INTRODUCTION:

For the past one decade, there has been an enhanced demand for more patient-friendly and compliant dosage forms. As a result, the demand for developing new technologies has been increasing annually.¹ Since the development cost of a new drug molecule is very high, efforts are now being made by pharmaceutical companies to focus on the development of new drug dosage forms for existing drugs with improved safety and efficacy together with reduced dosing frequency, and the production of more cost effective dosage forms. For most therapeutic agents used to produce systemic effects, the oral route still represents the preferred way of administration, owing to its several advantages and high patient compliance compared to many other routes². Tablets and hard gelatin capsules constitute a major portion of drug delivery systems that are currently available. However, many patient groups such as the elderly, children, and patients who are mentally retarded, uncooperative, nauseated, or on reduced liquid-intake/diets have difficulties swallowing these dosage forms. Those who are traveling or have little access to water are similarly affected.^3-5 To fulfill these medical needs, pharmaceutical technologists have developed a novel oral dosage form known as Orally Disintegrating Tablets (ODTs) which disintegrate rapidly in saliva, usually in a matter of seconds, without the need to take it water.

Drug dissolution and absorption as well as onset of clinical effect and drug bioavailability may be significantly greater than those observed from conventional dosage forms^6-8. Although chewable tablets have been on the market for some time, they are not the same as the new ODTs. Patients for whom chewing is difficult or painful can use these new tablets easily. ODTs can be used easily in children who have lost their primary teeth but do not have full use of their permanent teeth.⁹ Recent market studies indicate that more than half of the patient population prefers ODTs to other dosage forms¹⁰ and most consumers would ask their doctors for ODTs (70%), purchase ODTs (70%), or prefer ODTs to regular tablets or liquids (>80%)¹¹. The US Food and Drug Administration Center for Drug Evaluation and Research (CDER) defines, 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 upon the tongue”¹². The significance of these dosage forms is highlighted by the adoption of the term, “Orodispersible Tablet”, by the European Pharmacopoeia which describes it as a tablet that can be placed in oral cavity where it disperses rapidly before swallowing¹³. ODT products have been developed for numerous indications ranging from migraines (for which rapid onset of action is important) to mental illness (for which patient compliance is important for treating chronic indications such as depression and schizophrenia).¹⁴

Criteria for Fast dissolving Drug Delivery System:

The tablets should

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

· Be compatible with taste masking.

· Be portable without fragility concern.

· Have a pleasant mouth feel.

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

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

· Allow the manufacture of the tablet using conventional processing and packaging

· Equipments at low cost.

Silent features of Fast Dissolving Drug Delivery System:

· Ease of Administration to the patient who cannot swallow, such as the elderly, stroke victims, bedridden patients, patient affected by renal failure and patient who refuse to swallow such as pediatric, geriatric and psychiatric patients.

· No need of water to swallow the dosage form, which is highly convenient feature for

· Patients who are traveling and do not have immediate access to water.

· Rapid dissolution and absorption of the drug, which will produce quick onset of action.

· Some drugs are absorbed from the mouth, pharynx and esophagus as the saliva passes down into the stomach. In such cases bioavailability of drug is increased.

· Pregastric absorption can result in improved bioavailability and as a result of reduced dosage; improve clinical performance through a reduction of unwanted effects.

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

· The risk of chocking or suffocation during oral administration of conventional formulation due to physical obstruction is avoided, thus providing improved safety.

· New business opportunity like product differentiation, product promotion, patent extensions and life cycle management.

· Beneficial in cases such as motion sickness, sudden episodes of allergic attack or coughing, where an ultra rapid onset of action required.

· An increased bioavailability, particularly in cases of insoluble and hydrophobic drugs, due to rapid disintegration and dissolution of these tablets.

· Stability for longer duration of time, since the drug remains in solid dosage form till it is consumed. So, it combines advantage of solid dosage form in terms of stability and liquid

· dosage form in terms of bioavailability.

Benefits of fast dissolving tablets:

· Administered without water, anywhere, any time.

