9.6 19.4 9.8

03 25 19.4 29.2 9.8 9.73 87%

The amount of Ibuprofen in the sample was 87%

Titration Table for: B -2

Observati Ibuprofe Initial Final Volume Average Amount
on n Burette Burette Require Volume of
d NaOH of Ibuprofe
No Solution Reading Reading
(ml) n in the
(ml) (ml) (ml) NaOH
sample
(ml)
01 25 0 9.9 9.9

02 25 9.9 20 10.1

03 25 20 30.2 10.2 10.07 90.05%

The amount of Ibuprofen in the sample was 90.05%

Titration Table for: B -3

Observati Ibuprofe Initial Final Volume Average Amount
on n Burette Burette Require Volume of
d NaOH of Ibuprofe
No Solution Reading Reading
(ml) n in the
(ml) (ml) (ml) NaOH
sample
(ml)
01 25 0 10.8 10.8

02 25 10.8 20.9 10.1

03 25 20.9 30.5 9.6 10.17 91.00%

The amount of Ibuprofen in the sample was 91%

Titration Table for: B -4

Observati Ibuprofe Initial Final Volume Average Amount
on n Burette Burette Require Volume of
d NaOH of Ibuprofe
No Solution Reading Reading
(ml) n in the
(ml) (ml) (ml) NaOH
sample
(ml)
01 25 0 11.10 11.10

02 25 11.10 21.02 9.92

03 25 21.82 31.08 10.06 10.36 92.65%

The amount of Ibuprofen in the sample was 92.65%

Titration Table for: B -5

Observati Ibuprofe Initial Final Volume Average Amount
on n Burette Burette Require Volume of
d NaOH of Ibuprofe
No Solution Reading Reading
(ml) n in the
(ml) (ml) (ml) NaOH
sample
(ml)
01 25 0 10.5 10.5
 02 25 10.5 20.8 10.3 10.27 91.85%

03 25 20.8 30.8 10

The amount of Ibuprofen in the sample was 91.85%

3.15. RESULT & DISCUSSION:

Ibuprofen tablet of five different brand names from s different National
companies were taken with a product of multinational company.

Then studied the release pattern of drug in dissolution apparatus with in distilled
water as dissolution media at a temperature of 37o±5oc at 50 RPM. For 60 minutes
and withdraw 10 ml sample at 30, 45, 60, minutes. The present release of
Ibuprofen was plotted against time to get the zero order plots. Zero order plots
show the reasonably straight line with high correlation coefficient value.
 CONCLUSION
Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID), which
relieves pain and swelling (inflammation). It is used to treat headaches, muscle
aches, backaches, dental pain, menstrual cramps, arthritis, or athletic injuries. This
medication is also used to reduce fever and to relieve minor aches and pain due to
the common cold or flu. This drug works by blocking the enzyme in your body that
makes prostaglandins. Decreasing prostaglandins helps to reduce pain, swelling,
and fever.

In the prospect of the world demand for “OTC” drugs are increasing
day by day. Ibuprofen has huge demand for its anti-pyretic, analgesic effect and
also for its anti-inflammatory non- steroidal activity.

During the time of my study I perform “in vitro” tests in distilled

water media, to observe the Release of different sample with a 50 RPM. Our
dissolution test was done by using USP, paddle method. Temperature was
37±5oc.Drug content within solution was determined by taking absorbance at
Spectrophotometer at a λ max of 280 nm.

This Ibuprofen drug a manufacturing by both the national &

multinational companies & both are involve in competition with each other.
 BIBLIOGRAPHY

