INTRODUCTION:

The oral route of drug administration is the most important method of administering drugs for systemic effects. Of drugs that are administered orally, solid oral dosage forms represent the preferred class of product. The reasons for this preference are as follows (compared to liquid dosage forms):

i. Tablets and capsules unit dosage forms in which one usual dose of drug has been accurately placed.

ii. Drugs are less stable in liquid than in solid form than in a dry state and expiration dates tend to be shorter. ^[1]

The most popular solid dosage forms are being tablets and capsules, one important drawback of this dosage forms for some patients, is the difficulty to swallow. Drinking water plays an important role in the swallowing of oral dosage forms. Often times people experience inconvenience in swallowing conventional dosage forms such as tablet when water is not available, in case of motion sickness and sudden episodes of coughing during the common cold, allergic condition and bronchitis.

For these reason, tablets that can rapidly dissolve or disintegrate in the oral cavity have attracted a great deal of attention. Orally Disintegrating Tablets (ODTs) are not only indicated for people who have swallowing difficulties, but also are deal for active people. It has been reported that Dysphagia^[^2]
[3] (difficulty in swallowing) is common among all age groups and more specific with pediatric, geriatric population along with institutionalized patients and patients with nausea, vomiting. ODTs with good taste and flavor increase the acceptability of bitter drugs by various groups of population.

Definition:

The oral fast dissolving systems are defined as oral drug delivery systems that dissolve or disintegrate within a few seconds to a few minutes of placement in the mouth and that do not require water to aid swallowing.

ADVANTAGES OF ODTs: ^[^4]

1. For the patients who refuse to swallow such as pediatric, geriatric and psychiatric patients.

2. Rapid drug therapy intervention.

3. Increased bioavailability through pregastric absorption of drugs from mouth, pharynx and oesophagus as saliva passes down.

4. Good mouth feel property helps to change the perception of medication as bitter pill particularly in pediatric patients.

5. The risk of choking or suffocation during oral administration of conventional formulations due to physical obstruction is avoided thus providing improved safety.

DISADVANTAGES OF ODTs:

1. Drugs with larger doses are difficult to formulate into ODTs

2. ODTs do not prove useful for patients with dryness of mouth due to decreased saliva production.

SALIENT FEATURES OF ODTs:

1. Convenience of administration and accurate dosing as compared to liquids.

2. No need of water to swallow the dosage form (convenient during traveling).

3. Rapid dissolution of drug and absorption which may produce rapid onset of action.

4. Ability to provide advantages of liquid medication in the form of solid preparation.

CHALLENGES IN THE FORMULATION OF ODTs: ^[5]

1 Not require water to swallow, but it should dissolve or disintegrate in the mouth in matter of seconds.

2 Be compatible with taste masking.

3 Be portable without fragility concern.

4 Have a pleasant mouth feel.

5 Leave minimum or no residue in the mouth after oral administration.

6. Exhibit low sensitive to environmental condition as temperature and humidity.

7 Allow the manufacture of the tablet using conventional processing and packaging equipments at low cost.

IDEALS ODTs SHOULD:

1 Have pleasing mouth feel

2 Have an acceptable taste masking property

3 Leave minimal or no residue in mouth after administration

4 Exhibit low sensitivity to environmental conditions (temperature and humidity

MECHANISN OF ODTs USING SUPERDISINTEGRANTS:

Disintegrating agents are substances routinely included in the tablet formulations to aid in the breakup of the compacted mass when it is put into a fluid environment. They promote moisture penetration and dispersion of the tablet matrix. In recent years, several newer agents have been developed known as “Superdisintegrants”. These newer substances are more effective at lower concentrations with greater disintegrating efficiency and mechanical strength. On contact with water the superdisintegrants swell, hydrate, change volume or form and produce a disruptive change in the tablet. Effective superdisintegrants provide improved compressibility, compatibility and have no negative impact on the mechanical strength of formulations containing high-dose drugs.

