Orally Disintegrating Tablet - Rapid Disintegration, Sweet Taste, And Target Release Profile

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Orally Disintegrating Tablet (ODT) is a solid unit dosage form containing drugs that disintegrates rapidly and dissolves in the mouth without taking water within 60seconds or less. Drug absorption through local oral–mucosal and through pre and post gastric parts of G.I.T. ODTs are also called as Oro-disperse, mouth dissolving, rapidly disintegrating, fast melt, quick dissolve and freeze dried wafers1.

Definitions:

The Center for Drug Evaluation and Research2 defines ODT as a solid dosage form containing medicinal substances which disintegrates rapidly, usually within a matter of seconds, when placed under the tongue. ODT delayed release3 is a solid dosage form containing medicinal substances which disintegrates rapidly, usually within matter of seconds, when place upon the tongue, but which releases a drug (or drugs) at a time other than promptly after administration. The European Pharmacopiea4 however defines a similar term, orodispersible tablets, or tablets intended to be placed in the mouth where it disperses rapidly before swallowing.

Advantages and Limitations:

Reformulation is a strategy to prolong market exclusivity as it may reduce generic erosion and patent expiry. Generally ODT formuations4 are developed as a line extension of existing oral dosage form. Pharmaceutical companies develop this dosage form to extend the product lifecycle and to extend patent life. This delivery system has much more advantage than conventional oral dosage forms such as tablets and capsules, due to their convenient and ease of use. ODT formulations prescribed for patients suffering by swallowing difficulties, pediatric, geriatric and schizophrenia patients. ODT also are convenient under circumstances in which taking an oral dosage form with water may be inconvenient (example: while working or traveling).

Selection of drugs:

The ideal characteristics1 of a drug for in vivo dissolution from an ODT include

  • No bitter taste
  • Dose lower than 20mg
  • Small to moderate molecular weight
  • Good stability in water and saliva
  • Partially non ionized at the oral cavities pH
  • Ability to diffuse and partition into the epithelium of the upper GIT (logp>1, or preferably>2)
  • Ability to permeate oral mucosal tissue

Unsuitable drug characteristic for ODT;

  • Short half-life and frequent dosing
  • Very bitter or otherwise unacceptable taste because taste masking cannot be achieved
  • Required controlled or sustained release.

Taste masking Methods:

The success of this delivery system is because of good taste.  Taste is a chemical reaction derived from sensory responses from the four main taste perceptions salt, sour, bitter and sweet5. The drugs are mostly bitter in nature. Skillful taste masking is needed to hide the bitter taste in ODT formulations. This can be achieved by using combination of right flavour and right sweetners. The taste masking in ODT has more influences on dissolution method development, specifications, and testing. Following methods are used in Taste masking is given as follows:

·Simple wet granulation method or roller compaction6 of other excipients. Spray drying can also employed to shroud the drug.

·Co-sifting method the large quantities of water soluble polymers are used as an excipient. Drugs can be sifted twice or thrice in small particle size mesh with excipients such as sweetners and flavors etc.

·Hydroxy propyl methyl cellulose, Ethyl cellulose, Methacrylates, Kollicoat, Polyvinyl pyrollidone polymers can be used to coat to mask the taste.

·Cyclodextrins can be used to trap or complex, cyclodextrin help to solubilze many drugs.

·Drug complexation7 with resinates are insoluble and no taste in oral cavity. With the correct selection of the ion exchange resin, the drug will not be released in the mouth so that the patient does not taste the drug when it is swallowed. When the drug resinate comes into contact with the gastrointestinal fluids, such as the acid of the stomach, the drug is released from the resinate, directly into solution and then absorbed in the usual way. The resin passes through the GI tract without being absorbed. Examples of drugs where this technique has been successfully demonstrated include ranitidine, risperidone and paroxetine. 

·Other methods include hot melt and supercritical fluids.

Manufacturing Methods:

ODT can be made by compression, lyophilization, sublimation, spray drying and compression moulding process20. The ideal manufacturing method should produce patient friendly with a pleasant taste and mouth feel. ODT are highly friable in nature, so commonly packed in unit dose blisters. Patented orally disintegrating tablets technologies include Orasolv, DuraSolv, Zydis, FlashTab, WowTab and others are discussed below.

Conventional tableting methods:

In direct compression common excipeints and existing tablet press are used for maximum cost efficiency. This method of process may eliminate the need for special packaging such as blister packages. To disintegrate rapidly high levels of superdisintegrants are used, selections of superdisintegrants are critical in this method. It can be used 10-20 %w/w of the formulation based on desire dissolution release profile. Additional excipients8 include suitable flow aid, lubricant, sweetener and color may be added to improve elegance and identification of the product.