· Suitability for geriatric and pediatric patients, who experience difficulties in swallowing and for the other groups that may experience problems using conventional oral dosage form, due to being mentally ill, the developmentally disable and the patients who are un-cooperative, or are on reduced liquid intake plans or are nauseated.

· Beneficial in cases such as motion sickness, suede episodes of allergic attack or coughing, where an ultra rapid onset of action required.

· An increased bioavailability, particularly in cases of insoluble and hydrophobic drugs, due to rapid disintegration and dissolution of these tablets.

· Stability for longer duration of time, since the drug remains in solid dosage form till it is consumed. So, it combines advantage of solid dosage form in terms of stability and liquid dosage form in terms of bioavailability.

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.

Main ingredients used in preparation of MDT:

Important ingredients that are used in the formulation of MDTs should allow quick release of the drug, resulting in faster dissolution. This includes both the actives and the excipients. Disintegration and solubilzation of a directly compressed tablet depend on single or combined effects of disintegrants, water‐soluble excipients and effervescent agents. Excipient balances the properties of the actives in FDDTs. This demands a thorough understanding of the chemistry of these excipients to prevent interaction with the actives. Determining the cost of these ingredients is another issue that needs to be addressed by formulators. The role of excipients is important in the formulation of fast‐melting tablets. These inactive food‐grade ingredients, when incorporated in the formulation, impart the desired organoleptic properties and product efficacy. Excipients are general and can be used for a broad range of actives, except some actives that require masking agents. Binders keep the composition of these fast‐melting tablets together during the compression stage. The right selection of a binder or combination of binders is essential to maintain the integrity and stability of the tablet. The temperature of the excipient should be preferably around 30–35C for faster melting properties. Further, its incorporation imparts smooth texture and disintegration characteristics to the system. Binders can either be liquid, semi solid, solid or mixtures of varying molecular weights such as polyethylene glycol. The choice of a binder is critical in a fast‐ dissolving formulation for achieving the desired sensory and melting characteristics, and for the faster release of active ingredients. Commonly available fats such as cocoa butter and hydrogenated vegetable oils can also be used. The most important ingredients of a mouth dissolving tablets are:

Super disintegrants: Use of disintegrants is the basic approach in development of MDTs. Disintegrants play a major role in the disintegration and dissolution of MDT. It is essential to choose a suitable disintegrant, in an optimum concentration so as to ensure quick disintegration and high dissolution rates¹⁵. Super disintegrants provide quick disintegration due to combined effect of swelling and water absorption by the formulation. Due to swelling of superdisintegrants, the wetted surface of the carrier increases, which promotes the wettability and dispersibility of the system, thus enhancing the disintegration and dissolution.^16-18 The optimum concentration of the superdisintegrants can be selected according to critical concentration of disintegrants.

Fig. 1: Mechanism of Action of Superdisintegrants

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 increases¹⁹. Sodium starch glycolate, Ac‐di‐sol(crosscarmellose sodium), Crosspovidone, Microcrystalline cellulose, Pregelatinised starch are some of examples of disintegrants.

Mechanism of action of disintegrants:

The tablet breaks to primary particles by one or more of the mechanisms listed below:‐

a. By capillary action

b. By swelling

c. Because of heat of wetting

d. Due to release of gases

e. By enzymatic action

f. Due to disintegrating particle/particle repulsive forces

g. Due to deformation

a. By capillary action:

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 /excipient 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.

b. By 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.

Fig. 2: Disintegration of Tablet by Wicking and Swelling

c. Because of heat of wetting (air expansion):

When disintegrants with exothermic properties gets wetted, localized stress is generated due to capillary air expansion, which helps in disintegration of tablet. This explanation, however, is limited to only a few types of disintegrants and cannot describe the action of most modern disintegrating agents.

d. Due to release of gases:

Carbon dioxide released within tablets on wetting due to interaction between bicarbonate and carbonate with citric acid or tartaric acid. The tablet disintegrates due to generation of pressure within the tablet. This effervescent mixture is used when pharmacist needs to formulate very rapidly dissolving tablets or fast disintegrating tablet. As these disintegrants are highly sensitive to small changes in humidity level and temperature, strict control of environment is required during manufacturing of the tablets. The effervescent blend is either added immediately prior to compression or can be added in to two separate fraction of formulation.

