5 introduction

Chapter one: Introduction
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Chapter 1
Introduction
Chapter 1
Introduction

1.INTRODUCTION
1.1. A brief history on Diclofenac Sodium
Pain has been officially defined as an unpleasant sensory and emotional experience
associated with actual or potential tissue damage. Pain acts as a warning signal against
disturbances of the body and has a proactive function. NSAIDs are agents having anti-
inflammatory, analgesic and antipyretic effects. These drugs are used frequently and
commonly in humans as well as in animals to manage pain, fever and inflammation for
the treatment of different clinical conditions such as rheumatic disorders, musculo-
skeletal disorders, sports injuries, muscular cramps and other syndromes involving
pain and inflammation. These drugs have analgesic action at low dose and anti-
inflammatory action at high dose. As a class, NSAIDs account for about 5% of all
prescriptions in Europe and United States. Many athletes self-administer NSAIDs prior
to athletic participation to prevent pain and inflammation before it occurs.
Diclofenac sodium is a non-steroidal anti-inflammatory drug (NSAIDs) with analgesic
and antipyretic properties (Figure 1). It is widely used in management of mild to
moderate pain particularly when inflammation is also present as in cases of rheumatoid
arthritis, osteoarthritis, musculo-skeletal injuries and some post operative conditions.
Fig.1: Diclofenac Structure
Its pharmacological effects are believed to be due to blocking the conversion of
arachidonic acid to prostaglandins by inhibiting cyclooxygenase enzymes. Diclofenac
sodium is almost completely absorbed after oral administration. However, due to its
first pass metabolism, only about 50% of the absorbed dose is systematically available.
The half-life of diclofenac sodium in plasma varies from 1-3 hours, with mean peak
plasma levels of approximately 0.5µg/ml and 1.0 µg/ml occurring after about two hours
after a single dose of 25mg and 50mg of enteric coated tablets respectively. About 99%
of the drug is bound to human plasma proteins, mainly albumin.
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The standard quality control tests such as diameter, size and shape, uniformity of
weight, thickness, hardness, friability, percentage of medicament (Assay), rate of
disintegration, dissolution and solubility can be carried out on compressed tablets for
their evaluation. In the current work, five different brands of diclofenac tablets from
each of the companies were collected and subjected for the quality control tests such as
hardness, friability and dissolution rate in order to study the effect of composition of
formulations in drug release rate.
Diclofenac is commonly prescribed as non-steroidal anti-inflammatory substance
(NSAIS) that is taken to reduce inflammation, reducing pain in conditions such as acute
injury, musculoskeletal, especially to treat rheumatoid arthritis, osteoarthritis,
syondyarthritis, gout attacks, pain management in case of kidney stone. It is very
effective in the management of menstrualpain, ovulatory pain, acute migraines, post-
operative and post-traumatic pain, female breast cancer and pain associated with bony
metastases (Goodman and Gilman’s, 2001).Gastrointestinal disturbances are the major
adverse effect associated with diclofenac therapy (Haider etal.,2001) and thus, for oral
administration, the drug is usually formulated as coated tablets.
Thus, in the present study the equivalence of five brands of Diclofenac sodium tablets
sourced from retail pharmacies was determined using in vitro methods. This
preliminary study is aimed at obtaining baseline data towards the establishment of
bioequivalence of the tablets.
1.2 Mode of action
Inhibits prostaglandin synthesis by decreasing the activity of the enzyme,
cyclooxygenase, which results in decreased formation of prostaglandin precursors.
1.3. Pharmacological characteristics:
• Duration of action: The duration of action of one single dose is much longer (6 to
8 hours) than the very short half-life of the drug indicates. This could partly be
due to a particular high concentration achieved in synovial fluids.
• Onset of action: Potassium salt (Cataflam) is more rapid than sodium salt
(Voltaren) because it dissolves in the stomach instead of the duodenum.
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• Metabolism: Hepatic to several metabolites
• Elimination half-life: 2 hours
• Excretion: Urine (65%); feces (35%)
1.4. Pharmacological Properties
1.4.1. Pharmacodynamics Properties
Diclofenac is a non-steroidal agent with marked analgesic and anti-inflammatory
properties. It is also an inhibitor of prostaglandin syntheses.