Selection of Superdisintegrants:

Factors to be considered for selection of superdisintegrants9:

  • It should produce rapid disintegration(hydrophilic) when tablet meets saliva in the mouth
  • It should be compactable enough to produce less-friable tablets.
  • It can able to produce good mouth feel to the patient. Thus, small particle size are preferred to achieve patient compliance.
  • It shoud has good flow since it improve the flowability of the total blend.

Examples of exciepients:

·Super disintegrants: Crosspovidone, Microcrystalline cellulose, sodium starch glycollate, sodium carboxy methyl cellulose, pregelatinzed starch, calcium carboxy methyl cellulose, and modified corn starch. Sodium starch glycollate has good flowability than crosscarmellose sodium. Cross povidone is fibrous nature and highly compactable.

·Flavours: Peppermint flavour, cooling flavor, flavor oils and flavoring aromatic oil, peppermint oil, clove oil, bay oil, anise oil, eucalyptos oil thyme oil, oil of bitter almonds. Flavoring agnets include, vanilla, citus oils, fruit essences

·Sweetners: Aspartame, Sugars derivatives

·Fillers: Directly compressible spray dried Mannitol, Sorbitol, xylitol, calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulfate, pregelatinized starch, magnesium trisilicate, aluminium hydroxide.

·Surface active agents: sodiumdoecylsulfate, sodiumlaurylsulfate, polyoxyethylene sorbitan fatty acid esters (Tweens), sorbitan fatty acid esters (Spans), polyoxyethylene stearates.

·Lubircants: Stearic acid, Magnesium stearate, Zinc state, calcium state, talc, polyethylene glycol, liquid paraffin, magnesium laury sulfate, colloidal silicon dioxide.

Advantages:

·Hard tablets, not fragile and easy to handle.

·No specific packaging required, can be packaged in push through blisters.

·Smooth mouth feel and pleasant taste.

·Conventional manufacturing equipment, not difficult to transfer to final production site.

·Cost effective.

Other Technologies10,11:

The CIMA’s (US-pharmaceutical company) OraSolv6 is other manufacturing technology involves the direct compression of actives effervescent excipeints and taste masking agents. Effervescent disintegration agents evolve gas by means of chemical reaction called effervescent couple. The tablet rapidly disintegrates and carbon dioxide is produced by contact with saliva or aqueous fluid. The effervescent excipients and taste masking agents. The effervescent excipient is prepared by coating the organic acid crystals using stoichiometrically lesser amount of base material. The required end point is a evolution of carbondioxide. Then the excipeint is mixed with active ingredient or active microparticles and with other standard tableting excipients and then compressed into tablets. Carbonates such as sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate, acids such as citric, tartaric, amalic, fumeric, adipic and succinies are used.

The CIMA’s DuraSolv process is based on Oro-Solv technology, in this non compressible filler along with taste masking excipeint and actives used in dry blend then compressed into tablets. Taste masking sweetners and flavours such as mint, cherry and orange. Drug coating can also be used.

Prographarm laboratories has patented the Flash Tab technology. Flash Tab6 is a flash dispersal system which involves coating a drug with a Eudragit polymer (methacrylate copolymer) to provide rapid release of the drug in the stomach, and formulating this microencapsulated drug with an effervescent couple to produce a flash dispersal tablet. The process is thus a complicated and expensive one which also requires stringent environmental controls (<20°C/10% relative humidity and tablet hardness about.1-2.5kP) and also specialized packaging. The microencapsulation system currently uses an undesirable solvent based manufacturing process, and the cost is high. (Refer Figure 1)

Eurands (pharmaceutical company) Advatab18 is a new generation ODT. In this technology the (microcaps-coacervation) microencapsulation process completely envelops individual drug particles with gastro soluble polymer barrier coating between drug and taste buds in the mouth. Microencapsulation restrics the dissolution of API in the mouth, but allow rapid dissolution in the gastro intestinal tract, thus overcoming bioequivalence issues for generic products.

Figure 1: Micro-encapsulation restricts dissolution of the API in the mouth but allows rapid dissolution in the GI tract.

Micro-encapsulation restricts dissolution of the API in the mouth but allows rapid dissolution in<br />
the GI tract.

Specialized functional polymers and coating process to manufacture ODTs with controlled/modified release profiles. Eurands17 Diffucaps technology enables the development of sustained-release minibeads for absorption throughout the gastrointestinal tract by drug layering on inactive core (Refer Figure 2). By incorporating these small beads into the ODT formulation, release profile can be modified and taste masking effectively achieved.

