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Review Article

Available online throughwww.ditonline.info

*Corresponding author.Dr.Sudhir BharawajDean and Asst.ProfessorPharmaceutics Research Laboratory,Department Of Pharmaceutics,Shriram College of Pharmacy,Banmore, Morena, (M.P.), MobileTel.:+91-9669134020E-mail: sudhiritsbj@yahoo.com

INTRODUCTION

The most important drug delivery route is undoubtedly the oral route.It offers advantages of convenience of administration and potentialmanufacturing cost savings. Drugs that are administered orally,solid oral dosage forms in general and tablets in particular representthe preferred class of product. Today drug delivery companies arefocusing on solid oral drug delivery systems that offer greater pa-tient compliance and effective dosages.1

Tablet is the most popular among all dosage forms existing todaybecause of its convenience of self administration, compactness andeasy manufacturing. Many patients find it difficult to swallow tab-lets and hard gelatin capsules and do not take their medication asprescribed. In a survey conducted by Honda and Nakano, half of thepatients experienced difficulty taking medication, such as tablet andcapsule which results in a high incidence of non-compliance andineffective therapy. The difficulty is experienced in particular by pe-diatric and geriatric patients, but it also applies to people who are illin bed and to those active working patients who are busy or travel-ing, especially those who have no access to water. 2

Over a decade, the demand for development of orally disintegratingtablets (ODTs) has enormously increased as it has significant impacton the patient compliance. Orally disintegrating tablets offer an

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 ofPharmacy,Banmore, Morena (M.P.) (INDIA)

Received on: 10-06-2009; Revised on: 21-08- 2009; Accepted on:25-12-2009

ABSTRACTOver a decade, the demand for development of orally disintegrating tablets (ODTs) has enormously increased as it has significant impact on the patientcompliance. Orally disintegrating tablets offer an advantage for populations who have difficulty in swallowing. Prescription ODT products initially weredeveloped 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 formanufacturing 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 areimportant. Important ingredients that are used in the formulation of ODTs should allow quick release of the drug, resulting in faster dissolution. Evaluationof these tablets are done by following weight variation, friability, tensile strength, wetting time, water absorption ratio, In vitro dispersion time anddissolution test.

Keywords: Orally disintegrating tablets, Orasolv, tensile strength, sublimation

ISSN: 0975-7619

advantage for populations who have difficulty in swallowing. It hasbeen reported that Dysphagia (difficulty in swallowing) is commonamong all age groups and more specific with pediatric, geriatric popu-lation along with institutionalized patients and patients with nausea,vomiting, and motion sickness complications. ODTs with good tasteand flavor increase the acceptability of bitter drugs by various groupsof population.Orally disintegrating tablets are also called as orodispersible tablets,quick disintegrating tablets, mouth dissolving tablets, fast disinte-grating tablets, fast dissolving tablets, rapid dissolving tablets, po-rous tablets, and rapimelts.However, of all the above terms, United States pharmacopoeia (USP)approved these dosage forms as ODTs. Recently, European Pharma-copoeia has used the term orodispersible tablet for tablets that dis-perses 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 in-gredient which disintegrates rapidly usually within a matter of sec-onds when placed upon the tongue.” The disintegration time forODTs 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 friable5. Leave minimal or no residue in mouth after administration6. Exhibit low sensitivity to environmental conditions (tempera-

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ture and humidity).7. Allow the   manufacture   of tablet   using conventional  

processing  and   packaging equipments.

ADVANTAGES OF ODTs 4,5

1. Administration to the patients who can not swallow, such asthe elderly, stroke victims,  bedridden patients, patients affectedby renal failure & patients who refuse to swallow such as pedi-atric, geriatric & psychiatric patients.

2. Rapid drug therapy intervention.3. Achieve increased bioavailability/rapid absorption through

pregastric absorption of drugs from mouth, pharynx & oesopha-gus as saliva passes down.

4. Convenient for administration and patient compliant for dis-abled, 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 ofmedication as bitter pill particularly in pediatric patients.

6. The risk of chocking or suffocation during oral administrationof conventional formulations due to physical obstruction isavoided, thus providing improved safety.

7. New business opportunity like product differentiation, prod-uct promotion, patent extension and life cycle management.

SALIENT FEATURES OF ORALLY DISINTEGRATING TABLETS1. Ease of administration to patients who refuse to swallow a

tablet, such as paediatric and geriatric patients and, psychiat-ric patients.

