FORMULATION AND EVALUATION OF FAST DISINTERGRATING TABLET OF SODIUM DICLOFENAC

AProject Report Submitted to Uttar Pradesh Technical University For the award of the degree of
BACHELOR OF PHARMACY By Mr. SHAILENDER CHOUDHARY (Roll No. 0813350041)
Under the Guidance of Mrs. Swarupanjali Padhi Lecturer

Department of Pharmaceutical Technology, Noida Institute of Engineering and Technology,

Greater Noida-201306 MAY 2012

ACKNOWLEDGEMENTS: It is great pleasure for me to acknowledge all those who have contributed towards the conception, origin and nurturing of this project. With a deep sense of gratitude and the respect, I thank my esteemed research guide Mrs. Swarupanjalipadhi ,Lecturer Department Of Pharmaceutical Technology, Noida Institute of Technology,Greater Noida for his inestimable guidance, valuable suggestions and constant encouragement during the course of this study. I am thankful to DrS.P.Basu , Director General , Dr A. Mazumder, Director, andDr R. Mazumder, Dean (R& D) for their constant moral support, valuable suggestions, directions and selfless support throughout the investigation. I am also grateful to Non-TeachingStaff for their guidance during the project work. At this moment, I thank with deep gratitude to my classmates and friends for their moral support, constant encouragement and patience absolutely needed

to complete my entire study. It was the blessing of them that gave me courage to face the challenges and made my path easier.I am indebted infinitely to care, support and trust being shown by my parents without whom it would not be possible to complete this project.

Shailender Choudhary

Department of Pharmaceutical Technology, Noida Institute of Engineering and Technology, Greater Noida

CERTIFICATE
The work described in this thesis entitled Formulation and evaluation of fast disintegtating tablet of sodium diclofenac has been carried out by Mr. Atul Mishra under my supervision. I certify that this is his bonafide

work. The work described is original and has not been submitted for any degree to this or any other university. Date Guide Mrs.Swarupanjali Padhi Place Lecturer

Department Of Pharmaceutics Noida institute of Engineering & Technology

Forwarded .............................. ...............................

External : .............................. ..............................

Dr A. Mazumder Professor and Director, Department of Pharmaceutical Technology, Noida Institute of Engineering and Technology, Greater Noida

Statement by the candidate

As required by university regulation, I wish to state that this work embodied in this report titled Formulation and evaluation of fast disintegrating tablet of sodium diclofenac forms my own contribution to the research work carried out under the guidance of Mrs.

Swarupanjalipadhi (LECTURER, Institute. of Pharm. Tech., NIET).This work has not been submitted for any other degree of this or any other university. Whenever references have been made to previous work of others, it has been clearly indicated as such and included in the bibliography.

Mr. SHAILENDER CHOUDHARY Forwarded Through Guide __________________________ Name of Guide: Department of Pharmaceutical Technology, NIET, Greater Noida

DECLARATION

I hereby declare that the project work entitled as Formulation and evaluation of fast disintegrating tablet of sodium diclofenac is my own work and that, to the best of my knowledge and belief, it contains no material previously published or written.

Date: Place: GB Nagar

Shailender Choudhary B.Pharm (4 Year)

Roll No: 0813350041

CONTENTS Topic

Abstract List of Tables List of Figures List of Symbols and Abbreviations Chapter 1 Introduction Objectives I

Chapter 2 Chapter 3 Chapter 4

Review of Literature Methodology

Chapter 5

Results

Chapter 6

Discussion

Chapter 7

Conclusion

Chapter 1

FAST MOUTH DISSOLVING TABLETS (FMDT)

N T R O Most commonly employed oral dosage forms are tablets and capsules. D U C Compressed tablets are the most widely used dosage forms for a number of TI O reasons. They are convenient, easy to use, less expensive, tamper- proof, easy to N pack and ship and more stable than other oral dosage forms. Also tablets lend themselves to certain special release profile products such as enteric or delayed release products. 1

A Fast Mouth Dissolving Tablet (FMDT) can be defined as an oral solid dosage form which when placed on tongue, disintegrates rapidly, releasing the drug, which dissolves or disperses in the saliva and then swallowed. Some drugs are absorbed from the mouth, pharynx, and oesophagus as the saliva passes down in to the stomach. The main problem with the common oral dosage forms is that they have to

Fast Dissolve, Quick Dissolve, Rapid Melt, Quick Disintegrating, Mouth Dissolving, Orally Disintegrating, Oro Dispersible, Melt - in- Mouth etc. are terms that represent the same drug delivery systems. Recently Orally Disintegrating (OD) Tablet technology has been approved by United States Pharmacopoeia (USP), Centre for Drug Evaluation and Research (CDER). USFDA defined OD tablet as A solid dosage form containing medicinal substances, which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue. Recently European Pharmacopoeia also adopted the term Oro Dispersible tablet as a tablet that is to be placed in the mouth where it disperses rapidly before swallowing. These dosage forms dissolve or disintegrate in the patients mouth within 15 seconds to 3 minutes without the need of water or chewing. Despite various terminologies used, Oro Dispersible tablets are here to offer unique form of drug delivery with many advantages over the conventional oral solid dosage forms. Advantages of Fast Mouth Dissolving Tablets a) Ease of swallowing : Dysphagic population constitute 35% of the gene ral population, since this disorder is associated with a number of medical be conditions such as Stroke, Parkinsons disease, AIDS, Headto swallow tablets, swallowed along with water. Many patients find it difficult and Neck Radiation Therapy and other neurological disorders. active ingredient, usually sweetening agent and a flavour. swallowing unlike conventional dosage forms. This is very convenient for patients who are travelling or do not have immediate access to water.

b) No water needed : These fast dissolve dosage forms do not need water for c) Superior taste : Most fast dissolve dosage forms contains taste-masked d) Accurate dose : The fast dissolve dosage forms have the added advantages of convenience and accurate dosing as compared to liquids. e) More rapid drug absorption through pre- gastric absorption from the mouth, pharynx and oesophagus. f) Rapid drug therapy intervention is possible. g) New business opportunities like product differentiation, line extension and life cycle management, exclusivity of product promotion. Various Therapeutic areas in which the Fast-Dissolve Dosage forms are most applicable.