1. "WHO Model List of Essential Medicines" (PDF). World Health Organization

(March 2005). Retrieved on 2006-03-12.
2. International Ibuprofen Foundation, http://www.ibuprofen-
foundation.com/what-ibuprofen/story.htm
3. "Dr Stewart Adams: 'I tested ibuprofen on my hangover' - Telegraph".
Retrieved on 2008-01-20.
4. Zawada E (1982). "Renal consequences of non-steroidal anti-inflammatory
drugs.". Postgrad Med 71 (5): 223–30. PMID 7041104
5. Townsend K, Praticò D (2005). "Novel therapeutic opportunities for
Alzheimer's disease: focus on nonsteroidal anti-inflammatory drugs.". FASEB J
19 (12): 1592–601. doi:10.1096/fj.04-3620rev. PMID 1619536
6. Chen H, Jacobs E, Schwarzschild M, McCullough M, Calle E, Thun M, Ascherio
A (2005). "Non-steroidal anti-inflammatory drug use and the risk for
Parkinson's disease.". Ann Neurol 58 (6): 963–7. doi:10.1002/ana.20682.
PMID 16240369.
a b
7. Ovation Pharmaceuticals. "Neoprofen (ibuprofen lysine) injection". Package
insert. [1]
8. Geisslinger G, Dietzel K, Bezler H, Nuernberg B, Brune K (1989).
"Therapeutically relevant differences in the pharmacokinetic and
pharmaceutical behavior of ibuprofen lysinate as compared with ibuprofen
acid.". Int J Clin Pharmacol Ther Toxicol 27 (7): 324–8. PMID 2777420
9. Su PH, Chen JY, Su CM, Huang TC, Lee HS (2003). "Comparison of ibuprofen
and indomethacin therapy for patent ductus arteriosus in preterm infants".
 Pediatr Int 45 (6): 665–70. doi:10.1111/j.1442-200X.2003.01797.x. PMID
14651538
10.Kakuta H, Zheng X, Oda H, et al (April 2008). "Cyclooxygenase-1-selective
inhibitors are attractive candidates for analgesics that do not cause gastric
damage. design and in vitro/in vivo evaluation of a benzamide-type
cyclooxygenase-1 selective inhibitor". J. Med. Chem. 51 (8): 2400–11.
doi:10.1021/jm701191z. PMID 18363350
11. a b
(2004) in Rossi S: Australian Medicines Handbook, 2004, Australian
Medicines Handbook. ISBN 0-9578521-4-2.
12.Bergner T, Przybilla B. Photosensitization caused by ibuprofen. J Am Acad
Dermatol 1992;26(1):114-6. PMID 1531054
13.Thomson Healthcare. USP DI Advice for the Patient: Anti-inflammatory Drugs,
Nonsteroidal (Systemic) [monograph on the internet]. Bethesda (MD): U.S.
National Library of Medicine; c2006 [updated 2006 Jul 28; cited 2006 Aug 5].
Available from:
http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202743.htm
14.Hippisley-Cox J, Coupland C (2005). "Risk of myocardial infarction in patients
taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-
inflammatory drugs: population based nested case-control analysis.". BMJ
330 (7504): 1366. doi:10.1136/bmj.330.7504.1366. PMID 15947398
15.Chen CS, Shieh WR, Lu PH, Harriman S, Chen CY (1991). "Metabolic
stereoisomeric inversion of ibuprofen in mammals". Biochim Biophys Acta
1078 (3): 411–7. PMID 1859831.
16.Tracy TS, Hall SD (1992). "Metabolic inversion of (R)-ibuprofen. Epimerization
and hydrolysis of ibuprofenyl-coenzyme A". Drug Metab Dispos 20 (2): 322–7.
PMID 1352228.
17.Reichel C, Brugger R, Bang H, Geisslinger G, Brune K (1997). "Molecular
cloning and expression of a 2-arylpropionyl-coenzyme A epimerase: a key
enzyme in the inversion metabolism of ibuprofen". Mol Pharmacol 51 (4):
576–82. PMID 9106621. Free full text
18.http://www.rxlist.com/cgi/generic/ibup.htm
19.McElwee NE, Veltri JC, Bradford DC, Rollins DE. (1990). "A prospective,
population-based study of acute ibuprofen overdose: complications are rare
 and routine serum levels not warranted.". Ann Emerg Med 19 (6): 657–62.
doi:10.1016/S0196-0644(05)82471-0. PMID 2188537
20.Vale JA, Meredith TJ. (1986). "Acute poisoning due to non-steroidal anti-
inflammatory drugs. Clinical features and management.". Med Toxicol 1 (1):
12–31. PMID 3537613
21. a b
Volans G, Hartley V, McCrea S, Monaghan J. (2003). "Non-opioid analgesic
poisoning". Clinical Medicine 3 (2): 119–23. PMID 12737366
22.Seifert SA, Bronstein AC, McGuire T (2000). "Massive ibuprofen ingestion with
survival". J. Toxicol. Clin. Toxicol. 38 (1): 55–7. PMID 10696926
23."Position paper: Ipecac syrup" (2004). J. Toxicol. Clin. Toxicol. 42 (2): 133–43.
PMID 15214617
24.Hall AH, Smolinske SC, Conrad FL, et al (1986). "Ibuprofen overdose: 126
cases". Annals of emergency medicine 15 (11): 1308–13. doi:10.1016/S0196-
0644(86)80617-5. PMID 3777588.
25.. Aguiar, A.J., Krc, J., Kinkel, A.W., and Samyn, J.C. 1967 Effect of
Polymorphism on the Absorption of Chloramphenicol from Chloramphenicol
Palmitate, J. Pharm
26.. Antonin K-H, Bieck P, Scheurlen M, Jedrychowski M, Malchow H. Oxprenolol
absorption in man after single bolus dosing into two segments of the colon
compared with that after oral 30. Br J Clin Pharmacol. 1985; 19(Suppl 2)
27.Batchlor EE, Paulus HE. Principles of drug therapy. In: Moskovitz RW, Goldberg
VM, Mankin HJ, editors. Osteoarthritis: diagnosis and medical/surgical
management. Philadelphia, WB Saunders, 1992.