Figure 2: Layering of active drug on to neutral core(bead) followed by one or more rate controlling functional members, allows controlled/modified release.

Layering of active drug on to neutral core(bead) followed<br />
by one or more rate controlling functional members

Compression molded tablets:

Compression-molded tablets would be expected to have disintegration times that are similar to compressed tablets. In this technology, water-soluble ingredients are used so that tablet disintegrate and dissolve rapidly. The powder blend is moistened with a hydro alcoholic solvent and is molded in to tablet using compression pressure lower than used in conventional tablets compression. The solvent is then removed by air-drying. Molded tablets have a porous structure that enhances dissolution.

The WowTab17 is a successful manufacturing technique based on combination of modified polyssacharides that have water dissolution characteristics to facilitate fast disintegration. The manufacturing process involves granulating low-moldable sugars (e.g. mannitol, lactose, glucose, sucrose, and erythritol) that show quick dissolution characteristics with high moldable sugars (e.g. maltose, maltitol, and sorbitol). The result is a mixture of excipients that have fast-dissolving and highly moldable characteristics. The tablets are manufactured at a low compressed force followed by optional humidity conditioning treatment to increase tablet hardness.

Freeze-dried (Lyophilized) Wafers:

The (Cardinal Health’s) Zydis freeze drying technology requires specific characteristic for drug candidates and matrix forming materials. Lyophilized tablets disintegrates very fastly (<5secs), the tablets are often less robust and usually require special packaging. In this method bioavailability also improved for water insoluble drugs.  In this dosage form insoluble drugs are in suspension and it will be freeze dried in suitable molds (PVC blister) and results in content uniformity issues.

The material to be dried is first frozen12 and then subjected under a high vacuum to heat (supplied by conduction or radiation or by both), so that the frozen liquid sublimed leaving only the solid, dried components of the original liquid. The four components of freeze driers are vacuum chamber for drying, vacuum source, heat source and vapor removal system. Gole et al13 and Lawrence et al14 describes the inventive preparation of lyophilized matrix with gelatin, pectin, soy fibre protein and mannitol. The low soluble and bitter actives like risperidone and ibuprofen are coated by particulate coating with natural or synthetic polymer and organic solvents and dried by vapor removal system. The Matrix disperses rapidly with in 10 seconds in water and thus improves dissolution.

Examples of ODT technologies5,11,19 (Refer Table 1):

Table 1.

Technologies

Company Name

Products in the US Market

Technology base

Durasolv

Orasolv

CIMA Labs Inc

Tempera quicklet

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Compression

Organon USA, Inc  

Mirtazapine (Remeron soltab)

Effervescent disintegreant -compression

WowTab

Yamanouchi Pharmaceuticals Company

Benadryl fast melt

Compression molded tablets

Lyophilisation

Jannsen pharma

Risperidone(Risperdal quicklet)

Freeze drying (lyophilized wafers)

Glaxosmithkline

Ondansetron (Zofran ODT)

Olanzapine    (Zyprexa Zydis)

FlashTab

Ethypharm/BMS

Excdrin QuickTabs

Effervescent dintegrant-microencapsuled drug compression.

Dissolution Studies:

ODTs are characterized by high porosity, low density and low hardness. The method used to determine disintegration time is also critical, and the disintegration method stated in the United States Pharmacopoeia (USP) for conventional ‘hard’ tablets may not be appropriate. USP 26 states that method is: “provided to determine compliance with the limits on disintegration stated in the individual monographs except where the label states that the tablets or capsules are intended for use as troches, or are to be chewed.

For bioequivalent formulation15, USP monographs dissolution conditions should be followed in addition 0.1N hydrochloric acid, and pH4.5 and 6.8 buffers should be evaluated for orally disintegrating tablets. By experience the USPII (paddle speed of 50rpm) apparatus is most suitable for ODT. For tablet weight one gram or more then paddle speed to be increased. The taste-masking plays major role dissolution method development. Several companies developing their internal standards to get more discrimination of the product performance. In vivo disintegration depends upon how the patient use is saliva and tongue, it may vary with patient to patient. Invitro disintegration is less than 30seconds in dissolution vessel therefore not important factor in the resulting dissolution profile in terms of discrimination. The discrimination based on taste masked coating and the active ingredient itself.

Other important physical tests includes Friability, Hardness test and Fineness of dispersion or Invitro dispersion test(one tablet to be added into a beaker containing 50ml of water, stir continuously for 5mints and dispersion should pass in #25 mesh), this can be used as an internal test methods.

