Challenges in development of orally disintegrating and dispersible tablets.

By V.SRUJANA M.Pharm ( 1st SEM ) DEPARTMENT OF PHARMACEUTICS

CONTENTS
     

    

Introduction 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 substance, 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

Rapidly dissolving tablets are also known as


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 cocooperative.

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 halfCost 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 patients 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:

Taste masking with hydrophilic vehicle Hydrophilic vehicles- carbohydrates, proteins, gelatin, Zeolite vehiclesIon Exchange resins- Indion 204, 214, 224, 234 resinsCyclodextrins Flavors, sweeteners, amino acids.
1.

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

2.

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

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 Sweetness Bitterness Sourness Taste basic substance Sucrose Caffeine HCl Human tongue 1x10-2 0.7x10-3 9x10-4 Electronic tongue 2x10-6 1x10-6 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 receptors.

Sample Electronic 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 softvery low compression force, which makes the tablets friable and/or brittle, difficult to handle, and often requiring specialized peel-off blister packing that peelmay 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 fastfastdissolving 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 7easiest 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 matrixlike Mannitol which induces crystallinity and hence impart rigidity to the amorphous composite.

SHORT HALF-LIFE HALF

ODTs being immediately releasing dosage forms and the absorption of maximum amount of dose takes place in the pre-gastric region, these have presort 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 unitpackaging which may add to the cost of the dosage form.

Materials required:

Drug Excipients

THE IDEAL CHARACTERISTICS OF DRUG

For disintegration and dissolution in oral cavity i.e., the pre-gastric preabsorption from an ODT include, No bitter taste Dose lower than 20mg Small to moderate molecular weight Good solubility in water and saliva Partially nonionized at the oral cavitys pH. Ability to diffuse and partition into the epithelium of upper GIT. Ability to permeate oral mucosal tissue.

1. 2. 3. 4. 5. 6. 7.

EXCIPIENTS


FILLER

SUPERDISINTEGRANTS

Eg: More potent drugs like codeine are required in very low amount which require diluent such as lactose to makeup volume of drug.


Various fillers used are Lactose, Directly compressed spray dried mannitol, Sorbitol, Calcium carbonate, Pregelatinised starch, Magnesium trisilicate, Al(OH)3 etc.

Eg: Cross povidone, Crosscarmellose sodium, Sodium starch glycolate, calcium carboxy methyl cellulose, Alginates, Micro crystalline cellulose, Amberlite IRP 88, Guargums, Modified corn starch, Pregelatinized starch Chitin chitosan Smecta

BINDERS

ANTIFRICTIONAL AGENTS

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

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 NaturalArtificialArtificial- 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) (acid-

DEFORMATION AND REPULSION

a. Deformation

b. Repulsion

WICKING AND SWELLING

a. Wicking 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 hydromolded into tablets under pressure lower than that used in Conventional tablet compression. The solvent is then removed by air-drying. air-

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 DRYING


Spray drying can produce highly porous and fine powders that dissolve 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 QuickQuick-Dis Technology Nanocrystal Technology

ZYDIS TECHNOLOGY


A Zydis tablet is produced by lyophilizing or freeze-drying the drug in a freezematrix 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.

Eg: Maxalt-MLT (rizatriptan benzoate) - Migraine Maxalt-

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 water. 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 & sinus

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 mouththe 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. tasteMicro granules may be prepared by using conventional techniques like coacervation, micro encapsulation, and extrusion-spheronisation. All these extrusionprocesses utilize conventional tabletting technology. These taste-masked micro crystals of active drug, disintegrating agent, a tasteswelling 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 AntiAnthelmintics AntiAnti-gout Agents AntiAnti-hypertensive Agents AntiAnti-malarials AntiAnti-migraine Agents AntiAnti- muscarinic Agents AntiAnti- neoplastic Agents and Immunosuppressant's AntiAnti- protazoal Agents AntiAnti-thyroid Agents -Blockers Cardiac Inotropic Agents Corticosteroids Diuretics AntiAnti- parkinsonian Agents GastroGastro-intestinal Agents Histamine H,-Receptor Antagonists etc H,-

PREFORMULATION STUDIES


Compatability studies = FTIR / DSC Angle of repose = tan -1 (h/r)

Determination of Bulk density = W / Vo Tapped density = W / Vf Hausers Ratio= Tapped density/Bulk density compressibility index : CI = 100 (Vo Vf )/ Vo Moisture content

Some of the Marketed ODTs in India

Name of product Feldene Melt Zyprexa Zydis Nimulid -MD Claritin Reditab Pepcid RPD Active Ingredient Piroxicam(10-20 mg) Piroxicam(10Olanzapine (5, 10, 15 or 20 mg) Nimesulide Micronized Loratadine Famotidine (20-40 mg) (20-

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

FRIABILITY TEST


The pharmacopoeial limit of friability test for a tablet is not more than 1% using Tablet friability apparatus, carried out at 25 rpm for 4 min (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 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 (WaW 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.

ININ-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 m without leaving any residue on the mesh.

ININ-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.

ININ-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 lowpermeable drugs. 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.

REFERENCES
1. International journal of research in Ayurveda and Pharmacy. Pharmacy. 2. Journal of Chemical and Pharmaceutical Research, 2009, 1(1): 336-341. 2009, 336-341. 3. The Indian Pharmacist, Volume 3, Issue 19, p.72-75 (2004). 19, 722004) 4. United States Pharmacopoeia 24/NF 19. The Official Compendia of 24/NF 19. Standards. Standards. Asian ed. Rockville, MD: United States Pharmacopoeial ed. MD: Convention Inc; 2000:1913-1914. Inc; 2000:1913-1914. 5. Bentham science Publishers- Recent patents on Drug delivery and PublishersFormulations, Volume 4, Number 3, November 2010. 2010. 6. Aultons Pharmaceutics- The design and manufacture of medicines, Edited Pharmaceuticsby Michael E.Aulton- 3rd Edition, 2008. E.Aulton7. FDA, Guidance for Industry: Orally Disintegrating Tablets Draft Guidance, Guidance, (Rockville, MD, April 2007). 8. Review article- Recent Patents and Trends in Orally Disintegrating Tablets articleby Farhan A. AlHusban, Amr M. El-Shaer, Rhys J. Jones and Afzal R. ElMohammed

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