Target Population Therapeutic Areas Pediatric Antibiotics Anti- asthamatics Cough/Cold/Allergy Anti- epileptics Analgesics/Anti pyretics Anti depressants Adult and Elderly Parkinsons Anti migraine Alzheimers Anti- asthmatics Anti- emetics Cancer Diabetes

Characteristics of ideal Fast Dissolving Tablets

They should not require water for administration, yet dissolve or disintegrate in the mouth within a few seconds.

* * * *

They should be compatible with taste masking. They should be portable without fragility concerns. They should have a pleasing mouth feel. They should leave minimal or no residue in the mouth after oral administration.

* *

They should allow high drug loading They should exhibit low sensitivity to environmental conditions such as humidity and temperature.

They should be manufactured using conventional tablet processing and packaging equipments at low cost.

DEVELOPMENT CHALLENGES IN FAST DISSOLVING DELIVERY SYSTEMS 1) Taste of the Active Ingredient

in close proximity to the taste buds. Unless the drug is tasteless or does not have Fast dissolve dosage forms dissolve or disintegrate in the patients mouth an undesirable taste, the use of taste masking techniques becomes critical to patient compliance. Taste masking can be done simply with flavouring agents and sweeteners. If the active ingredient is extremely bitter, taste masking can be done through the use of ion exchange resins to render the drug insoluble in the saliva. The other methods of taste masking includes microencapsulation techniques, where the drug particles are covered by polymers through spray coating, spray congealing, or coacervation methods. These coatings mus t be specific to prevent the drug particle from coming in contact with the taste buds without negatively affecting drug dissolution. Effervescence is also used for the taste masking of bitter drugs.

2) Dose Molecules requiring high doses present mainly three challenges to the development of fast dissolve dosage forms ; a) taste masking of the active ingredient, b) mouth feel or grittiness and c) tablet size. These challenges are not unrelated because most drugs will require taste masking, the amount of taste masking materials used in different dosage forms will depend on the drugs degree of bitterness relative to its dose, which will in turn affect the final tablet size. As mentioned earlier, the drug may require coating, which will result in an increase in the particle size. The extent to which this increase will affect the mouth feel and the tablet size will depend on the dose of the drug and the amount of coating material required for masking.

3) Friability Most of the fast dissolving dosage forms are either very porous and inherently soft moulded matrices or tablets compressed at very low compression forces. This is to maximize the tablet porosity and minimize oral dissolution or disintegration time. This causes these class of tablets to be soft, friable and/or brittle, often requiring specialized peelable blister packaging.

PATENTED TECHNOLOGIES USED IN FAST DISSOLVING TABLETS a) Zydis Technology Zydis is the first fast dissolving dosage form in the market. This technology is based on the concept of forming an open matrix network containing active water soluble matrix material and drug, which is performed in blister packets and freeze dried to remove the water by sublimation. The resultant structures are very porous in nature and rapidly disintegrate or dissolve upon the contact with saliva. A secondary moisture proof foil pouch is often required because this type of dosage form is very moisture sensitive. Zydis matrix is formed by polymers such as of the Zydis units may be a useful additive. The limitations of this method is water may be added if necessary. Collapse protectants like glycine prevent the shrinkage porous dosage form. Preservatives, suspending agents and pH-adjusting excipients sorbitol may be added. The use of water as the medium ensures the formation of gelatine, dextrans or alginates. To impart crystallinity and hardness, mannitol or

Chapter 1

Introduction

soluble drug can be incorporated only to 60 mg, whereas water insoluble drug only upto 400 mg. or less.

b) Orasolv and Durasolv Technology

These methods utilizes the effervescent materials and taste masked active ingredient and requires only conve ntional manufacturing processes and equipments. Here the microparticles are prepared by novel technique involving dispersion of active ingredients into suitable polymer dispersion together with other excipients such as mannitol and magnesium oxide.

Orasolv dosage forms have been well developed, containing more than 1000 mg of active load and are capable of combinations of multiple active ingredients in a tablet. But the main drawback of this method is that they are soft and friable and hence packaged using an integrated packaging line that uses a specially robotic pick and pack system. In Orasolv systems, the active medicament is taste masked and the tablets are made by direct compression technique at low compression force.

c) Flashdose Technology

The Flashdose dosage form utilizes the association with Technology as needed to eliminate the bitter taste of the medicament. During process, a crystalline, granular powder of

mixed polysaccharides is converted into amorphous fibres, termed as floss. By applying controlled crystallization, the floss can be converted into crystalline structures with high surface areas and correspondingly rapid rates of dissolution. The major drawback of these dosage forms are that the tablets are highly friable, soft and moisture sensitive. To protect this, a specialized packaging is required. This dosage form accumulates only upto 600 mg of drug.

d) Wowtab Technology

This technology is based on the combination of low and high mouldability saccharides to produce fast dissolving tablets using a conventional manufactur ing process. Tablets produced from this technology will have sufficient hardness to maintain the physical characteristics of the dosage form during production until it comes in contact with moisture such as saliva in mouth.

before incorporation into the tablet. The excipients are first granulated by means of wet or dry granulation and then the coated drug is mixed with the excipient granules and compressed into tablets. The produced tablets are reported to have high mechanical strength and disintegrate in less than 1 minute.