1.4.2. Pharmacokinetic Properties
Diclofenac sodium is rapidly absorbed from the gut and is subject to first-pass
metabolism. Tablets give plasma peak concentrations after 1-4 hours. It is 99.7%
protein bound and has a plasma half-life of 1-2 hours. About 60% of the administered
dose is excreted via the kidneys in the form of metabolites and only less than 1% in the
unchanged form. The rest of the dose is excreted via the bile in metabolized form.
1.5. Clinical Particulars
1.5.1. Therapeutic Indications
Diclofenac sodium is a non-steroidal agent, with marked analgesic and anti-
inflammatory properties, used in rheumatoid arthritis; osteoarthritis; osteoarthritis;
low back pain; acute musculo-skeletal disorders and trauma such as per arthritis,
tendinitis, tenosynovitis, bursitis sprains, strains and dislocations; relief of pain in
fractures; ankylosing spondylitis; acute gout; control of pain and inflammation in
orthopedic, dental and other minor surgery.
1.5.2. Posology and Method of Administration
Undesirable effects may be minimized by using the lowest effective dose for the shortest
duration necessary to control symptoms.
Route of administration: Oral
Adults: 75-150 mg daily in two or three divided doses after meals. The recommended
maximum daily dose of diclofenac sodium is 150mg.
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1.6. Contraindications:
 Hypersensitivity to the active substance or any of the excipients.
 Patients who have previously shown hypersensitivity reactions (e.g. asthma,
angioedema, urticarial or acute rhinitis) to ibuprofen, aspirin or other non-
steroidal anti-inflammatory drugs.
 Patients with a history of, or active, gastro-intestinal ulcers, bleeding or
perforation (two or more distinct episodes of proven ulceration or bleeding).
 Severe hepatic, renal and heart failure.
 During the last trimester of pregnancy.
 History of gastrointestinal bleeding or perforation, relating to previous NSAID
therapy.
1.7. Special Warnings for Use
In all patients: Undesirable effects may be minimized by using the lowest effective dose
for the shortest duration necessary to control symptoms.The use of diclofenac with
concomitant NSAIDs including cyclooxygenase 2-selective inhibitors should be avoided.
Elderly: The elderly have increased frequency of adverse reactions to NSAIDs especially
to gastrointestinal bleeding and perforation which may be fatal.
Gastro-intestinal: Close medical surveillance is imperative in patients with symptoms
indicative of gastro-intestinal disorders, with a history suggestive of gastro-intestinal
ulceration, with ulcerative colitis or with Crohn's disease as these conditions may be
exacerbated. Patients with a history of GI toxicity, particularly when elderly, should
report any unusual abdominal symptoms (especially GI bleeding).
Gastro-intestinal bleeding or ulceration/perforation: Hematemesis, melena,
ulceration or perforation which can be fatal has been reported with all NSAIDs. They
can occur at any time during treatment with or without warning symptoms or a
previous history of serious GI events. In the rare instances where gastro-intestinal
bleeding or ulceration occurs in patients receiving diclofenac sodium the drug should be
withdrawn.
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The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses,
in patients with a history of ulcer, particularly if complicated with hemorrhage or
perforation and in the elderly. These patients should commence treatment on the
lowest dose available. Combination therapy with protective agents (e.g. misoprostol or
proton pump inhibitors) should be considered for these patients, and also for patients
requiring concomitant low dose aspirin or other drugs likely to increase gastrointestinal
risk.
Hypersensitivity reactions: As with other non-steroidal anti-inflammatory drugs,
allergic reactions, including anaphylactic/anaphylactic reactions, can also occur without
earlier exposure to the drug.
In patients with asthma, seasonal allergic rhinitis, swelling of the nasal mucosa (i.e.
nasal polyps), chronic obstructive pulmonary diseases or chronic infections of the
respiratory tract (especially if linked to allergic rhinitis-like symptoms), reactions with
NSAIDs such as exacerbation of asthma (so called intolerance to analgesics / analgesics-
asthma), Quincke'soedema (angioedema) or urticarial are more frequent than in other
patients. Therefore special precautions are recommended in such patients (readiness
for emergency). This is also applicable to patients who are allergic to other substances,
for example those with skin reactions, purities or urticarial.
