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Article ID: WMC00809 ISSN 2046-1690

A Review on Fast Dissolving Tablets

Corresponding Author: Mrs. Rajeshree Panigrahi, Lecturer, Royal College of Pharmacy and Health Sciences, 760001 - India

Submitting Author: Mrs. Rajeshree Panigrahi, Lecturer, Royal College of Pharmacy and Health Sciences, 760001 - India

Article ID: WMC00809 Article Type: Review articles Submitted on:29-Sep-2010, 10:18:47 AM GMT Published on: 29-Sep-2010, 02:48:11 PM GMT Article URL: http://www.webmedcentral.com/article_view/809 Subject Categories:QUALITY AND PATIENT SAFETY Keywords:A drug which gives no tension of swallowing, Bad taste fit for all How to cite the article:Panigrahi R , Behera S . A Review on Fast Dissolving Tablets . WebmedCentral QUALITY AND PATIENT SAFETY 2010;1(9):WMC00809

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A Review on Fast Dissolving Tablets

Author(s): Panigrahi R , Behera S

Abstract patient compliance. Many patients have difficulty swallowing tablets and hard gelatin capsules and consequently do not take as prescribed. It is estimated that50% of the population is affected by Recently, fast-dissolving drug delivery systems have this problem, which results in a high incidence of started gaining popularity and acceptance as new drug noncompliance and ineffective therapy. The demand delivery systems, because they are easy to administer for solid dosage forms that can be dissolved and and lead to better patient compliance. Usually, elderly suspended in water, chewed, or rapidly dissolved in people experience difficulty in swallowing the the mouth is particularly strong in the pediatric and conventional dosage forms (tablets, capsules, geriatric markets, with further application to other solutions and suspensions) because of tremors of patients who prefer the convenience of a readily extremities and dysphasia. Fast-dissolving drug administered dosage form. Because of the increase in delivery systems may offer a solution for these the average human life span and the decline, with age, problems. in swallowing ability, oral tablet administration to Key Words: Fast Dissolving Tablet, drug delivery patients is a significant problem and has become the system object of public attention. The problem can be Introduction resolved by the creation of rapidly dispersing or dissolving oral forms, which do not require water to aid swallowing. The dosages forms are placed in the Drug delivery systems (DDS) are a strategic tool for mouth, allowed to disperse or dissolve in the saliva, expanding markets/indications, extending product life and then are swallowed in the normal way. Less cycles and generating opportunities. Oral frequently, they are designed to be absorbed through administration is the most popular route for systemic the buccal and esophageal mucosa as the saliva effects due to its ease of ingestion, pain, avoidance, passé into the stomach. In the latter case, the versatility and most importantly, patient compliance. bioavailability of a drug from fast dispersing Also solid oral delivery systems do not require sterile formulations may be even greater than that observed conditions and are therefore, less expensive to for standard dosage forms. manufacture. Patient compliance, high-precision The concept of Mouth Dissolving Drug Delivery dosing, and manufacturing efficiency make tablets the System emerged from the desire to provide patient solid dosage form of choice .Excipients and with more conventional means of taking their equipments choices will be significantly affected . It is difficult for many patients to swallow should solid dosage form technologies change in tablets and hard gelatin capsules. Hence they do not response to the unprecedented shifts in the drug comply with prescription, which results in high discovery such as genomics. Should next generation incidence of non-compliance and ineffective therapy. drugs are predominantly protein or peptide based, In some cases such as motion sickness, sudden tablets may no longer may be the dominant format episodes of allergic attacks or coughing and give the difficulty of dosing such moiety. Injections unavailability of water, swallowing conventional tablets generally are not favored for use by patients unless may be difficult. Particularly the difficulty is facilitated by sophisticated auto injectors. Inhalation is experienced by pediatric and geriatric patients. Such one good alternative system to deliver these drugs, problems can be resolved by means of Fast Dissolving but the increased research into biopharmaceuticals so Tablet. When put on tongue, this tablet disintegrates far has generate predominantly chemical entities with instantaneously, releasing the drug, which dissolves or low molecular weights. The development of enhanced disperses in the saliva. Some drugs are absorbed from oral protein delivery technology by Fast dissolving the mouth, pharynx and esophagus as the saliva Tablets which may release these drugs in the mouth passes down into the stomach. In such cases, are very promising for the delivery of high molecular bioavailability of drug is significantly greater than those weight protein and peptide. The oral route remains the observed from conventional tablet dosage form. perfect route for the administration of therapeutic FDDTs disintegrate and/or dissolve rapidly in the agents because the low cost of therapy, manufacturing saliva without the need for water. Some tablets are and ease of administration lead to high levels of designed to dissolve in saliva remarkably fast, within a

