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Evaluation Seminar
“Fast Dissolving Tablets:
A Review”
PRESENTED BY
:
ARUN PRATAP SINGH
M.PHARM- II (DEPT OF P’CEUTICS)
K.L.E.S College of Pharmacy, Hubli
CONTENTS
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Introduction.
Advantages of an Fast dissolving drug delivery system.
Characteristics of an Ideal FDDDS.
Choice of drug candidate.
Basic approaches to develop FDDDS.
Techniques in preparation of orally disintegratingdrug delivery
system.
 List of Patented technologies.
 References.
Introduction
United States Food and Drug
Administration (FDA) Center for
Drug Evaluation and Research
(CDER) define orally
disintegrating tablets in the
‘Orange Book’ as
“A solid dosage form which
contain a medicinal substance or
active ingredient which
disintegrates rapidly within a
matter of seconds when placed
upon a tongue” .
European Pharmacopoeia described
orally disintegrating tablets as
“uncoated tablets intended to be
placed in the mouth where they
disperse rapidly before being
swallowed’ and as tablets which
should disintegrate within 3 min”.
APPROVED DRUG PRODUCTS WITH
THERAPEUTIC EQUIVALENCE
EVALUATIONS “Orange Book”
Advantages of an Fast dissolving drug
delivery system
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Improved patient compliance.
Rapid onset of action and may offer an improved bioavailability.
Useful for pediatric, geriatric and psychiatric patients.
Suitable during traveling where water is may not be available.
No specific packaging required, can be packaged in push through
blisters.
Smooth mouth feel and pleasant taste.
Conventional manufacturing equipment.
Cost effective.
Good chemical stability as conventional oral solid dosage form.
Characteristics of an Ideal FDDDS
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Utilizes cost effective production method.
Require no water for oral administration.
Dissolve / disperse/ disintegrate in mouth in a matter of seconds.
Have a pleasing mouth feel and taste masking.
Less friable and have sufficient hardness.
Leave minimal or no residue in mouth after administration.
Manufacturing using conventional manufacturing method.
Choice of drug candidate
• No bitter taste.
• Good stability in water and saliva.
• Dose should be low as possible.
Unsuitable drug candidate for orally disintegrating tablet should include:
• Short half-life and frequent dosing.
• Drug having very bitter taste.
• Required controlled or sustained release.
Dose/solubility ratio
10
250
500
1000
5000
10000
100000
I
(dissolution limited)
Good solubility
and permeability
II
Good
permeability,
poor solubility
(solubility limited absorption)
1
III
IV
Good solubility, poor
permeability
Poor solubility and
permeability
0.1
BCS plot
API Properties –
Biopharmaceutical Classification Scheme
• Class I – high solubility, high permeability
- rapid absorption, good bioavailability
- eg propanolol, metaprolol
• Class II – low solubility, high permeability
- particle size effects on bioavailability
- eg ketoprofen, carbamazepine
• Class III high solubility, low permeability
- APIs dissolve rapidly and poorly absorbed
- require fast API dissolution to maximise absorption
- particle size reduction
eg ranitidine, atenolol
• Class IV low solubility, low permeability
- challenging molecules, likely to exhibit low bioavailability
eg hydrochlorothiazide, furosemide,
- option to increase permeability - modify APIs as ‘prodrugs’
Basic approaches to develop FDDDS
porous
structure
FDDDS
highly water-soluble
excipients
appropriate
disintegrating agents
- Physical blending method
- Kneading method
- Milling / Co-grinding technique
- Co-precipitation technique
- Solution/ solvent evaporation method
- Atomization/Spray drying method
- Microwave irradiation method
- Neutralization precipitation method
- Supercritical antisolvent technique
 The degree of crystal damage can be directly correlated
with the energy of the milling process.
API Properties
Particle size, drug dissolution and bioavailability
• Dissolution related to particle size and particle surface area
(smaller particle size, larger surface area, faster dissolution)
 dm

 dt
dm
 kA C s  C 
dt
= dissolution rate, A = surface area of solid, k = dissolution
rate constant, Cs = saturation of drug, C = concentration of drug in solution)
• API stability, solubility (dissolution) and particle size are key
properties for effective formulation design
Techniques in preparation of Fast
dissolving drug delivery system.
