Drug Delivery Systems (DDS) are a strategic tool for expanding markets/indications, extending product life cycles and generating opportunities. DDS make a significant contribution to global pharmaceutical sales through market segmentation, and are moving rapidly. Despite of tremendous advancements in drug delivery, the oral route remains [1,2] the perfect route for the administration of therapeutic agents because of low cost of therapy, ease of administration, accurate dosage, self?medication, pain avoidance, versatility, leading to high levels of patient compliance.Tablets and capsules are the most popular dosage forms which have wide acceptance up to 50-60% of total dosage forms. Among all conventional dosage forms tablet is the most popular one till today because of ease of administration [3], compact in nature, easy to manufacture and it can deliver accurate dose. But the main drawback of solid dosage forms is the difficulty in swallowing which is referred as dysphagia in some patients particularly pediatric and geriatric patients. The dysphagia occurs in geriatric patients due to fear of choking, hand tremors and in paediatric patients due to underdeveloped muscular and nervous systems and in schizophrenic patients which leads to poor patient compliance. The difficulty of swallowing also occurs when water is not available[4,5], in diarrhoea, coughing during common cold, allergic conditions and bronchial infection and many other medical conditions including stroke, parkinson?s disease, AIDS, thyroidectomy, head and neck radiation therapy and other neurological disorders including cerebral palsy and it is also applicable to people who are ill in bed and those active working patients who are busy or travellingespecially those who have no access to water. Improved patient compliance has achieved enormous demand. Consequently demand for their technologies is also increasing many folds. It is always the aim of a scientist or a dosage form designer to enhance the safety of a drug molecule while maintaining its therapeutic efficacy. Recent advances in Novel Drug Delivery Systems (NDDS) aim for the same by formulating a dosage form, convenient to be administered so as to achieve better patient compliance. Pharmaceutical technologists have put in their best efforts to develop a Fast Dissolving Drug Delivery System, i.e Mouth Dissolving Tablet

The US Food and Drug Administration Centre for Drug Evaluation and Research (CDER) defines, [6,7],  in the „Orange Book?, an ODT as “a solid dosage form containing medicinal substances, which disintegrates rapidly, usually within a matter of seconds, when placed up          the tongue”. The significance of these dosage forms is highlighted by the adoption of the term, “Orodispersible Tablet”, [8] by the European Pharmacopoeia which describes it as a tablet that can be placed in oral cavity where it disperses rapidly before swallowing.

ORODISPERSIBLE TABLETS

It is a tablet that disintegrates and dissolves rapidly in the saliva [9], within a few seconds without the need of drinking water or chewing. An orodispersible tablet usually dissolves in the oral cavity within 15 s to 3 min [10,11] .Orodispersible tablets are also known as mouth-dissolving tablets, melt-in mouth tablets, Fast dissolving tablets, rapimelts, porous tablets, quick dissolving tablet. They have unique property of rapidly disintegrating and/or dissolving and releasing the drug as soon as they come in contact with saliva, thus obviating the requirement of water during administration and they turn into a soft paste or liquid form for easy swallowing, and it is free of risk of choking. Mainly these tablets are prepared by the use of superdisintegrants such as crosspovidone, croscarmellosesodium, sodium starch glycolate etc. The super disintegrants are added to this formulation to enhance the disintegration of tablet into smaller particles which provides rapid onset of action. Most fast dissolving tablets must include substances to mask the bitter taste of the active ingredient. This masked active ingredient is then swallowed by the patient's saliva along with the soluble and insoluble excipients. It has been concluded that faster the dissolution, faster the absorption and onset of action.[12] Some drugs are absorbed from the oral cavity, pharynx and oesophagus as the saliva passes down into the stomach and avoids the first pass metabolism. Thus the bioavailability of drug is significantly more than those observed from conventional tablets dosage form. Super disintegrants play a major role in the disintegration and dissolution of MDT. Super disintegrants provide quick disintegration due to combined effect of swelling and water absorption by the formulation which forms a porous structure. The optimum concentration of the superdisintegrant can be selected according to critical concentration of disintegrant. Below this concentration, the tablet disintegration time is inversely proportional to the concentration of the superdisintegrant, whereas if concentration of superdisintegrant is above critical concentration, the disintegration time remains almost constant or even increases.

