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IntroductionDefinition Significance Requirements of ODTs Formulation Methodologies Patented Technologies Superdisintegrants employed in ODT Preformulation Studies and Evaluation

An orally disintegrating tablet or orally dissolving tablet (ODT) is a drug dosage form available for a limited range of over-the-counter(OTC) and prescription medications.

ODTs differ from traditional tablets in that they are designed to be dissolved on the tongue rather than swallowed whole. The ODT serves as an alternative dosage form for patients who experience dysphagia (difficulty in swallowing) or for where compliance is a known issue and therefore an easier dosage form to take ensures that medication is taken. Common among all age groups, dysphagia is observed in about 35% of the general population, as well as up to 60% of the elderly institutionalized population and 18-22% of all patients in long-term care facilities 

ODTs also have a faster onset of effects than tablets or capsules, and have the convenience of a tablet that can be taken without water. During the last decade, ODTs have become available in a variety of therapeutic markets, both OTC and by prescription.

Fast Dissolving Tablets (FDTs) or “Orally dissolving tablets” (ODTs) which disintegrates or dissolves rapidly without water within few seconds in the mouth.

Products of ODT technologies entered the market in the 1980sThe first ODT form of a drug to get approval from the U.S. FDA was a Zydis ODT formulation of Claritin (loratadine) in December 1996.

DEFINITION

US FDA defined ODTs as “A solid dosage form containing medicinal substances or active ingredients which disintegrates rapidly within a few seconds when placed up on tongue”

Oral route ofadministration

Solid dosage formRapid

disintegrationon the tongue

Fast DissolveDosage Form

A stable, oral dosage formwith the dosing ease of a liquid

Clinical Formulation Marketing

Pregastric delivery Faster onset Better S&E Bioequivalence Local delivery

Compliance Convenience Stability Ease of use

New presentation Extend exclusivity Broader application USP

ODT

First generation ODTs

SECOND generation ODTs

THIRD generation ODTs

Preparation method Prepared by freeze –drying method.

Drug suspension along with specific additives was filled into the pockets of press through packing.

Wet granulation method

Drying the drug and additives after tabletting their wet mass(TUSHIMA 2001).

Dry granulation method

Dry mass including the drug and saccharides were tabletted.

ADVANTAGES RAPID DISINTEGRATION of ODTs

Rapid disintegration of ODTs

Rapid disintegration of ODTs

Less friable then first generation ODTs

DISADVANTAGES Handling was difficult because the tablets were very friable

Highly sensitive to moisture

No Taste masking compounds applied for bitter tasting drugs

Low density and hardness

LOW HARDNESS OF TABLETS

High porosity Low density

High porosity Low hardness Low density

1. Good for patients with swallowing difficulties.

2. Good for paediatric compliance

3. Convenient to administer during travelling or working without need of water

4. The pre-gastric drug absorption avoids the first-pass metabolism.5. Pregastric absorption leading to increased bioavaibility/ rapid absorption of drugs

from mouth, pharynx and oesophagus as saliva passes down to stomach, also avoids hepatic Metabolism.

6. Convenient for administration to traveling patients and busy people who do not have accesses to water.

7. Excellent mouths feel property produced by use of flavors and sweeteners help to change the perception of “medication as bitter pill” especially in pediatric population.

8. Fast disintegration of tablets leads to quick dissolution and rapid absorption which may produce rapid onset of action.

9. ODTs offer all the advantages of solid dosage forms and liquid dosage forms.10. Convenience of administration and accurate dosing compared to liquids.

Drug selection criteria

The ideal characteristics of a drug for oral dispersible tablet include:

Ability to permeate the oral mucosa.

At least partially non-ionized at the oral cavity pH.

Have the ability to diffuse and partition into the epithelium of the upper GIT.

Small to moderate molecular weight.

Low dose drugs preferably less than 50mg.

Short half life and frequent dosing drugs are unsuitable for ODT.

Drug should have good stability in saliva and water.

Very bitter or unacceptable taste and odor drugs are unsuitable for ODT.

IMPORTANT CRITERIA FOR EXCIPIENTS USED IN THE FORMULATION OF ODTs:

• It must be able to disintegrate quickly.

• Their individual properties should not affect the ODTs.

• It should not have any interactions with drug and other excipients.

