Challenges in development of Challenges in development of orally disintegrating and orally disintegrating and

dispersible tablets.dispersible tablets.

ByByV.SRUJANAV.SRUJANAM.Pharm ( 1M.Pharm ( 1stst SEM ) SEM )DEPARTMENT OF PHARMACEUTICSDEPARTMENT OF PHARMACEUTICS

CONTENTSCONTENTS

IntroductionIntroduction Advantages over conventional tablet dosage formsAdvantages over conventional tablet dosage forms Challenges in formulation and developmentChallenges in formulation and development Materials requiredMaterials required Mechanism of drug releaseMechanism of drug release Formulation techniquesFormulation techniques Conventional methodsConventional methods Patented technologiesPatented technologies Marketed productsMarketed products Evaluation testsEvaluation tests Future developmentsFuture developments ConclusionConclusion ReferencesReferences

INTRODUCTIONINTRODUCTION

Definitions of ODTs:Definitions of ODTs:

According to US FDA:According to US FDA:

““A solid dosage form containing medicinal substanceA solid dosage form containing medicinal substance, , whichwhich disintegrates rapidly usually within a matter of seconds, disintegrates rapidly usually within a matter of seconds, when placed upon the tongue”.when placed upon the tongue”.

According to European pharmacopoeia:According to European pharmacopoeia:

““A tablet that is to be placed in the mouth where it disperses rapidly before A tablet that is to be placed in the mouth where it disperses rapidly before swallowing”. swallowing”.

Terminologies for ODTsTerminologies for ODTs

Rapidly dissolving tablets are also known asRapidly dissolving tablets are also known as

Melt in Mouth tabletsMelt in Mouth tablets

Mouth dissolving tablets (MDT)Mouth dissolving tablets (MDT)

Fast disintegrating tablets (FDT)Fast disintegrating tablets (FDT)

Orally disintegrating tabletsOrally disintegrating tablets

Rapid disintegrating tablets (RDT)Rapid disintegrating tablets (RDT)

Oro dispersible tablets (ODT)Oro dispersible tablets (ODT)

Quick dissolving tablets.Quick dissolving tablets.

Advantages over the conventional dosage formAdvantages over the conventional dosage form

No risk of choking. No risk of choking.

Requires no water intake. Requires no water intake.

Overcomes unacceptable taste of the Drugs.Overcomes unacceptable taste of the Drugs.

Quick disintegration and dissolution of the dosage form.Quick disintegration and dissolution of the dosage form. Facilitates faster onset of therapeutic action.Facilitates faster onset of therapeutic action. Improved bioavailability can be achieved. Improved bioavailability can be achieved.

Avoids First Pass Metabolism due to pregastric absorption.Avoids First Pass Metabolism due to pregastric absorption.

Ideal dosage form for Peadiatric and geriatric patients. Ideal dosage form for Peadiatric and geriatric patients.

Ease of administration for patients who are mentally ill, disabled and un Ease of administration for patients who are mentally ill, disabled and un co-operative. co-operative.

Challenges in the product design, formulation Challenges in the product design, formulation and manufacture of ODTs.and manufacture of ODTs.

PalatabilityPalatability Mechanical strengthMechanical strength Amount of drugAmount of drug Size of tabletSize of tablet HygroscopicityHygroscopicity Aqueous solubilityAqueous solubility Short half-lifeShort half-life Cost of the tabletCost of the tablet

PALATABILITYPALATABILITY

As most of the drugs are unpalatable, orally disintegrating drug delivery As most of the drugs are unpalatable, orally disintegrating drug delivery

systems usually contain the medicament in a taste masked form.systems usually contain the medicament in a taste masked form.

Delivery systems disintegrate or dissolve in patient’s oral cavity, thus Delivery systems disintegrate or dissolve in patient’s oral cavity, thus

releasing the active ingredients which come in contact with the taste buds;releasing the active ingredients which come in contact with the taste buds;

hence taste masking of drugs become critical to patient compliance.hence taste masking of drugs become critical to patient compliance.

General taste masking technologies in oral solid dosage General taste masking technologies in oral solid dosage forms:forms:

1.1. Taste masking with hydrophilic vehicleTaste masking with hydrophilic vehicleHydrophilic vehicles- carbohydrates, proteins, gelatin, ZeoliteHydrophilic vehicles- carbohydrates, proteins, gelatin, ZeoliteIon Exchange resins- Indion 204, 214, 224, 234Ion Exchange resins- Indion 204, 214, 224, 234CyclodextrinsCyclodextrinsFlavors, sweeteners, amino acids.Flavors, sweeteners, amino acids.

2.2. Taste masking with lipophilic vehicleTaste masking with lipophilic vehicleEx: fats, fatty acids.Ex: fats, fatty acids.

3.3. Miscellaneous masking agentsMiscellaneous masking agentsEx: Effervescent agents, Rheological modifications, salt preparations, solid Ex: Effervescent agents, Rheological modifications, salt preparations, solid

dispersions etc.dispersions etc.