METHODS FOR DESIGNING FAST DISSOLVING TABLETS

1) Direct Compression by using Sugar Based Excipients

This method consists of directly compressing blend, which consists of an excipient, and an active ingredient. The excipient consists of a disintegrating agent and one soluble diluent selected from polyols having less than 13 carbon atoms. Polyols most commonly used are xylitol, sorbitol, mannitol, and maltitol. Directly compressible form or various ratios of compressible and powder form of polyols are used in these methods. Disintegrating agents most commonly used are Crospovidone, Croscaramellose sodium and Sodium starch glycollate. In addition to these ingredients, sweeteners and lubricants are incorporated in the formulation. Good aqueous solubility and sweeteners imparts a pleasing mouth feel and good taste masking. But not all sugar based excipients have fast dissolving action, and good compressibility and/or compatibility.

2) Spray Drying

Compressing highly porous support matrix, which is produc ed by spray drying, wit h active ingredient gives fast dissolving tablets. The support matrix composed of non-hydrolyzed gelatin or hydrolyzed gelatin, bulking agent, volatilizing agent like ethanol, acidifying or alkalizing agent to maintain the net charge . Most commonly used bulking agents are mannitol, sorbitol, sucrose, lactose, xylitol etc. Croscaramellose sodium, crospovidone, sodium starch glycollate and a small amount of effervescent material may be added to assist in the disintegration of the tablet. Additionally sweeteners, flavours and lubricants may be added.

3) Tablet Moulding

This method consists of suspending an active ingredient and a sugar in agar aqueous solution. Suspension is filled in moulds to solidify into a jelly form and subsequently dried the jelly. Drying can be affected by reduced pressure drying or aeration drying. Additional components like flavour, sweeteners, colours and preservatives may be added to improve taste, stability, appearance etc.

4) Wet/Dry Granulation by using Superdisintegrants

Wet/Dry granulation techniques with superdisintegrants can be used to prepare fast dissolving tablets. Crospovidone, croscaramellose sodium, and sodium starch glycollate, are used as superdisintegrants. Active drug, diluent, binder, lubricants, glidants are used along with disintegrants.

In wet granulation technique, disintegrants are added in both wet granulation step and dry blending step. Disintegrating agents have the ability to swell when exposed to GIT fluids resulting in rapid disintegration. Sweeteners and flavours are also added to dry blending step to improve palatability.

5) Sublimation

Tablets prepared by a water soluble material like mannitol give slow dissolution rates due to low porosity. Porosity can be increased by incorporating subliming materials like urea, ammonium bicarbonate, ammonium carbonate, camphor to the other tabletting ingredients and the mixture is comp ressed into tablets. The volatile materials are then removed by sublimation, which generates porous structures. Additionally several solvents such as water, cyclohexane, benzene can be used as pore forming agents.

6) Freeze Drying

Lyophilization can be used to create an amorphous, porous structure that

sealed with a peelable film. Instead of pushing the tablet through the foil, one must peel back the film to reveal the lyophilized disk). The lyophilization process imparts glossy amorphous structure to the bulking agent and sometimes to the drug, thus enhancing the dissolution characteristics of the formulation. But this method is not commonly used because of its high cost of equipment and processing. It also produces dosage forms with lack of physical resistance. The most commonly used matrix forming agents are gelatins and sugar based excipients.

7) Effervescence

Addition of an effervescent system in the formulation is one of the approaches by which Mouth Dissolving tablets can be prepared. The major advantages of this method are it is well established, easy to implement and masks the bitter taste of the drug. The effervescent system is generally composed of a dry acid and dry base which when react facilitate a mild effervescent action when the tablet contacts saliva. The effervescent reaction accelerates the disintegration of tablet through the release of carbon dioxide, water and salt. Due to the evolution of carbon dioxide, the bitter taste of the drug is also masked and a pleasant mouth feel is felt.,

EVALUATION ASPECTS OF MOUTH DISSOLVING TABLETS

Since mouth dissolving tablets are the recent advances in drug delivery system, there is no official methods for the evaluation of them. But various other methods have been developed by researchers to evaluate the fast mouth dissolving tablet characteristics. All of these are same or some modifications of the methods that are commonly used for tablets or other oral solid dosage forms. Researchers modified the evaluation procedures according to the drug used and method adopted for the manufacturing of .

By and large the evaluations of

includes testing for various physical

parameters, drug content, drug release as for conventional compressed tablets and powder or granule blend. Evaluation of powder blend includes tests for various powder characteristics such as powder flow properties, angle of repose, bulk density, bulk volume, granular volume, tapped density, percentage compressibility etc. Evaluation of prepared tablets are almost the same as official methods and

non-official methods for ordinary tablets. These include hardness and friability, vitro in vivo dispersion times, weight variation, tensile strength, content

uniformity test, porosity, moisture uptake, water absorption ratio, dispersion time and drug release, mouth feel, physical appearances, thickness and

dissolution studies as

diameter of tablet. volume of dissolution medium, and spectroscopic studies. For some

Drug

Profile
to

preparations using solid dispersion techniques, various phase solubility studies, Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) taken thermal studies, x- ray powder diffractometry, infra red spectroscopy are used. nfla an a Stability studies for ordinary tablets can be done in case of researchers have modified the stability studies of The mmation and

reduce i as

nalgesic reducing pain in

certain conditions. name

adopted for manufacturing and to the nature of the drug and ingredients for more

is derived from its chemical name: 2-(2,6-dichloranilino) phenylacetic acid. accurate, convenient and reproducible results. In the United Kingdom, India,Brazil and the United States, it may be supplied as either the sodium or potassium salt, in China most often as the sodium salt, while in some other countries only as the potassium salt. Diclofenac is available as a generic drug in a number of formulations.Over-the-counter (OTC) use is approved in some countries for minor aches and pains and fever associated with common infections. Chemical structure

Systematic (IUPAC) Name

2-(2-(2,6-dichlorophenylamino)phenyl)acetic acid

Clinical Data Trade Names Routes Chemical Data Formula C14H11Cl2NO2 Cataflam , voltaren Oral, rectal, im, iv (renal- and gallstones), topical

Mol.Mass 296.148 g/mol Medical uses 1.Diclofenac is used to treat pain, inflammatory disorders, and dysmenorrhea. 2.Inflammatory disorder may include musculoskeletal complaints, especially arthritis, rheumatoid arthritis, polymyositis,dermatomyositis,osteoarthritis, spondylitis, gout attacks, and pain dental

ain,TMJ, spondylarthritis, ankylosing

management in

cases of kidney stones and gallstones. An migraines. Diclofenac is used commonly

additional indication is the treatment of acute to treat mild to moderate post-operative is also present, and is

or post-traumatic pain, in particular when inflammation effective against menstrual pain and endometriosis.