• It should not interfere in the efficacy and organoleptic properties of the product.

• When selecting binder a (single or combination of binders) care must be taken in the final integrity and stability of the product.

• The binders may be in liquid, semi liquid, solid or polymeric mixtures11. (Ex: Polyethylene glycol, coca butter, hydrogenated vegetable oils)

Disintegrating agents:Disintegrating agents:

Super disintegrants

Commercially available grades

Mechanism ofaction

Special comment

CrosslinkedCellulose

Crosscarmellose®Ac-Di-Sol®,Nymce ZSX®Primellose®,Solutab®,Vivasol®, L-HPC

Swells 4-8 folds in < 10 seconds.Swelling andwicking both.

Swells in two dimensions.Direct compression or Granulation Starch free.

Crosslinked PVP

Crosspovidon M®Kollidon®Polyplasdone®

Swells very little and returns to original size after compression but act by capillary action.

Water insoluble andspongy in nature so get porous tablet.

Crosslinked starch

Explotab®Primogel®

Swells 7-12 folds in < 30 seconds.

Swells in three dimensionsand high level serve as sustain release matrix.

Crosslinked alginicAcid

Alginic acid NF

Rapid swelling in aqueous medium orwicking action.

Promote disintegrationin both dry or wet granulation.

SoyPolysaccharides

Emcosoy® Does not contain any starch or Sugar. Used inNutritional products.

Calcium silicate Wicking action Highly porous,Light weight.

Binders : SMCC (Silicified microcrystalline cellulose )SMCC1 SMCC2 SMCC3Starch paste , Natural Gums, Liquid Glucose , etc. )

Flavors:A bitter product - mint, cherry or anise may be used A salty product – peach, apricot or liquorice may be used A sour product - raspberry or liquorice may be used An excessively sweet product - vanilla may be used

Direct compression• Easiest way to manufacture tablets is direct compression.• Low manufacturing cost, conventional equipments and limited number of processing steps led this technique to be a preferable one. However disintegration and dissolution of directly compressed tablets depend on single or combined effect of disintegrant, water soluble excipients and effervescing agents.

• It is essential to choose a suitable and an optimum concentration of disintegrant to ensure quick disintegration and dissolution.

• Superdisintegrants are newer substances which are more effective at lower concentrations with greater disintegrating efficiency and mechanical strength.

• On contact with water, the superdisintegrants swell, hydrate, change volume or form and produce a disruptive change in the tablet. Effective superdisintegrants provide improved compressibility, compatibility and have no negative impact on the mechanical strength of formulations containing high dose drugs.

• The type of disintegrants and its proportion are of prime importance.

• Also factors to be considered are particle size distribution, contact angle, pore size distribution and water absorption capacity.

• Studies revealed that the water insoluble superdisintegrants like sodium starch glycolate and Croscarmellose sodium show better disintegration property than the slightly water soluble agents like Crospovidone, since they do not have a tendency to swell.

• Superdisintegrants that tend to swell show slight retardation of the disintegration property due to formation of viscous barrier. There is no particular upper limit regarding the amount of superdisintegrant as long as the mechanical properties of the tablet are compatible with its intended use. The superdisintegrant may be used alone or in combination with other superdisintegrants.

Freeze DryingA process in which water is sublimated from the product after freezing. Lyophilization is a pharmaceutical technology which allows drying of heat sensitive drugs and biological at low temperature under conditions that allow removal of water by sublimation.

ODTs formed by lyophilization have low mechanical strength, poor stability at higher temperature, and Humidity.

MouldingIn this method, molded tablets are prepared by using water-soluble ingredients so that the tablets dissolve completely and rapidly. The powder blend is moistened with a hydro-alcoholic solvent and is molded into tablets under pressure lower than that used in conventional tablet compression. The solvent is then removed by air-drying. Molded tablets are very less compact than compressed tablets. These possess porous structure that enhances dissolution.

SublimationThe slow dissolution of the compressed tablet containing even highly water-soluble ingredients is due to the low porosity of the tablets. Inert solid ingredients that volatilize readily (e.g.  urea,  ammonium  carbonate,  ammonium  bicarbonate, camphor etc.) were added to the other tablet ingredients and the mixture is compressed into tablets. The volatile materials were then removed via sublimation, which generates porous structures. Additionally, several solvents (e.g. cyclohexane, benzene) can be also used as pore forming agents.