As with other NSAIDs, diclofenac sodium may mask the signs and symptoms of infection
due to its pharmacodynamics properties
1.8. Precautions:
Hepatic: If abnormal liver function tests persist or worsen, clinical signs or symptoms
consistent with liver disease develop or if other manifestations occur (eosinophilia,
rash), diclofenac sodium should be discontinued. Hepatitis may occur without
prodromal symptoms.Use of diclofenac sodium in patients with hepatic porphyria may
trigger an attack. Use in acute porphyria is contraindicated.
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Renal: Patients with renal, cardiac or hepatic impairment, a history of hypertension and
the elderly, should be kept under surveillance, since the use of NSAIDs may result in
deterioration of renal function. The lowest effective dose should be used and renal
function monitored.
The importance of prostaglandins in maintaining renal blood flow should be taken into
account in patients with impaired cardiac or renal function, those being treated with
diuretics or other products that can significantly impact renal function, or those
recovering from major surgery. Effects on renal function are usually reversible on
withdrawal of diclofenac sodium.
Long-term treatment: All patients who are receiving non-steroidal anti-inflammatory
agents should be monitored as a precautionary measure e.g. renal function, hepatic
function (elevation of liver enzymes may occur) and blood counts. This is particularly
important in the elderly.
Hematological: Diclofenac sodium may reversibly inhibit platelet aggregation.
Patients with defects of hemostasis, bleeding diathesis or hematological abnormalities
should be carefully monitored.
Respiratory disorders: Like other drugs that inhibit prostaglandin synthetase activity,
diclofenac sodium and other NSAIDs can precipitate bronchospasm if administered to
patients suffering from, or with a previous history of, bronchial asthma.
Cardiovascular and cerebrovascular effects: Appropriate monitoring and advice are
required for patients with a history of hypertension and mild to moderate congestive
heart failure as fluid retention and edema have been reported in association with NSAID
therapy.
Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high
doses (150mg daily) and in long term treatment may be associated with a small
increased risk of arterial thrombotic events (for example myocardial infarction or
stroke).
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Patients with uncontrolled hypertension, congestive heart failure, established ischemic
heart disease, peripheral arterial disease, or cerebrovascular disease should only be
treated with diclofenac after careful consideration. Similar consideration should be
made before initiating longer-term treatment of patients with risk factors for
cardiovascular events (e.g. hypertension, hyperlipidemia, diabetes mellitus, and
smoking).
SLE and mixed connective tissue disease: In patients with systemic lupus
erythematous (SLE) and mixed connective tissue disorders there may be an increased
risk of aseptic meningitis.
Dermatological: Serious skin reactions, some of them fatal, including exfoliated
dermatitis, Stevens-Johnson syndrome and toxic epidermal necrosis, have been
reported very rarely in association with the use of NSAIDs, including diclofenac.
Patients appear to be at the highest risk of these reactions early in the course of therapy,
the onset of the reaction occurring in the majority of cases within the first month of
treatment.
Female fertility: The use of diclofenac sodium may impair female fertility and is not
recommended in women attempting to conceive. In women who may have difficulties
conceiving or who are undergoing investigation of infertility, withdrawal of diclofenac
sodium should be considered.
1.9. Interaction with Other Medicinal Products and Other Forms of Interaction
Lithium: Diclofenac sodium may increase plasma concentrations of lithium.
Anticoagulants: Although clinical investigations do not appear to indicate that
diclofenac sodium has an influence on the effect of anticoagulants, there are isolated
reports of an increased risk of hemorrhage with the combined use of diclofenac and
anticoagulant therapy. As with other non-steroidal anti-inflammatory agents, diclofenac
in a high dose can reversibly inhibit platelet aggregation.
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Antidiabetic agents: Clinical studies have shown that diclofenac sodium can be given
together with oral antidiabetic agents without influencing their clinical effect. However
there have been isolated reports of hypoglycemic and hyperglycemic effects which have
required adjustment to the dosage of hypoglycemic agents.