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few seconds, and are true fast-dissolving tablets. granules which slowly dissolve in the mouth. The Others contain agents to enhance the rate of tablet disintegration time for fast dissolving tablet varies from disintegration in the oral cavity, and are more a few seconds to more than a minute depending on appropriately termed fast-disintegrating tablets, as the formulation and the size of the tablet. they may take up to a minute to completely A fast disintegrating or dissolving system or tablet can disintegrate. When put on tongue, this tablet be defined as a solid dosage form that can disintegrates instantaneously, releasing the drug, disintegrate or dissolve within 30 seconds, in the oral which dissolves or disperses in the saliva. Some drugs cavity resulting in a solution or suspension without are absorbed from the mouth, pharynx and esophagus administration of water. The fast disintegrating tablets as the saliva passes down into the stomach. In such are synonymous with fast dissolving tablets; melt in cases, bioavailability of drug is significantly greater mouth tablets, rapimelts, Porous tablets, than those observed from conventional tablet dosage Orodispersible, quick dissolving or rapidly form.FDDTs, as a novel dosage form, have several disintegrating tablets. Their growing importance was characteristics to distinguish them from the more underlined recently when European pharmacopoeia traditional dosage forms. Taste-masking is of critical adopted the term “Orodispersible tablet” as a tablet importance in the formulation of an acceptable FDDT. that to be placed in the mouth where it disperses Traditional tablet formulations generally do not rapidly, before swallowing significance of this drug address the issue of taste masking, because it is delivery system includes administration without water, assumed that the dosage form will not dissolve until accuracy dosage, easy portability, alternative to liquid passing the oral cavity. Many oral suspensions, syrups, dosage forms ideal for pediatrics’ & geriatric patients and chewable tablets simply contain flavors, sugars and rapid onset of action. and other sweeteners to overwhelm or complement the bitter taste of the drug. Current methods of taste Biopharmaceutic masking in fast dissolving/ drug particles.FDTs are the Consideration disintegrating tablets include sweeteners and flavors; however, these are not a sufficient means for taste-masking many bitter drugs. Most of the FDDT When new drug delivery system put on, it is must that technologies incorporate unique forms of taste to consider Biopharmaceutical factor like metabolism masking as well. The primary methods of and excretion. taste-masking include adsorption onto or complexation Pharmacokinetics: with carriers and spray coating of solid dosage forms, In this consideration, study has done on absorption, which increase consumer choice, for the reason of distribution, metabolism and excretion. rapid disintegrate/dissolve in oral cavity within seconds After absorption, drug attains therapeutic level and and swallowed without the need of water or chewing. therefore elicits pharmacological effect, so both rate As tablet disintegrates in mouth this could enhance the and extend of absorption is important. In conventional clinical effect of the drug through pre-gastric dosage form there is delay in disintegration and absorption from the mouth, pharynx and esophagus. therefore dissolution while FDT is rapidly disintegrates This leads to an increase in bioavailability by avoiding in oral cavity and dissolution is fast. Due to first pass metabolism. disintegration of FDT in mouth absorption in started Fast dissolving drug delivery can be achieved various from mouth, pharynx and esophagus. Some factors techniques like direct compression, wet granulation, like age, GI pH, and blood flow through GI are taken compression moulding, volatization and freeze – into consideration, because elders may be considered drying. They involve different mechanisms like use of as separate unique Medicare population. high amounts of hydrophilic disintegrating agents Drug distribution depends on many factors like tissue which allow the dosage forms to disintegrate quickly in permeability, perfusion rate, binding of drug to tissue, the patient’s mouth on contact with saliva disease state, drug interaction etc. In geriatric patients, DEFINITION decrease in body mass and total body water result in The Center for Drug Evaluation and Research decreased volume of distribution of water-soluble (CDER), US FDA defined Oral Disintegrating Tablets drugs and increased volume of distribution (Vd) of lipid (ODT) as “A solid dosage form containing medicinal soluble drugs. substances, which disintegrates rapidly, usually within Duration and intensity of action depends upon rate of a matter of seconds, when placed upon the tongue.” drug removal from the body or site of action i.e. A fast dissolving tablet can be defined as a solid biotransformation. Decrease in liver volume, regional dosage form that can disintegrates into smaller blood flow to liver reduces the biotransformation of

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drug through oxidation, reduction and hydrolysis. disintegrate in the mouth within matter of seconds. Excretion by renal clearance is slowed, thus half-life of Be compatible with taste masking renal excreted drugs increase. Be portable without fragility concern. Pharmacodynamic: Have a pleasing mouth feel. Drug reception interaction impaired in elderly as well Leave minimal or no residue in the mouth after oral as in young adult due to undue development of organ. administration. Decreased ability of the body to respond baro reflexive Exhibit low sensivity to environmental condition as stimuli, cardiac output, and orthostatic hypotension humidity and temperature. may see in taking antihypertensive like prazosin. Be manufactured using conventional processing and Decreased sensitivity of the CVS to β-adrenergic packaging equipment at low cost. agonist and antagonist. Ease of administration to patients who refuse to Immunity is less and taken into consideration while swallow a tablet, such as pediatric and geriatric administered antibiotics. patients and psychiatric patients. Altered response to drug therapy-elderly show Convenience of administration and accurate dosing as diminished bronchodilator effect of theophylline shows compared to liquids. increased sensitivity to barbiturates. No need of water to swallow the dosage from, which is Concomitant illnesses are often present in elderly, highly convenient feature for patients who are traveling which is also taken into consideration, while multiple and do not have immediate access to water. drug therapy prescribed. Good mouth feel property of MDDS helps to change Research workers have clinically evaluated drug the basic view of medication as “bitter pill”, particularly combination for various classes’ cardiovascular agents, for pediatric patients. diuretics, anti-hypertensive in geriatrics. The Rapid dissolution and absorption of drug, which may combination choice depends on disease state of the produce rapid onset of action. patient. Some drugs are absorbed from the mouth, pharynx DIFFICULTIES WITH EXISTING ORAL DOSAGE and esophagus as the saliva passes down into the FORM stomach, and in such cases bioavailability of drugs in Patient may suffer from tremors therefore they have increased. difficulty to take powder and liquids. In dysphasia Ability to provide advantages of liquid medication in physical obstacles and adherence to an esophagus the form of solid preparation. may cause gastrointestinal ulceration. Pregastric absorption can result in improved Swallowing of solid dosage forms like tablet and bioavailability and as a result of reduced dosage, capsules and produce difficulty for young adult of improved clinical performance through a reduction of incomplete development of muscular and nervous unwanted effects. system and elderly patients suffer from dysphasia. IDEAL CHARACTERISTICS OF FAST DISSOLVING Liquid medicaments (suspension and emulsion) are DELIVERY SYSTEM packed in multidose container; therefore achievement Mouth-feel - Mouth-feel is critical, and patients should of uniformity in the content of each dose may be receive a product that feels pleasant. Any large difficult. particles from the disintegrating tablet that are Buccal and sublingual formation may cause irritation to insoluble or slowly soluble in saliva would lead to an oral mucosa, so patients refused to use such unpleasant gritty feeling. This can be overcome by medications keeping the majority of the particles below the Cost of products is main factor as parenteral detectable size limit. In some cases, certain flavors formulations are most costly and discomfort. can an improved mouth-feel perception, resulting in a product that is perceived as being less gritty, even if Salient Features Of Mouth the only change is the flavor. Effervescence can be Dissolving Drug Delivery added to aid disintegration and improve mouth-feel by System reducing the “dryness” of a product. Hygroscopicity - Several fast dissolving dosage forms are hygroscopic and cannot maintain physical integrity under normal conditions of temperature and humidity. DESIRED CRITERIA FOR MOUTH DISSOLVING Hence they need protection from humidity, which calls DRUG DELIVERY SYSTEM for specialized product packaging. Mouth Dissolving Tablet should- Friability - In order to allow fast dissolving tablets to Not require water to swallow, but it should dissolve or dissolve in the mouth, they are made of either very

