CONTENTS IntroductionAdvantages over conventional tablet dosage formsChallenges in formulation and developmentMaterials requiredMechanism of drug releaseFormulation techniques Conventional methods Patented technologiesMarketed productsEvaluation testsFuture developmentsConclusionReferences

INTRODUCTIONDefinitions of ODTs:

According to US FDA:

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

According to European pharmacopoeia:

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

Terminologies for ODTsRapidly dissolving tablets are also known as

Melt in Mouth tablets

Mouth dissolving tablets (MDT)

Fast disintegrating tablets (FDT)

Orally disintegrating tablets

Rapid disintegrating tablets (RDT)

Oro dispersible tablets (ODT)

Quick dissolving tablets.

Advantages over the conventional dosage form No risk of choking.

Requires no water intake.

Overcomes unacceptable taste of the Drugs.

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

Avoids First Pass Metabolism due to pregastric absorption.

Ideal dosage form for Peadiatric and geriatric patients.

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

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

PalatabilityMechanical strengthAmount of drugSize of tabletHygroscopicityAqueous solubilityShort half-lifeCost of the tablet

PALATABILITY

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

systems usually contain the medicament in a taste masked form.

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

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

hence taste masking of drugs become critical to patient compliance.

General taste masking technologies in oral solid dosage forms:1. Taste masking with hydrophilic vehicleHydrophilic vehicles- carbohydrates, proteins, gelatin, ZeoliteIon Exchange resins- Indion 204, 214, 224, 234CyclodextrinsFlavors, sweeteners, amino acids.

2. Taste masking with lipophilic vehicleEx: fats, fatty acids.

3. Miscellaneous masking agentsEx: Effervescent agents, Rheological modifications, salt

preparations, solid dispersions etc.

Detection threshold of sensors compared to Human receptorsPharmaceutical taste assessment requires human test panel that

increases 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 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 beneficial unless it has preference and acceptance by the patient. Thus, pleasant taste is important for the therapeutic success of the drug formulation.

Human tongue with taste receptors.

Sample Electronic tongue

Objectives of electronic tongue:

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

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

Identify drug preparations containing active substance and placebo substance.

Quantification of the effect of taste masking of bitter

substances by sweet ones.

MECHANICAL STRENGTH 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

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

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

may add to the cost.

AMOUNT OF DRUGApplication of technologies used for ODTs is limited by the

amount of

drug that can be incorporated into each unit dose.

In case of Lyophilized dosage forms, drug dose must be less than 400mg – insoluble drugs less than 60mg -- soluble drugs

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

SIZE OF TABLETThe 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

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

difficult to achieve

HYGROSCOPICITYSeveral orally disintegrating dosage forms are hygroscopic

and cannot

maintain physical integrity under normal conditions of temperature and

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

specialized product packaging.

AQUEOUS SOLUBILITYWater soluble drugs pose various formulation challenges because they form

eutectic mixtures, which result in freezing point depression and the formation of a glassy solid that may collapse upon drying because loss

of

supporting structure during the sublimation process.

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

like Mannitol which induces crystallinity and hence impart rigidity to the

amorphous composite.

SHORT HALF-LIFEODTs being immediately releasing dosage forms and the

absorption of

maximum amount of dose takes place in the pre-gastric region, these have

sort half life.

This character may render drug unsuitable for delivery as prolonged release

or sustained release dosage form.

COST OF THE TABLET

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

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

Drug

Excipients

THE IDEAL CHARACTERISTICS OF DRUG

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

1. No bitter taste2. Dose lower than 20mg3. Small to moderate molecular weight4. Good solubility in water and saliva5. Partially nonionized at the oral cavity’s pH.6. Ability to diffuse and partition into the epithelium of

upper GIT.7. Ability to permeate oral mucosal tissue.

EXCIPIENTS

FILLER

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

require diluent such as lactose to makeup volume of drug.

Various fillers used are Lactose,

Directly compressed spray dried mannitol,

Sorbitol, Calcium carbonate,

Pregelatinised starch, Magnesium trisilicate,

Al(OH)3 etc.