ADVANTAGES OF ODTS

1. Do not require water to swallow the tablet
2. It can easily administered to geriatric, paediatric and mentally disabled patients.
3. It provides accurate dosing compare to liquids.
4. Dissolution and absorption of drug is fast, thus providing rapid onset of action.
5. Advantageous over liquid medication in terms of administration as well as transportation.
6. Suitable for sustained/controlled release actives.[13]
7. It allows high drug loading.
8. Bioavailability of drugs is increased as some drugs are absorbed from mouth, pharynx and oesophagus through saliva passing down into the stomach and avoids first pass metabolism and thus reduced dose and side effects.

LIMITATIONS OF ODTs

1. The tablets generally have insufficient mechanical strength. Hence, careful handling is required during manufacturing process.
2. The tablets may leave unpleasant taste and/or grittiness in oral cavity if not formulated properly.
3. Drugs with larger doses are difficult to formulate into FDT e.g. rifampin (600 mg), ethambutol (1000 mg) etc.

Ideal properties of ODTs:

1. It requires no water for oral administration.
2. It should have adequate taste-masking properties.
3. It should have pleasant mouth-feel properties, adequate hardness.
4. It should leave little or no residue in mouth after oral administration.
5. It should be compatible with taste masking.
6. It allows high drug loading.
7. It should exhibit low sensitivity to environmental conditions such as temperature and humidity.[14]

TECHNOLOGIES USED FOR MANUFACTURING OF ODTS

1. Freeze drying or lyophilisation:

The drug is dissolved or dispersed in an aqueous solution of a carrier. The mixture is poured into the wells of the preformed blister packs. The trays holding the blister packs are passed through liquid nitrogen freezing tunnel to freeze the drug solution. Then the frozen blister packs are placed in refrigerated cabinets to continue the freeze drying. Finally the blisters are packaged and shipped. Highly porous, have high specific surface area,[15] dissolve rapidly and ultimately show improved absorption and bioavailability.

2. Tablet moulding:

Water-soluble ingredients with a hydro-alcoholic solvent is used and is moulded into tablets under pressure lower than that used in conventional tablet compression. Then the solvent is removed by air drying. Moulded tablets are very less compact than compressed tablet porous structure that enhances disintegration/dissolution and finally absorption increased.

3. Direct compression:

It is the easiest way to manufacture tablets.[16] Conventional equipment, commonly available excipients and a limited number of processing steps are involved in direct compression. Also high doses can be accommodated and final weight of tablet can easily exceed that of other production methods.

Characteristics:

It is most cost-effective tablet manufacturing technique.

4. Spray drying:

By hydrolyzed and non hydrolyzed gelatins as supporting agents, mannitol as bulking agent, sodium starch glycolate or crosscarmellose sodium as disintegrating agent and an acidic material (e.g. citric acid) and / or alkali material (e.g. Sodium bicarbonate) to enhance disintegration /dissolution.

Characteristics:

Prepared tablet disintegrates within 20 seconds when immersed in an aqueous medium.

5. Sublimation:

Inert solid ingredients that volatilize rapidly like urea, camphor ammonium carbonate, ammonium bicarbonate,[17] hexamethylene tetramine were added to the other tablet ingredients and the mixture is compressed into tablets. The volatile materials were then removed via sublimation, which generates porous structure.

Characteristics:

Porous structure that enhances dissolution by using volatile material or solvent e.g. cyclohexane, benzene etc.

       
           
       
    Figure No: 1 Sublimation process

6. Disintegrant addition method:

It involves the addition of superdisintegrants in optimum concentration to the formulation to achieve rapid disintegration/dissolution. For e.g.[18,19] Sodium starch glycolate, crystalline cellulose (AvicelPH-102) and low substituted HPEC, Crosspovidone and crosscarmellose Na.

Characteristics:

Similar to conventional tablets with higher % of disintegrants, lower hardness and higher % of friabilty.

7. Mass extrusion:

This method involves softening the active blend using the solvent mixture of water soluble polyethylene glycol,[20] 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.

8. Cotton candy process:

This process is so named as it utilizes a unique spinning mechanism to produce floss-like crystalline structure, which mimic cotton candy.[21] It 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.

9. Compaction:

a. Melt granulation:

Prepared by incorporating a hydrophilic waxy binder (super polystate) PEG-6-stearate. Super polystate not only acts as binder and increase physical resistance of tablet but also helps the disintegration of tablet. [22] The advantage of this technique compared to a conventional granulation is that no water or organic solvents is needed. Because there is no drying step, the process is less time consuming and uses less energy than wet granulation

Characteristics:

It melts in the mouth and solubilizes rapidly leaving no residue.

b. Phase transition process:

Prepared by compressing a powder containing two sugar alcohols with high and low melting points and subsequent heating at a temperature between their melting points. The tablet hardness was increased after heating process due to increase of inter particle bond induced by phase transition of lower melting point sugar alcohol.