Detection threshold of sensors compared to Human receptorsDetection threshold of sensors compared to Human receptors

Pharmaceutical taste assessment requires human test panel that increasesPharmaceutical taste assessment requires human test panel that increases

time and money to the development process. During the last decade, a time and money to the development process. During the last decade, a

multisensor system and a device for the liquid analysis that can be collected multisensor system and a device for the liquid analysis that can be collected

under the term “Electronic tongue” was developed.under the term “Electronic tongue” was developed.

TasteTaste Taste basic Taste basic substancesubstance

Human tongueHuman tongue Electronic Electronic tonguetongue

SweetnessSweetness SucroseSucrose 1x101x10-2-2 2x102x10-6-6

Bitterness Bitterness CaffeineCaffeine 0.7x100.7x10-3-3 1x101x10-6-6

Sourness Sourness HClHCl 9x109x10-4-4 5x105x10-6-6

The active moiety in pharmaceutical product cannot be therapeutically The active moiety in pharmaceutical product cannot be therapeutically beneficial unless it has preference and acceptance by the patient. Thus, beneficial unless it has preference and acceptance by the patient. Thus,

pleasant taste is important for the therapeutic success of the drug pleasant taste is important for the therapeutic success of the drug formulation. formulation.

Human tongue with taste Human tongue with taste receptors.receptors.

Sample Electronic Sample Electronic tongue tongue

Objectives of electronic tongue:Objectives of electronic tongue:

Identification between bitter, sweet and sour substances by using electronic Identification between bitter, sweet and sour substances by using electronic tongue.tongue.

Separating the different substances eliciting the same taste (sour, bitter, Separating the different substances eliciting the same taste (sour, bitter, sweet). sweet).

Identify drug preparations containing active substance and placebo Identify drug preparations containing active substance and placebo substance.substance.

Quantification of the effect of taste masking of bitter substances by sweet Quantification of the effect of taste masking of bitter substances by sweet

ones.ones.

MECHANICAL STRENGTHMECHANICAL STRENGTH

In order to allow ODTs to disintegrate in the oral cavity, they are made of In order to allow ODTs to disintegrate in the oral cavity, they are made of

either very porous and soft-molded matrices or compressed into tablets with either very porous and soft-molded matrices or compressed into tablets with

very low compression force, which makes the tablets friable and/or brittle, very low compression force, which makes the tablets friable and/or brittle,

difficult to handle, and often requiring specialized peel-off blister packing thatdifficult to handle, and often requiring specialized peel-off blister packing that

may add to the cost. may add to the cost.

AMOUNT OF DRUGAMOUNT OF DRUG

Application of technologies used for ODTs is limited by the amount of Application of technologies used for ODTs is limited by the amount of

drug that can be incorporated into each unit dose.drug that can be incorporated into each unit dose.

In case of In case of Lyophilized dosageLyophilized dosage forms, drug dose must be forms, drug dose must be

less than 400mg – insoluble drugsless than 400mg – insoluble drugs

less than 60mg -- soluble drugs less than 60mg -- soluble drugs

This parameter is particularly challenging when formulating a fast-This parameter is particularly challenging when formulating a fast-dissolving oral films.dissolving oral films.

SIZE OF TABLETSIZE OF TABLET

The degree of ease when taking a tablet depends on its size. It has been The degree of ease when taking a tablet depends on its size. It has been reported that the easiest size of tablet to swallow is 7-8 mm. While the reported that the easiest size of tablet to swallow is 7-8 mm. While the

easiest size to handle was one larger than 8 mm. easiest size to handle was one larger than 8 mm.

Therefore, the tablet size that is both easy to take and easy to handle is Therefore, the tablet size that is both easy to take and easy to handle is

difficult to achieve difficult to achieve

HYGROSCOPICITYHYGROSCOPICITY

Several orally disintegrating dosage forms are hygroscopic and cannot Several orally disintegrating dosage forms are hygroscopic and cannot

maintain physical integrity under normal conditions of temperature and maintain physical integrity under normal conditions of temperature and

humidity. Hence, they need protection from humidity which calls for humidity. Hence, they need protection from humidity which calls for

specialized product packaging. specialized product packaging.

AQUEOUS SOLUBILITYAQUEOUS SOLUBILITY

Water soluble drugs pose various formulation challenges because they form Water soluble drugs pose various formulation challenges because they form eutectic mixtures, which result in freezing point depression and the eutectic mixtures, which result in freezing point depression and the formation of a glassy solid that may collapse upon drying because loss of formation of a glassy solid that may collapse upon drying because loss of

supporting structure during the sublimation process.supporting structure during the sublimation process.

This collapse can be prevented by using various matrix-forming excipients This collapse can be prevented by using various matrix-forming excipients

like Mannitol which induces crystallinity and hence impart rigidity to the like Mannitol which induces crystallinity and hence impart rigidity to the

amorphous composite.amorphous composite.

SHORT HALF-LIFESHORT HALF-LIFE

ODTs being immediately releasing dosage forms and the absorption of ODTs being immediately releasing dosage forms and the absorption of

maximum amount of dose takes place in the pre-gastric region, these have maximum amount of dose takes place in the pre-gastric region, these have sort half life.sort half life.

