Sudhir Bharawaj et al.

/ Drug Invention Today 2010,2(1),81-88

ISSN: 0975-7619

Available online through www.ditonline.info Review Article

Orally Disintegrating Tablets: A Review

Sudhir Bharawaj*, Vinay Jain, Shailesh Sharma, R. C. Jat and Suman Jain *Pharmaceutics and Dosage Form Development Research Laboratory, Department of Pharmaceutics, Shriram College of Pharmacy,Banmore, Morena (M.P.) (INDIA) Received on: 10-06-2009; Revised on: 21-08- 2009; Accepted on:25-12-2009 ABSTRACT
Over a decade, the demand for development of orally disintegrating tablets (ODTs) has enormously increased as it has significant impact on the patient compliance. Orally disintegrating tablets offer an advantage for populations who have difficulty in swallowing. Prescription ODT products initially were developed to overcome the difficulty in swallowing conventional tablets with water among pediatric, geriatric, and psychiatric patients with dysphagia. Today, ODTs are more widely available as over-the-counter products for the treatment of allergies and cold and flu symptoms. Technologies used for manufacturing of orally disintegrating tablets are either conventional technologies or patented technologies. In conventional freeze drying, tablet molding, sublimation, spray drying etc. and in patented Zydis technology, Orasolv technology, Durasolv technology, Wowtab technology, Flashdose technology are important. Important ingredients that are used in the formulation of ODTs should allow quick release of the drug, resulting in faster dissolution. Evaluation of these tablets are done by following weight variation, friability, tensile strength, wetting time, water absorption ratio, In vitro dispersion time and dissolution test.

Keywords: Orally disintegrating tablets, Orasolv, tensile strength, sublimation INTRODUCTION The most important drug delivery route is undoubtedly the oral route. It offers advantages of convenience of administration and potential manufacturing cost savings. Drugs that are administered orally, solid oral dosage forms in general and tablets in particular represent the preferred class of product. Today drug delivery companies are focusing on solid oral drug delivery systems that offer greater patient compliance and effective dosages.1 Tablet is the most popular among all dosage forms existing today because of its convenience of self administration, compactness and easy manufacturing. Many patients find it difficult to swallow tablets and hard gelatin capsules and do not take their medication as prescribed. In a survey conducted by Honda and Nakano, half of the patients experienced difficulty taking medication, such as tablet and capsule which results in a high incidence of non-compliance and ineffective therapy. The difficulty is experienced in particular by pediatric and geriatric patients, but it also applies to people who are ill in bed and to those active working patients who are busy or traveling, especially those who have no access to water. 2 Over a decade, the demand for development of orally disintegrating tablets (ODTs) has enormously increased as it has significant impact on the patient compliance. Orally disintegrating tablets offer an *Corresponding author.
Dr.Sudhir Bharawaj Dean and Asst.Professor Pharmaceutics Research Laboratory, Department Of Pharmaceutics, Shriram College of Pharmacy, Banmore, Morena, (M.P.), Mobile Tel.:+91-9669134020 E-mail: sudhiritsbj@yahoo.com

advantage for populations who have difficulty in swallowing. It has been reported that Dysphagia (difficulty in swallowing) is common among all age groups and more specific with pediatric, geriatric population along with institutionalized patients and patients with nausea, vomiting, and motion sickness complications. ODTs with good taste and flavor increase the acceptability of bitter drugs by various groups of population. Orally disintegrating tablets are also called as orodispersible tablets, quick disintegrating tablets, mouth dissolving tablets, fast disintegrating tablets, fast dissolving tablets, rapid dissolving tablets, porous tablets, and rapimelts. However, of all the above terms, United States pharmacopoeia (USP) approved these dosage forms as ODTs. Recently, European Pharmacopoeia has used the term orodispersible tablet for tablets that disperses readily and within 3 min in mouth before swallowing. United States Food and Drug Administration (FDA) defined ODT as A solid dosage form containing medicinal substance or active ingredient which disintegrates rapidly usually within a matter of seconds when placed upon the tongue. The disintegration time for ODTs generally ranges from several seconds to about a minute. 3 IDEAL ODTs SHOULD4 1. Require no water for oral administration, yet dissolve / disperse/ disintegrate in mouth in a matter of seconds. 2. Have a pleasing mouth feel. 3. Have an acceptable taste masking property. 4. Be harder and less friable 5. Leave minimal or no residue in mouth after administration 6. Exhibit low sensitivity to environmental conditions (tempera81-88