e. By enzymatic reaction:

Here, enzymes present in the body act as disintegrants. These enzymes destroy the binding action of binder and helps in disintegration. Actually due to swelling, pressure exerted in the outer direction or radial direction, it causes tablet to burst or the accelerated absorption of water leading to an enormous increase in the volume of granules to promote disintegration.

f. Due to disintegrating particle/particle repulsive forces:

Another mechanism of disintegration attempts to explain the swelling of tablet made with ‘non‐swellable’ disintegrants. Guyot‐ Hermann has proposed a particle repulsion theory based on the observation that non swelling 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.

g. Due to deformation:

Hess had proved that 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.

Fig.3: Disintegration by Deformation and Repulsion

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.

Sugar based excipients: Sugar based excipients are used for taste masking and as bulking agents. Most of the drugs are having unpleasant or bitter taste. And the basic requirement for designing MDTs is that the drug should not have disagreeable taste. So taste masking is necessary in most of the cases. Sorbitol, mannitol, xylitol, dextrose, fructose, etc. are mainly used. Aqueous solubility and sweetness impart a pleasing mouth feel and good taste masking²⁰. But not all sugar‐based materials have fast dissolution rate and good developed to make use of the sugar based excipients in the design of fast dissolving tablets. Other ingredients commonly used are water soluble diluents, lubricants, antistatic agents, plasticizers, binders, colors, flavors.

Conventional Techniques used for preparation of FDDDS:^21-23

Disintegrant Addition:

Disintegrant addition technique is one popular technique for formulating Fast-dissolving tablets because of its easy implementation and cost-effectiveness. The basic principle involved in formulating Fast-dissolving tablets by disintegrant addition technique is addition of superdisintegrants in optimum concentration so as to achieve rapid disintegration along with the good mouth feel. Microcrystalline cellulose and low substituted hydroxypropylcellulose were used as disintegrating agents in the range of 8:2 – 9.1 to prepare fast dissolving tablet. Agar powder is used as disintegrant for the development of rapidly disintegration tablets by enhancing the porosity of agar by water treatment. Rapidly disintegrating tablets of bitter drugs oxybutynin and pirenzepine were prepared by using the taste masked granules and h mixture of excipients consisting of crystalline cellulose (Avicel PH 02) and low-substituted hydroxypropy cellulose HPC, LH-11), Ishikawa et al. prepared rapidly disintegrating tablets using microcrystalline cellulose (Avicel PH-M series) that was spherical and had a very small particle size 7-32 ìm). Instead of conventional microcrystalline cellulose (PH 102). Tablets prepared using microcrystalline cellulose; PH-M06 and L-HPC in the ratio of 9:1 were very rapidly disintegrating) in saliva. They concluded that Avicel PH-M06 was superior to Avicel PH 102 in terms of the feeling of roughness in the mouth. Fast dissolving tablet of efavirenz (anti HIV agent) were formulated by using combination of microcrystalline cellulose and sodium starch glycolate as super disintegrants. Gillis et al, prepared a fast-dissolving tablet of galanthamine hydrobromide which comprises of spray dried mixture of lactose monohydrate and microcrystalline cellulose (75:25) as a diluents, a cross linked polymeric disintegrants such as crosspovidone and with a direct compression process of preparing such fast-dissolving tablets. Fast-dissolving tablets having analgesic activity was formulated using a combination of superdisintegrants. Rapid oral disintegration tablets were developed by direct compression using co-ground mixture of D-mannitol and Crosspovidone. CIMA labs patented Orasolv technology by employing the evolution of carbon dioxide or the effervescence as disintegration mechanism in the formulation of fast-dissolving tablets. The OraSolv technology is an oral dosage form, which combines taste-masked drug ingredients with a quick dissolving effervescent excipient system. Taste masking is achieved through a process of microencapsulation, which coats or entraps the active compound in an immediate release matrix. The effervescent excipient system aids in rapid disintegration of the tablet, permitting swallowing of pharmaceutical ingredients before they come in contact with the taste bud. The OraSolv tablet dissolves quickly without chewing or without water and allows for effective taste masking of a wide variety of active drug ingredients, both prescription and nonprescription. Flashtab technology™ is a patented technology of Prographarm, which employ combination of taste-masked multiparticulate active drug substances, a disintegrating agent, a swelling agent and other excipients to form a multiparticulate tablet that disintegrates rapidly. Rapidly disintegrating multiparticulate tablet was prepared by using taste-masked microcrystals of drugs, crosslinked disintegrating agent and soluble diluents with binding properties.

