FORMULATION AND EVALUATION OF FAST DISINTERGRATING TABLET OF SODIUM DICLOFENAC

AProject Report Submitted to Uttar Pradesh Technical University For the award of the degree ofBACHELOR 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

CERTIFICATEThe 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 candidateAs 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

Profileto

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