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porous or soft molded matrices or compressed into nystatin, sulconazole nitrate, terbinafine HCl, tablets with very low compression force, which makes , tioconazole, undecenoic acid. the tablets friable and/or brittle which are difficult to Anti-gout Agents: Allopurinol,probenecid, handle, often requiring specialized peel off blister sulphinpyrazone. packing. To overcome this problem, some companies Anti-hypertensive Agents: introduced more robust forms of fast dissolving tablets, , , benidipine, darodipine, such as Wowtab by Yamanouchi-Shadlee and Dura dilitazem HCl, diazoxide, , guanabenz Solve by CIMA labs acetate, indoramin, isradipine, minoxidil, POTENTIAL CANDIDATE FOR FDT. HCl, , nimodipine, HCl, Analgesics and Anti-inflammatory Agents: prazosin HCL, , terazosin HCl. Aloxiprin, auranofin,azapropazone, benorylate, Anti-malarials: diflunisal, etodolac, fenbufen, fenoprofen calcim, Amodiaquine, chloroquine, chlorproguanil HCl, flurbiprofen, ibuprofen, indomethacin, ketoprofen, halofantrine HCl, mefloquine HCl, proguanil HCl, meclofenamic acid, mefenamicacid, nabumetone, pyrimethamine, quinine sulphate. naproxen, oxaprozin,oxyphenbutazone, Anti-migraine Agents: phenylbutazone,piroxicam, sulindac. mesylate, tartrate, : methysergidemaleate, maleate, ,bephenium succinate. hydroxynaphthoate,cambendazole, Anti-muscarinicAgents: ,, , , Atropine, benzhexol HCl,biperiden, ethopropazine HCl, oxfendazole, embonate, , hyoscine butyl bromide, hyoscyamine, mepenzolate embonate, thiabendazole. bromide,, oxyphencylcimineHCl, Anti-Arrhythmic Agents: tropicamide. HCl, Disopyramide, flecainide Anti-neoplasticAgents and Immunosuppressants: acetate,quinidine sulphate. Aminoglutethimide, amsacrine, azathioprine, Anti-bacterial Agents: busulphan, chlorambucil, cyclosporin, dacarbazine, Benethamine penicillin, cinoxacin, HCl, estramustine, etoposide, lomustine, melphalan, clarithromycin,clofazimine, cloxacillin, demeclocycline, mercaptopurine, methotrexate, mitomycin, mitotane, doxycycline,, ethionamide, mitozantrone, procarbazine HCl, tamoxifen citrate, imipenem,nalidixic acid, nitrofurantoin, testolactone. , spiramycin, sulphabenzamide, Anti-protazoalAgents: sulphadoxine, sulphamerazine, Benznidazole, clioquinol,decoquinate, sulphacetamide,sulphadiazine, sulphafurazole, diiodohydroxyquinoline,diloxanide furoate, dinitolmide, sulphamethoxazole, sulphapyridine,, furzolidone, metronidazole, nimorazole, nitrofurazone, trimethoprim. omidazole, tinidazole. Anti-coagulants: Anti-thyroid Agents:Carbimazole, propylthiouracil. Dicoumarol,dipyridamole, nicoumalone, phenindione. Anxiolytic, Sedatives, Hypnotics and Neuroleptics: Anti-depressants: Alprazolam, amylobarbitone, barbitone, bentazepam, , ciclazindol, HCl, bromazepam, bromperidol, brotizolam, butobarbitone, HCl, HCl, HCl, carbromal, chlordiazepoxide, maleate. chlormethiazole,, clobazam, Anti-diabeticsAcetohexamide,chlorpropamide, clotiazepam,, diazepam, glibenclamide,gliclazide, glipizide, tolazamide, ,ethinamate, flunanisone, flunitrazepam, tolbutamide. fluopromazine, flupenthixol decanoate, Anti-epileptics: decanoate, flurazepam, , Beclamide,, clonazepam, ethotoin, Cardiac InotropicAgents:Amrinone, digitoxin,digoxin, methoin, methsuximide, methylphenobarbitone, enoximone, lanatoside C, medigoxin. oxcarbazepine, paramethadione,phenacemide, Corticosteroids: phenobarbitone,, phensuximide, primidone, Beclomethasone,betamethasone, sulthiame, valproic acid. budesonide,cortisone acetate, desoxymethasone, Anti-fungal Agents: , fludrocortisoneacetate, flunisolide, Amphotericin, butoconazolenitrate, , flucortolone,fluticasone propionate, hydrocortisone, econazolenitrate, fluconazole, flucytosine,, , ,prednisone, ,, miconazole, natamycin, triamcinolone.