Freeze Drying:

A process in which water is sublimated from the product after freezing. Lyophilization is a pharmaceutical technology which allows drying of heat sensitive drugs 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 dissolve rapidly and show improved absorption and bioavailability.

Moulding:

In this method, 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 molded into tablets under pressure lower than that used in conventional tablet compression. The solvent is then removed by air-drying. Molded tablets are very less compact than compressed tablets. These possess porous structure that enhances dissolution. Sublimation The slow dissolution of the compressed tablet containing even highly water-soluble ingredients is due to the low porosity of the tablets. Inert solid ingredients that volatilize readily (e.g. urea, ammonium carbonate, ammonium bicarbonate, hexamethylenetetramine, camphor etc.) 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 structures. Additionally, several solvents (e.g. cyclohexane, benzene) can be also used as pore forming agents,

Figure 4 : Steps Involved in sublimation

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.

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.

Direct Compression:

It is the easiest way to manufacture tablets. 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. Directly compressed tablet’s disintegration and solubilization depends on single or combined action of disintegrants, water soluble excipients and effervescent agent.

Phase transition process:

It is concluded that a combination of low and high melting point sugar alcohols, as well as a phase transition in the manufacturing process, are important for making FDTs without any special apparatus. FDT were produced by compressing powder containing erythritol (melting point: 122 °C) and xylitol (melting point: 93 95 °C), and then heating at about 93 °C for 15 min. After heating, the median pore size of the tablets was increased and tablet hardness was also increased. The increase of tablet hardness with heating and storage did not depend on the crystal state of the lower melting point sugar alcohol

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. Cotton candy process involves formation of matrix of polysaccharides or saccharides by simultaneous action of flash melting and spinning. The matrix formed is partially recrystallized to have improved flow properties and compressibility. This candy floss matrix is then milled and blended with active ingredients and excipients and subsequently compressed to ODT. This process can accommodate larger drug doses and offers improved mechanical strength. However, high-process temperature limits the use of this process.

Sublimation:

In this method a subliming material like camphor, is removed by sublimation from compressed tablets and high porosity is achieved due to the formation of many pores where camphor particles previously existed in the compressed tablets prior to sublimation of the camphor. A high porosity was achieved due to the formation of many pores where camphor particles previously existed in the compressed mannitol tablets prior to sublimation of the camphor. These compressed tablets which have high porosity (approximately 30%) rapidly dissolved within 15 seconds in saliva.8 Granules containing nimusulide, camphor, crospovidone, and lactose were prepared by wet granulation technique. Camphor was sublimed from the dried granules by vacuum exposure.9 Conventional methods like dry granulation, wet granulation and direct compression with highly soluble excipients, super disintegrants and/or effervescent systems can also be used.

Desired characteristics and development challenges of FDTs:

Because administration of FDTs is different from administration of conventional tablets, the FDTs should maintain several unique properties, as listed below^29,30,31

A. Fast Disintegration

FDTs should disintegrate in the mouth without additional water or with a very small amount (e.g., 1–2 mL) of water. The disintegration fluid is provided by the saliva of the patient. The disintegrated tablet should become a soft paste or liquid suspension, which can provide good mouth feel and smooth swallowing. The “fast disintegration” usually means disintegration of tablets in less than 1 minute, but it is preferred to have disintegration as soon as possible.