SUPERDISINTEGRANTS

Eg: Cross povidone, Crosscarmellose sodium,Sodium starch glycolate,calcium carboxy methyl

cellulose,Alginates, Micro crystalline cellulose, Amberlite IRP 88, Guargums, Modified corn starch, Pregelatinized starchChitin chitosanSmecta

BINDERS

Acacia

Cellulose derivatives

Gelatin

Polyvinyl pyrollidine

Tragacanth

ANTIFRICTIONAL AGENTS

GLIDANTS corn starch, talc,

silica derivatives

LUBRICANTS Stearic acid,

magnesium stearate, talc, PEG, liquid paraffin

ANTIADHERENTS talc, corn starch,

colloidal silica, sodium lauryl sulphate.

OTHER EXCIPIENTSCOLOURS Eg: Carotene, chlorophyll, brilliant blue, Indigotene,

Erythrosine

FLAVOURING AGENTS Eg: Menthol, Vanilla, Liquorice, Citrus fruits flavour, Anise

oil, Clove oil, Pippermint oil, Eucalyptus oil.

SWEETENERS Eg: Natural- Mannitol, Lactose, Sucrose, Dextrose Artificial- Saccharin, Aspartame, Cyclamate

MECHANISMS OF DRUG RELEASEThe drug releases from the FDT due to the action of super

disintegrants and generally by swelling of the porous matrix.

MECHANISM OF SUPERDISINTEGRANTS

Due to deformation

Due to disintegrating particle/repulsive forces

Capillary action and porosity (wicking)

Chemical reaction (acid-base)

DEFORMATION AND REPULSION a. Deformation b. Repulsion

WICKING AND SWELLING a. Wicking b. Swelling

FORMULATION TECHNIQUES

COVENTIONAL TECHNIQUES

Tablet moulding

Direct compression Spray drying

Sublimation

Freeze drying (or) Lyophilization Mass extrusion

Cotton candy process

Tablet MoldingMolded tablets are prepared by using water soluble ingredients so

that the

tablets dissolve completely and rapidly.

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

molded into tablets under pressure lower than that used in Conventional

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

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

DIRECT COMPRESSIONEasiest way to manufacture tablets is direct compression.

Low manufacturing cost, conventional equipments and limited number of

processing steps led this technique to be a preferable one.

However disintegration and dissolution of directly compressed tablets

depend on single or combined effect of disintegrant, water

soluble

excipients and effervescing agents.

SPRAY DRYINGSpray drying can produce highly porous and fine powders that dissolve

rapidly.

The formulations are incorporated by hydrolyzed and non hydrolyzed

gelatins as supporting agents, Mannitol as Bulking agent, sodium starch

glycolate or crosscarmellose sodium as disintegrating and an acidic material (e.g. citric acid) and / or alkali material (e.g. I sodium bicarbonate) to enhance disintegration and dissolution.

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

SUBLIMATIONTo generate porous matrix in ODTs, volatile ingredients are

incorporated in the formulation which is subjected to sublimation (by vacuum drying) leaving behind the porous matrix.

FREEZE DRYING OR LYOPHILIZATION

It is a process in which water is sublimed from the product after freezing.

Lyophilization is a pharmaceutical technology which allows drying

of

HEAT SENSITIVE DRUG and biological at low temperature under

conditions that allow removal of water by sublimation.

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

high specific surface area, which dissolves rapidly and show improved

absorption and bioavailability.

MASS EXTRUSIONThis technology involves softening the active blend using the solvent

mixture of water soluble polyethylene glycol, using methanol and expulsion

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

product into even segments using heated blade to form tablets.

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

and thereby masking their bitter taste.

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

the

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

An ODT matrix is formed from saccharides or polysaccharides processed

into amorphous floss by a simultaneous action of flash melting and

centrifugal force.