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Diuretics: (granulocyte-colony stimulating factor), EPO Acetazolamideamiloride, bendrofluazide, bumetanide, (erythropoitin). chlorothiazide, chlorthalidone, ethacrynic SexHormones: acid,frusemide, metolazone, , Clomiphenecitrate, danazol, triamterene. ethinyloestradiol,medroxyprogesterone acetate, Enzymes: All the enzymes. mestranol,methyltestosterone, Anti-parkinsonianAgents: norethisterone,norgestrel, oestradiol,conjugated mesylate,lysuride maleate. oestrogens, ,stanozolol, Gastro-intestinal Agents: stiboestrol,testosterone, tibolone. Bisacodyl, , , diphenoxylate HCl, Spermicides:Nonoxynol. domperidone, , loperamide, Stimulants: , dexamphetamine, mesalazine,, , , , mazindol, pemoline. HCL, HCl, sulphasalazine Advantages of Fast Dissolving Drug Delivery System H,-Receptor Antagonists: FDDTs , , , , Fast dissolving technology offers: HCl, , HCl, Improved compliance/added convenience , meclozine HCl, oxatomide, , No water needed . No chewing needed Lipid Regulating Agents: Better taste Bezafibrate, clofibrate, fenofibrate, gemfibrozil, Improved stability probucol. Suitable for controlled/sustained release actives Local Anaesthetics : Lidocaine Allows high drug loading. Neuro-muscular Agents: Pyridostigmine. Ability to provide advantages of liquid medication in Nitrates and otherAnti-anginal Agents: the form of solid preparation. Amyl nitrate, glyceryltrinitrate, isosorbide dinitrate, Adaptable and amenable to existing processing and isosorbide mononitrate, pentaerythritol tetranitrate. packaging machinery NutritionalAgents: Cost- effective Betacarotene, vitamin A, vitamin B2, vitamin D,vitamin OTHER EXCIPIENTS E, vitamin K.Opioid Analgesics: codeine, Excipients balance the properties of the actives in dextropropyoxyphene, diamorphine,dihydrocodeine, fast-melting tablets. This demands a thorough meptazinol,methadone, morphine, nalbuphine, understanding of the chemistry of these excipients to pentazocine. prevent interaction with the actives. Determining the OralVaccines: cost of these ingredients is another issue that needs to Vaccines designed toprevent or reduce the symptoms be addressed by formulators. The role of excipients is of diseases of which the following is a representative important in the formulation of fast-melting tablets. Influenza, Tuberculosis, Meningitis, Hepatitis, These inactive food-grade ingredients, when Whooping Cough, Polio, Tetanus,Diphtheria, Malaria, incorporated in the formulation, impart the desired Cholera, Herpes, Typhoid, HIV, AIDS, Measles, Lyme organoleptic properties and product efficacy. disease, TravellersAtrophic rhinitis, Erysipelas, Foot Excipients are general and can be used for a broad and Mouth disease, Swine, pneumonia, andother range of actives, except some actives that require disease conditions and other infections and masking agents. auto-immune diseaseconditions affecting companion BULKING MATERIALS: and farm animals.etc. Bulking materials are significant in the formulation of Proteins,PeptidesandRecombinantdrugs: fast-melting tablets. The material contributes functions Insulin, glucagon, growth hormone of a diluent, filler and cost reducer. Bulking agents (somatotropin),polypeptides or their derivatives, , improve the textural characteristics that in turn calcitonins and synthetic modifications thereof, enhance the disintegration in the mouth, besides; enkephalins, interferons, LHRH and analogues adding bulk also reduces the concentration of the (nafarelin, buserelin, zolidex), GHRH, secretin, active in the composition. The recommended bulking bradykin antagonists, GRF, THF,TRH, ACTH agents for this delivery system should be more analogues,IGF (insulin like growth sugar-based such as mannitol, polydextrose, lactitol, factors),CGRP(calcitoningene related peptide), atrial DCL (direct compressible lactose) and starch natriurecticpeptide, vasopressin and hydrolystate for higher aqueous solubility and good analogues(DDAVP, lypressin),factor VIII, G-CSF sensory perception. Mannitol in particular has high

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aqueous solubility and good sensory perception. Mechanism of Action: Water wicking, swelling and Bulking agents are added in the range of 10 percent to possibly some deformation recovery. Rapidly about 90 percent by weight of the final composition . disperses and swells in water, but does not gel even EMULSIFYING AGENTS: after prolonged exposure. Greatest rate of swelling Emulsifying agents are important excipients for compared to other disintegrants. Greater surface area formulating fast-melting tablets they aid in rapid to volume ratio than other sisintegrants. disintegration and drug release without chewing, 3) Low-substituted hydroxyl propyl cellulose,l which is swallowing or drinking water. In addition, incorporating insoluble in water. Rapidly swells in water. Grades emulsifying agents is useful in stabilizing the LH-11 and LH-21 exhibit the greatest degree of immiscible blends and enhancing bioavailability. A swelling. Certain grades can also provide some wide range of emulsifiers is recommended for binding properties while retaining disintegration fast-tablet formulation, including alkyl sulfates, capacity. Recommended concentration 1-5% propylene glycol esters, lecithin, sucrose esters and 4) Cross linked carboxy methyl cellulose sodium (i.e. others. These agents can be incorporated in the range Ac-Di-sol) Croscarmellose sodium: of 0.05 percent to about 15 percent by weight of the Mechanism of Action: Wicking due to fibrous structure, final composition. swelling with minimal gelling. Effective Concentrations: LUBRICANTS: 1-3% Direct Compression, 2-4% Wet Granulation Lubricants, though not essential excipirnts, can further Gas producing disintegrants assist in making these tablets more palatable after Gas producing disintegrants are used especially they disintegrate in the mouth. Lubricants remove where extra rapid disintegration or readily soluble grittiness and assist in the drug transport mechanism formulation is required. They have also been found of from the mouth down into the stomach. value when poor disintegration characteristics have FLAVOURS AND SWEETENERS: resisted other methods of improvement. Care should Flavours and taste-masking agents make the products be taken during tab letting, particularly on moisture more palatable and pleasing for patients. The addition level. Composition is based upon the same principles of these ingredients assists in overcoming bitterness as those used for effervescent tablets, the most and undesirable tastes of some active ingredients. common being mixtures of citric & tartaric acids plus Both natural and synthetic flavours can be used to carbonates or bicarbonates. improve the organoleptic characteristic of fast-melting In many instances lower concentration can be used tablets. Formulators can choose from a wide range of with gas producing disintegrants than are required by sweeteners including sugar, dextrose and fructose, as other disintegrating agents. Certain peroxides that well as non-nutritive sweeteners such as aspartame, release oxygen have been tried, but they do not sodium saccharin, sugar alcohols and sucralose. The perform as well as those releasing carbon dioxide addition of sweeteners contributes a pleasant taste as well as bulk to the composition. SUPER DISINTEGRANTS: Conventional Technique Used A disintegrant is an excipient, which is added to a In The Preparation Of MFDTS tablet or capsule blend to aid in the break up of the compacted mass when it is put into a fluid environment. * Freeze drying technique ADVANTAGES: * Tablet molding technique Effective in lower concentrations * Spray drying technique Less effect on compressibility and flowability * Direct compression technique More effective intragranularly * Sublimation technique Some super disintegrants are: * Mass extrusion technique 1) Sodium Starch Glycolate (Explotab, primogel) used Freeze Drying Technology (Zydis Technology) [20] in concentration of 2-8 % & optimum is 4%. Lyophilization can be used to prepare tablets that have Mechanism of Action: Rapid and extensive swelling very porous open matrix network into which saliva with minimal gelling. Microcrystalline cellulose rapidly moves to disintegrate lyophilized mass after it (Synonym: Avicel, celex) used in concentration of is placed in mouth. 2-15% of tablet weight. And Water wicking The drug is entrapped in a water soluble matrix which 2) Cross-linked Povidone (crospovidone) (Kollidone) is freeze dried to produce a unit which rapidly used in concentration of 2-5% of weight of tablet. disperses when placed in mouth. Apart from the matrix Completely insoluble in water.