2. Convenience of administration and accurate dosing as com-pared to liquids.

3. No need of water to swallow the dosage from, which is highlyconvenient feature for patients who are traveling and do nothave immediate access to water.

4. Good mouth feels properly of ODTs helps to change the basicview of medication as “bitter pill”, particularly for paediatricpatients.

5. Rapid dissolution of drug and absorption which may producerapid, onset of action.

6. Some drugs are absorbed from the month pharynx and oe-sophagus as the saliva passes down into the stomach, in suchcases bioavailability of drugs is increased.

7. Ability to provide advantages of liquid medication in the formof solid preparation.

8. Pregastric absorption can result in improved bioavailabilityand as a result of reduced dosage, improved clinical perfor-mance through a reduction of unwanted effects.

CHALLENGES IN THE FORMULATION OF ORALLY DISINTE-GRATING TABLETS

1. Mechanical strength and disintegration time: ODTs are for-mulated to obtain disintegration time usually less than a minute.While doing so, maintaining a good mechanical strength is aprime challenge. Many ODTs are fragile and there are manychances that such fragile tablet will break during packing, trans-port or handling by the patients. Tablets based on technolo-

gies like Zydis need special type of packaging. It is very natu-ral that increasing the mechanical strength will delay the disin-tegration time. So a good compromise between these two pa-rameters is always essential.

2. Taste masking: Many drugs are bitter in taste. A tablet ofbitter drug dissolving/ disintegration in mouth will seriouslyaffect patient compliance and acceptance for the dosage form.So effective taste masking of the bitter drugs must be done sothat the taste of the drug is not felt in the oral cavity.

3. Mouth feel: The ODT should not disintegrate into larger par-ticles in the oral cavity. The particles generated after disinte-gration of the ODT should be as small as possible. ODT shouldleave minimal or no residue in mouth after oral administration.Morever addition of flavours and cooling agents like mentholimprove the mouth feel.

4. Sensitivity to environmental conditions: ODT generally shouldexhibit low sensitivity to environment conditions such as hu-midity and temperature as most of the materials used in a ODTare meant to dissolve in minimum quantity of water.

5. Cost: The technology used for a ODT should be acceptable interms of cost of the final product. Methods like Zydis andOrasolv that require special technologies and specific packag-ing increase the cost to a remarkable extent6.

LIMITATIONS OF ORALLY DISINTEGRATING TABLETS1. Drugs with relatively larger doses are difficult to formulate into

MDT e.g. antibiotics like ciprofloxacin with adult dose tabletcontaining about 500 mg of the drug.

Patients who concurrently take anticholinergic medications may notbe the best candidates for MDT. Similarly patients with Sjögren’ssyndrome or dryness of the mouth due to decreased saliva produc-tion may not be good candidates for these tablet formulations.

TECHNOLOGIES USED FOR MANUFACTURING OF ORALLYDISINTEGRATING TABLETS

Conventional Technologies

1. Freeze Drying.2. Tablet Molding.3. Sublimation.4. Spray Drying.

Mass extrusion.5. Direct Compression

Patented Technologies

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

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Conventional Technologies7-9

Freeze dryingA process in which water is sublimated from the product after freez-ing. Lyophilization is a pharmaceutical technology which allows dry-ing of heat sensitive drugs and biological at low temperature underconditions that allow removal of water by sublimation. Lyophilizationresults in preparations, which are highly porous, with a very highspecific surface area, which dissolve rapidly and show improved ab-sorption and bioavailability.Tablet moldingIn this method, molded tablets are prepared by using water-solubleingredients so that the tablets dissolve completely and rapidly. Thepowder blend is moistened with a hydro-alcoholic solvent and ismolded into tablets under pressure lower than that used in conven-tional tablet compression. The solvent is then removed by air-drying.Molded tablets are very less compact than compressed tablets. Thesepossess porous structure that enhances dissolution.SublimationThe slow dissolution of the compressed tablet containing even highlywater-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, cam-phor etc.) are added to the other tablet ingredients and the mixture iscompressed into tablets. The volatile materials are then removed viasublimation, which generates porous structures. Additionally, sev-eral solvents (e.g. cyclohexane, benzene) can be also used as pore