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.

Feldene Melt (Piroxicam 20 mg )

Claritin Reditab (Loratidine 10 mg )

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. Durasolv is an appropriate technology for products requiring low amounts of active ingredients.

Parcopa® (levodopa and carbidopa) NuLev® (hyoscyamine)

Orasolv TechnologyIn 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. Conventional blenders and tablet machine is used to produce the tablets. The tablets produced are soft and friable and packaged in specially designed pick and place system.

FazaClo® (clozapine) Orapred ODT®** (prednisolone sodium phosphate)

Melting point test Solubility study Compatibility study Flow properties of API’s Density

Density1. Bulk Density

Formulaρb = M / V

Where : ρb - Bulk density, M- Weight of powder, and V- Volume of powder.

2. Tapped Density

Formulaρt = M / Vt

Where : ρt - Tapped density, M- Weight of powder, and Vt- Minimum volume occupied after tapping

Flow properties of API’s

Flow property % C.I. Hosner ratio

Excellent ≤10 1.00-1.11Good 11-15 1.12-1.18Fair 16-20 1.19-1.25

Passable 21-25 1.26-1.34Poor 26-31 1.35-1.45

Very poor 32-37 1.46-1.59Very, very

poor>38 >1.6

Afterword withdraw & analyse for physical characterization (visual defects, hardness, friability, disintegration, dissolution etc.) drug content.

Evaluation of Mixed Blend Of drug And Excipients: DICLOFENAC SODIUM

Parameter A B C D Angle of repose(0) 27.52 24.51 27.21 27.05 Bulk Density (gm/cm3 ) 0.56 0.54 0.51 0.58 Tapped Density (gm/cm3 ) 0.65 0.66 0.66 0.65 % Compressibility 14.25 18.95 1.24 16.32 Flowability Good Good Good Good

Table 2:

Evaluation of Fast Dissolving TabletParameters A B C D M*

Drug Content Uniformity (%)

99.643 ± 0.1305

99.972 ± 0.1009

99.237 ±

0.5338

99.499 ±

0.0768

100

Weight (mg) 500.257 ± 0.2332

500.293 ± 0.2901

500.289 ±

0.2904

500.594 ±

0.4513

-

Weight Variation

Passes Passes Passes Passes -

Tablet Hardness (kg/ cm2 )

6.5 ± 0.1 6.2 ± 0.1 6.4 ± 0.3

5.9 ± 0.2

7.5 ± 0.1

Tablet thickness (mm)

3.5 ± 0.2 3.4 ± 0.2 3.6 ± 0.5

3.65 ± 0.14

3.2± .01

Friability (%) 0.77 ± 0.0316

0.75 ± 0.2156

0.68 ± 0.6854

0.64 ± 0.8182

-

In-Vitro Dispersion Time (Sec.)

22 23 26 25 195

M*=marketed preparation.

Table 3:

Today we are thinking of developing unique delivery system for immediate

release of drugs only due to recent advances in technology. In this step fast

dissolving tablets were prepared by direct compression technique using

sorbitol and mannitol as super disintegrates.

For each designed formulation, blend of drug and excipients was prepared

and evaluated. Bulk density was found between 0.51 to 0.58 gm/cm3 and

tapped density between 0.64 – 0.68 gm/cm3. For density data,

%compressibility was calculated. Flowability of the material was found to

excellent as indicated by compressibility-flowability correlation data. Angle of

repose was found in the range of 240 -280. As it below 300 it indicates good

flow property of blend. (Table 2)

Tablets were prepared by direct compression method. As the material

was free flowing, tablets were obtained of uniform weight due to

uniform die fill, with acceptable variation as per I.P. Specification

(Table 3). Drug content was found to be 99.237 to 99.890 which are in

acceptable limit. (Table 3) Hardness of the tablet for each formulation

was 5.5-6.5 kg/cm2. Friability was below than 1.0% shows an

indication of good mechanical strength resistance of the tablet. Tensile

strength for all formulation was between 7.07- 8.13 kg / cm2 (Table 3).

The In-Vitro dispersion time was 8-10s for pure drug with super

disintegrates was found to 20-23s but in the marketed preparation

found to approx 03 minutes. (Table 3)