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and active constituents, the final formulation may seconds. contain other excipients, which improve the process Direct Compression Method [20] characteristics or enhance the quality of final product. In this method, tablets are compressed directly from These include suspending agents, wetting agents, the mixture of the drug and excipients without any preservatives, antioxidants, colors and flavors. The preliminary treatment. The mixture to be compressed preferred drug characteristics for freeze drying must have adequate flow properties and cohere under formulations are water insoluble, low dose, chemically pressure thus making pretreatment as wet granulation stable, small particle size and tasteless. unnecessary. Few drugs can be directly compressed Corveleyn and Remon investigated the influence of into tablets of acceptable quality. A type of disintegrant various formulation and process parameters on the and its proportion are of prime importance. The other characteristics of rapidly disintegrating tablets in factors to be considered are particle size distribution, lyophilized form using hydrochlorthiazide as a model contact angle, pore size distribution, tablet hardness drug. They have concluded that maltodxtrins are and water absorption capacity. All these factors useful in the formulation of fast dissolving tablets determine the disintegration. The disintegrant addition made by freeze-drying. technology is cost effective and easy to implement at Lyophilization is relatively expensive and time industrial level. consuming manufacturing process. Other drawback Cousin et al, using carboxymethyl cellulose as includes fragility, which make the use of conventional disintegrating agent and one swelling agent consisting packing difficult and poor stability during storage under of modified starch or microcrystalline cellulose stressful condition. formulated rapidly disintegrable multi particular tablets. Tablet Molding [20] The tablets disintegrate in the mouth in less than 60 In this technology, water-soluble ingredients are used seconds. so that tablet disintegrate and dissolve rapidly. The Gas Evolving disintegrants have been used to powder blend is moistened with a hydro alcoholic formulate fast dissolving tablets. The evolution of solvent and is molded in to tablet using compression carbon dioxide as a disintegration mechanism called pressure lower than used in conventional tablets OROSOLV and DURASOLV have been described in compression. The solvent is then removed by two US Patents assigned to CIMA Labs J. Michaelson air-drying. Molded tablets have a porous structure that described the use of intimate mixture of alginic acid enhances dissolution. Two problems commonly and a water-soluble metal carbonic acid to prepare encountered are mechanical strength and poor taste tablets. When tablet was placed in water, an acid base masking characteristics. Using binding agents such as reaction takes place forming a metal alginic acid salt sucrose, acacia or poly vinyl pyrrolidone can increase and carbonic acid. The salt caused the tablet to swell the mechanical strength of the tablet. and the carbonic acid produced carbon dioxide within To overcome poor taste masking characteristic Van the swelling tablet whereby rapid disintegration of Scoik incorporated drug containing discrete particles, tablet was effected. which were formed by spray congealing a molten Sublimation Technique [20] mixture of hydrogenated cottonseed oil, sodium The basis of this technique is to add inert solid bicarbonate, lecithin, polyethylene glycol and active ingredients that volatilize readily, (e.g. camphor, ingredient into a lactose based tablet triturate form. ammonium bicarbonate, naphthalene, urea, urethane Spray Drying [20] etc) to other tablet excipients and the mixture is then Spray dryers are widely used in pharmaceuticals and compressed into tablets. Volatile material is then biochemical processes. Due to processing solvent is removed via sublimation, which generate a porous evaporated rapidly; spray drying can produce highly structure. porous, fine powder. Spray drying can be used to Koizumi et al applied the sublimation technique to prepare rapidly disintegrating tablets. This technique is prepare highly porous compressed tablets that were based on a particulate support matrix, which is rapidly soluble in saliva. Mannitol and camphor were prepared by spray drying an aqueous composition used as a tablet matrix material and subliming the containing support matrix and other components to material respectively. Camphor was iminated by forma highly porous and fine powder. This is then subliming in vacuum at 80 0C for 30 minutes to mixed with active ingredients and compressed into develop pores in the tablets. tablets. Makino et al described a method of producing a fast Allen et al used a spray drying technique to prepare dissolving tablet using water as a pore forming fast dissolving tablets. The tablets made from this material. A mixture containing active ingredient and technology are claimed to disintegrate within 20 carbohydrates (glucose, manitol, xylitol etc) were

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moistened with water (1- 3 %w/w) and compressed * Buccal pharyngeal and gastric regions are all areas into tablets. The water was then removed yielding of absorption from this formulation. Any pre-gastric highly porous tablet that exhibited excellent ; absorption avoids first-pass metabolism and can be an Mass-Extrusion(Mass-Extrusion) [20] advantage in drugs that udergo a great deal of hepatic This technology involves softening the active blend metabolism. using the solvent mixture of water-soluble * The zydis formulation self-preserving because the polyethylene glycol and methanol and subsequent final water concentration in the freeze-dried product is expulsion of softened mass through the extruder or too low to allow for microbial growth. syringe to get a cylinder of the product into even Disadvantages segments using heated blade to form tablets. The * The process of freeze-drying is a relatively expensive dried cylinder can also be used to coat granules for manufacturing process. bitter drugs and thereby achieve taste masking. * The formulation is very lightweight and fragile, and PATENTED TECHNOLOGIES OF FDTs [20] therefore should not be stored in backpacks or the Currently, four fast-dissolving/disintegrating bottom of purses. technologies have reached the U.S. market: * It has poor stability at higher temperatures and * Zydis (R.P. Scherer, Inc.), humidities. * WOWTAB (Yamanouchi Pharma Technologies, Inc.), * The freeze-drying is time consuming process * OraSolv (Cima Labs, Inc.). * It has poor physical resistance * DuraSolv (Cima Labs, Inc.). * Loading of high dose of water-soluble drugs is not Three others are available outside the U.S. : possible * FlashDose (Fuisz Technologies, Ltd.), Durasolv Technology [20, 21] * Flashtab (Prographarm Group), Durasolv is the patented technology of CIMA labs. The * OraQuick (KV Pharmaceutical Co., Inc.) tablets made by this technology consist of a drug, Zydis Technology [20, 21] fillers and a lubricant. Tablets are prepared by using Zydis formulation is a unique freeze dried tablet in conventional tableting equipment and have good which drug is physically entrapped or dissolved within rigidity. These can be packaged into conventional the matrix of fast-dissolving carrier material. When packaging system like blisters. Durasolv is an zydis units are put into the mouth, the freeze-dried appropriate technology for products requiring low structure disintegrates instantaneously and does not amounts of active ingredients. require water to aid swallowing. The zydis matrix is Advantages composed of many materials designed to achieve a * Durasolv has much higher mechanical strength than number of objectives. To impart strength and its predecessor due to the use of higher compaction resilience during handling, polymers such as gelatin, pressures during tabletting. dextran or alginates are incorporated. These forms a * The Durasolv product is thus produced in a faster glossy amorphous structure, which imparts strength. and in more effective manner. To obtain crystallinity, elegance and hardness, Disadvantages saccharides such as mannitol or sorbitol are * It is not compatible with larger doses of active incorporated. Water is used in the manufacturing ingredients because the formulation is subjected to process to ensure production of porous units to high pressures on compaction. achieve rapid disintegration. Various gums are used to * The drug powder coating may fractured during prevent sedimentation of dispersed drug particles in compaction, exposing the bitter tasting drug to the manufacturing process. Collapse protectants such patient’s taste buds. as glycine prevent the shrinkage of zydis units during Orasolv Technology [20, 21] freeze drying process or long term storage. Zydis Orasolv Technology has been developed by CIMA products are packed in blister packs to protect the labs. In this system active medicament is taste formulation from moisture in the environment. masked. It also contains effervescent disintegrating Limitations agent. Tablets are made by direct compression * The amount of drug could be incorporated should technique at low compression force in order to generally be less than 400mg for insoluble drugs and minimize oral dissolution time. Conventional blenders less that 60mg for soluble drugs. and tablet machine is used to produce the tablets. The * The particle size of the insoluble drugs should not be tablets produced are soft and friable and packaged in less than 50µm and not more than 200µm to prevent specially designed pick and place system. sedimentation during processing. Advantages Advantages * The Orosolv formulations are not very hygroscopic