B. Taste of Active Ingredients

Because FDTs dissolve or disintegrate in the patient’s mouth, the drug will be partially dissolved in close proximity to the taste buds. After swallowing, there should be minimal or no residue in the mouth. A pleasant taste inside the mouth becomes critical for patient acceptance. Unless the drug is tasteless or does not have an undesirable taste, taste-masking techniques should be used. An ideal taste-masking technology should provide drugs without grittiness and with good mouth feel. The amount of taste-masking materials used in the dosage forms should be kept low “as low as possible” to avoid excessive increase in tablet size. The taste-masking technology should also be compatible with FDT formulations. For example, if drug particles are coated to minimize unpleasant taste, the coating should not be broken during compression or dissolved during wet granulation. Taste masking of bitter tasting drugs is critical to the success of the FDT formulations.

C. Drug Properties

For the ideal FDT technology, the drug properties should not significantly affect the tablet property. Many drug properties could potentially affect the performance of FDTs. For example, the solubility, crystal morphology, particle size, hygroscopicity, compressibility, and bulk density of a drug can significantly affect the final tablet’s characteristics, such as tablet strength and disintegration. Th e FDT technology should be versatile enough to accommodate unique properties of each drug.

D. Tablet Strength and Porosity

Because FDTs are designed to have a quick dissolution/disintegration time, the tablet porosity is usually maximized to ensure fast water absorption into the tablets. The key properties of the tablets are fast absorption or wetting of water into the tablets and disintegration of associated particles into individual components for fast dissolution. This requires that excipients should have high wettability, and the tablet structure should also have a highly porous network. Because the strength of a tablet is related to compression pressure, and porosity is inversely related to compression pressure, it is important to find the porosity that allows fast water absorption while maintaining high mechanical strength. In addition, low compression pressure causes fast dissolving dosage forms to be soft, friable, and unsuitable for packaging in conventional blisters or bottles. A strategy to increase tablet mechanical strength without sacrificing tablet porosity or requiring a special packaging to handle fragile tablets should be provided.

E. Moisture Sensitivity

FDTs should have low sensitivity to humidity. This problem can be especially challenging because many highly water-soluble excipients are used in formulation to enhance fast dissolving properties as well as to create good mouth feel. Those highly water-soluble excipients are susceptible to moisture; some will even deliquesce at high humidity. A good package design or other strategy should be created to protect FDTs from various environmental conditions.

Advantages: ^32-34

· FDT can be administer to the patients who cannot swallow tablets/cap., such as the elderly, stroke victims, bedridden patients, and patients who refuse to swallow Such as pediatric, geriatric and psychiatric patients.

· Rapid drug therapy is possible certain studies concluded increased bioavailability/proved.

· rapid absorption of drugs through pregastric absorption of drugs from mouth, pharynx and esophagus as saliva passes down.

Disadvantages of fast dissolving tablets ³⁵

· Fast dissolving tablet is hygroscopic in nature so must be keep in dry place.

· Some time it possesses mouth feeling.

· It is also show the fragile, effervesces granules property.

· FDT requires special packaging for properly stabilization and safety of stable product.

Evaluation of fast dissolving tablets: ^38-40

Weight variation:

20 tablets were selected randomly from the lot and weighted individually to check for weight variation. Weight variation specification as per I.P. is shown in Table

Table no.03 Weight variation specification as per I.P.

Average weight of tablet	% deviation
80mg or less	± 10
more than 80mg but less than 250mg	± 7.5
250mg ormore	± 5

Assay:

Twenty tablets from each batch were weighed accurately and powdered powder equivalent to 100mg drug was shaken with 100 ml of 0.1N Hydrochloric acid in 100 ml amber coloured volumetric flask and from this 10 ml was pipette out and then dilute up to 100 ml. From standard solution again 10 ml pipette out and diluted up to 100 ml .

Hardness/crushing/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, respectively23. Though, this is a widely used and accepted method for hardness testing, it is not applicable to very delicate tablets prepared by Lyophilisation 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 aluminium 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 test19-20. 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.

Friability:

To achieve % friability within limits for an FDT is a challenge to the formulator since all methods of manufacturing of FDT are responsible for increasing the % friability values. Thus, it is necessary that this parameter should be evaluated and the results are within bound limits (0.1-0.9%).