This character may render drug unsuitable for delivery as prolonged This character may render drug unsuitable for delivery as prolonged release release

or sustained release dosage form.or sustained release dosage form.

COST OF THE TABLETCOST OF THE TABLET

As ODTs are easily fragile, these products require special unit-dose As ODTs are easily fragile, these products require special unit-dose

packaging which may add to the cost of the dosage form.packaging which may add to the cost of the dosage form.

Materials required:Materials required:

DrugDrug

ExcipientsExcipients

THE IDEAL CHARACTERISTICS OF DRUG THE IDEAL CHARACTERISTICS OF DRUG

For disintegration and dissolution in oral cavity i.e., the pre-gastric For disintegration and dissolution in oral cavity i.e., the pre-gastric absorption from an ODT include,absorption from an ODT include,

1.1. No bitter tasteNo bitter taste

2.2. Dose lower than 20mgDose lower than 20mg

3.3. Small to moderate molecular weightSmall to moderate molecular weight

4.4. Good solubility in water and salivaGood solubility in water and saliva

5.5. Partially nonionized at the oral cavity’s pH.Partially nonionized at the oral cavity’s pH.

6.6. Ability to diffuse and partition into the epithelium of upper GIT.Ability to diffuse and partition into the epithelium of upper GIT.

7.7. Ability to permeate oral mucosal tissue.Ability to permeate oral mucosal tissue.

EXCIPIENTSEXCIPIENTS

FILLERFILLER

Eg: More potent drugs like codeine are Eg: More potent drugs like codeine are required in very low amount which required in very low amount which

require diluent such as lactose to makeup require diluent such as lactose to makeup volume of drug.volume of drug.

Various fillers used are Various fillers used are Lactose, Lactose,

Directly compressed spray Directly compressed spray dried mannitol, dried mannitol,

Sorbitol, Sorbitol, Calcium carbonate, Calcium carbonate,

Pregelatinised starch, Pregelatinised starch, Magnesium trisilicate, Magnesium trisilicate,

Al(OH)Al(OH)3 3 etc. etc.

SUPERDISINTEGRANTSSUPERDISINTEGRANTS

Eg: Cross povidone, Eg: Cross povidone, Crosscarmellose sodium,Crosscarmellose sodium,Sodium starch glycolate,Sodium starch glycolate,calcium carboxy methyl cellulose,calcium carboxy methyl cellulose,Alginates, Alginates, Micro crystalline cellulose, Micro crystalline cellulose, Amberlite IRP 88, Amberlite IRP 88, Guargums, Guargums, Modified corn starch, Modified corn starch, Pregelatinized starchPregelatinized starchChitin chitosanChitin chitosanSmectaSmecta

BINDERSBINDERS

AcaciaAcacia

Cellulose derivativesCellulose derivatives

GelatinGelatin

Polyvinyl pyrollidinePolyvinyl pyrollidine

TragacanthTragacanth

ANTIFRICTIONAL ANTIFRICTIONAL AGENTSAGENTS

GLIDANTSGLIDANTS corn starch, talc, silica corn starch, talc, silica

derivativesderivatives

LUBRICANTSLUBRICANTS Stearic acid, magnesium Stearic acid, magnesium

stearate, talc, PEG, liquid stearate, talc, PEG, liquid paraffinparaffin

ANTIADHERENTSANTIADHERENTS talc, corn starch, colloidal talc, corn starch, colloidal

silica, sodium lauryl silica, sodium lauryl sulphate.sulphate.

OTHER EXCIPIENTSOTHER EXCIPIENTS

COLOURSCOLOURS

Eg: Carotene, chlorophyll, brilliant blue, Indigotene, ErythrosineEg: Carotene, chlorophyll, brilliant blue, Indigotene, Erythrosine

FLAVOURING AGENTSFLAVOURING AGENTS

Eg: Menthol, Vanilla, Liquorice, Citrus fruits flavour, Anise oil, Clove oil, Eg: Menthol, Vanilla, Liquorice, Citrus fruits flavour, Anise oil, Clove oil, Pippermint oil, Eucalyptus oil.Pippermint oil, Eucalyptus oil.

SWEETENERSSWEETENERS

Eg: Natural- Mannitol, Lactose, Sucrose, DextroseEg: Natural- Mannitol, Lactose, Sucrose, Dextrose

Artificial- Saccharin, Aspartame, CyclamateArtificial- Saccharin, Aspartame, Cyclamate

MECHANISMS OF DRUG RELEASEMECHANISMS OF DRUG RELEASE

The drug releases from the FDT due to the action of super disintegrants The drug releases from the FDT due to the action of super disintegrants and generally by swelling of the porous matrix.and generally by swelling of the porous matrix.