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Sudhir Bharawaj et al. / Drug Invention Today 2010,2(1),81-88 7. ture and humidity). Allow the manufacture of tablet using conventional processing and packaging equipments. gies like Zydis need special type of packaging. It is very natural that increasing the mechanical strength will delay the disintegration time. So a good compromise between these two parameters is always essential. 2. Taste masking: Many drugs are bitter in taste. A tablet of bitter drug dissolving/ disintegration in mouth will seriously affect patient compliance and acceptance for the dosage form. So effective taste masking of the bitter drugs must be done so that the taste of the drug is not felt in the oral cavity. 3. Mouth feel: The ODT should not disintegrate into larger particles in the oral cavity. The particles generated after disintegration of the ODT should be as small as possible. ODT should leave minimal or no residue in mouth after oral administration. Morever addition of flavours and cooling agents like menthol improve the mouth feel. 4. Sensitivity to environmental conditions: ODT generally should exhibit low sensitivity to environment conditions such as humidity and temperature as most of the materials used in a ODT are meant to dissolve in minimum quantity of water. 5. Cost: The technology used for a ODT should be acceptable in terms of cost of the final product. Methods like Zydis and Orasolv that require special technologies and specific packaging increase the cost to a remarkable extent6. LIMITATIONS OF ORALLY DISINTEGRATING TABLETS 1. Drugs with relatively larger doses are difficult to formulate into MDT e.g. antibiotics like ciprofloxacin with adult dose tablet containing about 500 mg of the drug. Patients who concurrently take anticholinergic medications may not be the best candidates for MDT. Similarly patients with Sjgrens syndrome or dryness of the mouth due to decreased saliva production may not be good candidates for these tablet formulations. TECHNOLOGIES USED FOR MANUFACTURING OF ORALLY DISINTEGRATING TABLETS Conventional Technologies 1. 2. 3. 4. 5. Freeze Drying. Tablet Molding. Sublimation. Spray Drying. Mass extrusion. Direct Compression

ADVANTAGES OF ODTs 4,5 1. Administration to the patients who can not swallow, such as the elderly, stroke victims, bedridden patients, patients affected by renal failure & patients who refuse to swallow such as pediatric, geriatric & psychiatric patients. 2. Rapid drug therapy intervention. 3. Achieve increased bioavailability/rapid absorption through pregastric absorption of drugs from mouth, pharynx & oesophagus as saliva passes down. 4. Convenient for administration and patient compliant for disabled, bedridden patients and for travelers and busy people, who do not always have access to water. 5. Good mouth feel property helps to change the perception of medication as bitter pill particularly in pediatric patients. 6. The risk of chocking or suffocation during oral administration of conventional formulations due to physical obstruction is avoided, thus providing improved safety. 7. New business opportunity like product differentiation, product promotion, patent extension and life cycle management. SALIENT FEATURES OF ORALLY DISINTEGRATING TABLETS 1. Ease of administration to patients who refuse to swallow a tablet, such as paediatric and geriatric patients and, psychiatric patients. 2. Convenience of administration and accurate dosing as compared to liquids. 3. No need of water to swallow the dosage from, which is highly convenient feature for patients who are traveling and do not have immediate access to water. 4. Good mouth feels properly of ODTs helps to change the basic view of medication as bitter pill, particularly for paediatric patients. 5. Rapid dissolution of drug and absorption which may produce rapid, onset of action. 6. Some drugs are absorbed from the month pharynx and oesophagus as the saliva passes down into the stomach, in such cases bioavailability of drugs is increased. 7. Ability to provide advantages of liquid medication in the form of solid preparation. 8. Pregastric absorption can result in improved bioavailability and as a result of reduced dosage, improved clinical performance through a reduction of unwanted effects. CHALLENGES IN THE FORMULATION OF ORALLY DISINTEGRATING TABLETS 1. Mechanical strength and disintegration time: ODTs are formulated to obtain disintegration time usually less than a minute. While doing so, maintaining a good mechanical strength is a prime challenge. Many ODTs are fragile and there are many chances that such fragile tablet will break during packing, transport or handling by the patients. Tablets based on technoloDrug Invention Today Vol.2.Issue.1.January 2010

Patented Technologies 1. 2. 3. 4. 5. 6. 7. Zydis Technology. Orasolv Technology. Durasolv Technology. Wowtab Technology. Flashdose Technology. Flashtab Technology. Oraquick Technology