Friability of tablets:

Fribrater consist of a plastic-chamber that revolves at 25 rpm, dropping those tablets at a distance of 6 inches with each revolution. The tablets were rotated in the fribrater for at least 4 minutes. At the end of test tablets were dusted and reweighed, 106 the loss in the weight of tablet is the measure of friability and is expressed in percentage as,

%Friability = initial weight –final Weight/initial weight x 100

Wetting time:

In this method measure tablet wetting time. Simple tissue paper (12 cm X 10.75cm) folded twice was placed in a small petri dish (ID = 6.5 cm) containing 6 ml of Sorenson’s buffer pH 6.8. A tablet was put on the paper, and the time for complete wetting was measured. Three trials for each batch and the standard deviation were also determined.

Solution volume:

In this test take one tablet in a Petri –dish with suitable solvent. One or two drop of solvent used until the tablet shows soluble property that is called soluble or solution volume. V = Final volume of blend in cm 3

In Vitro Disintegration test: ^41-43

In Vitro disintegration time was measured by dropping a tablet in a beaker containing 50 ml of Sorenson’s buffer Ph 6.8. Three tablets from each formulation were randomly selected and In Vitro dispersion time was performed.

In Vivo Disintegration test: ⁴³

The test was carried out on 2 or 3 tablets using in the mouth and the time in second taken for complete disintegration of the tablet was measured in few seconds.

In Vitro Dissolution Test:^41-44

In-vitro dissolution study was performed by using USP Type II Apparatus (Paddle type) [Electro lab (ETC-11L) Tablet Dissolution Tester] at 50 rpm. Phosphate buffer pH 6.8, 900 ml was used as dissolution medium which maintained at 37±0.5°C. Aliquot of dissolution medium (10 ml) was withdrawn at specific time intervals (2 min) and was filtered. The amount of drug dissolved was determined by UV spectrophotometer (Shimadzu, Japan) by measuring the absorbance of the sample at 248.0 nm. Three trials for each batch were performed and average percentage drug release with standard deviation was calculated and recorded. 107

Stability Study (Temperature Dependent): ^41-45

The fast dissolving tablets are packed in suitable packaging and stored under the following conditions for a period as prescribed by ICH guidelines for accelerated studies. (i) 40 ± 1 °C (ii) 50 ± 1°c (iii)37 ±1 ° C and RH 75% ± 5% The tablets were withdrawn after a period of 15 days and analyzed for physical characterization (Visual defects, Hardness, Friability, Disintegrations, and Dissolution etc.) and drug content. The data obtained is fitted into first order equations to determine the kinetics of degradation. Accelerated stability data are plotting according Arrhenius equation to determine the shelf life at 25 ° C.

Packaging of FDT:

Packing is one of the important aspects in manufacturing FDT. The products obtained by various technologies vary in some of the parameters especially in mechanical strength to a good extent.The products obtained by lyophilization process including various technologies such as Zydis, Lyoc, Quicksolv, and Nanocrystal are porous in nature, have less physical resistance, sensitive to moisture, and may degrade at higher humidity conditions. For the above reasons products obtained require special packing. Zydis units are generally packed with peelable backing foil. Paksolv is a special packaging unit, which has a dome-shaped blister, which prevents vertical movement of tablet within the depression and protect tablets from breaking during storage and transport, which is used for Orasolv tablet. Some of the products obtained from Durasolv. WOW Tab, Pharmaburst oraquick, Ziplets, etc. technologies have sufficient mechanical strength to withstand transport and handling shock so they are generally packed in push through blisters or in bottles.

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

Future Prospects:

These dosage forms may be suitable for the oral delivery of drugs such as protein and peptide-based therapeutics that have limited bioavailability when administered by conventional tablets. These products usually degrade rapidly in the stomach. Should next generation drugs be predominantly protein or peptide based, tablets may no longer be the dominant format for dosing such moieties. Injections generally are not favored for use by patients unless facilitated by sophisticated auto-injectors. Inhalation is one good alternative system to deliver these drugs, but the increased research into biopharmaceuticals so far has generated predominantly chemical entities with low molecular weights. The developments of enhanced oral protein delivery technology by ODTs which may release these drugs in the oral cavity are very promising for the delivery of high molecular weight protein and peptide.