Cyclosporine and tacrolimus: Cases of nephrotoxicity have been reported in patients
receiving concomitant ciclosporin and NSAIDs, including diclofenac sodium. Possible
increased risk of nephrotoxicity when NSAIDs are given with tacrolimus. This might be
mediated through combined renal anti-prostaglandin effects of both the NSAID and
calcineurin inhibitor.
Methotrexate: Cases of serious toxicity have been reported when methotrexate and
NSAIDs are given within 24 hours of each other. This interaction is mediated through
accumulation of methotrexate resulting from impairment of renal excretion in the
presence of the NSAID.
Quinolone antimicrobials: Convulsions may occur due to an interaction between
quinolones and NSAIDs. This may occur in patients with or without a previous history of
epilepsy or convulsions. Therefore, caution should be exercised when considering the
use of a quinolone in patients already receiving an NSAID.
Other NSAIDs including cyclo-oxygenase-2 selective inhibitors and corticosteroids: Co-
administration of diclofenac sodium with these agents may increase the risk of gastro-
intestinal bleeding or ulceration. Avoid concomitant use of two or more NSAIDs.
Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased
risk of gastrointestinal bleeding.
Diuretics: Like other NSAIDs, diclofenac sodium may inhibit the activity of diuretics.
Concomitant treatment with potassium-sparing diuretics may be associated with
increased serum potassium levels, which should therefore be monitored frequently.
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Antihypertensive: Concomitant use of NSAIDs with antihypertensive drugs (i.e. beta-
blockers, angiotensin converting enzyme (ACE) inhibitors, diuretics) may cause a
decrease in their antihypertensive effect via inhibition of vasodilator prostaglandin
synthesis.
Cardiac glycosides: Concomitant use of cardiac glycosides and NSAIDs in patients may
exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.
Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone
administration as NSAIDs can reduce the effects of mifepristone.
Baclofen: NSAIDs possibly reduce excretion of baclofen (increased risk of toxicity).
Drospirenone: Risk of hyperkalemia when given with drospirenone.
Ketorolac: Increased side effects and hemorrhage if used with NSAIDs.
Penicillamine: Possible increased risk of nephrotoxicity. Erlotinib, iloprost,
pentoxifylline, sibutramine, venlafaxine: Possible increased risk of bleeding.
Phenytoin: NSAIDS possibly enhance effects of phenytoin.
Ritonavir: Plasma concentration of NSAIDs possibly increased by ritonavir.
Zidovudine: Increased risk of haematological toxicity when NSAIDs given with
zidovudine.
1.10. Pregnancy and Lactation
Pregnancy
Congenital abnormalities have been reported in association with the administration of
NSAIDs in man, however, these are low in frequency and do not appear to follow any
discernible pattern.
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In view of the known effects of NSAIDs on the fetal cardiovascular system (e.g. a
premature closure of the ductusarteriosus) and in causing uterine inertia, use in the last
trimester of pregnancy is contraindicated. The onset of labor may be delayed and the
duration increased with an increased bleeding tendency in both mother and child.
NSAIDs should not be used during the first two trimesters of pregnancy or labor unless
the potential benefit outweighs the potential risk to fetus. The lowest effective dose
should be used and duration kept as short as possible.
Lactation
Following doses of 50mg enteric coated tablets every 8 hours, traces of active substance
have been detected in breast milk, but in quantities so small that no adverse effects on
the breast fed infant are to be expected.NSAIDs should if possible be avoided when
breast-feeding.
1.11. Undesirable Effects
Adverse reactions are ranked under heading of frequency, the most frequent first, using
the following convention: common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100);
rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000), including isolated reports.
The following undesirable effects include those reported with diclofenac gastro-
resistant tablets and other pharmaceutical forms of diclofenac, with either short-term
or long-term use.
Blood and lymphatic system disorders
Very rare: Thrombocytopenia, leukopenia, anemia (including hemolytic and aplastic
anemia), agranulocytosis.
Immune system disorders
Rare: Hypersensitivity, anaphylactic and anaphylactic reactions (including hypotension
and shock).
Very rare: Angioneuroticoedema (including face edema).
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Psychiatric disorders
Very rare: Disorientation, depression, insomnia, nightmare, irritability, psychotic
disorder/reactions, confusion, and hallucinations.