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Sudhir Bharawaj et al. / Drug Invention Today 2010,2(1),81-88 Conventional Technologies 7-9 Freeze drying A process in which water is sublimated from the product after freezing. Lyophilization is a pharmaceutical technology which allows drying of heat sensitive drugs and biological at low temperature under conditions that allow removal of water by sublimation. Lyophilization results in preparations, which are highly porous, with a very high specific surface area, which dissolve rapidly and show improved absorption and bioavailability. Tablet molding In this method, molded tablets are prepared by using water-soluble ingredients so that the tablets dissolve completely and rapidly. The powder blend is moistened with a hydro-alcoholic solvent and is molded into tablets under pressure lower than that used in conventional tablet compression. The solvent is then removed by air-drying. Molded tablets are very less compact than compressed tablets. These possess porous structure that enhances dissolution. Sublimation The slow dissolution of the compressed tablet containing even highly water-soluble ingredients is due to the low porosity of the tablets. Inert solid ingredients that volatilize readily (e.g. urea, ammonium carbonate, ammonium bicarbonate, hexa methelene tetramine, camphor etc.) are added to the other tablet ingredients and the mixture is compressed into tablets. The volatile materials are then removed via sublimation, which generates porous structures. Additionally, several solvents (e.g. cyclohexane, benzene) can be also used as pore solve rapidly. The formulations are incorporated by hydrolyzed and non hydrolyzed gelatins as supporting agents, mannitol as bulking agent, sodium starch glycolate or crosscarmellose sodium as disintegrating and an acidic material (e.g. citric acid) and / or alkali material (e.g. I sodium bicarbonate) to enhance disintegration and dissolution. Tablet compressed from the spray dried powder disintegrated within 20 seconds when immersed in an aqueous medium. Mass-extrusion This technology involves softening the active blend using the solvent mixture of water soluble polyethylene glycol, using methanol and expulsion of softened mass through the extruder or syringe to get a cylinder of the product into even segments using heated blade to form tablets. The dried cylinder can also be used to coat granules of bitter tasting drugs and thereby masking their bitter taste. Direct compression Easiest way to manufacture tablets is direct compression. Low manufacturing cost, conventional equipments and limited number of processing steps led this technique to be a preferable one. However disintegration and dissolution of directly compressed tablets depend on single or combined effect of disintegrant, water soluble excipients and effervescing agents. It is essential to choose a suitable and an optimum concentration of disintegrant to ensure quick disintegration and dissolution. Superdisintegrants are newer substances which are more effective at lower concentrations with greater disintegrating efficiency and mechanical strength. On contact with water the superdisintegrants swell, hydrate, change volume or form and produce a disruptive change in the tablet. Effective superdisintegrants provide improved compressibility, compatibility and have no negative impact on the mechanical strength of formulations containing high dose drugs. The type of disintegrants and its proportion are of prime importance. Also factors to be considered are particle size distribution, contact angle, pore size distribution and water absorption capacity. Studies revealed that the water insoluble superdisintegrants like sodium starch glycolate and Croscarmellose sodium show better disintegration property than the slightly water soluble agents like Crospovidone, since they do not have a tendency to swell. Superdisintegrants that tend to swell show slight retardation of the disintegration property due to formation of viscous barrier. There is no particular upper limit regarding the amount of superdisintegrant as long as the mechanical properties of the tablet are compatible with its intended use. The superdisintegrant may be used alone or in combination with other superdisintegrants.

Figure. 1 Steps Involved in sublimation Spray-drying Spray drying can produce highly porous and fine powders that dis-

Table 1 Various commercially available superdisintegrants along with their properties.

Sr. 1. 2. 3. 4. Name Crospovidone Croscarmellose Sodium. Sodium starch Glycolate Indion 414 Type Polyvinyl-pyrrolidone Modified cellulose Modified Starch Ion exchange Resin Properties Crossed linked Polyvinlypyrrolidone Rapidly disperses and swells in water Cross linked sodium carboxy methylcellulose. Excellent swelling and water wicking properties. Sodium salt of carboxy methyl ether of starch. High swelling capacity and rapid water uptake Cross linked polyacrylic with a -COO - functional group and K + ionic form. High water intake facility. Brand name Polyplasdone XL, Kollidon CL Ac-di-sol, Primellose, Solutab. Primogel, Explotab, Glycolys. Indion 414.

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Sudhir Bharawaj et al. / Drug Invention Today 2010,2(1),81-88 dichlorophen, ivermectin, mebendazole, oxamniquine, oxfendazole, Patented Technologies 10-14 oxantel embonate, praziquantel, pyrantel embonate, thiabendazole. Zydis technology Anti-arrhythmic Agents Zydis, the best known of the fast-dissolving/disintegrating tablet Amiodarone HCl, Disopyramide, flecainide acetate, quinidine preparations was the first marketed new technology tablet. The tablet sulphate. dissolves in the mouth within seconds after placement on the tongue. Anti-bacterial Agents A Zydis tablet is produced by lyophilizing or freeze-drying the drug Benethamine penicillin, cinoxacin, ciprofloxacin HCl, clarithromycin, in a matrix usually consisting of gelatin. The product is very light- clofazimine, cloxacillin, demeclocycline, doxycycline, erythromycin, weight and fragile, and must be dispensed in a special blister pack. ethionamide, imipenem, nalidixic acid, nitrofurantoin, rifampicin, Patients should be advised not to push the tablets through the foil spiramycin, sulphabenzamide, sulphadoxine, sulphamerazine, film, but instead peel the film back to release the tablet. The Zydis sulphacetamide, sulphadiazine, sulphafurazole, sulphamethoxazole, product is made to dissolve on the tongue in 2 to 3 seconds. The sulphapyridine, tetracycline, trimethoprim. Zydis formulation is also self-preserving because the final water con- Anti-coagulants centration in the freeze-dried product is too low to allow for microbial Dicoumarol, dipyridamole, nicoumalone, phenindione. growth. Anti-depressants Amoxapine, ciclazindol, maprotiline HCl, mianserin HCl, nortriptyline Durasolv technology HCl, trazodone HCl, trimipramine maleate. Durasolv is the patented technology of CIMA labs. The tablets made Anti-diabetics by this technology consist of a drug, fillers and a lubricant. Tablets Acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, are prepared by using conventional tableting equipment and have tolazamide, tolbutamide. good rigidity. These can be packed into conventional packaging sys- Anti-epileptics tem like blisters. Durasolv is an appropriate technology for products Beclamide, carbamazepine, clonazepam, ethotoin, methoin, requiring low amounts of active ingredients. methsuximide, methylphenobarbitone, oxcarbazepine, parame Orasolv technology thadione, phenacemide, phenobarbitone, phenytoin, phensuximide, Orasolv Technology has been developed by CIMA labs. In this sys- primidone, sulthiame, valproic acid. tem active medicament is taste masked. It also contains effervescent Anti-fungal Agents disintegrating agent. Tablets are made by direct compression tech- Amphotericin, butoconazole nitrate, clotrimazole, econazole nitrate, nique at low compression force in order to minimize oral dissolution fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, time. Conventional blenders and tablet machine is used to produce Table2 Comparison of Orally Disintegrating Tablets Technologies
ZYDIS (R.P. SCHERER, INC.) Novelty First to market Freeze Dried ORASOLV (CIMA LABS, INC.) Novelty Unique taste masking Lightly compressed DURASOLV (CIMA LABS, INC.) Novelty Similar to Orasolv, but with better mechanical strength Handling/Storage Do not push tablet through foil Do not use dosage form from damaged package Sensitive to degradation at humidities >65% Handling/Storage Packaged in patented foil packs Drug Release/Bioavailability Dissolves in 2 to 10 seconds May allow for pre-gastric absorption leading to enhanced bioavailability