Characteristics:

The compatibility increased and so sufficient hardness gained by the formulation.

10.Nanonization:

A recently developed nanomelt technology involves reduction in the particle size of drug to nanosize by milling the drug using a proprietary wet-milling technique. 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. [23] 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).

11. Fast dissolving films:

A non-aqueous solution is prepared containing water soluble film forming polymer (pullulan, cellulose derivatives, polyvinyl pyrrolidone, polyvinyl alcohol or sodium alginate, etc.),[24] drug and other taste masking ingredients are used to form a film after evaporation of solvent. In case of a bitter drug, resin adsorbate or coate micro particles of the drug can be incorporated into the film. This film, when placed in mouth, melts or dissolves rapidly,[24] releasing the drug in solution or suspension form.

Characteristics:

The thin films size less than 2X2 inches, dissolution in 5 sec, instant drug delivery and flavoured after taste.

Patented techniques

1. Zydis technology:

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,[25] which imparts strength. Zydis products are packed in blister packs to protect the formulation from moisture in the environment.

2. Orosolv 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.

3. Durasolv technology:

The tablets made by this technology consist of drug, filler and a lubricant. Tablets are prepared by using conventional punching 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.

4. 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,[26] micro encapsulation and extrusion spheronisation. All the processing utilized conventional tableting technology.

5. Wowtab technology:

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, and mannitol)[27] and granulated with a high mouldability saccharide (eg. Maltose, oligosaccharides) and compressed into tablet.

6. Oroquick technology:

The OraQuick fast-dissolving/disintegrating tablet formulation utilizes a patented taste masking technology. It is microsphere technology, known as MicroMask, has superior mouthfeel over taste-masking alternatives. The taste masking process does not utilize solvents of any kind, and therefore leads to faster and more efficient production. Also, lower heat of production than alternative fast- dissolving/disinte-grating technologies makes OraQuick appropriate for heat-sensitive drugs. The matrix surrounds and protects the drug powder in microencapsulated particles is more pliable,[28] meaning tablets can be compressed to achieve significant mechanical strength without disrupting taste masking. OraQuick claims quick dissolution in a matter of seconds, with good taste-masking. There are no products using the OraQuick technology currently on the market, but KV Pharmaceutical has products in development such as analgesics, scheduled drugs, cough and cold, psychotropics, and anti-infectives

7. Flash dose technology:

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.

8. Ziplet technology:

AdvaTab is distinct from other ODT technologies as it can be combined with Eurand?s complimentary particle technologies like its world leading Microcaps® taste-masking technology and its Diffucaps® ,[29] controlled release technology. The pairing of AdvaTab with Microcaps creates products that offer the dual advantage of a patient preferred dosage form, together with a superior taste and smooth mouth feel.

Disintegrants are substance or mixture of substances added to the drug formulations, which facilitate dispersion or breakup of tablet content of capsule in to smaller particles for quick dissolution [30]. The major function of disintegrants is to oppose the efficiency of the tablet binder and physical forces that act under compression to structure the tablet. Superdisintegrants [31] are those substances which facilitate the faster disintegration with smaller quantity in contrast to disintegration. Superdisintegrants are another version of super-absorbing materials with tailor-made swelling properties. These materials are not planned to absorb significant amounts of water or aqueous fluids, but planned to swell very fast. Superdisintegrants are used as a structural weakener for the disintegrable solid dosage forms. They are physically dispersed within the matrix of the dosage form and will expand when the dosage form is exposed to the wet environment [32]. These newer substances are more effective at lower concentrations with greater disintegrating efficiency and mechanical strength. Superdisintegrants are generally used at a low level in the solid dosage form, typically 1 - 10 % by weight relative to the total weight of the dosage unit. Their particles are generally small and porous, which allow for rapid tablet disintegration in the mouth without an objectionable mouth-feel from either large particles or gelling. Mainly two types of superdisintegrant are available such as  synthetic superdisintegrant  and natural superdisintegrant. Synthetic superdisintegrants are frequently used in tablet formulations to improve the rate and extent of tablet disintegration thereby increasing the rate of drug dissolution. Superdiintigrants mechanism of action and properties are reported in Table 3 and Table 4 respectively.The most widely used synthetic superdisintegrants are illustrated below