Figure. 1 Steps Involved in sublimation

Spray-dryingSpray drying can produce highly porous and fine powders that dis-

solve rapidly. The formulations are incorporated by hydrolyzed andnon hydrolyzed gelatins as supporting agents, mannitol as bulkingagent, sodium starch glycolate or crosscarmellose sodium as disinte-grating and an acidic material (e.g. citric acid) and / or alkali material(e.g. I  sodium bicarbonate) to enhance disintegration and dissolu-tion. Tablet compressed from the spray dried powder disintegratedwithin 20 seconds when immersed in an aqueous medium.Mass-extrusionThis technology involves softening the active blend using the sol-vent mixture of water soluble polyethylene glycol, using methanoland expulsion of softened mass through the extruder or syringe toget a cylinder of the product into even segments using heated bladeto form tablets. The dried cylinder can also be used to coat granulesof bitter tasting drugs and thereby masking their bitter taste.Direct compressionEasiest way to manufacture tablets is direct compression. Low manu-facturing cost, conventional equipments and limited number of pro-cessing steps led this technique to be a preferable one. Howeverdisintegration and dissolution of directly compressed tablets dependon single or combined effect of disintegrant, water soluble excipientsand effervescing agents.It is essential to choose a suitable and an optimum concentration ofdisintegrant to ensure quick disintegration and dissolution.Superdisintegrants are newer substances which are more effective atlower concentrations with greater disintegrating efficiency and me-chanical strength. On contact with water the superdisintegrants swell,hydrate, change volume or form and produce a disruptive change inthe tablet. Effective superdisintegrants provide improved compress-ibility, compatibility and have no negative impact on the mechanicalstrength of formulations containing high dose drugs. The type ofdisintegrants and its proportion are of prime importance. Also factorsto be considered are particle size distribution, contact angle, pore sizedistribution and water absorption capacity. Studies revealed that thewater insoluble superdisintegrants like sodium starchglycolate and Croscarmellose sodium show better disintegration prop-erty than the slightly water soluble agents like Crospovidone, sincethey do not have a tendency to swell. Superdisintegrants that tend toswell show slight retardation of the disintegration property due toformation of viscous barrier. There is no particular upper limit regard-ing the amount of superdisintegrant as long as the mechanical prop-erties of the tablet are compatible with its intended use. Thesuperdisintegrant may be used alone or in combination with othersuperdisintegrants.

Table 1 Various commercially available superdisintegrants along with their properties.

Sr. Name Type Properties Brand name1. Crospovidone Polyvinyl-pyrrolidone Crossed linked Polyvinlypyrrolidone Polyplasdone XL, Kollidon CL

Rapidly disperses and swells in water2. Croscarmellose Sodium. Modified cellulose Cross linked sodium carboxy methylcellulose. Ac-di-sol, Primellose, Solutab.

Excellent swelling and water wicking properties.3. Sodium starch Glycolate Modified Starch Sodium salt of carboxy methyl ether of starch. Primogel, Explotab, Glycolys.

High swelling capacity and rapid water uptake4. Indion 414 Ion exchange Resin Cross linked polyacrylic with a -COO- functional group Indion 414.

and K + ionic form. High water intake facility.

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Patented Technologies 10-14

Zydis technologyZydis, the best known of the fast-dissolving/disintegrating tabletpreparations was the first marketed new technology tablet. The tabletdissolves in the mouth within seconds after placement on the tongue.A Zydis tablet is produced by lyophilizing or freeze-drying the drugin a matrix usually consisting of gelatin. The product is very light-weight and fragile, and must be dispensed in a special blister pack.Patients should be advised not to push the tablets through the foilfilm, but instead peel the film back to release the tablet. The Zydisproduct is made to dissolve on the tongue in 2 to 3 seconds. TheZydis formulation is also self-preserving because the final water con-centration in the freeze-dried product is too low to allow for microbialgrowth.