Drug Release/Bioavailability Disintegrates in 5 to 45 seconds depending upon the size of the tablet No significant change in drug bioavailability Drug Release/Bioavailability Disintegrates in 5 to 45 seconds depending upon the size of the tablet No significant change in drug bioavailability Drug Release/Bioavailability Disintegrates in 5 to 45 seconds depending upon the size of the tablet No significant change in drug bioavailability

Handling/Storage Packaged in foil or bottles If packaged in bottles, avoid exposure to moisture or humidity WOWTAB (YAMANOUCHI PHARMA TECHNOLOGIES, INC.) Novelty Handling/Storage Compressed dosage form Package in bottles Proprietary taste masking Avoid exposure to moisture or humidity SMOOTHMELT action gives superior mouth feel

DRUGS TO BE PROMISING INCORPORATED IN ORALLY DISINTEGRATINGTABLETS 15-23 There are no particular limitations as long as it is a substance which is used as a pharmaceutical active ingredient. Analgesics and Anti-inflammatory Agents Aloxiprin, auranofin, azapropazone, benorylate, diflunisal, etodolac, fenbufen, fenoprofen calcim, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam, sulindac. Anthelmintics Albendazole, bephenium hydroxynaphthoate, cambendazole, Drug Invention Today Vol.2.Issue.1.January 2010

miconazole, natamycin, nystatin, sulconazole nitrate, terbinafine HCl, terconazole, tioconazole, undecenoic acid. Anti-gout Agents Allopurinol, probenecid, sulphinpyrazone. Anti-hypertensive Agents Amlodipine, carvedilol, benidipine, darodipine, dilitazem HCl, diazoxide, felodipine, guanabenz acetate, indoramin, isradipine, minoxidil, nicardipine HCl, nifedipine, nimodipine, phenoxybenzamine HCl, prazosin HCL, reserpine, terazosin HCl. Anti-malarials Amodiaquine, chloroquine, chlorproguanil HCl, halofantrine HCl, mefloquine HCl, proguanil HCl, pyrimethamine, quinine sulphate. 81-88