MECHANISM OF SUPERDISINTEGRANTSMECHANISM OF SUPERDISINTEGRANTS

Due to deformationDue to deformation

Due to disintegrating particle/repulsive forcesDue to disintegrating particle/repulsive forces

Capillary action and porosity (wicking)Capillary action and porosity (wicking)

Chemical reaction (acid-base)Chemical reaction (acid-base)

DEFORMATION AND REPULSIONDEFORMATION AND REPULSION

a. Deformation b. Repulsiona. Deformation b. Repulsion

WICKING AND SWELLINGWICKING AND SWELLING

a. Wicking b. Swellinga. Wicking b. Swelling

FORMULATION TECHNIQUESFORMULATION TECHNIQUES

COVENTIONAL TECHNIQUESCOVENTIONAL TECHNIQUES

Tablet moulding Tablet moulding

Direct compressionDirect compression

Spray drying Spray drying

Sublimation Sublimation

Freeze drying (or) LyophilizationFreeze drying (or) Lyophilization

Mass extrusion Mass extrusion

Cotton candy processCotton candy process

Tablet MoldingTablet Molding

Molded tablets are prepared by using water soluble ingredients so that the Molded tablets are prepared by using water soluble ingredients so that the

tablets dissolve completely and rapidly.tablets dissolve completely and rapidly.

The powder blend is moistened with a hydro-alcoholic solvent and is The powder blend is moistened with a hydro-alcoholic solvent and is

molded into tablets under pressure lower than that used in Conventional molded into tablets under pressure lower than that used in Conventional

tablet compression. The solvent is then removed by air-drying.tablet compression. The solvent is then removed by air-drying.

Eg: Benadryl, Fastmelt(diphenhydramine citrate, pseudoephidrine HCl) – Eg: Benadryl, Fastmelt(diphenhydramine citrate, pseudoephidrine HCl) – Allergy, sinus Allergy, sinus

DIRECT COMPRESSIONDIRECT COMPRESSION

Easiest way to manufacture tablets is direct compression. Easiest way to manufacture tablets is direct compression.

Low manufacturing cost, conventional equipments and limited number of Low manufacturing cost, conventional equipments and limited number of

processing steps led this technique to be a preferable one. processing steps led this technique to be a preferable one.

However disintegration and dissolution of directly compressed tablets However disintegration and dissolution of directly compressed tablets

depend on single or combined effect of disintegrant, water soluble depend on single or combined effect of disintegrant, water soluble

excipients and effervescing agents. excipients and effervescing agents.

SPRAY DRYINGSPRAY DRYING

Spray drying can produce highly porous and fine powders that dissolve Spray drying can produce highly porous and fine powders that dissolve

rapidly. rapidly.

The formulations are incorporated by hydrolyzed and non hydrolyzed The formulations are incorporated by hydrolyzed and non hydrolyzed gelatins as supporting agents, Mannitol as Bulking agent, sodium starch gelatins as supporting agents, Mannitol as Bulking agent, sodium starch glycolate or crosscarmellose sodium as disintegrating and an acidic material glycolate or crosscarmellose sodium as disintegrating and an acidic material

(e.g. citric acid) and / or alkali material (e.g. I sodium bicarbonate) to (e.g. citric acid) and / or alkali material (e.g. I sodium bicarbonate) to enhance disintegration and dissolution. enhance disintegration and dissolution.

Tablet compressed from the spray dried powder disintegrated within 20 Tablet compressed from the spray dried powder disintegrated within 20 seconds when immersed in an aqueous medium seconds when immersed in an aqueous medium

SUBLIMATIONSUBLIMATION

To generate porous matrix in ODTs, volatile ingredients are incorporated To generate porous matrix in ODTs, volatile ingredients are incorporated in the formulation which is subjected to sublimation (by vacuum drying) in the formulation which is subjected to sublimation (by vacuum drying) leaving behind the porous matrix.leaving behind the porous matrix.

FREEZE DRYING OR LYOPHILIZATIONFREEZE DRYING OR LYOPHILIZATION

It is a process in which water is sublimed from the product after freezing. It is a process in which water is sublimed from the product after freezing. Lyophilization is a pharmaceutical technology which allows drying of Lyophilization is a pharmaceutical technology which allows drying of

HEAT SENSITIVE DRUGHEAT SENSITIVE DRUG and biological at low temperature under and biological at low temperature under

conditions that allow removal of water by sublimation.conditions that allow removal of water by sublimation.

Lyophilization results in preparations, which are highly porous, with a very Lyophilization results in preparations, which are highly porous, with a very

high specific surface area, which dissolves rapidly and show improved high specific surface area, which dissolves rapidly and show improved

absorption and bioavailability.absorption and bioavailability.

MASS EXTRUSIONMASS EXTRUSION

This technology involves softening the active blend using the solvent This technology involves softening the active blend using the solvent

mixture of water soluble polyethylene glycol, using methanol and mixture of water soluble polyethylene glycol, using methanol and expulsion expulsion

of softened mass through the extruder or syringe to get a cylinder of the of softened mass through the extruder or syringe to get a cylinder of the

product into even segments using heated blade to form tablets. product into even segments using heated blade to form tablets.