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

good flow properties and compressibility. The candy floss can then be milled

and blended with active ingredients and Excipients and subsequently

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

technology to Thermo stable compounds only

PATENTED TECHNOLOGIES

Zydis Technology

Orasolv Technology

Durasolv Technology

Wow tab Technology

Flash Dose Technology ( Ceform Technology )

Flash Tab Technology

Oraquick Technology

Quick-Dis Technology

Nanocrystal Technology

ZYDIS TECHNOLOGYA Zydis tablet is produced by lyophilizing or freeze-drying the drug in

a

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

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

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

dissolve on the tongue in 2 to 3 seconds.

Eg: Maxalt-MLT (rizatriptan benzoate) - Migraine

ORASOLV TECHNOLOGY

In this system active medicament is taste masked.

It also contains effervescent disintegrating agent.

Tablets are made by direct compression technique at low compression force in order to minimize oral dissolution

time.

Eg: Remeron ( mirtazapine) - Depression

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

lubricant.

Tablets are prepared by using conventional tableting equipment and have

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

blisters.

Eg: Fazaclo (clozapine) - antipsychotic

WOWTAB TECHNOLOGYYamanauchi pharmaceutical company patented this technology.

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

50% w/w of the tablet.

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

compressed.

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

FLASH DOSE TECHNOLOGYThis technology is patented by Fuisz.

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

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

drugs.

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 Biovail Corporation.

FLASH TAB TECHNOLOGYPrographarm labs have a patent over this technology.

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

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

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

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

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

PREFORMULATION STUDIES

Compatability studies = FTIR / DSC

Angle of repose Ө = tan -1 (h/r)

Determination of Bulk density = W / Vo

Tapped density = W / Vf

Hauser’s Ratio= Tapped density/Bulk density

compressibility index : CI = 100 (Vo – Vf )/ Vo

Moisture content

Some 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 TESTS

WEIGHT VARATION TEST I.P. procedure for uniformity of weight was followed,

twenty tablets were taken and their weight was determined individually and collectively on a digital weighing balance. The average weight of one tablet was determined from the collective weight.

The weight variation test would be a satisfactory

method of determining the drug content uniformity

FRIABILITY TESTThe 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 rotations).

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

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

WETTING TIME AND WATER ABSORPTION RATIO

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. 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 the water absorption ratio, R, was determined according to equation.

R = 100 (Wa−W b) /Wb

Wb and Wa are the weights of tablet before and after water absorption

HARDNESS TEST

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 hardness tester.

Monsanto hardness tester Phyzer type hardness tester

MOISTURE UPTAKE TEST

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 drying of the tablets.

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 sodium chloride solution in the dessicator for 24 hrs.

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

MEASUREMENT OF TABLET POROSITY

The mercury penetration porosimeter can be used to measure the tablet

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

the formulation, responsible for its fast disintegration.

IN-VITRO DISPERSION TIMEThe test is performed by placing two tablets in 100 ml

water and stirring it gently, till the tablets get completely disintegrated.

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

IN-VITRO DISINTEGRATION TESTThis test are carried out by using any one of the following

method

Tablet disintegration apparatus

Modified dissolution apparatus (as per J.Pharm)

Disintegration Test on Shaking Water Bath

Disintegration Test with Rotary Shaft Method

Disintegration Test using Texture Analyzer

Disintegration Test using Electro Force

DISINTEGRATION APPARATUS

Apparatus with wire basket in a beaker.

DISINTEGRATION USING TEXTURE ANALYZERThe in vitro disintegration behavior of fast dissolving

systems manufactured by the main commercialized technologies was studied using the texture analyzer (TA) instrument.

IN-VITRO DISSOLUTION STUDY

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

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

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

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

FUTURE DEVELOPMENTSODTs can offer several biopharmaceutical advantages over

conventional solid dosage forms such as,

Improved efficacy

Require small amount of the drug to be effective

Offer better drug bioavailability

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

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 may be suitable for delivering relatively low-molecular weight and highly permeable drugs.

CONCLUSION

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

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

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

REFERENCES1. International journal of research in Ayurveda and Pharmacy.2. Journal of Chemical and Pharmaceutical Research, 2009,

1(1): 336-341.3. The Indian Pharmacist, Volume 3, Issue 19, p.72-75 (2004).4. United States Pharmacopoeia 24/NF 19. The Official

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

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

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

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

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