Mechanism of superdisintegrants[6-19]:

Swelling:

Perhaps the most widely accepted general mechanism of action for tablet disintegration is swelling. Tablets with high porosity show poor disintegration due to lack of adequate swelling force. On the other hand, sufficient swelling force is exerted in the tablet with low porosity. It is worthwhile to note that if the packing fraction is very high, fluid is unable to penetrate in the tablet and disintegration is again slows down.

Porosity and capillary action (Wicking):

Disintegration by capillary action is always the first step. When we put the tablet into suitable aqueous medium, the medium penetrates into the tablet and replaces the air adsorbed on the particles, which weakens the intermolecular bond and breaks the tablet into fine particles. Water uptake by tablet depends upon hydrophilicity of the drug /excipients and on tableting conditions. For these types of disintegrants maintenance of porous structure and low interfacial tension towards aqueous fluid is necessary which helps in disintegration by creating a hydrophilic network around the drug particles.

Due to disintegrating particle/particle repulsive forces:

Another mechanism of disintegrants attempts to explain the swelling of tablet made with ‘nonswellable’ disintegrants. Guyot-Hermann has proposed a particle repulsion theory based on the observation that nonswelling particle also cause disintegration of tablets. The electric repulsive forces between particles are the mechanism of disintegration and water is required for it. Researchers found that repulsion is secondary to wicking.

Due to deformation:

During tablet compression, disintegrated particles get deformed and these deformed particles get into their normal structure when they come in contact with aqueous media or water. Occasionally, the swelling capacity of starch was improved when granules were extensively deformed during compression. This increase in size of the deformed particles produces a breakup of the tablet. This may be a mechanism of starch and has only recently begun to be studied.

TECHNIQUES FOR PREPERARING ODTS:

Freeze Drying :^{[1, 2, 20 ]}

A process, which involves sublimation of water from the product after freezing, is called freeze-drying. Freeze-dried forms offer more rapid dissolution than other available solid products as process imparts glossy amorphous structure to the bulking agent and sometimes to the drugs.

A tablet that rapidly disintegrates in aqueous solution includes a partially collapsed matrix network that has been vacuum dried above the collapse temperature of the matrix. The matrix is partially dried below the equilibrium freezing point of the matrix. Vacuum drying of the tablet above its collapse temperature instead of freeze drying below its collapse temperature provides a process for producing tablets with enhanced structural integrity, while rapidly disintegrating in normal amounts of saliva.

However, the use of freeze-drying is limited due to high cost of the equipment and processing. Other major disadvantages of the final dosage forms include lack of physical resistance in standard blister packs.

Following Figure Represents The Mechanism Of ODTs

Figure 1: Mechanism of ODT

Moulding :^{[1, 2, 4, 21]}

Mouldability is defined as the capacity of the compound to get moulded or compressed. Low mouldability means that the compound show reduced compressibility by tablet and rapid dissolution while high moulding compounds show excellent compressibility and slow dissolution.

Tablets produced by moulding are solid dispersions. Physical forms of the drug in the tablets depend whether and to what extent it dissolves in the molten carrier. The drug can exist as discrete particles or micro particles dispersed in the matrix. It can dissolve totally in the molten carrier to form solid solution or dissolve partially in the molten carrier and the remaining particles stay undissolved and dispersed in the matrix. Disintegration time, drug dissolution rate and mouth feel will depend on the type of dispersion or dissolution. Moulded tablets disintegrate more rapidly and offer improved taste because the dispersion matrix is, in general, made from water-soluble sugars.

Types of Moulded Tablets:

I. Compression Moulding:

Compressed moulded tablets are prepared from soluble ingredients by compressing a powder mixture previously moistened with solvent (usually water or ethanol) into mould plates to form wetted mass.

II. Heat Moulding:

In this, moulded form have been prepared directly from the molten matrix in which drug is dissolved or dispersed.

III. No-Vacuum Lyophilization:

Moulded form prepared by no-vacuum evaporation method involves evaporation of solvent from the suspension at standard pressure.