3.As long-term use of diclofenac and similar NSAIDs predisposes for peptic ulcer, many patients at risk for this complication are prescribed a combination (Arthrotec) of diclofenac and misoprostol, a synthetic prostaglandin(PGE1) analogue, to protect the gastric mucosa.

4.An external, gel-based formulation containing 3% of diclofenac (Solaraze) is available for the treatment of facial actinic keratosis caused by over-exposure to sunlight. Some countries have also approved the external use of diclofenac 1% gel to

treat musculoskeletal conditions. 5.In many countries, eye-drops are sold to treat acute and chronic non-bacterial inflammations of the anterior part of the eyes (e.g., postoperative states). A common brand name is Voltaren-optha.

Investigational uses

1.Diclofenac is often used to treat chronic pain associated with cancer, in particular if inflammation is also present (Step I of the World Health Organization(WHO) Scheme for treatment of chronic pain). Good results (sometimes better than those with opioids) have been seen in female breast cancer and in the pain associated with bony metastases. Diclofenac can be combined with opioids if needed. Combaren, a fixed combination of diclofenac and codeine (50 mg each), is available for cancer treatment in urope. Combinations with psychoactive drugs such also been investigated and found useful in a number of cancer patients. 2.Fever due to malignant lymphogranulomatosis (Hodgkin's lymphoma) often responds to diclofenac.Treatment can be terminated as soon as the usual treatment with radiation and/or chemotherapy causes remission of fever. 3.Diclofenac has been found to increase the blood pressure in patients with Shy-Drager syndrome and diabetes mellitus. Currently, this use is highly investigative and cannot as chlorprothixene and/oramitriptyline have

be recommended as routine treatment. 4.Diclofenac has been found to be effective against all strains of multi drug resistant E. coli, with a MIC of 25 micrograms/mL. Therefore, it may be suggested that diclofenac has the capacity to treat uncomplicated urinary tract infections (UTI) caused by E. coli.It has also been shown to be effective in

treating Salmonella infections in mice and is under investigation for the treatment of tuberculosis. Contraindication:

Hypersensitivity against diclofenac History of allergic reactions (bronchospasm, shock, rhinitis, urticaria) following the use of aspirin or another NSAID

Third-trimester pregnancy Active stomach and/or duodenal ulceration or gastrointestinal bleeding Inflammatory intestinal disorders such as Crohn's disease or ulcerative colitis Severe insufficiency of the heart (NYHA III/IV) Recently, a warning has been issued by the FDA not to use for the treatment of patients recovering from heart surgery

Severe liver insufficiency (Child-Pugh Class C) Severe renal insufficiency (creatinine clearance <30 ml/min) Caution in patients with preexisting hepatic porphyria, as diclofenac may trigger Attacks.

Caution in patients with severe, active bleeding such as cerebral hemorrhage NSAIDs in general should be avoided during dengue fever, as it induces (often severe) capillary leakage and subsequent heart failure.

Side Effects 1.Diclofenac is among the better tolerated NSAIDs. Though 20% of patients on long-term treatment experience side-effects, only 2% have to discontinue the drug, mostly due to gastrointestinal complaints.

Cardiac

Diclofenac has similar COX-2 selectivity to celecoxib. A review by FDA Medical Officer David Graham concluded in September, 2006 that diclofenac does increase the risk of Myocardial Infarction.

Gastrointestinal

Gastrointestinal complaints are most often noted (see above). The development of ulceration and/or bleeding requires immediate termination of treatment with diclofenac. Most patients receive an ulcer-protective drug as prophylaxis during long-term treatment bedtime). (misoprostol, ranitidine 150 mg at bedtime or omeprazole 20 mg at

Hepatic

Liver damage occurs infrequently, and is usually reversible. Hepatitis may occur

rarely without any warning symptoms and may be fatal. Patients with osteoarthritis more often develop symptomatic liver disease than patients with rheumatoid arthritis. Liver function should be monitored regularly during long-term treatment. If used for the short-term treatment of pain or fever, diclofenac has not been found to be more hepatotoxic than other NSAIDs.

Mental Health Mental Health side effects have been reported, these symptoms are rare but exist in significant enough numbers to be included as potential side effects. These effects include: depression, anxiety, irritability, nightmares, and psychotic reactions.

Other

Bone marrow depression is noted infrequently (leukopenia, agranulocytosis, thrombopenia with/without purpura, aplastic anemia). These conditions may be life-threatening and/or irreversible, if detected too late. All patients should be monitored closely. Diclofenac is a weak and reversible inhibitor of thrombocytic aggregation needed for normal coagulation. Induces warm antibody hemolytic anemia by inducing antibodies to Rh antigens, ibuprofen also does this.

Diclofenac may disrupt the normal menstrual cycle.

Mechanism of action The exact mechanism of action is not entirely known, but it is thought that the primary mechanism responsible for its anti-inflammatory, antipyretic, and analgesic action is inhibition of prostaglandin synthesis by inhibition of cyclooxygenase (COX). It also appears to exhibit bacteriostatic activity by inhibiting bacterial DNA synthesis. Inhibition of COX also decreases prostaglandins in the epithelium of the stomach, making it more sensitive to corrosion by gastric acid. This is also the main sideeffect of diclofenac. Diclofenac has a low to moderate preference to block the COX2isoenzyme (approximately 10-fold) and is said to have, therefore, a somewhat lower incidence of gastrointestinal complaints than noted with indomethacin and aspirin.