The dried cylinder can also be used to coat granules of bitter tasting drugs The dried cylinder can also be used to coat granules of bitter tasting drugs

and thereby masking their bitter taste. and thereby masking their bitter taste.

COTTON CANDY PROCESSCOTTON CANDY PROCESS Cotton candy process is also known as “candy floss” process and forms the Cotton candy process is also known as “candy floss” process and forms the

basis of the technologies such as Flash Dose (Fuisz technology).basis of the technologies such as Flash Dose (Fuisz technology).

An ODT matrix is formed from saccharides or polysaccharides processed An ODT matrix is formed from saccharides or polysaccharides processed

into amorphous floss by a simultaneous action of flash melting and into amorphous floss by a simultaneous action of flash melting and

centrifugal force.centrifugal force.

The matrix is cured or partially recrystallised to provide a compound with The matrix is cured or partially recrystallised to provide a compound with

good flow properties and compressibility. The candy floss can then be milled good flow properties and compressibility. The candy floss can then be milled and blended with active ingredients and Excipients and subsequently and blended with active ingredients and Excipients and subsequently

compressed into ODT. compressed into ODT. Limitation: Limitation: The high processing temperature limits the use of this technology to The high processing temperature limits the use of this technology to

Thermo stable compounds onlyThermo stable compounds only

PATENTED TECHNOLOGIESPATENTED TECHNOLOGIES

Zydis Technology Zydis Technology

Orasolv TechnologyOrasolv Technology

Durasolv TechnologyDurasolv Technology

Wow tab TechnologyWow tab Technology

Flash Dose Technology ( Ceform Technology )Flash Dose Technology ( Ceform Technology )

Flash Tab Technology Flash Tab Technology

Oraquick Technology Oraquick Technology

Quick-Dis Technology Quick-Dis Technology

Nanocrystal TechnologyNanocrystal Technology

ZYDIS TECHNOLOGYZYDIS TECHNOLOGY

A Zydis tablet is produced by lyophilizing or freeze-drying the drug in a A Zydis tablet is produced by lyophilizing or freeze-drying the drug in a

matrix usually consisting of gelatin. The product is very lightweight and matrix usually consisting of gelatin. The product is very lightweight and

fragile, and must be dispensed in a special blister pack. fragile, and must be dispensed in a special blister pack.

Patients should be advised not to push the tablets through the foil film, but Patients should be advised not to push the tablets through the foil film, but

instead peel the film back to release the tablet. The Zydis product is made to instead peel the film back to release the tablet. The Zydis product is made to

dissolve on the tongue in 2 to 3 seconds.dissolve on the tongue in 2 to 3 seconds.

Eg: Maxalt-MLT (rizatriptan benzoate) - MigraineEg: Maxalt-MLT (rizatriptan benzoate) - Migraine

ORASOLV TECHNOLOGYORASOLV TECHNOLOGY

In this system active medicament is taste masked. In this system active medicament is taste masked.

It also contains effervescent disintegrating agent. It also contains effervescent disintegrating agent.

Tablets are made by direct compression technique at low compression Tablets are made by direct compression technique at low compression

force in order to minimize oral dissolution time.force in order to minimize oral dissolution time.

Eg: Remeron ( mirtazapine) - DepressionEg: Remeron ( mirtazapine) - Depression

DURASOLV TECHNOLOGYDURASOLV TECHNOLOGY

The tablets made by this technology consist of a drug, fillers and a The tablets made by this technology consist of a drug, fillers and a

lubricant. lubricant.

Tablets are prepared by using conventional tableting equipment and have Tablets are prepared by using conventional tableting equipment and have

good rigidity. These can be packed into conventional packaging system good rigidity. These can be packed into conventional packaging system like like

blisters. blisters.

Eg: Fazaclo (clozapine) - antipsychoticEg: Fazaclo (clozapine) - antipsychotic

WOWTAB TECHNOLOGYWOWTAB TECHNOLOGY

Yamanauchi pharmaceutical company patented this technology.Yamanauchi pharmaceutical company patented this technology.

‘‘Wow’Wow’ means  means ‘without water’‘without water’. The active ingredients may constitute up to . The active ingredients may constitute up to

50% w/w of the tablet. 50% w/w of the tablet.

In this technique, saccharides of both low and high mouldability are used to In this technique, saccharides of both low and high mouldability are used to

prepare the granules. Mouldability is the capacity of a compound to be prepare the granules. Mouldability is the capacity of a compound to be

compressed.compressed.

Eg: Fast melt (diphenhydramine citrate, pseudoephidrine HCl) – allergy & sinusEg: Fast melt (diphenhydramine citrate, pseudoephidrine HCl) – allergy & sinus

FLASH DOSE TECHNOLOGYFLASH DOSE TECHNOLOGY

This technology is patented by Fuisz. This technology is patented by Fuisz.

A sugar based matrix, called ‘Floss’ is used, which is made up of a A sugar based matrix, called ‘Floss’ is used, which is made up of a

combination of excipients (crystalline sugars) alone or in combination with combination of excipients (crystalline sugars) alone or in combination with

drugs. drugs.