Durasolv technologyDurasolv is the patented technology of CIMA labs. The tablets madeby this technology consist of a drug, fillers and a lubricant. Tabletsare prepared by using conventional tableting equipment and havegood rigidity. These can be packed into conventional packaging sys-tem like blisters. Durasolv is an appropriate technology for productsrequiring low amounts of active ingredients.Orasolv technologyOrasolv Technology has been developed by CIMA labs. In this sys-tem active medicament is taste masked. It also contains effervescentdisintegrating agent. Tablets are made by direct compression tech-nique at low compression force in order to minimize oral dissolutiontime. Conventional blenders and tablet machine is used to produce

Table2 Comparison of Orally Disintegrating Tablets TechnologiesZYDIS (R.P. SCHERER, INC.)Novelty Handling/Storage Drug Release/BioavailabilityFirst to market Do not push tablet through foil Dissolves in 2 to 10 secondsFreeze Dried Do not use dosage form from damaged package May allow for pre-gastric absorption leading to enhanced bioavailability  Sensitive to degradation at humidities >65%  ORASOLV (CIMA LABS, INC.)Novelty Handling/Storage Drug Release/BioavailabilityUnique taste masking Packaged in patented foil packs Disintegrates in 5 to 45 seconds depending upon the size of the tabletLightly compressed   No significant change in drug bioavailabilityDURASOLV (CIMA LABS, INC.)Novelty Handling/Storage Drug Release/BioavailabilitySimilar to Orasolv, but with better mechanical strength Packaged in foil or bottles Disintegrates in 5 to 45 seconds depending upon the size of the tablet  If packaged in bottles, avoid exposure to moisture or humidity No significant change in drug bioavailabilityWOWTAB (YAMANOUCHI PHARMA TECHNOLOGIES, INC.)Novelty Handling/Storage Drug Release/BioavailabilityCompressed dosage form Package in bottles Disintegrates in 5 to 45 seconds depending upon the size of the tabletProprietary taste masking Avoid exposure to moisture or humidity No significant change in drug bioavailabilitySMOOTHMELT action gives superior mouth feel    

DRUGS TO BE PROMISING INCORPORATED IN ORALLYDISINTEGRATINGTABLETS 15-23

There are no particular limitations as long as it is a substance which isused as a pharmaceutical active ingredient.Analgesics and Anti-inflammatory AgentsAloxiprin, auranofin, azapropazone, benorylate, diflunisal, etodolac,fenbufen, fenoprofen calcim, flurbiprofen, ibuprofen, indomethacin,ketoprofen, meclofenamic acid, mefenamic acid, nabumetone,naproxen, oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam,sulindac.AnthelminticsAlbendazole, bephenium hydroxynaphthoate, cambendazole,

dichlorophen, ivermectin, mebendazole, oxamniquine, oxfendazole,oxantel embonate, praziquantel, pyrantel embonate, thiabendazole.Anti-arrhythmic AgentsAmiodarone HCl, Disopyramide, flecainide acetate, quinidinesulphate. Anti-bacterial AgentsBenethamine penicillin, cinoxacin, ciprofloxacin HCl, clarithromycin,clofazimine, cloxacillin, demeclocycline, doxycycline, erythromycin,ethionamide, imipenem, nalidixic acid, nitrofurantoin, rifampicin,spiramycin, sulphabenzamide, sulphadoxine, sulphamerazine,sulphacetamide, sulphadiazine, sulphafurazole, sulphamethoxazole,sulphapyridine, tetracycline, trimethoprim.Anti-coagulantsDicoumarol, dipyridamole, nicoumalone, phenindione.Anti-depressantsAmoxapine, ciclazindol, maprotiline HCl, mianserin HCl, nortriptylineHCl, trazodone HCl, trimipramine maleate.Anti-diabeticsAcetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide,tolazamide, tolbutamide. Anti-epilepticsBeclamide, carbamazepine, clonazepam, ethotoin, methoin,methsuximide, methylphenobarbitone, oxcarbazepine, paramethadione, phenacemide, phenobarbitone, phenytoin, phensuximide,primidone, sulthiame, valproic acid.Anti-fungal AgentsAmphotericin, butoconazole nitrate, clotrimazole, econazole nitrate,fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole,

miconazole, natamycin, nystatin, sulconazole nitrate, terbinafine HCl,terconazole, tioconazole, undecenoic acid.Anti-gout AgentsAllopurinol, probenecid, sulphinpyrazone.Anti-hypertensive AgentsAmlodipine, carvedilol, benidipine, darodipine, dilitazem HCl,diazoxide, felodipine, guanabenz acetate, indoramin, isradipine,minoxidil, nicardipine HCl, nifedipine, nimodipine, phenoxybenzamineHCl, prazosin HCL, reserpine, terazosin HCl.Anti-malarialsAmodiaquine, chloroquine, chlorproguanil HCl, halofantrine HCl,mefloquine HCl, proguanil HCl, pyrimethamine, quinine sulphate.