\The action of one single dose is much longer (6 to 8 hours) than the very short halflife that the drug indicates. This could be partly because it persists for over 11 hours in synovial fluids.

Diclofenac may also be a unique member of the NSAIDs. There is some evidence that diclofenac inhibits the lipoxygenase pathways, thus reducing formation of the leukotrienes (also pro-inflammatory autacoids). There is also speculation that

diclofenac may inhibit phospholipase A2 as part of its mechanism of action. These additional actions may explain the high potency of diclofenac it is the most potent NSAID on a broad basis.{Scholer. Pharmacology of Diclofenac Sodium. Am J of Medicine Volume 80 April 28, 1986}

Trade Names Diclo M (India & Myanmar) V.I.P Pharma Dicloberl Diclofenac Diclofenac-Asteria (USA and Korea) Diclofenaco Normon (Spain) Diclofenacum Dicloflex Diclogem Diclogesic (Jordan and Romania) Diclohexal Diclomax Diclowin Plus (India) Diclon Diclopar (Tanzania) Diclotab (Laos) Diklofenak T Actavis (Sweden) Difen Difenac (Venezuela) Difene Dioxaflex (Latin America, Central America) Disflam K (diclofenac potassium, Central America) Dolex

Dolphin (Egypt)

OBJECTIVES Need for Study Fast Mouth Dissolving Tablets (FMDT) are the oral solid dosage forms which when placed on tongue, disintegrates rapidly, releasing the drug, which dissolves or disperses in the saliva and swallowed without the need of drinking water. Thus they are beneficial to patients who find it difficult to swallow tablets particularly the geriatric and pediatric patients. Moreover some of the drugs which are soluble in saliva are absorbed from the mouth, pharynx and oesophagus as the saliva passes down into stomach, which enhances bioavailability by avoiding first pass metabolism. Keeping all these factors in mind, it was considered appropriate to formulate FMDT of Diclofenac Sodium. The literature survey reveals that FMDT of Terbutaline Sulphate have not been prepared so far. Hence an attempt was made to formulated and evaluate FMDT of Diclofenac Sodium using various techniques with the following objectives. To improve the patient compliance To develop a new dosage form convenient for use by geriatric and pediatric patients.

Objectives of the Study 1) To Formulate and Evaluate FMDT of Diclofenac Sodium by A. Direct Compression Method 2) To Evaluate the FMDT formulations of Diclofenac Sodium for A. General Appearance and Physical Parameters such as i. Hardness and ii.Friability of Tablets iii. Weight Variation iv. In-vitro Dispersion time v. In-vitro Dissolution Studies

REVIEW OF LITERATURE Ito, A. and Sugihara, M. (1996)32 prepared Rapidly Disintegrating Tablets as the oral dosage form for elderly patients. In these formulations, they added treated agar powder as the disintegrating agent in various ratios and found that the tablets are showing rapid disintegration in the tongue and thus they can be swallowed easily by the elderly persons having difficulties in swallowing. They proposed that the rapid disintegration of tablets is due to larger pore size. The tablets prepared using treated agar powder have larger pore size that allows faster penetration of saliva into the tablets and results in rapid disintegration in the mouth, and it can be swallowed easily with saliva even in the absence of water. So these tablets are mainly intended for elderly having hand tremors and dysphagia condition. Koizumi, K. et al. (1997)33 prepared Rapidly Disintegrating Tablets as the ideal oral soled dosage form for pediatric and geriatric patients. They prepared these type of tablets by forming highly porous, rapidly saliva soluble compressed tablets using the principle of sublimation. In this method, the addition of a volatile salt to the tabletting components, mixing the components to obtain a substantially homogenous mixture and volatilizing the volatile salt, which causes pores on the tablet. The volatile material used was camphor and the diluent used was mannitol and prepared highly porous compressed tablets. The tablets were subjected to vacuum at 80C for 30 minutes to eliminate camphor and thus creates pores in the tablet, which helps in achieving rapid disintegration when the tablet comes in contact with saliva within 20 seconds and have sufficient hardness also.

Roser, B.J. and Blair, J. (1998)34 described a Method of Preparing highly Porous and Rapidly Dissolving Tablets, which includes the addition of a sublime salt to the tabletting components, compressing the blend and removing the salt by the process of sublimation. The active ingredient, a diluent (eg. lactose and trehalose), a sublime salt (e.g. ammonium bicarbonate, ammonium carbonate and ammonium acetate), a binder and other excipients are blended and tablets are prepared. Then volatile salt is removed by sublimation, by exposing the tablet to reduced atmospheric pressure for a time sufficient to completely remove the salt. Bhushan, S.Y. et al. (2000)35 described Rapidly Disintegrating Oral tablets and Fast Dissolving Dosage forms in the mouth as the New Drug Delivery Systems for the elderly patients. Due to age dependant changes such as physiological and pharmacokinetic changes, elderly patients do not respond to the drug therapy in the same manner as younger adults. Pharmacodynamic changes also play a major role in these age related changes. They described about the various difficulties elderly may experience with existing dosage forms. Various new drug delivery systems for elderly such as jelly preparations, rapidly disintegrating and fast dissolving tablet dosage forms in the mouth were also mentioned. In this they suggested various technologies for the development of rapid disintegrating and fast dissolving tablet dosage forms, and concluded these trends are patient friendly and will be a major area of research in the near future. L.H. et al. (2002)36Reddy,described Fast Dissolving Drug Delivery Systems as the ideal dosage forms for children and elderly, which have the advantages of both solid and liquid dosage forms, and are having various