Sudhir Bharawaj et al. / Drug Invention Today 2010,2(1),81-88 Local Anaesthetics Anti-migraine Agents Dihydroergotamine mesylate, ergotamine tartrate, methysergide Lidocaine Neuro -muscular Agents maleate, pizotifen maleate, sumatriptan succinate. Pyridostigmine. Anti-muscarinic Agents Atropine, benzhexol HCl, biperiden, ethopropazine HCl, hyoscine Nitrates and other Anti-anginal Agents butyl bromide, hyoscyamine, mepenzolate bromide, orphenadrine, Amyl nitrate, glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate, pentaerythritol tetranitrate. oxyphencylcimine HCl, tropicamide Nutritional Agents Anti-neoplastic Agents and Immunosuppressants Aminoglutethimide, amsacrine, azathioprine, busulphan, chloramb Betacarotene, vitamin A, vitamin B 2 , vitamin D, vitamin E, vitamin K. ucil, cyclosporin, dacarbazine, estramustine, etoposide, lomustine, Opioid Analgesics melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, Codeine, dextropropyoxyphene, diamorphine, dihydrocodeine, meptazinol, methadone, morphine, nalbuphine, pentazocine. mitozantrone, procarbazine HCl, tamoxifen citrate, testolactone. Oral Vaccines Anti-protazoal Agents Benznidazole, clioquinol, decoquinate, diiodohydroxyquinoline, Vaccines designed to prevent or reduce the symptoms of diseases of diloxanide furoate, dinitolmide, furzolidone, metronidazole, nimorazole, which the following is a representative Influenza, Tuberculosis, Meningitis, Hepatitis, Whooping Cough, Polio, Tetanus, Diphtheria, nitrofurazone, omidazole, tinidazole. Malaria, Cholera, Herpes, Typhoid, HIV AIDS, Measles, Lyme disease, , Anti-thyroid Agents Travellers Diarrhea, Hepatitis A, B and C, Otitis Media, Dengue Fever, Carbimazole, propylthiouracil. Rabies, Parainfluenza, Rubella, Yellow Fever, Dysentery, Legionnaires Anxiolytic , Sedatives, Hypnotics and Neuroleptics Alprazolam, amylobarbitone, barbitone, bentazepam, bromazepam, Disease, Toxoplasmosis, Q-Fever, Haemorrhegic Fever, Argentina bromperidol, brotizolam, butobarbitone, carbromal, chlordiazepoxide, Haemorrhagic Fever, Caries, Chagas Disease, Urinary Tract Infection chlormethiazole, chlorpromazine, clobazam, clotiazepam, clozapine, caused by E.coli, Pneumoccoccal Disease, Mumps, and Chikungunya. diazepam, droperidol, ethinamate, flunanisone, flunitrazepam, Vaccines to prevent or reduce the symptoms of other disease fluopromazine, flupenthixol decanoate, fluphenazine decanoate, syndromes of which the following is a representative not exclusive flurazepam, haloperidol, lorazepam, lormetazepam, medazepam, list of causative organisms: Vibrio species, Salmonella species, meprobamate, methaqualone, midazolam, nitrazepam, oxazepam, Bordetella species, Haemophilus species, Toxoplasmosis gondii, pentobarbitone, perphenazine pimozide, prochlorperazine, sulpiride, Cytomegalovirus, Chlamydia species, Streptococcal species, Norwalk Virus, Escherischia coli, Helicobacter pylori, Rotavirus, Neisseria temazepam, thioridazine, triazolam, zopiclone. gonorrhae, Neisseria meningiditis, Adenovirus, Epstein Barr Virus, -Blockers Acebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol, Japanese Encephalitis Virus, Pneumocystis carini, Herpes simplex, Clostridia species, Respiratory Syncytial Virus, Klebsielia species, oxprenolol, pindolol,propranolol. Shigella species, Pseudomonas aeruginosa, Parvovirus, Cardiac Inotropic Agents Campylobacter species, Rickettsia species, Varicella zoster, Yersinia Amrinone, digitoxin, digoxin, enoximone, lanatoside C, medigoxin. species, Ross River Virus, J.C. Virus, Rhodococcus equi, Moraxella Corticosteroids Beclomethasone, betamethasone, budesonide, cortisone acetate, catarrhalis, Borrelia burgdorferi and Pasteurella haemolytica. Vaccines desoxymethasone, dexamethasone, fludrocortisone acetate, directed to non-infections immuno-modulated disease conditions flunisolide, flucortolone, fluticasone propionate, hydrocortisone, such as topical and systematic allergic conditions such as Hayfever, Asthma, Rheumatoid Arthritis and Carcinomas. methylprednisolone, prednisolone, prednisone, triamcinolone. Vaccines for veterinary use include those directed to Coccidiosis, Diuretics Acetazolamide, amiloride, bendrofluazide, bumetanide, chlorothiazide, Newcastle Disease, Enzootic pneumonia, Feline leukaemia, Atrophic chlorthalidone, ethacrynic acid, frusemide, metolazone, rhinitis, Erysipelas, Foot and Mouth disease, Swine, pneumonia, and other disease conditions and other infections and auto-immune spironolactone, triamterene. disease conditions affecting companion and farm animals. Anti-parkinsonian Agents Proteins, Peptides and Recombinant drugs Bromocriptine mesylate, lysuride maleate. Insulin (hexameric/dimeric/monomeric forms), glucagon, growth Gastro-intestinal Agents Bisacodyl, cimetidine, cisapride, diphenoxylate HCl, domperidone, hormone (somatotropin), polypeptides or their derivatives, (preferably famotidine, loperamide, mesalazine, nizatidine, omeprazole, with a molecular weight from 1000 to 300,000), calcitonins and ondansetron HCL, ranitidine HCl, sulphasalazine. synthetic modifications thereof, enkephalins, interferons (especially Alpha-2 interferon for treatment of common colds), LHRH and Histamine H,-Receptor Antagonists Acrivastine, astemizole, cinnarizine, cyclizine, cyproheptadine HCl, analogues (nafarelin, buserelin, zolidex), GHRH (growth hormone dimenhydrinate, flunarizine HCl, loratadine, meclozine HCl, oxatomide, releasing hormone), secretin, bradykin antagonists, GRF (growth releasing factor), THF, TRH (thyrotropin releasing hormone), ACTH terfenadine, triprolidine. analogues, IGF (insulin like growth factors), CGRP (calcitonin gene Lipid Regulating Agents related peptide), atrial natriurectic peptide, vasopressin and analogues Bezafibrate, clofibrate, fenofibrate, gemfibrozil, probucol. (DDAVP, lypressin), factor VIII, G-CSF (granulocyte-colony stimulatingfactor),EPO(erythropoitin). Drug Invention Today Vol.2.Issue.1.January 2010 81-88