T. Makino, et al have developed compression moulded mixtures containing drug and combination of starches and sugars with surface that have been wetted with suitable amount of water. The wetted mass is compression moulded and dried porous tablets with sufficient mechanical strength have been obtained.

Moulded tablets typically do not possess great mechanical strength. Erosion and breakage of the moulded tablet often occur during handling and opening of blister packs.

Sublimation : ^{[1, 2, 4, 21]}

Compressed tablets composed of highly water-insoluble excipients do not dissolve rapidly in the water because of its low porosity, so porous tablets that exhibit good mechanical strength and dissolve quickly is the best remedy for above problem.

Heinemann and Rose et. al. have produced porous tablet by addition of inert solid ingredients such as urea, urethane, ammonium bicarbonate, camphor, naphthalene with other tablet excipients and the blend was compressed into tablet. Then, volatile material from compressed tablet is removed by sublimation so as to impart porosity to the tablet.

A method of producing fast dissolving tablet using water as the pore forming material has been described by Makino, et al. Koizumi, et al have developed a new method of preparing high porosity tablet that dissolve rapidly within 10-20 seconds and exhibit sufficient mechanical strength using mannitol with camphor, a subliming material.

Spray Drying: ^{[1, 2, 4, 21]}

As the processing solvent is evaporated rapidly during spray drying, it gives highly porous and fine powders. Allen and Wang have employed spray-drying technique to prepare fast dissolving tablets. They developed formulation by using mannitol as bulking agent, hydrolyzed and non-hydrolyzed gelatin as support matrix, sodium starch glycolate as disintegrant and acidic material (citric acid) and /or alkali material (ex. NaHCO₃) to enhance disintegration and dissolution. When immersed in an aqueous medium the tablets compressed from spray -dried powder, disintegrated within 20 seconds.

Mass-Extrusion:^[2]

In this technology the active blend is softened by using the solvent mixture of water soluble polyethylene glycol, methanol and then softened mass is expulsed 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 in order to mask their bitter taste.

Direct Compression: ^[2]

Direct compression is the easiest way to manufacture tablets. It can be done with conventional equipment, commonly available excipients and a limited number of processing steps. It also allows to accommodate high doses , and final weight of tablet can easily exceed that of the other production methods.

Directly compressed tablet’s disintegration and solubilization depends on various factors such as single or combined action of disintegrants, water-soluble excipients and effervescent agent. Disintegrant efficacy is based on force equivalent concept, which is the combined measurement of swelling force development and amount of water absorption and defines the capability of disintegrant to transform absorbed water into swelling force. Disintegrant efficacy is strongly affected by tablet size and hardness. Large and hard tablet require more disintegration time. As consequences, products with optimal disintegration properties often have medium to small size and high friability and low hardness. The tablet with high friability and low hardness has less physical resistance, which cause breakage of tablet edges during the opening of blister alveolus.

Mouth dissolving tablet prepared by direct compression method involves use of superdisintegrant. Superdisintegrant are the agent, which are completely effective in very low concentration (2-5%). So to ensure a high disintegration rate of MDDS, choice of suitable type and an optimal amount of disintegrant is important. Other formulation components such as water-soluble excipients or effervescent agents can further enhance dissolution or disintegration properties but main drawback of using effervescent excipients is their highly hygroscopic nature.

The simultaneous presence of disintegrant with a high swelling force called disintegrating agent and substances with low swelling force (starch, cellulose and direct compression sugar) defined as “swelling agent” was claimed to be a key factor for rapid disintegration of tablet, which also offers physical resistance.

PATENTED TECHNOLGIES FOR ODTs:

1. Zydis Technology : ^{[1,
2, 21,22, 23]}

Zydis formulation is a unique freeze dried tablet in which drug is physically entrapped or dissolved within the matrix of fast dissolving carrier material. When zydis units are put into the mouth, the freeze-dried structure disintegrates instantaneously and does not require water to aid swallowing. The zydis matrix is composed of many material designed to achieve a number of objectives. To impart strength and resilience during handling, polymers such as gelatin, dextran or alginates are incorporated. These form a glossy amorphous structure, which imparts strength.