advantages over the conventional oral solid dosage forms. The characteristics of Fast Dissolving Delivery Systems such as taste of medicament, hygroscopicity, friability are playing a major role in the manufacture of these systems. The various conventional techniques used in the preparation of Fast Dissolving Drug Delivery Systems includes tablet moulding, spray drying, lyophilization, sublimation, Addition of disintegrants, taste masking, also about the various patented technologies such as Zydis, Orasolv, Durasolv, Flashdose, Wowtab, Flashtab were nicely discussed by them. They concluded that the introduction of rapidly disintegrating dosage forms has solved some of the problems encountered in administration of drugs to pediatric and elderly patients, and because of increased patient demand, these dosage forms are expected to become more popular. Indurwade, N. H. et al. (2002)37 have indicated that Fast Dissolving Tablets are accepted widely because it is a novel approach in drug delivery system in adults and children. The swallowing of solid dosage forms like tablet and capsules and improper dosing of suspension and emulsion may produce difficulty for young and adult, and elderly patients suffering from dysphagia, tremors etc. Because of these disadvantages, fast dissolving tablets were developed. They suggested that the main ingredients of these dosage forms are appropriate disintegrating agents, maximizing porous structure of matrix and highly hydrophilic excipients, and should possess some ideal characteristics, pharmacokinetic and pharmcodynamic considerations. The author pointed out the fundamentals of designing and the different technologies to the formulation of fast dissolving tablets such as moulding, spray drying, sublimation, disintegrant addition, Zydis, Wowtab, Orasolv technologies.

Kuchekar, B.S. et al. (2003)38 have described the Mouth Dissolving Tablets as a novel drug delivery system and the concept of these emerged from the desire to provide patients with more conventional means of taking their medication. Mouth dissolving tablets are the ideal dosage form for the patients who can not swallow tablets and hard gelatin capsules, especially for pediatric and geriatric patients. The author pointed out the various criteria for mouth dissolving drug delivery system, their salient features and methods for their preparation such as freez drying, moulding, sublimation, spray drying, mass-extrusion, direct compression, and also the various patented technologies for their manufacture. Finally listed out various examples of marketed preparations of melt-in-mouth tablets. Mane Avainash, R. et al. (2003)39 carried out the Preparation of Mouth Dissolving Tablets of Domperidone using the principle of sublimation, prepared by Using two different components in different ratios, which sublime readily (camphor, ammonium bicarbonate). Here accurately weighed quantities of Domperidone, volatilizable component, mannitol and sodium saccharin were blended, granulated using solution of PEG-4000 in ethanol and after lubrication compressed in to tablets in 8 mm punches in a Cip10 station tablet press. Then these tablets were kept in a hot air oven at 50C for specified time period t allow o for sublimation of volatile constituents. Four formulations with each volatilizable components were prepared. Then the tablets were subjected to various quality control tests and the results were compared with a marketed formulation of Domperidone.

Joel Peres Ashtamkar, et al. (2003)40 prepared Fast Dissolving Tablets of Nabumetone using wet granulation method with diluents like lactose, starch and MCC, binders like starch paste 10%, CMC in water 10% and PVP in alcohol 10%, and superdisintegrants like sodium starch glycollate, croscaramellose sodium, and crospovidone. The granules and tablets prepared were studied for granule yield, particle size distribution, carrs index, hardness of granules, tensile strength of tablets, in vitro disintegration time and in vitro release studies by dissolution test. In-vitro release profiles were compared with the marketed Nabumetone tablets. Sridevi Nayak, M. et al. (2003)41 carried out the Design and Optimization of Fast Dissolving Tablets of PromethazineTheoclate using Fast Dissolving technologies like effervescent melt, superdisintegrant addition and melt technology. All the prepared formulations were evaluated for various granule and tablet characteristics including dissolution rate. Significant rapid release of drug from the formulated tablets was observed in comparison to the control tablet. All optimized tablets released more than 70% of drug within 10 minutes. Tablets from effervescent melt and superdisintegrant addition technique released 92% and 89% of the drug at the end of 10 minutes respectively. But tablets from melt technology released only 71% of the drug at the end of 10 minutes. They concluded that the fast dissolving tablets of Promethazine Theoclate could be successfully prepared, and are tablets with added patient benefits and increased consumer satisfaction. (2004)42 Gohel, M.etal. prepared The Formulation Design and Optimization of Mouth Dissolve Tablets of Nimesulide using Vacuum Drying technique. Granules Containing Nimesulide, camphor, crospovidone, and lactose

were prepared by wet granulation technique. Camphor was sublimed from the dried granules by exposure to vacuum. The porous granules were then compressed into tablets and again exposed to vacuum. Then the tablets were evaluated for percentage friability, wetting time and disintegration time, a 32 full factorial design was used to investigate the joint influence of two formulation variables such as amount of camphor and crospovidone. By the use of multiple linear regression analysis and contour plot, it is revealed that for obtaining a rapidly disintegrating dosage form, tablets should be prepared using an optimum concentration of camphor and higher concentration of crospovidone, and also the effect of the independent variables on the disintegration time and percentage friability. Sublimation of camphor from the tablets resulted in superior tablets as compared with the tablets prepared from granules that were exposed to vacuum. Mahajan, H. S. et al. (2004)43 prepared Mouth Dissolve Tablets of Sumatriptan Succinate, using Disintegrants sodiumstarch glycollate, carboxymethyl cellulose sodium and treated agar by direct compression method. The prepared tablets were evaluated for thickness, uniformity of weight, content uniformity, hardness, tensile strength, porosity, friability, wetting time, water absorption ratio, in vitro and in vivo disintegration time and in vitro drug release. The tablets disintegrated in vitro and in vivo within 10-16 seconds and 12 - 18 seconds respectively. Almost 90% of drug was released from all formulations within 10 minute. The formulations containing combination of sodium starch glycollate and carboxy methyl cellulose was found to give best results. The tablets apart from fulfilling all official and other specifications, exhibits higher rate of drug release.