Sudhir Bharawaj et al. / Drug Invention Today 2010,2(1),81-88 Sex Hormones Clomiphene citrate, danazol, ethinyloestradiol, medroxyprogesterone acetate, mestranol, methyltestosterone, norethisterone, norgestrel, oestradiol, conjugated oestrogens, progesterone, stanozolol, stiboestrol, testosterone, tibolone. INGREDIENTS TO BE USED FOR ODTS Important ingredients that are used in the formulation of ODTs should allow quick release of the drug, resulting in faster dissolution. This includes both the actives and the excipients. Excipients balance the properties of the actives in ODTs. This demands a thorough understanding of the chemistry of these excipients to prevent interaction with the actives. Determining the cost of these ingredients is another issue that needs to be addressed by formulators. The role of excipients is important in the formulation of fast-melting tablets. These inactive food-grade ingredients, when incorporated in the formulation, impart the desired organoleptic properties and product efficacy. Excipients are general and can be used for a broad range of actives, except some actives that require masking agents. Binders keep the composition of these fast-melting tablets together during the compression stage. The right selection of a binder or combination of binders is essential to maintain the integrity and stability of the tablet. The temperature of the excipient should be preferably around 3035C for faster melting properties. Further, its incorporation imparts smooth texture and disintegration characteristics to the system. Binders can either be liquid, semi solid, solid or mixtures of varying molecular weights such as polyethylene glycol. The choice of a binder is critical in a fast- dissolving formulation for achieving the desired sensory and melting characteristics, and for the faster release of active ingredients. Commonly available fats such as cocoa butter and hydrogenated vegetable oils can also be used. MARKETED FAST DISSOLVING TABLETS IN INDIA Table 3 List of Marketed Formulation Available in India
Name of the Product Imodium Lingual Pepcidin Rapitab Mosid MT Calritin Reditabs Nimulid MD Zyrof Meltab Claritin Reditab Feldene Melt Maxalt-MLT Pepcid RPD Zyprexa Zydis Zofran ODT Remeron Soltab Active Ingredients Imodium Quick releasing antiulcer preparation of pepcid Mouth melt tablet of Mosapride citrate. Immediate Dissolving formulation of Calritin Nimesulide Rofecoxib micronized loratadine piroxicam (10 or 20 mg), rizatriptan (5 or 10 mg), peppermint flavour famotidine (20 or 40 mg), olanzapine (5, 10, 15 or 20 mg), ondansetron (4 or 8 mg), strawberry flavor mirtazepine (15, 30, or 45 mg), orange flavor

Table 4 Weight Variation

Average weight of Tablets (mg) 130 or less 130-324 More than 324 Maximum percentage different allowed 10 7.5 5

Friability24 Friability is a crucial parameter for evaluation of ODT. Attempts for decreasing the disintegration time increase the friability of ODTs than the conventional tablets. Dosage forms like Zydis are very fragile. Friability is a measure of mechanical strength of the tablet. If a tablet has more friability it may not remain intact during packaging, transport or handling. Roche friabilator is used to determine the friability by following procedure. Pre weighed tablets are placed in the friabilator. Friabilator consist of a plastic chamber that revolves at 25 rpm, dropping those tablets at a distance of 6 inches with each revolution. The tablets are rotated in the friabilator for at least 4 minutes. At the end of test tablets are dusted and reweighed; the loss in the weight of tablet is the measure of friability and is expressed in percentage as: % Friability = (loss in weight / Initial weight) X 100 (1) Hardness (Crushing load) 24 Tablet hardness is measured with hardness testers like Monsanto. A tablet is placed in the hardness tester and load required to crush the tablet is measured. The hardness of MDTs is generally kept lower than conventional tablets as increased hardness delays the disintegration of the tablet. A good compromise between mechanical strength and disintegration time is achieved for a satisfactory mouth dissolving formulation. Tensile strength25 Tablet tensile strength is calculated using following equation T = 2F/dt (2) Where, T = Tensile strength of the tablet, F = Crushing load,d = Diameter of the tablet and t = Thickness of the tablet. Wetting time 26 The initial process in the disintegration of a MDT involves water uptake and wetting of the tablet. So determination of wetting time is also important. It also helps in studying the effect of various excipients in the disintegration of the tablet. A petridish containing 6 ml of distilled water is taken and a tissue paper folded twice is placed in it. A tablet containing a small quantity of amaranth colour is placed on this. Time required for the upper surface of the tablet to become complete red is the wetting time.

EVALUATION PARAMETERS FOR MDT Weight variation23 I.P. procedure for uniformity of weight was followed, twenty tablets were taken and their weight was determined individually and collectively on a digital weighing balance. The average weight of one tablet was determined from the collective weight. The weight variation test would be a satisfactory method of determining the drug content uniformity. Drug Invention Today Vol.2.Issue.1.January 2010