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Anti-migraine AgentsDihydroergotamine mesylate, ergotamine tartrate, methysergidemaleate, pizotifen maleate, sumatriptan succinate.Anti-muscarinic AgentsAtropine, benzhexol HCl, biperiden, ethopropazine HCl, hyoscinebutyl bromide, hyoscyamine, mepenzolate bromide, orphenadrine,oxyphencylcimine HCl, tropicamideAnti-neoplastic Agents and ImmunosuppressantsAminoglutethimide, amsacrine, azathioprine, busulphan, chlorambucil, cyclosporin, dacarbazine, estramustine, etoposide, lomustine,melphalan, mercaptopurine, methotrexate, mitomycin, mitotane,mitozantrone, procarbazine HCl, tamoxifen citrate, testolactone.Anti-protazoal AgentsBenznidazole, clioquinol, decoquinate, diiodohydroxyquinoline,diloxanide furoate, dinitolmide, furzolidone, metronidazole, nimorazole,nitrofurazone, omidazole, tinidazole.Anti-thyroid AgentsCarbimazole, propylthiouracil.Anxiolytic , Sedatives, Hypnotics and NeurolepticsAlprazolam, amylobarbitone, barbitone, bentazepam, bromazepam,bromperidol, brotizolam, butobarbitone, carbromal, chlordiazepoxide,chlormethiazole, chlorpromazine, clobazam, clotiazepam, clozapine,diazepam, droperidol, ethinamate, flunanisone, flunitrazepam,fluopromazine, flupenthixol decanoate, fluphenazine decanoate,flurazepam, haloperidol, lorazepam, lormetazepam, medazepam,meprobamate, methaqualone, midazolam, nitrazepam, oxazepam,pentobarbitone, perphenazine pimozide, prochlorperazine, sulpiride,temazepam, thioridazine, triazolam, zopiclone. ß-BlockersAcebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol,oxprenolol, pindolol,propranolol. Cardiac Inotropic AgentsAmrinone, digitoxin, digoxin, enoximone, lanatoside C, medigoxin.CorticosteroidsBeclomethasone, betamethasone, budesonide, cortisone acetate,desoxymethasone, dexamethasone, fludrocortisone acetate,flunisolide, flucortolone, fluticasone propionate, hydrocortisone,methylprednisolone, prednisolone, prednisone, triamcinolone.DiureticsAcetazolamide, amiloride, bendrofluazide, bumetanide, chlorothiazide,chlorthalidone, ethacrynic acid, frusemide, metolazone,spironolactone, triamterene.Anti-parkinsonian AgentsBromocriptine mesylate, lysuride maleate.Gastro-intestinal AgentsBisacodyl, cimetidine, cisapride, diphenoxylate HCl, domperidone,famotidine, loperamide, mesalazine, nizatidine, omeprazole,ondansetron HCL, ranitidine HCl, sulphasalazine.Histamine H,-Receptor AntagonistsAcrivastine, astemizole, cinnarizine, cyclizine, cyproheptadine HCl,dimenhydrinate, flunarizine HCl, loratadine, meclozine HCl, oxatomide,terfenadine, triprolidine.Lipid Regulating AgentsBezafibrate, clofibrate, fenofibrate, gemfibrozil, probucol.