To obtain crystallinity, elegance and hardness, saccharides such as mannitol or sorbitol are incorporated. Water is used in the manufacturing process to ensure production of porous units to achieve rapid disintegration while various gums are used to prevent sedimentation of dispersed drug particles in the manufacturing process. Collapse protectants such as glycine prevent the shrinkage of Zydis units during freeze-drying process or long-term storage. Zydis products are packed in blister packs to protect the formulation from moisture in the environment.

2. Durasolv Technology :^[2]

Durasolv is the patented technology of CIMA labs. The tablets made by this technology consist of drug, filler and a lubricant. Tablets are prepared by using conventional tabletting equipment and have good rigidity. These can be packaged into conventional packaging system like blisters. Durasolv is an appropriate technology for product requiring low amounts of active ingredients.

3. Orasolv Technology:^{[2, 21]}

CIMA labs have developed 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. Conventional blenders and tablet machine is used to produce the tablets. The tablets produced are soft and friable.

4. Flash Dose Technology : ^{[1, 2]}

Flash dose technology has been patented by fuisz. Nurofen meltlet, a new form of ibuprofen as melt in mouth tablets prepared using flash dose technology is the first commercial product launched by biovail corporation. Flash dose tablets consist of self-binding shear form matrix termed as “floss”. Shear form matrices are prepared by flash heat processing.

5. Wowtab Technology:^{[1, 2, 21]}

Wowtab technology is patented by Yamanouchi Pharmaceutical Co. WOW means “Without Water”. In this process, combination of low mouldability saccharides and high mouldability saccharides is used to obtain a rapidly melting strong tablet. The active ingredient is mixed with a low mouldability saccharide (eg. lactose, glucose, mannitol) and granulated with a high mouldability saccharide (eg. Maltose, oligosaccharides ) and compressed into tablet.

6. Flashtab Technology:^{[1, 2]}

Prographarm laboratories have patented the Flashtab technology. Tablet prepared by this system consists of an active ingredient in the form of micro crystals. Drug micro granules may be prepared by using the conventional techniques like coacervation, micro encapsulation and extrusion spheronisation. All the processing, utilized conventional tabletting technology.

EVALUATION OF ODTS:

1. General Appearance:

The general appearance of a tablet, its visual identity and over all "elegance" is essential for consumer acceptance. Include in are tablet's size, shape, colour, presence or absence of an odour, taste, surface texture, physical flaws and consistency and legibility of any identifying marking.

2. Size and Shape:

The size and shape of the tablet can be dimensionally described, monitored and controlled.

3. Weight Variation :²⁴

With a tablet designed to contain a specific amount of drug in a specific amount of formula, the weight of a tablet being made is routinely measured to ensure that a tablet contains proper amount of drug.

Procedure:

First weight of 20 tablets was determined. From that average weight was calculated. Then individual tablets were weighed and the individual weight was compared with an average weight.

Table 1: Specification as per IP:

Average Weight of Tablet	% Deviation
80 mg or less	10
More than 80 mg but less than 250 mg	7.5
250 mg or more	5

4. Hardness and Friability :²⁵

Tablets require certain amount of strength, or hardness and resistance to friability. It is necessary or important to withstand mechanical shocks of handling in manufacture, packaging and shipping.

Adequate tablet hardness and resistance to powdering and friability are necessary requisites for consumer acceptance. More recently, relationship of hardness to tablet, disintegration and dissolution of drug had become apparent. Monitoring of tablet hardness is especially important for drug products that possess real bioavailability problems and/ or those, which are sensitive to altered dissolution profile as the function of compressive force employed.

