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Evaluation Seminar

Fast Dissolving Tablets: A Review

PRESENTED BY

ARUN PRATAP SINGH M.PHARM- II (DEPT OF PCEUTICS) K.L.E.S College of Pharmacy, Hubli

CONTENTS
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


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


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

250

500

1000

5000

10000

100000

10

I
Good solubility and permeability (dissolution limited)

II

Good permeability, poor solubility (solubility limited absorption)

III
Good solubility, poor permeability
0.1

IV
Poor solubility and permeability

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

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- Physical blending method - Milling / Co-grinding technique - Solution/ solvent evaporation method - Atomization/Spray drying method - Microwave irradiation method

- Kneading method

- Co-precipitation technique
- 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 ! kA C s  C dt
dm 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

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)

Cotton candy process - involves the formation of matrix of

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. Crospovi done (intragra nula & Extragra nular) Cross linked povidon e Avicel ph 101 Mcc,Aerosil, Mag. stearate, stearic acid Tech. used Disint. Time 50 sec (for 125 mgTab.) NSAID S Wet granulation & Direct Compression

Silden afil granul es Ascorb ic acid

Lemon flavor, aspartame, mannitol Pregelatiniz ed starch,

Freeze drying

< 30 sec

Moulding, Direct Compression

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) 3) Wowtab(Comp. Molded Tab.) 5) Durasolv (Moulding) 2) Lyoc (Multiparticulate Compressed tab.) 4) Flashtab (Lyophilization) 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 - Carrs 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 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

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

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: 3637. Watanabe Y.New compressed tablet rapidly disintegrating in the mouth using crystalline cellulose and adisintegrant.Biol Pharm Bull. 2004; 18: 13081310 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: 127131. 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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