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* The formulation can accommodate high doses. technologies makes Oraquick appropriate for * It also provides a distinct, pleasant sensation of heat-sensitive drugs. KV Pharmaceutical also claims effervescence in the mouth. that the matrix that surrounds and protects the drug Disadvantages powder in microencapsulated particles is more pliable, * A weaker and more brittle tablet in comparison with meaning tablets can be compressed to achieve conventional tablets. significant mechanical strength without disrupting * Poor mechanical strength. taste-masking Oraquick claims quick dissolution in a * The cost of fast dissolving tablets is higher than the matter of seconds, with good taste-masking. There are cost of standard tablets made by direct compression no products using the Oraquick technology currently * Manufacturing requires a controlled environment at on the market, but KV pharmaceutical has products in low relative humidity. development such as analgesics, scheduled drugs, Wowtab Technology [20, 21] cough and cold, psychotropics, and anti-infectives. Wowtab Technology is patented by Yamanouchi Each technology has a different mechanism, and each Pharmaceutical Co. WOW means "Without Water ". In fast-dissolving/disintegrating dosage form varies this process, combination of low mouldability regarding the following: [23] saccharides and high mouldability saccharides is used * Mechanical strength of final product; to obtain a rapidly melting strong tablet. The active * Drug and dosage form stability; ingredient is mixed with a low mouldability saccharide * Mouth feel; and granulated with a high mouldability saccharide * Taste; and compressed into tablet. * Rate of dissolution of drug formulation in saliva; Advantages * Swallow ability; * Offers Superior mouthfeel due to the smooth melt * Rate of absorption from the saliva solution; and action * Overall bioavailability. * It is suitable for both conventional bottle and blister packaging Evaluation Of Blend * Bit more stable to the environment than the zydis and orasolv. Flash Dose Technology [20, 21] The prepared blend was evaluated by following tests. Flash dose technology has been patented by Fuisz. Angle of repose Nurofen meltlet, a new form of ibuprofen as Bulk density melt-in-mouth tablets, prepared using flash dose Tapped density technology is the first commercial product launched by Carr’s index Biovail Corporation. Flash dose tablets consists of self Hauser’s ratio binding shearform matrix termed as "floss". Shearform Angle of repose matrices are prepared by flash heat processing. Angle of repose was determined by using funnel Flashtab Technology [20, 21] method. The accurately weighed blend was taken in a Prographarm laboratories have patented the Flashtab funnel. The height of the funnel was adjusted in such a technology. Tablets prepared by this system consist of way that the tip of the funnel just touches the apex of an active ingredient in the form of microcrystals. Drug the heap of blend. The drug (as solid microgranules may be prepared by using the dispersion)-excipient blend was allowed to flow conventional techniques like coacervation, through the funnel Freely on to the surface. The microencapsulation, and extrusion- spheronisation. All diameter of the powder cone was measured and angle the processing utilized conventional tabletting of repose was calculated using the following equation. technology. Tan θ = h/r Oraquick Technology [20, 21, 22] Where h and r are the height and radius of the powder The Oraquick fast dissolving/disintegrating tablet conc. formulation utilizes a patented taste masking Bulk density technology. KV Pharmaceutical claims its micro Apparent bulk density was determined by pouring a sphere technology, known as Micro Mask, has weighed quantity of blend into graduated cylinder and superior mouth feel over taste-masking alternatives. measuring the volume and weight. The taste masking process does not utilize solvents of BD =Weight of the powder / Volume of the packing. any kind, and therefore leads to faster and more Tapped Density efficient production. Also, lower heat of production It was determined by placing a graduated cylinder, than alternative fast-dissolving/disintegrating containing a known mass of drug-excipients blend.