Kaushik, D. et al. (2004)24 have indicated that Mouth Dissolve Tablet is a novel type of oral solid dosage form which disintegrates and dissolves rapidly in saliva and swallowed without the need of drinking water, and is mainly suited for aged patients, mentally ill, uncooperative and nauseated patients, and in pediatric patients. The author mentioned in detail that, to improve patient compliance, mouth dissolving tablets have emerged as an alternative to conventional oral dosage forms. Freeze-drying, sublimation, spray drying, disintegrant addition, tablet moulding and use of sugar based excipients are the current techniques available for the formulati o Mouth Dissolving Tablets Fuiz Technology, Shearform Technology, Ceform Technology, Yamanouchi Pharma Technology are the patented technologies utilizing sugar based excipients for formulating mouth dissolving tablets. Despite the different mechanisms involved in these technologies, the aim is to provide the tablet that quickly disintegrates upon the contact with saliva and also to provide a good mouth feel. Kaushik D. et al. (2004)44 carried out the Formulation and Evaluation of Olanzapine Mouth Dissolving Tablets by Effervescent Formulation Approach. Addition of an effervescent system in the formulation is one of the approaches by which mouth dissolving tablets can be prepared, which have the advantage of easiness to implement, masking of the bitter taste of drug, and aids in rapid disintegration of tablets in the oral cavity. In the study, sodium bicarbonate and citric acid were used as effervescent agents and their ratio in the formulation was optimized. The study revealed that 10:8 ratio of sodium bicarbonate and citric acid in the Olanzapine mouth dissolving tablets gave a soothing fizz, excellent mouth feel, good palatability and quick dissolution profile.

Dandagi, P.M. et al. (2005)50 prepared Taste Masked Mouth Disintegrating Tablets of Ofloxacin. The tablets were prepared by addition of sweeteners and disintegrants using aspartame and sodium starch glycollate, and by mass extrusion technique. Six formulations were prepared by wet granulation method. The prepared tablets were evaluated for uniformity of thickness, hardness test, friability test, weight variation test, drug content uniformity and in-vitro disintegration test. The tablets were also evaluated for special parameters like wetting time, in-vivo disintegration, mouth feel, in-vitro dissolution studies and stability studies. The formulations prepared by mass extrusion techniques was found to be with rapid disintegration and dispersion characteristics, which is due to the tablet porosity, hydrophilicity, swelling ability, and inter particular force.

Instruments Used

Equipments Model/Company

1. UV Visible Recording 2. Electronic Balance

Spectrophotometer

3. Single Stroke Tabletting Compression

4. Vacuum Desiccator

5. Roche Tablet Friabilator

6. Tablet Dissolution Tester

7. Tablet Hardness Tester

METHODS 1) (A) CALIBRATION CURVE OF DICLOFENAC SODIUM a) Preparation of Standard Stock solution of Diclofenac sodium b) Spectrophotometric scanning of Diclofenac sodium (B) PREPARATION OF REAGENTS 2) FORMULATION OF FAST MOUTH DISSOLVING TABLETS OF DICLOFENAC SODIUM Preparation of FMDT of Diclofenac Sodium by Direct Compression 3) EVALUATION OF FAST MOUTH DISSOLVINGTABLETS OF DICLOFENAC SODIUM a) Hardness b) Friability of Tablets c) Weight variation d) In vitro Dispersion Time e) In-vitro Dissolution Studies DETERMINATION OF MAX AND PREPARATION OF

1) (A) DETERMINATION OF MAX AND PREPARATION OF CALIBRATION CURVE OF DICLOFENAC SODIUM a) Preparation of Standard Stock Solution 100 mg of Diclofenac sodium was accurately weighed and transferred in to a 100 ml volumetric flask and dissolved in distilled water. Then volume was made up to 100 ml. This was the standard stock solution containing 1 mg/ml i.e. (1000 /) of Diclofenac Sodium (Stock I) b) Take 100 mg powder of Diclofenac Sodium and dissolve in 100 ml of pH 6.8 phosphate buffer. This is stock solution. Pipette out 10 ml from this and dilute up to 100 ml using pH 6.8 phosphate buffer. Now pipette out 1, 2, 3, 4 and 5 ml from above solution and dilute up to 10 ml. Measure the absorbance at 283 nm using UV/Visible spectrophotometer and plot the graph of concentration (g/ml) versus absorbance.

(B)PREPARATION OF REAGENTS

Preparation of 0.2 M Potassium dihydrogen phosphate

Dissolve 27. 218 gm of Potassium dihydrogen phosphate in distilled water and diluted the volume to 1000 ml with distilled water

Preparation of 0.2 M Sodium Hydroxide

Dissolve 8.0 gm of Sodium Hydroxide in distilled water and dilut ed the volume to 1000 ml with distilled water.

Preparation of pH 6.8 phosphate buffer (Simulated saliva pH

Place 50 ml of 0.2 M Potassium dihydrogen phosphate in a 200 ml

volumetric flask, added 22.4 ml of 0.2M Sodium Hydroxide, mixed, and volume was made upto 200 ml with distilled water.