Summary:

Orally Disintegrating Tablets is the general form of nomenclature for tablets that disintegrate rapidly or instantly in the oral cavity. ODTs can be prepared in different ways and product performance depends upon the drug suitability and excipients selections in the delivery system. In combination with other technologies such as modified release and microencapsulation, ODTs will continue to provide enhanced commercial and therapeutic benefits. ODT is a growing technology, offering considerable benefits for lifecycle management16, development timelines, patient convenience and market share. The ODTs available in various therapeutic areas such as Schizophrenia, migraine, nausea, pain, allergies, parkinsons disease, Alzheimer disease, diahorrhea. The successful marketed ODTs have good taste and rapid release properties. With rapid acceptance of ODTs by patients and pharmaceutical companies, the market for this dosage form is promising, and the product pipeline continues to grow rapidly.

References:

1.    William R.P. fister, Tapash .K.Ghosh. Orally disintegrating tablets. Pharmaceutical Technology (Product, Technologies, and Development issues in Oct 2005).

2.    Guidance for industry oral disintegrating tablets published by centre for drug   evolution and research, accessed at http://www.fda.gov/cder/guidance/index.htm

3.   htpp://www.fda.gov/cder/dsm/DRG/drg00201.htm - CDER Data standards manual.

4.   European directorate for the quality of medicines, Pharmaeuropa, 10(4), 547(1988), acessed online at htpp://www.pheur.org/.  European pharmacopiea 5.2,3151(2006).

5.   David Brown, Orally disintegrating tablets – taste over speed. Drug Delivery Technology. http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=164 ,  accessed on Apr 02/2008.

6.    Venkatesh et al. Process for manufacturing bite dispersion tablets. US patent no: 6475510 ( Nov 05/2002).

7.    http://www.rohmhaas.com/ionexchange/Pharmaceuticals/Tastemasking.htm accessed on Apr 06/2008.

8.  Gothoskar, A.V.; Parakh, S.R. A Review of mouth dissolving tablet technologies. (Drug Delivery). Pharmaceutical Technology.(Nov01/2003,

9.   Wayne Camarco, Dipan Ray, Ann Druffner. Selecting superdisintegrants for Orally   Disintegrating Tablet Formulations in Phrmaceutical Technology Oct 01/2006.

10. Wehling F, Shuehle S, Madamala N:  Base coated acid particles and effervescent formulation incorporating same. US Patent No. 5,503,846, 1996.

11.  Troy M.Harmon .Beyond the first generations of orally disintegrating Tablets. Emerging technology. Tablets and Capsules, 3 Sep 2006.

12.  Leon Lachman, Herbert A. Lieberman, and Joseph L. Kanig. Text book ‘The Theory and Practice of Industrial Pharmacy’ by 3rd Indian, edition

13.  Gole et al. Pharmaceutical and other dosage forms. United States Patent No:5648093  (July 15/1997).

14.   Lawrence et al. Biconvex rapidly disintegrating tablets. United States Patent No 6224905 (May 01/2001).

15.  James Klancke. Dissolution Testing of Orally Disintegrating Tablets. Dissolution Technologies/May2003. accessed at http://www.dissolutiontech.com/DTresour/0503art/DT0503art1.pdf

16.  Troy M.Harmon. Orally disintegrating tablets: A valuable life cycle management Strategy. Pharmaceutical commerce, march 2007, available online  www.pharmaceuticalcommerce.com.

17.  Yamanouchi Pharma Technologies, Inc. WOWTAB. 20 June 2001  http://www.ypharma.com/wowtab.shtml

18.  http://www.eurand.com/Technologies/Dosage-Form-Technology/AdvaTab/

19. FDA, Electronic Orange Book; Approved Drug product with Therapeutic Equivalent Evaluations Current through February 2008. http://www.fda.gov/cder/ob/default.htm acessed March, 15, 2008

20. Reddy L.H, Ghosh B, Rajneesh: Fast Dissolving Drug Delivery Systems: A Review  of the literature. Ind. J. Pharm. Sci., 64 (4): 331-336, 2002

About Author:

C.Kumaresan

C.Kumaresan
Dr.Reddy's Laboratories, Survey No:42,43, IPDO(Innovation Plaza), Bachupally village, Qutuullapur Mandal, Hyderabad(AP), India.
Email: ckumaresan@gmail.com; Mobile No: +919962989048

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Comments

Sai's picture

Nice article. It is well written and up to the point. I thing your industry exposure is making you a good writer.

Sowmya Bharadwaj's picture

Great article.....I have seen many articles and literature about the orally disintegarting dosages forms, but this is the one article where i have found the total information...

Really great......