Nervous system disorders
Common: Headache, dizziness.
Rare: Somnolence, drowsiness, tiredness, hypotension.
Very rare: Par aesthesia, memory impairment/disturbance, convulsion, anxiety, tremor,
taste disturbances, cerebrovascular accident, disturbances of sensation, taste
disturbances, malaise, aseptic meningitis (especially in patients with existing auto-
immune disorders, such as systemic lupus erythematous and mixed tissue disease) with
symptoms such as fever, stiff neck, headache, nausea and vomiting.
Eye disorders
Very rare: Visual disturbance, vision blurred, diplopia, optic neuritis.
Ear and labyrinth disorders
Common: Vertigo.
Very rare: Tinnitus, hearing impaired.
Cardiac disorders
Very rare: Palpitations, chest pain, cardiac failure/congestive heart failure, myocardial
infarction.Clinical trial and epidemiological data suggest that use of diclofenac,
particularly at high doses (150 mg daily) and in long term treatment may be associated
with a small increased risk of arterial thrombotic events, for example, myocardial
infarction or stroke.
Vascular disorders
Very rare: Hypertension, vasculitis.
Hepatobiliary disorders
Common: Transaminases (serum aminotransferase enzymes) increased (AST, ALT).
Rare: Hepatitis, jaundice, liver disorder.
Very rare: Fulminant hepatitis.
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Gastrointestinal disorders
Common: Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain or cramps, anorexia.
Rare: Gastritis, gastrointestinal hemorrhage or bleeding, hematemesis,
diarrhoeahaemorrhagic/bloody, melena, gastrointestinal ulcer, with or without
bleeding or perforation (sometimes fatal, particularly in the elderly).
Very rare: Lower gut disorders such as colitis (including colonic damage, non
specifichaemorrhagic colitis/ hemorrhagic colitis and exacerbation of ulcerative colitis
constipation, stomatitis, glossaries, esophageal disorder/lesions, diaphragm-like
intestinal strictures/stricture formation, pancreatitis.
Skin and subcutaneous tissue disorders.
Common: Rash, skin eruptions.
Rare: Urticarial.
Very rare: Bullous eruptions, eczema, erythema, erythema multiform, Stevens-Johnson
syndrome, toxic epidermal necrosis/acute toxic epidermolysis (Lyell's syndrome),
dermatitis exfoliated (erythroderma), loss of hair, photosensitivity reactions, purpura,
allergic purpura, pruritus.
Respiratory, thoracic and mediastina disorders
Rare: Asthma (including dyspnoea), alveolitis, pulmonary eosinophilia.
Very rare: Pneumonitis. Aggravated asthma or bronchospasm have also been reported.
Renal and urinary disorders
Rare: Interstitial fibrosis has been reported with NSAIDs and may lead to renal failure.
Very rare: Acute renal failure or insufficiency, urinary abnormalities (eghaematuria,
proteinuria), nephrotic syndrome, interstitial nephritis, renal papillary necrosis.
1.12. Overdose
1.12.1. Symptoms:
Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal
bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, tinnitus,
fainting, occasionally, convulsions. In rare cases of significant poisoning acute renal
failure and liver damage are possible.
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1.12.2. Therapeutic measures:
Patients should be treated symptomatically as required. Within one hour of ingestion of
a potentially toxic amount, activated charcoal should be considered.
Alternatively, in adults gastric lavage should be considered within one hour of ingestion
of potentially toxic amounts. Frequent or prolonged convulsions should be treated with
intravenous diazepam. Other measures may be indicated by the patient's clinical
condition.
1.13. Pharmaceutical Particulars
1.14. List of Excipients
Diclofenac Tablets 50 mg:
Core ingredients Coating ingredients
Povidone K25 BP Magnesium stearate BP Cellulose acetate phthalate BP
Starch maize BP Lactose BP
Purified talc BP
1.15. Shelf Life
2 years.
1.16. Possible Side Effects
Like all medicines, DICLOFENAC tablets can cause side effects, although not everybody
gets them.