Using tablet hardness tester, hardness of the tablet was checked. Using Roche Friabilator friability of the tablet was checked. This device subjects tablets to the combined effect of abrasions and shock by utilizing a plastic chamber that revolves at 25 rpm dropping the tablets at distance of 6 inches with each revolution. Preweighed sample of 10 tablets was placed in the Friabilator, which was then operated for 100 revolutions. Tablets were dusted and weighed. The friability was determined using following formula:

Friability = [(Initial weight – Final weight)/ (Initial weight)] x 100 %

5. Measurment of tablet tensile strength:

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. For measuring the hardness of the tablets, the plunger of the hardness tester is driven down at a speed of 20 mm/min. Tensile strength for crushing (T) is calculated using equation:

Eq. T= 2F / πdt

Where F is the crushing load, and d and t denote the diameter and thickness of the tablet, respectively^[^26]. Though, this is a widely used and accepted method for hardness testing, it is not applicable to very delicate tablets prepared by Lyophilization technique wherein the liquid suspension of drug and excipients is freeze dried in the blister pocket and the dried tablets are finally sealed in the blister. Special aluminum blisters with peel off blister covers are used as packaging material for these tablets. Flash dose tablets prepared by cotton candy process are also poor candidates for this test^[^27,
28]. This test is best suited for tablets prepared by direct compression and moulding methods. However, the tensile strength of these tablets is always kept low which needs to be compromised to keep the disintegration time as minimum as possible.

6. Moisture uptake study:

MDTs usually contain high concentration of hydrophilic excipients with the minimum possible hardness which together contributes to their increased susceptibility to moisture uptake. In order to maintain their physical integrity and surface texture, special attention is required during the storage and packaging of these dosage forms. Therefore, moisture Uptake studies are strongly recommended for MDTs. The test can be carried out by keeping ten tablets along with calcium chloride in a desiccators 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 desiccators 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. The materials with high moisture resistant properties should be used for packaging for e.g. alu strip pack, alu-alu blister or polyethylene sealing on blister. The use of appropriate quantity of desiccant in HDPE bottle packs with minimum head space is highly recommended to ensure stability of the product during its shelf life^[^29-32].

7. Disintegration time:

The methods for evaluation of in-vivo disintegration time had been explained in literature^[^33-35]. However, the results from this type of test typically reveal unsatisfactory reproducibility and are not reliable as the difference in disintegration time is few seconds in most cases. In addition, the in-vivo disintegration test has its own limitation of issues related to ethics and the safety of the volunteers. At present, the disintegration time of MDTs is measured using the disintegration test for conventional tablets that is described in the Pharmacopoeias. EP has set the limit of 3 mins for disintegration time of MDTs using conventional disintegration apparatus. However, no special apparatus is mentioned in the pharmacopoeias for disintegration test of MDTs and the conventional method available seems to be inappropriate for MDTs. This is because of the extreme operating conditions in the disintegration apparatus which fails to provide a significant discrimination among the rapidly disintegrating tablets. Furthermore, the conventional test employs a relatively huge volume of test solution (900 ml) compared to the volume of saliva in human buccal cavity, which is less than 6 ml.

8. Disintegration test with rotary shaft method:

In another study, proposed a better disintegration method for MDTs. In the experimental method, the MDT was placed on the wire gauze (D), slightly immersed in the medium, and then compressed by a rotary shaft (E) which was employed to provide mechanical stress on the tablet by means of its rotation and weight. Purified water at temperature 37 °C was used as the medium. The critical parameters of the proposed method were the rotation speed and the mechanical stress. Using this new method, it would be possible to predict a more realistic disintegration rate in human. The compression force can be easily adjusted using the weight (A). The rotary shaft crushes the MDT which disintegrates into the medium. The endpoint was measured visually using a stopwatch. The below mentioned apparatus was modified by Harada et^[^36] al by placing a sponge at the surface of shaft weight to increase friction with the MDT. Therefore, the weight transmits the torque of the rotating shaft to the ODT and grinds it on the stainless steel perforated plate which is used in place of wire gauge. The electrodes are attached on each side of the plate. The rotation speed and weight were optimized to set the mechanical pressure. When the weight makes contact with separated plates, the electric sensor conveys a signal that indicates the end point of the disintegration test of the ODT^[^37].