Figure 2. In vitro Wetting Property 81-88

Sudhir Bharawaj et al. / Drug Invention Today 2010,2(1),81-88 Water absorption ratio26 A pre weighed tablet is placed in a petridish in the similar way as described in the wetting time test. When the tablet has absorbed water completely, it is removed and weight is noted. Water absorption ratio is calculated as % Friability = (difference in weight / original weight) X 100 (3) Disintegration Time (DT) 27, 28 As described in pharmacopoeia, tablets are placed in the disintegration tubes and time is noted. According to the European pharmacopoeia the fast disintegrating/ Orodispersible tablets should disintegrate within 3 minutes without leaving any residue on the screen. However it is difficult to assess the disintegration rate even in small amounts of water. Further the conventional test employs a volume of 900 ml of distilled water compared to the volume of saliva in humans, which is limited to a few ml. Thus the disintegration rate obtained from conventional test does not appear to reflect the actual disintegration rate in human mouth. To overcome these problems, several new methods have been proposed. One of these methods Disintegration of fast dissolving tablets is achieved by saliva in the mouth, however amount of saliva in the mouth is limited and no tablet disintegration test was found in USP and IP to simulate in vivo conditions. A modified version of the simple but novel method was used to determine disintegration time of the tablets. A cylindrical vessel was used in which 10-mesh screen was placed in such way that only 4 ml of disintegrating medium would be placed below the sieve (Figure 1). To determine disintegration time, 6ml of Sorensons buffer (pH 6.8), was placed inside the vessel in such way that 4ml of the media was below the sieve and 2ml above the sieve. Tablet was placed on the sieve and the whole assembly was then placed on a shaker. The time at which all the particles pass through the sieve was taken as a disintegration time of the tablet. Six tablets were chosen randomly from the composite samples and the average value was determined. Dissolution test30 The dissolution method for oral disintegrating tablets is the same as that of conventional tablets. USP 2 paddle apparatus is most suitable and common choice for dissolution test of oral disintegrating tablets, where the paddle speed is 50 rpm is used. The USP 1 (basket) apparatus may have certain application for such tablets but is used less frequently due to specific physical properties of tablets. Specifically tablet fragments or disintegrating tablet masses become trapped on the inside top of the basket spindle where little or no effective stirring occurs, yielding irreproducible results in dissolution profiles. Counseling Points for ODTs Pharmacists are in the ideal position to become familiar with the different technologies, and educate their patients on what to expect upon taking their first dose. The majority of patients receiving ODTs preparations have little understanding of this new dosage form. Patients may be surprised when tablets begin to dissolve in the mouth. They might expect a faster onset of therapeutic action. Clarification from the pharmacist can avoid any confusion or misunderstanding. As with all dosage form technologies, some patient populations are better served by their use than others. Patients who concurrently take anticholinergic medications may not be the best candidates for these drugs. Similarly, patients with Sjgrens syndrome or dryness of the mouth due to decreased saliva production may not be good candidates for these tablet formulations. Although no water is needed to allow the drug to disperse quickly and efficiently, most technologies utilize the bodys own salivation. Decreased volume of saliva may slow the rate of dissolution/disintegration and decrease the bioavailability of the product. Although chewable tablets have been on the market for some time, they are not the same as the new ODTs. Patients for whom chewing is difficult or painful can use these new tablets easily. ODTs can be used easily in children who have lost their primary teeth, but do not have full use of their permanent teeth. Patients may mistake fast-dissolving/disintegrating for effervescent tablets. Pharmacists may wish to stress the difference between the use of quick-dissolving and effervescent tablets. The Cima technologies, OraSolv and DuraSolv, use slight effervescence. Patients may experience a pleasant tingling on the tongue with OraSolv and DuraSolv. Pharmacists have been alerted to exercise additional care when dispensing new prescriptions for ODT formulations. Most such products are available in the same strengths as traditional dosage forms. Prescribing physicians must make an additional notation for the dispensing of a ODT. A physician may also mistakenly believe the drug brand name is Zydis, for example, without identifying a specific drug. Verification with the prescribing practitioner may be necessary in some cases and can clear up any confusion. There are not commercially available fast-dissolving/disintegrating products for all of our patients needs. Pharmacists may wish to consider compounding as a unique way to treat the unmet needs of individual patients. When a manufactured ODT is not available, compounding pharmacists can consider tablet triturates. These largely forgotten dosage forms have fast-disintegrating properties similar to many manufactured products. All of the patients described earlier will benefit greatly from ODT formulations. The elderly patient, for example, could be prescribed 81-88

Figure 3. Device Used to Determine the Disintegration Time of Fast Disintegrating Tablets In vitro Dispersion Time 29 Tablet was added to 10ml of Sorensons buffer solution (pH 6.8) and time required for complete dispersion was measured (Figure 3). Three tablets from each formulation were randomly selected and in vitro dispersion time was performed [12].

Figure 4. In Vitro Disintegration Property Drug Invention Today Vol.2.Issue.1.January 2010