Common side effects:
• Headache, dizziness, nausea, vomiting
• Aches and pains in the stomach area
• Constipation, diarrhoea
• Gas, indigestion, heartburn
• Loss of appetite.
• Rare side effects:
1.17. Other side effects
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Effects on the heart:
• Fluid retention, high blood pressure
• Chest pain, a fast or irregular heart beat
• Heart failure.
Effects on the liver or kidneys:
• Liver function disorders, including hepatitis
• Raised levels of liver enzymes in the blood
• Kidney problems, which may lead to swelling of the face and ankles, kidney
failure or the presence of blood or protein in the urine.
Effects on the blood:
Reduction in red blood cells (anemia), which can make the skin pale and cause
weakness
Other effects:
• Numbness or tingling in the fingers, shaking, blurred or double vision, sudden
loss of vision or pain on movement of the eye, hearing loss or impairment,
ringing in the ears, sleeplessness, nightmares, feeling irritable, depression,
anxiety, nervousness mental disorders, confusion, hallucinations, loss of
memory, fits
• Drowsiness, a feeling of dizziness or spinning (vertigo), tiredness, general illness
• Difficulty breathing
• Loss of hair, disturbances in sensation
• A red swollen tongue, mouth ulcers, taste changes
• Worsening of ulcerative colitis or Cohn’s disease
• An inflamed pancreas, which can cause severe pain in the stomach area and back.
If any of the side effects become serious, or if you notice any side effects not listed in this
leaflet, please tell your doctor or pharmacist.
1.18. Storage of Diclofenac Sodium
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Diclofenac should be stored below 25°C in the original package or container and kept
the container tightly closed.
Medicines should not be disposed of via wastewater or household waste. Ask your
pharmacist how to dispose of medicines no longer required. These measures will help
to protect the environment
1.19. Types of modified release dosage forms
In 1985, the USP-XXI/NF-XVI adopted the term modified release dosage form to
describe dosage forms that alter the timing and rate of release of the drug substance
from the drug product. A modified release dosage form is defined by the USP/NF – “As
one for which the drug release characteristics of time course and/or location are chosen
to accomplish therapeutic or convenience objectives not offered by conventional dosage
forms such as solutions, or promptly dissolving dosage forms.”
The USP/NF presently recognizes several types of modified release dosage forms:
• Extended release dosage form: A dosage form which allows at least a twofold
reduction is dosage frequency as compared to that drug presented as an immediate-
release (conventional) dosage form. Examples of extended release dosage forms
include controlled release and sustained release drug products.
• Delayed release dosage form: A dosage form that release a discrete portion or
portions of drug at a time or times other than promptly after administration,
although one portion may be released promptly after administration. Enteric coated
dosage forms are the most common delayed release products.
• Targeted release dosage form: A dosage form that releases drug at or near the
intended physiologic site of action. Targeted release dosage forms may have either
immediate or extended release characteristics.
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Fig 2: Traditional vs. Controlled Release Drug Dosing
With traditional administration, the drug active must remain between a maximum
blood level value which may represent a toxic level and a minimum value below which
the drug is no longer effective whereas with controlled administration, the blood levels
are constant between the desired maximum and minimum for an extended period of
time
1.20. Enteric coatings
Enteric coatings are those which remain intact in the stomach, but will dissolve and
release the contents once it reaches the small intestine. Their prime intension is to delay
the release of drugs which are inactivated by the stomach contents or may cause nausea
or bleeding by irritation of gastric mucosa.
1.21. Field of application of enteric coated dosage forms
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Enteric coated dosage forms, such as coated tablets, sugar-coated tablets, soft and hard
gelatin capsules, granulates or pellets, have their ﬁrm place in the medical arsenal.
Nowadays, enteric coatings are in particular used to:
 Protect active substances destroyed by the acidic gastric juice,
 Improve tolerability of medicaments irritating the stomach by only releasing
them in the small intestine,
 Making active substances available after a time delay (sustained release),
 Achieving targeted release and concentration in the small intestine.
1.22. Evaluation of Tablets
Tablets are evaluated by a variety of methods.