1. Freeze drying or Lyophilization
2. Spray Drying
3. Direct Compression
4. Sublimation
5. Cotton Candy Process
6. Mass Extrusion
7. Moulding
8. Nanonization
9. Fast Dissolving Films
10. Phase transition process
11. Melt granulation
• Freeze drying or Lyophilization
Lyophilization means drying at low temperature under condition that
involves the removal of water by sublimation. Drug in a water
soluble matrix which is then freeze dried to give highly porous
structure. The tablets prepared by lyophilization disintegrate rapidly
in less than 5 seconds due to quick penetration of saliva in pores
when placed in the oral cavity. Lyophilization is useful for heat
sensitive drugs i.e. thermo-labile substances
Ex. Loratidine (Claritin Reditab and Dimetapp Quick Dissolve)
• Spray drying
Spray drying can produce highly porous and fine powders that
dissolve rapidly. This technique is based on a particulate support
matrix, which is prepared by spray drying an aqueous composition
containing support matrix and other components to form a highly
porous and fine powder. This then mixed with active Ingredients and
compressed into tablets
Ex. Hyoscyamine Sulfate ODT
• Freeze drying or Lyophilization
“Spray drying”
• Direct compression
This is most popular technique because of its easy implementation
and cost-effectiveness. The basic principle involves addition of
disintegrants and/or water soluble excipients and/or effervescent
agents. Superdisintegrants in optimum concentration (about 2- 5%)
are mostly used so as to achieve rapid disintegration along with the
good mouth feel.
• Ex. Paracetamol (Tempra Quicklets), Zolmitriptan (Zolmig Repimelt)
•
Sublimation
This technique is based on the use of volatile ingredients (e.g.
camphor, ammonium bicarbonate, naphthalene, urea, urethane etc.)
to other tablet excipients and the mixture is then compressed into
tablets. Entrapped volatile material is then removed via sublimation,
which leads to formation of a porous structure.
Ex. Phloroglucinol Hydrate (Spasfon Lyoc)
MANUFACTURING STEPS FOR DIRECT COMPRESSION
Steps Involved in sublimation
• Cotton candy process - involves the formation of matrix of
polysaccharides by simultaneous action of flash melting and
spinning. This candy floss matrix is then milled and blended
with active ingredients and excipients after re-crystallization and
subsequently compressed to FDT.
Characteristics: It can accommodate high doses of drug and offers
improved mechanical strength
Ex- Tramadol HCl (Relivia Flash dose)
• Mass-Extrusion - involves softening the active blend using the
solvent mixture of water soluble polyethylene glycol, methanol and
expulsion of softened mass through the extruder or syringe to
get a cylindrical shape of the product into even segments using
heated blade to form tablets.
Characteristics: The dried product can be used to coat
granules of bitter tasting drugs and thereby masking their
bitter taste.
Ex. Zolmitriptan (Zolmig ZMT)
• Moulding
- water-soluble ingredients with a hydro-alcoholic solvent
is used and is molded into tablets under pressure lower than that used
in conventional tablet compression.
Characteristics: Molded tablets are very less compact than
compressed tablet porous structure that enhances
disintegration/dissolution and finally absorption increased.
• Nanonization - involves size reduction of drug to nanosize by
milling the drug using a proprietary wet-milling technique. The
nanocrystals of the drug are stabilized against agglomeration by surface
adsorption on selected stabilizers, which are then incorporated into FDTs.
Characteristics: It is used for poorly water soluble drugs. It leads to
higher bioavailability and reduction in dose, cost effective manufacturing
process, conventional packaging due to exceptional durability and wide
range of doses (up to 200 mg of drug per unit).
Ing. and Tech. Used for Formulating FDT:
Drug
Disint.Ag Other form.
ents
Ing.
Tech. used
Disint.
Time
NSAID
S
Crospovi
done
(intragra
nula &
Extragra
nular)
Mcc,Aerosil,
Mag.
stearate,
stearic acid
Wet
granulation &
Direct
Compression
50 sec
(for 125
Cross
linked
povidon
e
Lemon
flavor,
aspartame,
mannitol
Freeze drying
Avicel
ph 101
Pregelatiniz
ed starch,
Moulding,
Direct
Compression
Silden
afil
granul
es
Ascorb
ic acid
mgTab.)
< 30 sec
31-37 sec
List of Patented technologies.
The various technologies are developed for the of Orally Disintegrating
Drug Delivery System that are:
1) Zydis (Lyophilization)
2) Lyoc (Multiparticulate Compressed tab.)