Local AnaestheticsLidocaine Neuro -muscular AgentsPyridostigmine. Nitrates and other Anti-anginal AgentsAmyl nitrate, glyceryl trinitrate, isosorbide dinitrate, isosorbidemononitrate, pentaerythritol tetranitrate.Nutritional AgentsBetacarotene, vitamin A, vitamin B 2 , vitamin D, vitamin E, vitamin K.Opioid AnalgesicsCodeine, dextropropyoxyphene, diamorphine, dihydrocodeine,meptazinol, methadone, morphine, nalbuphine, pentazocine.Oral VaccinesVaccines designed to prevent or reduce the symptoms of diseases ofwhich the following is a representative Influenza, Tuberculosis,Meningitis, Hepatitis, Whooping Cough, Polio, Tetanus, Diphtheria,Malaria, Cholera, Herpes, Typhoid, HIV, AIDS, Measles, Lyme disease,Travellers Diarrhea, Hepatitis A, B and C, Otitis Media, Dengue Fever,Rabies, Parainfluenza, Rubella, Yellow Fever, Dysentery, LegionnairesDisease, Toxoplasmosis, Q-Fever, Haemorrhegic Fever, ArgentinaHaemorrhagic Fever, Caries, Chagas Disease, Urinary Tract Infectioncaused by E.coli, Pneumoccoccal Disease, Mumps, and Chikungunya.Vaccines to prevent or reduce the symptoms of other diseasesyndromes of which the following is a representative not exclusivelist of causative organisms: Vibrio species, Salmonella species,Bordetella species, Haemophilus species, Toxoplasmosis gondii,Cytomegalovirus, Chlamydia species, Streptococcal species, NorwalkVirus, Escherischia coli, Helicobacter pylori, Rotavirus, Neisseriagonorrhae, Neisseria meningiditis, Adenovirus, Epstein Barr Virus,Japanese Encephalitis Virus, Pneumocystis carini, Herpes simplex,Clostridia species, Respiratory Syncytial Virus, Klebsielia species,Shigella species, Pseudomonas aeruginosa, Parvovirus,Campylobacter species, Rickettsia species, Varicella zoster, Yersiniaspecies, Ross River Virus, J.C. Virus, Rhodococcus equi, Moraxellacatarrhalis, Borrelia burgdorferi and Pasteurella haemolytica. Vaccinesdirected to non-infections immuno-modulated disease conditionssuch as topical and systematic allergic conditions such as Hayfever,Asthma, Rheumatoid Arthritis and Carcinomas.Vaccines for veterinary use include those directed to Coccidiosis,Newcastle Disease, Enzootic pneumonia, Feline leukaemia, Atrophicrhinitis, Erysipelas, Foot and Mouth disease, Swine, pneumonia, andother disease conditions and other infections and auto-immunedisease conditions affecting companion and farm animals.Proteins, Peptides and Recombinant drugsInsulin (hexameric/dimeric/monomeric forms), glucagon, growthhormone (somatotropin), polypeptides or their derivatives, (preferablywith a molecular weight from 1000 to 300,000), calcitonins andsynthetic modifications thereof, enkephalins, interferons (especiallyAlpha-2 interferon for treatment of common colds), LHRH andanalogues (nafarelin, buserelin, zolidex), GHRH (growth hormonereleasing hormone), secretin, bradykin antagonists, GRF (growthreleasing factor), THF, TRH (thyrotropin releasing hormone), ACTHanalogues, IGF (insulin like growth factors), CGRP (calcitonin generelated peptide), atrial natriurectic peptide, vasopressin and analogues(DDAVP, lypressin), factor VIII, G-CSF (granulocyte-colonystimulatingfactor),EPO(erythropoitin).

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Sex HormonesClomiphene citrate, danazol, ethinyloestradiol, medroxyprogesteroneacetate, mestranol, methyltestosterone, norethisterone, norgestrel,oestradiol, conjugated oestrogens, progesterone, stanozolol,stiboestrol, testosterone, tibolone.

INGREDIENTS TO BE USED FOR ODTSImportant ingredients that are used in the formulation of ODTs shouldallow quick release of the drug, resulting in faster dissolution. Thisincludes both the actives and the excipients. Excipients balance theproperties of the actives in ODTs. This demands a thorough under-standing of the chemistry of these excipients to prevent interactionwith the actives. Determining the cost of these ingredients is anotherissue that needs to be addressed by formulators. The role of excipi-ents is important in the formulation of fast-melting tablets. Theseinactive food-grade ingredients, when incorporated in the formula-tion, 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 togetherduring the compression stage. The right selection of a binder or com-bination of binders is essential to maintain the integrity and stabilityof the tablet. The temperature of the excipient should be preferablyaround 30–35C for faster melting properties. Further, its incorpora-tion imparts smooth texture and disintegration characteristics to thesystem. Binders can either be liquid, semi solid, solid or mixtures ofvarying molecular weights such as polyethylene glycol. The choiceof a binder is critical in a fast- dissolving formulation for achievingthe desired sensory and melting characteristics, and for the fasterrelease of active ingredients. Commonly available fats such as cocoabutter 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 Active Ingredients