Eg: Nurofen meltlet, a new form of Ibuprofen, as a mouth-dissolving tablet is Eg: Nurofen meltlet, a new form of Ibuprofen, as a mouth-dissolving tablet is the first commercial product prepared by this technology and launched by the first commercial product prepared by this technology and launched by Biovail Corporation. Biovail Corporation.

FLASH TAB TECHNOLOGYFLASH TAB TECHNOLOGY

Prographarm labsPrographarm labs have a patent over this technology. have a patent over this technology.

In this technology, microgranules of the taste-masked active drug are used. In this technology, microgranules of the taste-masked active drug are used.

Micro granules may be prepared by using conventional techniques like Micro granules may be prepared by using conventional techniques like coacervation, micro encapsulation, and extrusion-spheronisation. All these coacervation, micro encapsulation, and extrusion-spheronisation. All these processes utilize conventional tabletting technology. processes utilize conventional tabletting technology.

These taste-masked micro crystals of active drug, disintegrating agent, a These taste-masked micro crystals of active drug, disintegrating agent, a swelling agent and other excipients like soluble diluents etc are swelling agent and other excipients like soluble diluents etc are compressed to form a multiparticulate tablet that disintegrates rapidly.compressed to form a multiparticulate tablet that disintegrates rapidly.

Eg: Excedrin Quick Tabs (acetaminophen, caffeine) – head acheEg: Excedrin Quick Tabs (acetaminophen, caffeine) – head ache

DRUGS INCORPORATED IN ODTsDRUGS INCORPORATED IN ODTs Analgesics and Anti-inflammatory Agents Analgesics and Anti-inflammatory Agents Anthelmintics Anthelmintics Anti-gout Agents Anti-gout Agents Anti-hypertensive Agents Anti-hypertensive Agents Anti-malarials Anti-malarials Anti-migraine Agents Anti-migraine Agents Anti- muscarinic Agents Anti- muscarinic Agents Anti- neoplastic Agents and Immunosuppressant's Anti- neoplastic Agents and Immunosuppressant's Anti- protazoal Agents Anti- protazoal Agents Anti-thyroid Agents Anti-thyroid Agents ß-Blockers ß-Blockers Cardiac Inotropic Agents Cardiac Inotropic Agents Corticosteroids Diuretics Corticosteroids Diuretics Anti- parkinsonian Agents Anti- parkinsonian Agents Gastro-intestinal Agents Gastro-intestinal Agents Histamine H,-Receptor Antagonists etc… Histamine H,-Receptor Antagonists etc…

PREFORMULATION STUDIESPREFORMULATION STUDIES

Compatability studies = FTIR / DSC Compatability studies = FTIR / DSC

Angle of repose Ө = tan Angle of repose Ө = tan -1-1 (h/r) (h/r)

Determination of Bulk density = W / VDetermination of Bulk density = W / Voo

Tapped density = W / VTapped density = W / Vff

Hauser’s Ratio= Tapped density/Bulk density Hauser’s Ratio= Tapped density/Bulk density

compressibility index : CI = 100 (Vcompressibility index : CI = 100 (Voo – V – Vff )/ Vo )/ Vo

Moisture content Moisture content

Some of the Marketed ODTs in IndiaSome of the Marketed ODTs in India

Name of productName of product Active IngredientActive Ingredient

Feldene MeltFeldene Melt Piroxicam(10-20 mg)Piroxicam(10-20 mg)

Zyprexa ZydisZyprexa Zydis Olanzapine (5, 10, 15 or 20 mg)Olanzapine (5, 10, 15 or 20 mg)

Nimulid -MDNimulid -MD NimesulideNimesulide

Claritin ReditabClaritin Reditab Micronized LoratadineMicronized Loratadine

Pepcid RPDPepcid RPD Famotidine (20-40 mg)Famotidine (20-40 mg)

EVALUATION TESTSEVALUATION TESTS

WEIGHT VARATION TESTWEIGHT VARATION TEST

I.P. procedure for uniformity of weight was followed, twenty tablets I.P. procedure for uniformity of weight was followed, twenty tablets were taken and their weight was determined individually and collectively were taken and their weight was determined individually and collectively on a digital weighing balance. The average weight of one tablet was on a digital weighing balance. The average weight of one tablet was determined from the collective weight. determined from the collective weight.

The weight variation test would be a satisfactory method of determining The weight variation test would be a satisfactory method of determining

the drug content uniformitythe drug content uniformity

FRIABILITY TESTFRIABILITY TEST

The pharmacopoeial limit of friability test for a tablet is not more than 1% The pharmacopoeial limit of friability test for a tablet is not more than 1% using Tablet friability apparatus, carried out at 25 rpm for 4 min (100 using Tablet friability apparatus, carried out at 25 rpm for 4 min (100 rotations). rotations).