1.22.1. Weight determination of tablet
The weight variation of the tablets can be measured by weighing each individual tablets
and determining the percent difference from the intended amount. Guidelines in the
USP 24/NF19 Supplement 1 indicate that each tablet "shall be not less than 90% and
not more than 110% of the theoretically calculated weight for each unit."
Fig 3: Analytical Balance
1.22.2. Tablet Friability
Friability of tablet is defined as the capacity to withstand shock and packaging, handling
and shipping. It is determined by the following formula-
Friability= (Iw-Fw)/Iw x 100
Where,
Iw = Total initial weight of tablets
Fw = Total final weight of tablets
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Fig 4: Tablet Friability Machine
1.22.2.1. Acceptable range of friability:
Conventional compressed tablets that loss than 0.5% to 1% (after 100 revolutions) of
their weight are generally acceptable.
1.22.2.2. Purpose of friability:
Tablet friability results in weight loss of tablet in packaging containers owing to
chipping or fragmentation of the tablet to alteration of wear.Weight loss due to
excessive friability causes the loss of dose which may cause loss of therapeutic activity.
So friability study is essential.
Tablets are chipped or mechanically ended and no longer have sharp edges are of
reduced pharmaceutical elegance and reduced quality.Friability often reflects lacks of
cohesiveness on comparison of the drug granulation from which the tablets are made.
1.22.2.3. Possible causes of friability problem:
• Excessive moisture content.
• Over dried granulation.
• Inadequate amount of binder.
• Excessive pressure.
1.22.2.4. Remedy of friability:
1. Sufficient quantity of binder should be used.
2. Optimum drying is needed.
3. Proper pressure should be used.
4. Excess moisture should be removed.
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1.22.3. Tablet hardness:
The tablets must be hard enough to withstand mechanical stress during packaging,
shipment, and handling by the consumer. A standard tablet friability test applicable to
manufactured tablets should be performed. The principle of measurement involves
subjecting the tablet to an increasing load until the tablet breaks or fractures. The load
is applied along the radial axis of the tablet.
Tablet hardness testers only provide accurate and reliable results if the mechanical
components and electronics of the tester fulfill a whole set of design requirements.
When comparing results from different testers, it is important to look at how the testers
meet these requirements in order to identify possible reasons for variations.
1.22.4. Hardness variation: Most manufacturers consider hardness for a tablet should
be 4-5 kg/cm2
. But some tablets such as chewable tablets may have hardness more than
10 kg/cm2
. The hardness is influenced by-
• The nature of the binder
• Concentration of the binder
1.22.4.1. Measurement of hardness: To ensure the hardness of the prepared tablet
different testers are available. These are:
• The Monsanto tester.
• The strong-cobb tester
• The Pfizer tester
• The Erweka tester
• The Schleuniger tester
1.22.5. Tablet disintegration
There are commercially available disintegration and dissolution apparatus. Most
pharmacists will not have this equipment. However, a simple disintegration apparatus
can be made. Start by supporting a 10 mesh screen about 2 inches above the bottom of a
1000 ml beaker. Fill the beaker with 1000 ml of water, add a stirring bar, and place the
beaker on a magnetic stirring plate. Stir at a moderate speed. Drop the tablets onto the
mesh screen and record the time needed for the tablets to disintegrate. A reasonable
disintegration time should be between 15 and 30 minutes, although the time will
depend on the product, the stirring speed, etc.
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1.22.5.1. Purpose of disintegration:
It is directly influence the-
• Dissolution of the tablet
• Onset of the drug
• Rate of absorption of the drug
• Rate of bioavailability of the drug
1.22.5.2. Factors affecting the disintegrating time
• Disintegrating agent
• Binder
• Particle size
• Drying of powder
• Mixing of powder
1.22.5.3. Variation of the of disintegration time: According to B.P 1-2 hours for
enteric coated or acid resistant tablets.
1.22.6. Tablet dissolution:
Disintegration time determination is a useful tool for production control, but
disintegration of a tablet does not imply that the drug has dissolved. A tablet can have a
rapid disintegration time yet be biologically unavailable. The dissolution rate of the
drug from the primary particles of the tablet is the important factor in drug absorption
and for many formulations is the rate-limiting step. Therefore, a dissolution time is
more indicative of the availability of a drug from a tablet than the disintegration test.
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