9. Disintegration test texture analyzer:

In another study, a texture analysis apparatus was used to measure the start and end time points of tablet disintegration. A constant penetration force was applied to tablets via a cylindrical flatended probe. The tablet, under constant force, is immersed in a defined volume of distilled water and the time is plotted against the distance, which the probe travelled into the tablet. Typical time–distance profiles, generated by the texture-analysis software, enabled the calculation of the starting and ending time of disintegration^[^38-39].

10. Disintegration test using electro force 3100:

An instrument “Electro Force® 3100” has recently been designed by the Bose Corporation with an objective to simulate the disintegration condition of the MDTs in mouth. It is based on application of low force to measure small displacements and disintegration rate as a function of manufacturing process of a variety of MDTs. The instrument typically consists of a lower plate to hold the tablet on which a force of about 10 mN is applied followed by addition of approximately 5 ml of water maintained at 37 °C. It has the advantage of providing better resolution than those available instruments with moderate to high force test[36]. This is the first equipment of its type which is available in the market for evaluation of ODT. This tabletop system can be used by the manufacturers and regulatory agencies to monitor and evaluate the different fabrication technologies of MDTs.

11. Water Absorption Ratio :⁴⁰

A piece of tissue paper folded twice was placed in a small petri dish containing 6 ml of water. A tablet was put on the tissue paper and allowed to completely wet. The wetted tablet was then weighed. Water absorption ratio, R, was determined using following equation:

R = 100 x W_a – W_b / W_b

Where

W_b= Weight of tablet before water absorption

W_a = Weight of tablet after water absorption.

12. Uniformity of Content:⁴¹

The test is applicable for tablets that contain less than 10 mg or less than 10% w/w of active ingredients. The test for uniformity of content should be carried out only after the content of active ingredient in a pooled sample and tablets has been shown to be within acceptable limits of the stated content. The test is carried out as follows:

Crush one tablet, add 1 ml of dilute Hydrochloric acid and 30 ml of water and shake for 15 minutes. Add sufficient water to produce 50 ml and centrifuge. To 5 ml of the clear supernatant liquid add 10 ml of 0.1 M hydrochloric acid and sufficient water to produced 100ml, measure the absorption of the resulting solution at the maximum of about 227.5 nm. Same procedure was followed for remaining 9 tablets.

13. Dissolution Study:⁴²

Dissolution rate was studied by using USP type II apparatus under following experimental condition:

· 100 rpm

· 900 ml of water as dissolution medium

· 37 ± 0.5 ⁰C as a temperature of dissolution medium.

Aliquot equal to 5 ml of dissolution medium was withdrawn at specific time interval and it was filtered. Absorption of filtered solution was checked by UV spectroscopy at 227.5 nm and drug content was determined from standard calibration curve. The dissolution testing was carried out in triplicate.

14. Evaluation of effectiveness of taste masking:

The formulation’s organoleptic properties like taste, mouth-feel and appearance are of considerable importance in differentiating products in the market and can ultimately determine the success of a product.

MARKETED PRERPERATION OF ODTs:

The current pharmaceutical market for mouth dissolving tablets is on increasing trend. Because of strong patient demand, several products have been commercialized.

Table 2: Examples of Marketed Preparation of Melt-in-Mouth Tablet

Name of the Product	Manufacturer and Country	Remark
Imodium Lingual	R. P. Scherer corp., USA	Fast Dissolving Formulation of Imodium
Pecidin Rapitab	Mktd. by Merck and co., USA	Quick Releasing Anti Ulcer Preparation of Pepcid
Mosid –MT	Torrent Pharmaceuticals, India	Mouth Melt Tablet of Mosapride Citrate
Claritin Reditabs	Mktd. By Schering plough Corp., USA	Immediate dissolving Formulation of Claritin
Nimulid –MD	Panacea Biotech, India	Mouth Dissolving Tablet of Nimesulide
Zyrof Meltab	Zydus Cadila, India	Melt In Mouth Tablet of Rofecoxib

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Received on 05.03.2013 Accepted on 07.06.2013

Asian J. Pharm. Tech. 2013; Vol. 3: Issue 3, Pg 125-131