Sudhir Bharawaj et al. / Drug Invention Today 2010,2(1),81-88 Remeron SolTab for depression. With a pharmacists intervention and 7. Makino, T., Yamada, M. and Kikuta, J., Fast dissolving tablet and its production, 1993, European Patent, 0553777 A2. assistance, all of these patients could be more properly treated with 8. Reddy, L. H., Ghosh, B., and Rajneesh, 2002, Fast dissolving drug greater convenience. delivery systems: a review of the literature, Indian J. Pharm. Sci., CONCLUSION Orally disintegrating tablets (ODTs) have better patient acceptance and compliance and may offer improved biopharmaceutical properties, improved efficacy, and better safety compared with conventional oral dosage forms. Prescription ODT products initially were developed to overcome the difficulty in swallowing conventional tablets with water among pediatric, geriatric, and psychiatric patients with dysphagia. Today, ODTs are more widely available as over-the-counter products for the treatment of allergies and cold and flu symptoms. The target population has expanded to those who want convenient dosing anywhere, anytime, without water. The future potential for ODTs is promising because of the availability of new technologies combined with strong market acceptance and patient demand. Dozens of ODT products have been commercialized, and the market size for ODTs will continue to expand as the technology is used to deliver large-molecular weight biopharmaceutical therapeutics such as proteins and peptides when coupled with the appropriate permeation enhancers. By paying close attention to advances in technologies, pharmaceutical companies can take advantage of ODTs for product line extensions or for first-to-market products. Future possibilities for improvements in ODTs and drug delivery are bright, but the technology is still relatively new. Several drug delivery technologies that can be leveraged on improving drug therapy from ODTs have yet to be fully realized. REFERENCES
1. 2. 3. 4. 5. 6. Fu Y, Yang S, Jeong SH, Kimura S, Park K. Orally Fast Disintegrating Tablets: Developments, Technologies, Taste-masking and Clinical Studies. Crit Rev Ther Drug Carrier Sys 2004; 21:433-476. Seager H. Drug-delivery products and the Zydis fast-dissolving dosage. J Pharm Pharmacol. 1998 Apr; 50(4):375-82. Brown D. Orally Disintegrating Tablets-Taste over Speed. Drug Del Tech 2003; 3:58-61. Bradoo, R., Fast Dissolving Drug Delivery Systems, JAMA India, 2001, 4 (10), 27-31. Kuchekar, B. S., Atul, Badhan, C., Mahajan, H. S., 2003, Mouth dissolving tablets: A novel drug delivery system, Pharma Times, 35, 7-9. Habib W, Khankari R and Hontz J. Fast-dissolve drug delivery system. Crit. Rev. Ther. Drug Carrier Syst. 2000;17:61-72. 9. 10. 11. 64(4), 331-336. Seager, H., 1998, Drug-deliver products and the zydis fast-dissolving dosage form, J. Pharm. Pharmacol., 50,375-382. Modi, A., Tayade, P., 2006 , Enhancement of dissolution profile by solid dispersion (kneading) technique, AAPS Pharm. Sci. Tech., 18;7(3), 68 Reig, A. R., Plazas, F., Galvan, C. J., Heras, N. J., Artes, F. M., Gabarron, H. E., 2006, Acceptance survey of a fast dissolving tablet pharmaceutical formulation in allergic patients. Satisfaction and expectancies,Allergol. Immunopathol. (Madr.), 34(3), 107-12. Ahmed, I. S., Nafadi, M. M., Fatahalla, F. A., 2006, Formulation of a fast-dissolving ketoprofen tablet using freeze-drying in blisters technique,Drug Dev. Ind.Pharm., 32(4), 437-42. Cirri, M., Valleri, M., Mura, P., Maestrelli, F., Ballerini, R., 2005, Development of fast-dissolving tablets of flurbiprofen-cyclodextrin complexes,Drug Dev. Ind. Pharm., 31(7), 697-707. Takagi, H., Kajiyama, A., Yanagisawa, M., 2005, Rapidly disintegrable pharmaceutical composition, U.S.Patent 6,899,899. Caramella, C., Drug Dev. Ind. Pharma., 1990, 16 (17), 2561-2577. Allen, L.V.,Wang, B. and Davies, J.D., US Patent, No. 5807576, 1998. Allen, L.V. and Wang, B., US Patent, No. 5595761, 1997. Makino, T., Yamada, M. and Kikuta,J., US Patent, No. 5720974, 1998. Makino, T., Yamada, M. and Kikuta, J., European Patent, 0553777 A2, 1993. Reddy, L. H., Ghosh, B. and Rajneesh, Indian J.Pharma.Sci., 2002, 64(4), 331-336. Mizumoto, T., Masuda, Y. and Kukui, M., US Patent, No. 5576014, 1996. Redkar, M.R,Gore, S.P. and Devrajan, P.V., Ind. J. Pharma.Sci., 2002, 64(3), 291-292. Indian Pharmacopoeia 1996. The Controller of Publication. Delhi, Vol-2, p-735. Lachman L, Liberman H and Kanig J. In: The theory and practice of industrial pharmacy, 3rd edn. Varghese Publishing House, Mumbai 1987. Yunxia B, Sunada H, Yonezawz Y, Danjo K. Evaluation of rapidly disintegrating tablets prepared by direct compression method. Drug Dev. Ind. Pharm. 1999;25(5):571-581. Patel D, Patel N. Studies in formulation of orodispersible tablets of rofecoxib. Indian J. Pharm. Sci. 2004;66: 621. Khan S, Kataria P, Nkhat P, Yeole P. Taste masking of ondansetron hydrochloride by polymer carrier system and formulation of rapiddisintegrating tablets. AAPS PharmSciTech. 2007;8(2):46. Late SG, Yi-Ying Y, Banga AK. Effect of disintegration promoting agent, lubricants and moisture treatment on optimized fast disintegrating tablets. Int J Pharm 2009; 365: 4-11. Gohel MC, Bansal G, Bhatt N. Formulation and evaluation of orodispersible taste masked tablets of famotidine. Pharma Biol World 2005; 3: 75-80. United States Pharmacopoeia 29-NF 24. The Official Compendia of Standards. Asian ed. Rockville, MD: United States Pharmacopoeial Convention Inc. 2006; 2679-2681.

12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.

Source of support: Nil, Conflict of interest: None Declared

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