Imodium Lingual ImodiumPepcidin Rapitab Quick releasing antiulcer preparation of pepcidMosid – MT Mouth melt tablet of Mosapride citrate.Calritin Reditabs Immediate Dissolving formulation of CalritinNimulid – MD NimesulideZyrof Meltab RofecoxibClaritin Reditab micronized loratadineFeldene Melt piroxicam (10 or 20 mg),Maxalt-MLT rizatriptan (5 or 10 mg), peppermint flavourPepcid RPD famotidine (20 or 40 mg),Zyprexa Zydis olanzapine (5, 10, 15 or 20 mg),Zofran ODT ondansetron (4 or 8 mg), strawberry flavorRemeron Soltab mirtazepine (15, 30, or 45 mg), orange flavor

EVALUATION PARAMETERS FOR MDT

Weight variation23

I.P. procedure for uniformity of weight was followed, twenty tabletswere taken and their weight was determined individually and collec-tively on a digital weighing balance. The average weight of one tab-let was determined from the collective weight. The weight variationtest would be a satisfactory method of determining the drug contentuniformity.

Table 4 Weight Variation

Average weight of Tablets (mg) Maximum percentage different allowed130 or less 10130-324 7.5More than 324  5

Friability24

Friability is a crucial parameter for evaluation of ODT. Attempts fordecreasing the disintegration time increase the friability of ODTs thanthe conventional tablets. Dosage forms like Zydis are very fragile.Friability is a measure of mechanical strength of the tablet. If a tablethas more friability it may not remain intact during packaging, trans-port or handling. Roche friabilator is used to determine the friabilityby following procedure. Pre weighed tablets are placed in the friabilator.Friabilator consist of a plastic chamber that revolves at 25 rpm, drop-ping those tablets at a distance of 6 inches with each revolution. Thetablets are rotated in the friabilator for at least 4 minutes. At the end oftest tablets are dusted and reweighed; the loss in the weight of tabletis 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. Atablet is placed in the hardness tester and load required to crush thetablet is measured. The hardness of MDTs is generally kept lowerthan conventional tablets as increased hardness delays the disinte-gration of the tablet. A good compromise between mechanical strengthand disintegration time is achieved for a satisfactory mouth dissolv-ing formulation.Tensile strength25

Tablet tensile strength is calculated using following equation T = 2F/πdt (2)

Where, T = Tensile strength of the tablet, F = Crushing load,d =Diameter of the tablet and t = Thickness of the tablet.Wetting time26

The initial process in the disintegration of a MDT involves wateruptake and wetting of the tablet. So determination of wetting time isalso important. It also helps in studying the effect of various excipi-ents in the disintegration of the tablet. A petridish containing 6 ml ofdistilled water is taken and a tissue paper folded twice is placed in it.A tablet containing a small quantity of amaranth colour is placed onthis. Time required for the upper surface of the tablet to become com-plete red is the wetting time.

Figure 2. In vitro Wetting Property

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Water absorption ratio26

A pre weighed tablet is placed in a petridish in the similar way asdescribed in the wetting time test. When the tablet has absorbedwater completely, it is removed and weight is noted. Water absorp-tion 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 disintegra-tion tubes and time is noted. According to the European pharmaco-poeia the fast disintegrating/ Orodispersible tablets should disinte-grate within 3 minutes without leaving any residue on the screen.However it is difficult to assess the disintegration rate even in smallamounts of water. Further the conventional test employs a volume of900 ml of distilled water compared to the volume of saliva in humans,which is limited to a few ml. Thus the disintegration rate obtainedfrom conventional test does not appear to reflect the actual disinte-gration rate in human mouth. To overcome these problems, severalnew methods have been proposed. One of these methods Disintegra-tion of fast dissolving tablets is achieved by saliva in the mouth,however amount of saliva in the mouth is limited and no tablet disin-tegration test was found in USP and IP to simulate in vivo conditions.A modified version of the simple but novel method was used to deter-mine disintegration time of the tablets. A cylindrical vessel was usedin which 10-mesh screen was placed in such way that only 4 ml ofdisintegrating medium would be placed below the sieve (Figure 1). Todetermine disintegration time, 6ml of Sorenson’s buffer (pH 6.8), wasplaced inside the vessel in such way that 4ml of the media was belowthe sieve and 2ml above the sieve. Tablet was placed on the sieve andthe whole assembly was then placed on a shaker. The time at which allthe particles pass through the sieve was taken as a disintegrationtime of the tablet. Six tablets were chosen randomly from the compos-ite samples and the average value was determined.