3) Wowtab(Comp. Molded Tab.)
4) Flashtab (Lyophilization)
5) Durasolv (Moulding)
6) Orasolv (Compressed Tablets)
7) Flashdose(Cotton-candy process) 8) OraQuick (Micromask taste Masking)
9) Ziplets (Moulding)
10) Fast Melt (Moulding)
- Preformulation studies of fast dissolving tablets :Bulk Density (Db)
Tapped Density (Dt)
Angle of Repose
Powder flow properties - Carr’s index (or) % compressibility
Hausner ratio
- Identification of drug sample and Drug excipient
Compatibility study: by FTIR(KBr pellet method) and DSC
- Evaluation test for fast dissolving tablets:
General Appearance
Hardness
Drug Content
In-Vitro drug release
Modified disintegration test
Moisture uptake study
Weight variation
Friability (F)
Wetting time & Water absorption Ratio
Powder X-ray diffraction
In-vitro dispersion time
Stability study
• Disintegration Test using Modified Dissolution Apparatus
Limitations of Mouth Dissolving Tablets
• The tablets usually have insufficient mechanical strength.
Hence, careful handling is required.
• The tablets may leave unpleasant taste and/or grittiness in
mouth if not formulated properly.
• Drugs with larger doses are difficult to formulate into FDT e.g. rifampin
(600 mg), ethambutol (1000mg) etc.
List of commercially Available
Fast dissolving tablets
Trade Name
Active Drug
Felden fast melt
Piroxicam
Claritin redi Tab
Loratidine
Maxalt MLT
Rizatriptan
Zyprexia
Olanzapine
Pepcid RPD
Famotidine
Zofran ODT
Ondansetron
Zoming-ZMT
Zolmitriptan
Zeplar TM
Selegilline
Tempra Quiclets
Acetaminophen
Febrectol
Paracetamol
Nimulid MDT
Nimesulide
Torrox MT
Rofecoxib
Olanex instab
Olanzapine
Romilast
Montelukast
Benadryl Fastmelt Diphenhydramine
and pseudoephedrine
Manufacturer
Pfiser Inc., NY, USA
Schering plough Corp., USA
Merck and Co., NJ, USA
Eli lilly, Indianapolis, USA
Merck and Co., NJ, USA
Glaxo Wellcome, Middlesex, UK
AstraZeneca, Wilmington, USA
Amarin Corp., London, UK
Bristol myers Squibb, NY, USA
Prographarm, Chateauneuf, France
Panacea Biotech, New delhi , India
Torrent pharmaceuticals , India
Ranbaxy lab. Ltd. New-delhi, India
Ranbaxy lab. Ltd. New-delhi, India
Warner Lambert, NY, USA
Industrial Applications
Industrial applications include the following:
• To develop an orally disintegrating dosage forms and to work with
existing disintegrants
• To further improvise upon the existing technology of ODTs
• To optimize the blend of disintegrants or excipients to achieve ODTs
• To select and develop proper packaging material and system for
enhanced stability of the product and also develop a cost-effective
product
• To arrive at various taste-masking agents and prepare palatable
dosage forms thereby increasing patient compliance
• To develop disintegrants from different polymers which are used as
coating materials by certain modifications and use them for formulating
ODTs
References
• Virely P, Yarwood R. Zydis - a novel, fast dissolving dosage form.
Manuf Chem. 1990; 61: 36–37.
• Watanabe Y.New compressed tablet rapidly disintegrating in the
mouth using crystalline cellulose and adisintegrant.Biol Pharm Bull.
2004; 18: 1308–1310
• Koizumi KI, Watanabe Y, Morita K, Utoguchi N, Matsumoto M.New
method for preparing high porosity rapidly saliva soluble
compressed tablets using mannitol with camphor, a subliming
material.Int J Pharm. 2009; 152: 127–131.
• Dali Shukla, Subhashis Chakraborty, Sanjay singh, Brahemeshwar
mishra. Mouth dissolving tablet I: An overview of formulation
technology. Scientica Pharmaceutica. 2009; 77: 309-26.
• Jaysukh J Hirani, Dhaval A Rathod, Kantilal R Vadalia. Orally
disintegrating tablets: A Review. Tropical Journal of Pharmaceutical
Research. 2009; 8(2): 161-72.
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