This test is again not applicable for lyophilized and flash dose tablets, but This test is again not applicable for lyophilized and flash dose tablets, but is always recommended for tablets prepared by direct compression and is always recommended for tablets prepared by direct compression and moulding techniques to ensure that they have enough mechanical strength moulding techniques to ensure that they have enough mechanical strength to withstand the abrasion during shipping and shelf life.to withstand the abrasion during shipping and shelf life.

Percentage friability = 100(initial weight-final weight)/initial weightPercentage friability = 100(initial weight-final weight)/initial weight

WETTING TIME AND WATER ABSORPTION WETTING TIME AND WATER ABSORPTION RATIORATIO

Wetting time and water absorption ratio reported the use of a piece of Wetting time and water absorption ratio reported the use of a piece of double folded tissue paper placed in a Petri dish containing 6 ml of water. double folded tissue paper placed in a Petri dish containing 6 ml of water. One tablet was placed on this paper and the time for complete wetting of One tablet was placed on this paper and the time for complete wetting of tablet was noted as wetting time. The wetted tablet was then weighed and tablet was noted as wetting time. The wetted tablet was then weighed and the water absorption ratio, R, was determined according to equation. the water absorption ratio, R, was determined according to equation.

R = 100 (WR = 100 (Wa−W −W b) /W) /Wb

WWb and Wand Waa are the weights of tablet before and after water absorption are the weights of tablet before and after water absorption

HARDNESS TESTHARDNESS TEST

The tablet tensile strength is the force required to break a tablet by The tablet tensile strength is the force required to break a tablet by compressing it in the radial direction and is measured using a tablet compressing it in the radial direction and is measured using a tablet hardness tester.hardness tester.

Monsanto hardness tester Phyzer type hardness testerMonsanto hardness tester Phyzer type hardness tester

MOISTURE UPTAKE TESTMOISTURE UPTAKE TEST

The test can be carried out by keeping ten tablets along with calcium The test can be carried out by keeping ten tablets along with calcium chloride in a desiccator maintained at 37 °C for 24 hrs to ensure complete chloride in a desiccator maintained at 37 °C for 24 hrs to ensure complete drying of the tablets. drying of the tablets.

The tablets are then weighed and exposed to 75% RH, at room temperature The tablets are then weighed and exposed to 75% RH, at room temperature for 2 weeks. The required humidity can be achieved by keeping saturated for 2 weeks. The required humidity can be achieved by keeping saturated sodium chloride solution in the dessicator for 24 hrs. sodium chloride solution in the dessicator for 24 hrs.

The tablets are reweighed and the percentage increase in weight is The tablets are reweighed and the percentage increase in weight is recorded. If the moisture uptake tendency of a product is high, it requires recorded. If the moisture uptake tendency of a product is high, it requires special dehumidified area for manufacturing and packing. special dehumidified area for manufacturing and packing.

MEASUREMENT OF TABLET POROSITYMEASUREMENT OF TABLET POROSITY

The mercury penetration porosimeter can be used to measure the tablet The mercury penetration porosimeter can be used to measure the tablet

porosity which is a relative assessment of the degree of water penetration in porosity which is a relative assessment of the degree of water penetration in

the formulation, responsible for its fast disintegration. the formulation, responsible for its fast disintegration.

IN-VITRO DISPERSION TIMEIN-VITRO DISPERSION TIME

The test is performed by placing two tablets in 100 ml water and stirring it The test is performed by placing two tablets in 100 ml water and stirring it gently, till the tablets get completely disintegrated. gently, till the tablets get completely disintegrated.

The formulation is considered to form a smooth dispersion if the complete The formulation is considered to form a smooth dispersion if the complete dispersion passes through a sieve screen with a nominal mesh aperture of dispersion passes through a sieve screen with a nominal mesh aperture of 710 μm without leaving any residue on the mesh. 710 μm without leaving any residue on the mesh.

IN-VITRO DISINTEGRATION TESTIN-VITRO DISINTEGRATION TEST

This test are carried out by using any one of the following method This test are carried out by using any one of the following method

Tablet disintegration apparatus Tablet disintegration apparatus

Modified dissolution apparatus (as per J.Pharm) Modified dissolution apparatus (as per J.Pharm)

Disintegration Test on Shaking Water Bath Disintegration Test on Shaking Water Bath

Disintegration Test with Rotary Shaft Method Disintegration Test with Rotary Shaft Method

Disintegration Test using Texture Analyzer Disintegration Test using Texture Analyzer

Disintegration Test using Electro Force Disintegration Test using Electro Force

DISINTEGRATION APPARATUSDISINTEGRATION APPARATUS

Apparatus with wire basket in a beaker.Apparatus with wire basket in a beaker.

DISINTEGRATION USING TEXTURE ANALYZERDISINTEGRATION USING TEXTURE ANALYZER

The in vitro disintegration behavior of fast dissolving systems The in vitro disintegration behavior of fast dissolving systems manufactured by the main commercialized technologies was studied using manufactured by the main commercialized technologies was studied using the texture analyzer (TA) instrument. the texture analyzer (TA) instrument.

IN-VITRO DISSOLUTION STUDYIN-VITRO DISSOLUTION STUDY

The dissolution method for oral disintegrating tablets is the same as that of The dissolution method for oral disintegrating tablets is the same as that of conventional tablets. conventional tablets.