Preparation of tablets:

Weigh all the ingredients accurately according to Table 1and pass through sieve # 40. Mix all the ingredients geometrically except, Talc and Magnesium Stearate. Then lubricate the blend with, Talc and Magnesium Stearate. Powder mixture was compressed on eight station rotary tableting machine (Hardik engineering works, Ahmedabad, India). Tablets, each weighing 260 mg, were prepared. Table 1 illustrates the formulation design of tablets

Tablet Ingredients (mg) Diclofenac Sodium Mannitol

F1 25

F2 25

F3 25

F4 25

F5 25

F6 25

29

30

30

30

30

30

MCC

120

114

109

111

100

97

Lactose

50

50

50

50

54

50

Sodim Starch Glycolate PVP

20

25

30

20

25

30

10

12

Mint

Talc

Magnesium Stearate

EVALUATION PARAMETERS OF DRUG Weight Variation Twenty tablets were selected at a random and average weight was determined. Then individual tablets were weighed and the individual weight was compared with a average weight . Hardness and Friability Friability of tablets was checked by using Roche Friabilator. The device subjects a number of tablets to the combined effect of abrasions and shock by utilizing a plastic chamber that revolves at 25 rpm, dropping the tablets at distance of 6 inches with each revolution. Preweighed sample of tablets was placed in the friabilator, which was then operated for 100 revolutions. Tablets were dusted and reweighed. Tablet requires certain amount of hardness to withstand mechanical shock. Tablet hardness has been defined as the force required to break a tablet in a diametric compression test. The Pfizer tester and Monsanto tester are mainly used to measure tablet hardness . In-vitro Disintegration Time Tablet was added to 20 ml of water containing beaker, at 37 0.5 C. Time required for complete disintegration of a tablet was measured. Table 3 illustrates disintegration time of various formulations

Thickness Thickness is measured by sliding calliper scale (Vernier callipers). Tablet thickness should be controlled within 5% variation of a standard value

Dissolution Study
TESTS Weight Variation ( %) Hardness (Kg/cm2) Friability (%) In-vitro Disintegration Time (sec) F1 3.0 3.2 0.76 106 F2 3.3 3.4 0.80 91 F3 3.4 3.6 0.86 69 F4 2.3 3.9 0.74 52 F5 2.4 3.7 0.72 40 F6 2.6 3.3 0.96 32

Dissolution rate was studied by using USP type II apparatus, rotated at 75 rpm; 900 ml of Phosphate buffer pH 6.8 was used as dissolution medium. Temperature of dissolution medium was maintained at 37 0.5 C. Aliquot of dissolution medium was withdrawn at specific time interval and it was filtered. Absorption of filtered solution was checked by UV spectroscopy at 283 nm and drug content was determined from standard calibration curve. Dissolution rate was studied for all designed formulations. Table 4 illustrates dissolution data of tablets. Figure 2 and 3 illustrate the graph of cumulative % drug release versus Time and % Dissolution efficiency versus Formulation batches respectively

Cumulative % Drug Release

Time(Min) 0 3 6 9 12

F1 0 29.2 49.3 65.8 78.2

F2 0 32.8 53.4 71.2 79.8

F3 0 36.7 61.9 75.8 86.5

F4 0 39.9 64.3 78.7 87.2

F5 0 41.1 67.4 84.7 92.3

F6 0 42.8 68.9 85.9 93.2

15

85.9

87.1

90.2

92.3

95.9

96.1

18

92.3

93.5

94.8

95.6

97.8

97.9

0100090000032a0200000200a20100000000a201000026060f003a03574d4643010000000000 010059290000000001000000180300000000000018030000010000006c000000000000000000000035 0000006f0000000000000000000000614c0000d037000020454d4600000100180300001200000002000 0000000000000000000000000000013000008190000ce0000000f010000000000000000000000000000 b024030098220400160000000c000000180000000a0000001000000000000000000000000900000010 0000000a1200002d0d0000250000000c0000000e000080250000000c0000000e0000805200000070010

00001000000a4ffffff000000000000000000000000900100000000000004400022430061006c0069006 2007200690000000000000000000000000000000000000000000000000000000000000000000000000 0000000000000000000000000000000001100b0b311001000000014b7110094b411005251603214b71 1000cb41100100000007cb51100f8b611002451603214b711000cb411002000000049642f310cb41100 14b7110020000000fffffffffc46d600d0642f31ffffffffffff0180ffff01800fff0180ffffffff00000b000008000 00008000010bf120001000000000000005802000025000000372e90010000020f0502020204030204ef 0200a07b20004000000000000000009f00000000000000430061006c0069006200720000000000c091e 20270a0603203a169a7dc46d600b444c70040b411009c38273106000000010000007cb411007cb41100 e878253106000000a4b41100fc46d6006476000800000000250000000c00000001000000250000000c0 0000001000000250000000c00000001000000120000000c00000001000000180000000c00000000000 00254000000540000000000000000000000350000006f00000001000000bd868740b25487400000000 057000000010000004c0000000400000000000000000000000b1200002f0d0000500000002000104636 00000046000000280000001c0000004744494302000000ffffffffffffffff0b1200002d0d00000000000046 00000014000000080000004744494303000000250000000c0000000e000080250000000c0000000e000

RESULT AND DISCUSSION The compositions of the formulations are shown in the table.The evaluation parameters like Weight variation , friability , hardness , thickness and disintegration time of the prepared fastdisintegrating tablets were satisfactory. The last two formulations { f5 and f6 } showed suffiecently decrease in disintegration time i.e. 40 Sec and 32 sec respectively. The Concept of super disintegrant addition method proved to be beneficial in oeder to lower the disintegration time. The quicker disintegration time may be attributed to faster water uptake by the tablets. When Sodim Starch Glycolate was used alone in the formulations,decrease in the disintegration time was noticed . Dissolution profiles revealed that, after 20 minutes, formulations F1-F2 shows %Drug release of 78.2,79.8,86.5 87.3,92.3 and 93.2 respectively . As fast disintegrating for formulations F5 and F6 showed almost similar % drug release and disintegration time and there is no rationable behind using higher amount of super disintegration ; formulation batch F5 can be said optimized for fast disintegrating tablets. Friabillty of all batches was in the range of standard limit (less than 1%). CONCLUSION:The fast disintegrating tablets of Diclofenac sodium were formulated by using the super disintegrant, Sodim Starch Glycolate. The super disintegrants, Sodim Starch Glycolate at a concentration of 10 % of the dosage from was found successful to prepare fast disintegrating tablets by direct compression method. The Proposed fast disintegrating formulation possessed ideal and reproducible characteristics of disintegration time and drug release profile.