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The cylinder was allowed to fall under its own weight formulation were weighed and placed in Roche onto a hard surface from the height of 10cm at 2- friabilator that rotated at 25 rpm for 4 minutes. The second intervals. The tapping was continued until no tablets were dedusted and weighed again. The further change in volume was noted. percentage of weight loss was calculated again. The TBD =Weight of the powder / volume of the tapped percentage of weight loss was calculated using the packing. formula Compressibility Index % Friability = [(W1-W2)100]/W1 The Compressibility Index of the blends was Where, determined by Carr’s compressibility index. W1= Weight of tablet before test Carr’s compressibility index (%) = [(TBD-LBD) X 100] / W2 = Weight of tablet after test TBD Disintegration test: A similar index has been defined by Hausner The USP device to rest disintegration was six glass Hauser’s ratio = Tapped density/ Poured density tubes that are “3 long, open at the top, and held Hausner’s ratio against 10” screen at the bottom end of the basket 1.25 – Poor flow =33% Carr rack assembly. One tablet is placed in each tube and b) Compression the basket rack is poisoned in 1 liter beaker of distilled Mixed Blends were compressed by direct compression water at 37± 2 oC, such that the tablets remain below method using Cadmach single punch machine. Caput the surface of the liquid on their upward movement punches and die (8 mm.) were used in this study. and descend not closer than 2.5cm from the bottom of EVALUATION OF TABLETS the beaker. All the formulated Gliclazide fast dissolving tablets Uniformity of dispersion: were subjected to the following quality control tests: Two tablets were kept in 100ml water and gently Weight variation stirred for 2 minutes. The dispersion was passed Friability through 22 meshes. The tablets were considered to Hardness pass the test if no residue remained on the screen. Disintegration Wetting Time: Wetting Time The wetting time of the tablets was measured using a Water absorption Ratio simple procedure. Five circular tissue papers of 10cm Taste / Mouth feel diameter were placed in a petridish containing 0.2% In vitro Dissolution w/v solution (3ml). a tablet was carefully placed on the Stability studies surface of the tissue paper. The time required for Evaluation Parameter of MFDTs develop blue color on the upper surface of the tablets Weight variation: was noted as the wetting time. The weight variation test is carried out in order to Water Absorption Ratio: ensure uniformity in the weight of tablets in a batch. A small piece of tissue paper folded twice was placed The total weight of 20 tablets from each formulation in a small petridish containing 6ml of water. A tablet was determined and the average was calculated. The was put on the paper and the time required for individual weights of the tablets were also determined complete wetting was measured. The wetted tablet accurately and the weight variation was calculated .. was then reweighed. Water absorption ratio, R was Hardness: determined by using following formula were given The hardness of tablet is an indication of its strength. R= 100 x Wa-Wb / Wb Measuring the force required to break the tablet Wb is the weight of tablet before water absorption across tests it. The force is measured in kg and the Wa is the weight of tablet after water absorption hardness of about 3-5 kg/cm2 is considered to be Taste/ Mouth sensation satisfactory for uncoated tablets. Hardness of 10 Mouth-feel is critical, and patients should receive a tablets from each formulation was determined by product that feels pleasant. One tablet from each Monsanto hardness tester. batch was tested for the sensation by placing the Friability test: tablet on the tongue. The healthy human volunteers Friability is the loss of weight of tablet in the container were used for evaluation of mouth feel. Taste due to removal of fine particles from the surface. evaluation was done by a panel of 5 members using Friability test is carried out to access the ability of the time intensity method. Sample equivalent to 40 mg i.e tablet to withstand abrasion in packaging, handling dose of drug was held in mouth for 10 secs. Taste and transport. Roche friabilator was employed for were recorded instantly and then after 10 secs, 1, 2, 4 finding the friability of the tablets. 20 tablets from each and 6 minutes. Volunteer’s opinion for the taste were

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rated by giving different score values i.e. .0 = good, 1 interval choosen. For example , the index DE30 would = tasteless, 2 = slightly bitter, 3 = bitter, 4 = awful. relate to the dissolution of the drug from a particular In vitro drug release studies formulation after 30 mins could only be compared with The Gliclazide fast dissolving tablets were subjected to DE30 of other formulations. in vitro drug release studies in pH 6.8 phosphate One way ANOVA buffer for 30 minutes to access the ability of the One way analysis of variance (ANOVA) compares the formulation for providing immediate drug delivery. means of three or more groups.The null hypothesis is Drug release studies were carried out in eight stage that all column means are equal,and P value testing dissolution test apparatus (DISSO 2000, Lab India) this null hypothesis. using 900ml ml of dissolution medium (pH 6.8 The one way ANOVA test assumes that data are phosphate buffer) maintained at 37±10C. The tablets randomly sampled from larger populations ( or at least were kept in the cylindrical basket and rotated at 100 are representative of those populations ) , that each rpm value was obtained independently of others,that the 5ml of the sample from the dissolution medium were populations are scattered accordingly to a Gaussian withdrawn at each time interval (2, 3, 5, 10, 15&30 distribution,and that the SD of the two populations are minutes) and 5ml of fresh medium was replaced each equal. time. The samples were filtered and from the filtrate It shows intermediate calculations that laed to 1ml was taken and diluted to 10ml with pH 6.8 calculate F value.if the calculated value is less than Phosphate buffer. The absorbances of the sample tabulated value , it can be concluded that the data are λ were measured at max 227.2 nm using UV unlikely to be sampled from populations with equal spectrophotometer. means. In vitro dissolution kinetic studies Two way ANOVA The drug released data were plotted and tested with When it is believed that two independent factors might zero order ( Cumulative % drug released Vs time),First have an effect on the response variable of interest, it is order (Log % Remained Vs time).The zero order possible to design the test so that an analysis of release kinetics was shown in Figures variance can be used to test for the effects of the two The First order release kinetics were shown in figures factors simultaneously. Such a test is called a The in vitro dissolution kinetic parameters,dissolution Two-Factor analysis of variance. With this we can test rate constants (K),correlation coefficient ® , the times two sets of hypothesis with the same data at the same (t50) for50% drug released ( half life) and dissolution time. efficiency were calculated and presented in the tables In this the data are classified according to two different of following chapters.From the slopes of linear plots, criteria of factors. The procedure for analysis of the dissolution rates were calculated. variance is somewhat different than the one followed First – order release kinetics log Q1 = logQo + k1t while dealing with problems of one-way 2.303 ANOVA.(statistical methods – S.P.Gupta,34th The First order equation describes the release from edn,2005-pg no.-1019) systems where release rate is concentration Similarity and Dis-similarity factor dependent.Where Qo is the initial amount of the drug,t Purpose of dissolution profile comparison: is in minutes and k1 describes the dissolution rate For accepting product sameness under constant for first-order release kinetics.A plot of the SUPAC-related changes. logarithm of the percent drug remained against time To waive bioequivalence requirements for lower will be linear if the release obeys first-order release strengths of a dosage form. kinetics.values of release rate constant k1 were To support waivers for other bioequivalence obtained in each case from the slope of the log % drug requirements. remained versus time plots Dissolution profiles may be considered similar by Dissolution efficiency virtue of (1) overall profile similarity and (2) similarity at DE is defined as the area under the dissolution curve every dissolution sample time point. The dissolution upto the time “t” expressed as a percentage of the profile comparison may be carried out using model area of the trapezoid described by 100% dissolution in independent or model dependent methods. the same time. Model Independent Approach Using a Similarity Factor DE = ∫td y.dt A simple model independent approach uses a Yidd.t difference factor (f1) and a similarity factor (f2) to This has a range of values depending on the time compare dissolution profiles. The difference factor (f1) calculates the percent (%) difference between the two