CONCLUSION:

Orally disintegrating tablets have better patient acceptance and compliance and may offer improved biopharmaceutical properties, improved efficacy, and better safety compared with conventional oral dosage forms. Prescription ODT products initially were developed to overcome the difficulty in swallowing conventional tablets among pediatric, geriatric, and psychiatric patients with dysphasia. Today, ODTs are more widely available as OTC products for the treatment of allergies, cold, and flu symptoms. The target population has expanded to those who want convenient dosing anywhere, anytime, without water. The potential for such dosage forms is promising because of the availability of new technologies combined with strong market acceptance and patient demand. By paying close attention to advances in technologies, pharmaceutical companies can take advantage of ODTs for product line extensions or for first-to-market products. With continued development of new pharmaceutical excipients, one can expect the emergence of more novel technologies for ODTs in the days to come.

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Received on 12.09.2011 Modified on 05.10.2011

Research J. Pharm. and Tech. 5(2): Feb. 2012; Page 143-151

Technique	Basis	Drug release	Patent owner
Zydis	Lyophilisation	dissolve in 2-10 sec enhanced bioavaibility	R.P.Scherer Inc.
OraSolv	Compressed Tablets	5-45 sec .depending upon size of the tablet significant change in bioavailability	Cima Labs Inc.
Durasolv	Compressed Tablets	5-45 sec. significant change in bioavailability	Cima Labs Inc
Wowtab	Compressed Moulded Tablet	15 sec. no significant change in bioavailability	Yamanouchi Pharma technology ltd.
Flashdose	Cotton-candy process	within 1 min. enhanced bioavailability	Fuisz Technology ltd.
Flashtab	Multiparticulate Compressed Tablets	within 1 min.	Prographarm group

S. No	Category	example
1	Antibacterial agents	Ciprofloxacin, tetracycline, erythromycin, rifampicin, penicillin, doxycyclin, nalidixic acid, trimethoprim, sulphacetamide, sulphadiazine etc.
2	Anthelmentics	Albendazole, mebendazole, thiabendazole, livermectin, praziquantel, pyrantel embonate dichlorophen etc
3	Antidepressants	Trimipramine maleate, nortriptyline HCl, trazodone HCl, amoxapine, mianserin HCl, etc.
4	Antidiabetics	Glibenclamide, glipizide, tolbutamide, tolazamide, gliclazide, chlorpropamide
5	Analgesics	Diclofenac sodium, ibuprofen, ketoprofen, mefenamic acid, oxyphenbutazone, indomethacin, piroxicam, phenylbutazone, etc
6	Antihypertensive	Amlodipine, carvedilol, diltiazem, felodipine, minoxidil, nifedipine, prazosin HCl, nimodipine, terazosin HCl etc.
7	Antiarrhythmics	Disopyramide, quinidine sulphate, amiodarone HCl, etc.
8	Antihistamines	Acrivastine, cetrizine, cinnarizine, loratadine, fexofenadine, triprolidine
9	Anxiolytics,sedative hypnotics and neuroleptics	Alprazolam, diazepam, clozapine, mylobarbitone, lorazepam, haloperidol, nitrazepam , midazolam phenobarbitone,thioridazine, oxazepam, etc.
10	Diuretics	Acetazolamide, clorthiazide, amiloride, furosemide, spironolactone, bumetanide, ethacrynic acid, etc.
11	Gastro-intestinal agents	Cimetidine, ranitidine HCl, famotidine, domperidone, omeprazole, ondansetron HCl, granisetron HCl, etc
12	Corticosteroids	Betamethasone, beclomethasone, hydrocortisone, prednisone, prednisolone, methyl, prednisolone, etc.
13	Antiprotozoal agent	metronidazole, tinidazole, omidazole, benznidazole, clioquinol, decoquinate etc