Challenges in development of orally disintegrating and dispersible tablets

 Introduction
CONTENTS
 Advantages over conventional tablet dosage forms
 Challenges in formulation and development
 Materials required
 Mechanism of drug release
 Formulation techniques
Conventional methods
Patented technologies
 Marketed products
 Evaluation tests
 Future developments
 Conclusion
 References

INTRODUCTION
Definitions 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 ODTs also known as
Rapidly dissolving tablets are
 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.

Palatability
Mechanical strength
Amount of drug
Size of tablet
Hygroscopicity
Aqueous solubility
Short half-life
Cost 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 vehicle
Hydrophilic vehicles- carbohydrates, proteins, gelatin, Zeolite
Ion Exchange resins- Indion 204, 214, 224, 234
Cyclodextrins
Flavors, sweeteners, amino acids.

2. Taste masking with lipophilic vehicle
Ex: fats, fatty acids.

3. Miscellaneous masking agents
Ex: Effervescent agents, Rheological modifications, salt preparations,
solid dispersions etc.

Detection threshold of sensors compared to Human receptors
 Pharmaceutical 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.
Taste Taste basic Human tongue Electronic
substance tongue
Sweetness Sucrose 1x10-2 2x10-6

Bitterness Caffeine 0.7x10-3 1x10-6

Sourness HCl 9x10-4 5x10-6

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
Sample Electronic
receptors.
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 DRUG
 Application 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 TABLET
 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

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

HYGROSCOPICITY
 Several 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 SOLUBILITY
 Water 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

SHORT HALF-LIFE
 ODTs 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.

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 taste
2. Dose lower than 20mg
3. Small to moderate molecular weight
4. Good solubility in water and saliva
5. 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  SUPERDISINTEGRANTS

Eg: More potent drugs like codeine are
required in very low amount which Eg: Cross povidone,
require diluent such as lactose to Crosscarmellose sodium,
makeup volume of drug. Sodium starch glycolate,
calcium carboxy methyl cellulose,
 Various fillers used are
Lactose, Alginates,
Directly compressed spray Micro crystalline cellulose,
dried mannitol, Amberlite IRP 88,
Sorbitol, Guargums,
Calcium carbonate, Modified corn starch,
Pregelatinised starch, Pregelatinized starch
Magnesium trisilicate, Chitin chitosan
Al(OH)3 etc. Smecta

BINDERS ANTIFRICTIONAL
AGENTS
Acacia
GLIDANTS
Cellulose derivatives corn starch, talc, silica
derivatives
Gelatin
LUBRICANTS
Stearic acid, magnesium
Polyvinyl pyrollidine stearate, talc, PEG, liquid
paraffin
Tragacanth
ANTIADHERENTS
talc, corn starch,
colloidal silica, sodium
lauryl sulphate.

OTHER EXCIPIENTS
 COLOURS
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 RELEASE
 The 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

WICKINGa. Wicking
AND SWELLING b. Swelling

FORMULATION TECHNIQUES
COVENTIONAL TECHNIQUES

 Tablet moulding

 Direct compression

 Spray drying

 Sublimation

 Freeze drying (or) Lyophilization

 Mass extrusion

 Cotton candy process

Tablet Molding
 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.

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

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.

SPRAY DRYINGcan produce highly porous and fine powders that dissolve
 Spray drying

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

SUBLIMATION
 To 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 EXTRUSION
 This 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 TECHNOLOGY
 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

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.

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 TECHNOLOGY
 The 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 TECHNOLOGY
 Yamanauchi 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

FLASH DOSE TECHNOLOGY
 This 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 TECHNOLOGY
 Prographarm 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 ODTs
 Analgesics 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 product Active Ingredient

Feldene Melt Piroxicam(10-20 mg)
Zyprexa Zydis Olanzapine (5, 10, 15 or 20 mg)
Nimulid -MD Nimesulide
Claritin Reditab Micronized Loratadine
Pepcid RPD 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

 The pharmacopoeial limit of friability test for a tablet is not more than
FRIABILITY TEST friability apparatus, carried out at 25 rpm for 4 min
1% using Tablet
(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 TIME
 The 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 TEST
This 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 ANALYZER
 The 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 DEVELOPMENTS
 ODTs 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.

1. International journal of research in Ayurveda and Pharmacy.
REFERENCES
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

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