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curves at each time point and is a measurement of the mouth feel & in vitro release profile were determined at relative error between the two curves: interval of 15& 30 days. where n is the number of time points, Rt is the dissolution value of the reference (prechange) batch at Acknowledgement(s) time t, and Tt is the dissolution value of the test (postchange) batch at time t. The similarity factor (f2) is a logarithmic reciprocal Mrs.Rajeshree Panigrahi would like to acknowledge square root transformation of the sum of squared error the support during this research received from Royal and is a measurement of the similarity in the percent college of pharmacy and health sciences, Berhampur (%) dissolution between the two curves. for its esteemed support and encouragement A specific procedure to determine difference and similarity factors is as follows: References Determine the dissolution profile of two products (12 units each) of the test (postchange) and reference (prechange) products. 1. S.S. Biradar, et al ., “Fast dissolving drug delivery Using the mean dissolution values from both curves at systems: a brief overview”, The Internet Journal of each time interval, calculate the difference factor (f1) Pharmacology.,2006;4(2). and similarity factor (f2) using the above equations. 2. M.Slowson , et al ., “What to do when patients For curves to be considered similar, f1 values should cannot swallow their medications", Pharm. Times ., be close to 0, and f2 values should be close to 100. 1985; 51:90-96. Generally, f1 values up to 15 (0-15) and f2 values 3. R.K.Chang, et al ., “Fast-dissolving tablets”, Pharm greater than 50 (50-100) ensure sameness or Technology., 2000;24(6):52-58. equivalence of the two curves and, thus, of the 4. L.Lachmann, et al . , The theory and practice of performance of the test (postchange) and reference Industrial Pharmacy:293-303. (prechange) products. 5. Available from URL: This model independent method is most suitable for http://www.ispub.com/ostia/index.php?Xmlfilepath=jou dissolution profile comparison when three to four or nals/jjpharm/front.Xml. more dissolution time points are available. As further 6. L.H.Reddy, et al., “Fast dissolving drug delivery suggestions for the general approach, the following systems:A review of the literature”, IJPS. , July 2002 recommendations should also be considered: :331-336. The dissolution measurements of the test and 7. N.H. Indurwade, et al., “Novel approach – Fast reference batches should be made under exactly the dissolving tablets” , Indian drugs., August 2002 same conditions. The dissolution time points for both ;39(8):405-409. the profiles should be the same (e.g., 15, 30, 45, 60 8. B.S.Kuchekar, et al., “Mouth dissolving tablets: A minutes). The reference batch used should be the novel drug delivery system”, most recently manufactured prechange product. 9. Pharma times., June 2003; 35:7-9. Only one measurement should be considered after 10. H.Seager, “Drug Delivery Products and the Zydis 85% dissolution of both the products. Fast DissolvingDosageForm,” J.Pharm. To allow use of mean data, the percent coefficient of Pharmacol.,1998: 375–382 variation at the earlier time points (e.g., 15 minutes) 11. L. Mallet, “Caring for the Elderly Patient,”J. Am. should not be more than 20%, and at other time points Pharm. Assoc., 1996; 36 (11): 628. should not be more than 10%. 12. T.Hanawa et al.,“New Oral Dosage Form for The mean dissolution values for Rt can be derived Elderly Patients: Preparation and either from (1) last t prechange (reference) batch or (2) 13. Characterization of Silk Fibroin Gel,” Chem. last two or more consecutively manufactured Pharm.Bull.,1995; 43 (2) :284–288. prechange batches.(same above-pg-1006) 14. R. Yarwood, “Zydis — A Novel, Fast Dissolving Stability studies Dosage Form,”Man. Chem., February 1990: 36–37. The best formulation of Gliclazide MFDTs containing 15. Seager, H., " Drug-deliver Products and the Zydis (CPV + CCM in 75:25 ratio) were subjected to stability Fast-dissolving Dosage Form", J.Pharm and study by keeping them at 40oC/75% RH for 1 month to Pharmacol., 1998;50:375-382. assess their stability with respect to their physical 16. Bradoo, R., Shahani, S., Poojary, S., Deewan, B. appearance and release characteristics. The physical and Sudarshan, S., JAMA India., 2001; 4(10) :27-31. characteristics like weight variation, hardness, friability, 17. Chang RK, Guo X, Burnside B, Couch R. wetting time, water absorption ratio, disintegration time, Fast-Dissolving Tablets, Pharm Technology.,

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2000;24(6):52-58. 18. Leon Lachmann, Herbert A , Liberman , Joseph L.Kaing , The theory and practice of Industrial Pharmacy:293-303. 19. Reddy.L.H et al., “Fast dissolving drug delivery systems:A review of the literature , IJPS. , July 2002 :331-336. 20. Indurwade N.H.et al., “Novel approach – Fast Dissolving Tablets , Indian drugs., August 2002 ;39(8):405-409. 21. B.S.Kuchekar , et al., “Mouth Dissolving Tablets: A Novel Drug Delivery System, Pharma times., June 2003:35. 22. http://www.phamacast.com/patents100/Yr2004/May20 04/051104/6733781_Fast Dissolving 051104.htm. Seager, H., J.Pharma . Pharmacol., 1998;50:375-382. 23. Shangraw, R., Mitrevej, A. and Shah, M., Pharma . Tech., 1980;4(10): 49-57 24. Yoshio, K., Masazumi, K., Shuichi A., and Hiroaki N.,2005, Evaluation of rapidly disintegrating tablets manufactured by phase transition of sugar alcohols, J. Control. Release, 105(1-2), 16-22. 25. Available from URL: http://www.ispub.com/ostia/index.php?mlFilepath=inde x.Xml 26. K.A.Khan, “Invitro dissolution rate studies and dissolution efficiency”, J.Pharm.Pharmacol., 1975;27(48). 27. J.G.Wagner , “ Kinetics of drug release” , J.Pharma Sciences., 1963;58. 28. S.P.Gupta , Statistical Methods,34th edn., 2005:1019.

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