Figure 3. Device Used to Determine the Disintegration Time of FastDisintegrating Tablets In vitro Dispersion Time29

Tablet was added to 10ml of Sorenson’s buffer solution (pH 6.8) andtime required for complete dispersion was measured (Figure 3). Threetablets from each formulation were randomly selected and in vitrodispersion time was performed [12].

Figure 4. In Vitro Disintegration Property

Dissolution test30

The dissolution method for oral disintegrating tablets is the same asthat of conventional tablets. USP 2 paddle apparatus is most suitableand common choice for dissolution test of oral disintegrating tablets,where the paddle speed is 50 rpm is used. The USP 1 (basket) appara-tus may have certain application for such tablets but is used lessfrequently due to specific physical properties of tablets. Specificallytablet fragments or disintegrating tablet masses become trapped onthe inside top of the basket spindle where little or no effective stirringoccurs, yielding irreproducible results in dissolution profiles.Counseling Points for ODTsPharmacists are in the ideal position to become familiar with the dif-ferent technologies, and educate their patients on what to expectupon taking their first dose. The majority of patients receiving ODTspreparations have little understanding of this new dosage form. Pa-tients may be surprised when tablets begin to dissolve in the mouth.They might expect a faster onset of therapeutic action. Clarificationfrom the pharmacist can avoid any confusion or misunderstanding.As with all dosage form technologies, some patient populations arebetter served by their use than others. Patients who concurrentlytake anticholinergic medications may not be the best candidates forthese drugs. Similarly, patients with Sjögren’s syndrome or drynessof the mouth due to decreased saliva production may not be goodcandidates for these tablet formulations. Although no water is neededto allow the drug to disperse quickly and efficiently, most technolo-gies utilize the body’s own salivation. Decreased volume of salivamay slow the rate of dissolution/disintegration and decrease thebioavailability 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 isdifficult or painful can use these new tablets easily. ODTs can beused easily in children who have lost their primary teeth, but do nothave full use of their permanent teeth.Patients may mistake fast-dissolving/disintegrating for effervescenttablets. Pharmacists may wish to stress the difference between theuse of quick-dissolving and effervescent tablets. The Cima technolo-gies, OraSolv and DuraSolv, use slight effervescence. Patients mayexperience a pleasant tingling on the tongue with OraSolv andDuraSolv.Pharmacists have been alerted to exercise additional care when dis-pensing new prescriptions for ODT formulations. Most such prod-ucts are available in the same strengths as traditional dosage forms.Prescribing physicians must make an additional notation for the dis-pensing of a ODT. A physician may also mistakenly believe the drugbrand name is Zydis, for example, without identifying a specific drug.Verification with the prescribing practitioner may be necessary insome cases and can clear up any confusion.There are not commercially available fast-dissolving/disintegratingproducts for all of our patients’ needs. Pharmacists may wish to con-sider compounding as a unique way to treat the unmet needs ofindividual patients. When a manufactured ODT is not available, com-pounding pharmacists can consider tablet triturates. These largelyforgotten dosage forms have fast-disintegrating properties similar tomany manufactured products.All of the patients described earlier will benefit greatly from ODTformulations. The elderly patient, for example, could be prescribed

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

Remeron SolTab for depression. With a pharmacist’s intervention andassistance, all of these patients could be more properly treated withgreater convenience.

CONCLUSIONOrally disintegrating tablets (ODTs) have better patient acceptanceand compliance and may offer improved biopharmaceutical proper-ties, improved efficacy, and better safety compared with conventionaloral dosage forms. Prescription ODT products initially were devel-oped to overcome the difficulty in swallowing conventional tabletswith water among pediatric, geriatric, and psychiatric patients withdysphagia. Today, ODTs are more widely available as over-the-counterproducts for the treatment of allergies and cold and flu symptoms.The target population has expanded to those who want convenientdosing anywhere, anytime, without water. The future potential forODTs is promising because of the availability of new technologiescombined with strong market acceptance and patient demand. Doz-ens of ODT products have been commercialized, and the market sizefor ODTs will continue to expand as the technology is used to deliverlarge-molecular weight biopharmaceutical therapeutics such as pro-teins and peptides when coupled with the appropriate permeationenhancers. By paying close attention to advances in technologies,pharmaceutical companies can take advantage of ODTs for productline extensions or for first-to-market products.Future possibilities for improvements in ODTs and drug delivery arebright, but the technology is still relatively new. Several drug deliverytechnologies that can be leveraged on improving drug therapy fromODTs have yet to be fully realized.

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