USP 2 paddle apparatus is most suitable and common choice for USP 2 paddle apparatus is most suitable and common choice for dissolution test of oral disintegrating tablets, where the paddle speed is 50 dissolution test of oral disintegrating tablets, where the paddle speed is 50 rpm is used. rpm is used.

The USP 1 (basket) apparatus may have certain application for such tablets The USP 1 (basket) apparatus may have certain application for such tablets but is used less, frequently due to specific physical properties of tablets. but is used less, frequently due to specific physical properties of tablets.

Specifically tablet fragments or disintegrating tablet masses become Specifically tablet fragments or disintegrating tablet masses become trapped on the inside top of the basket spindle where little or no effective trapped on the inside top of the basket spindle where little or no effective stirring occurs, yielding irreproducible results in dissolution profiles. stirring occurs, yielding irreproducible results in dissolution profiles.

FUTURE DEVELOPMENTSFUTURE DEVELOPMENTS

ODTs can offer several biopharmaceutical advantages over conventional ODTs can offer several biopharmaceutical advantages over conventional solid dosage forms such as,solid dosage forms such as,

Improved efficacyImproved efficacy

Require small amount of the drug to be effectiveRequire small amount of the drug to be effective

Offer better drug bioavailabilityOffer better drug bioavailability

ODTs may be suitable for oral delivery of drugs such as ODTs may be suitable for oral delivery of drugs such as proteins and proteins and peptide based therapeuticspeptide based therapeutics that has limited bioavailability when that has limited bioavailability when administered by conventional tablets.administered by conventional tablets.

Because drugs delivered in ODTs may be absorbed in the pre gastric sites Because drugs delivered in ODTs may be absorbed in the pre gastric sites of highly permeable buccal and mucosal tissues of the oral cavity, they of highly permeable buccal and mucosal tissues of the oral cavity, they may be suitable for delivering relatively may be suitable for delivering relatively low-molecular weight and highly low-molecular weight and highly permeable drugspermeable drugs..

CONCLUSIONCONCLUSION

Orally disintegrating tablets (FDTs) have better patient acceptance and Orally disintegrating tablets (FDTs) have better patient acceptance and compliance and may offer improved biopharmaceutical properties, compliance and may offer improved biopharmaceutical properties, improved efficacy, and better safety compared with conventional oral improved efficacy, and better safety compared with conventional oral dosage forms. dosage forms.

Prescription FDT products initially were developed to overcome the Prescription FDT products initially were developed to overcome the difficulty in swallowing conventional tablets with water among pediatric, difficulty in swallowing conventional tablets with water among pediatric, geriatric, and psychiatric patients with dysphagia. geriatric, and psychiatric patients with dysphagia.

Future possibilities for improvements in FDTs and drug delivery are Future possibilities for improvements in FDTs and drug delivery are bright, but the technology is still relatively new. bright, but the technology is still relatively new.

REFERENCESREFERENCES

1. International journal of research in Ayurveda and Pharmacy.1. International journal of research in Ayurveda and Pharmacy.2. Journal of Chemical and Pharmaceutical Research, 2009, 1(1): 336-341.2. Journal of Chemical and Pharmaceutical Research, 2009, 1(1): 336-341.3. The Indian Pharmacist, Volume 3, Issue 19, p.72-75 (2004).3. The Indian Pharmacist, Volume 3, Issue 19, p.72-75 (2004).4. United States Pharmacopoeia 24/NF 19. The Official Compendia of 4. United States Pharmacopoeia 24/NF 19. The Official Compendia of

Standards. Asian ed. Rockville, MD: United States Pharmacopoeial Standards. Asian ed. Rockville, MD: United States Pharmacopoeial Convention Inc; 2000:1913-1914.Convention Inc; 2000:1913-1914.

5. Bentham science Publishers- Recent patents on Drug delivery and 5. Bentham science Publishers- Recent patents on Drug delivery and Formulations, Volume 4, Number 3, November 2010.Formulations, Volume 4, Number 3, November 2010.

6. 6. Aulton’s Pharmaceutics- The design and manufacture of medicines, Edited Aulton’s Pharmaceutics- The design and manufacture of medicines, Edited by Michael E.Aulton- 3by Michael E.Aulton- 3rdrd Edition, 2008. Edition, 2008.

7. 7. FDA, Guidance for Industry: FDA, Guidance for Industry: Orally Disintegrating Tablets Draft Orally Disintegrating Tablets Draft GuidanceGuidance, (Rockville, MD, April 2007)., (Rockville, MD, April 2007).

8. 8. Review article- Recent Patents and Trends in Orally Disintegrating Tablets Review article- Recent Patents and Trends in Orally Disintegrating Tablets by Farhan A. AlHusban, Amr M. El-Shaer, Rhys J. Jonesby Farhan A. AlHusban, Amr M. El-Shaer, Rhys J. Jones and and Afzal R. Afzal R. MohammedMohammed

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