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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

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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.

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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”

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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.

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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.

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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.

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250 500 1000 10000 100000 Dose/solubility ratio 10 1 0.1 5000 I Good solubility and permeability II Good permeability, poor solubility III Good solubility, poor permeability IV Poor solubility and permeability BCS plot (dissolution limited) (solubility limited absorption)

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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’

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Basic approaches to develop FDDDS FDDDS 27

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- Physical blending method - Kneading method - Milling / Co-grinding technique - Co-precipitation technique - Solution/ solvent evaporation method - Neutralization precipitation method - Atomization/Spray drying method - Supercritical antisolvent technique - Microwave irradiation method The degree of crystal damage can be directly correlated with the energy of the milling process.

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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) = 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

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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

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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

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Freeze drying or Lyophilization

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“Spray drying”

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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)

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Steps Involved in sublimation

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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)

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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).

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Ing. and Tech. Used for Formulating FDT:

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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)

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- 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 Weight variation Hardness Friability (F) Drug Content Wetting time & Water absorption Ratio In-Vitro drug release Powder X-ray diffraction Modified disintegration test In-vitro dispersion time Moisture uptake study Stability study

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Disintegration Test using Modified Dissolution Apparatus

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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.

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List of commercially Available Fast dissolving tablets Trade Name Felden fast melt Claritin redi Tab Maxalt MLT Zyprexia Pepcid RPD Zofran ODT Zoming-ZMT Zeplar TM Tempra Quiclets Febrectol Nimulid MDT Torrox MT Olanex instab Romilast Benadryl Fastmelt Piroxicam Loratidine Rizatriptan Olanzapine Famotidine Ondansetron Zolmitriptan Selegilline Acetaminophen Paracetamol Nimesulide Rofecoxib Olanzapine Montelukast Diphenhydramine and pseudoephedrine 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

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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

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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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!!!! Thank you !!!!

Summary: literature about fast dissolving tablets