INTRODUCTION:

The Oral route of administration is even till today continues to be the most preferred and common route of drug administration due to its advantages like ease of ingestion, pain avoidance, versatility and importantly patient compliance is more. Therefore, oral solid dosage forms are very popular dosage form. Among all the pharmaceutical dosage forms, the conventional tablets seem to be most popular, because of its ease of transport and comparatively lower manufacturing cost.

The oral solid dosage forms like tablets and capsules are more commonly employed. The tablets have advantages than capsules in that they are tamper resistant and any adulterant of the tablet after its manufacture is almost certain to be observed.

The adulteration can be easily found if it is done in either liquid form or solid form since deformation takes place if it is done in liquid form and powders cannot be added to the tablet if once they are formed. The major disadvantage of capsules when compare to tablets is their higher cost. The capsules either hard or soft capsule are susceptible to breakage if they are not stored properly.

Tablets are popular for several reasons:¹

· The oral route represents a convenient and safe route of drug administration.

· The preparation procedure enables accurate dosing of the drug.

· Tablets are convenient to handle and can be prepared in a versatile way with respect to their use and to the delivery of the drug.

· Tablets can be mass produced with robust and quality controlled production, procedures giving an elegant appearance to the preparation of consistent quality and, in relative terms, low price.

Tablets are the manufacturer’s dosage form of choice because of their relatively low cost of manufacture, package and shipment, increased stability and virtual tamper resistance.²

Oral administration is the most common route due to relief of ingestion, flexibility, pain elimination and most importantly. Solid oral delivery systems are doing not required sterile conditions and are, therefore, less expensive to manufacture ^{1, 2}. Orally disintegrating tablet (ODT) is moderately novel solid dosage form that includes rapid dissolution and disintegration in the mouth without require of drinking water. They are well-known as fast disintegrating, fast melt or fast dissolving tablet³. Recently, European Pharmacopoeia has used in the term orodispersible tablets. ODTs differ from traditional tablets in that they are designed to be dissolved on the tongue slightly than swallowed complete. the oral route fragments the perfect route for administration of therapeutic agents because of little rate of remedy, ease of administration, perfect dosage form, self-medication, pain prevention, flexibility, high levels of patient compliance. All mouth dissolving tablet approved by the Food and drug administration are classified as orally disintegrating tablets. Mouth dissolving tablet results in quick dissolution and rapid absorption which provide rapid onset of action .it provides good stability, accurate dosing and easy manufacturing. These are useful for paediatric, geriatric patients, prominent to improved patient compliance. Tablets and capsules are the most standard dosage forms. But one important problem of such dosage forms are difficulty in absorbing^4,5.

Advantages of Fast dissolving tablets^{5, 6}:

· Ease of administration to patients who refuses to swallow a tablet such as paediatrics, geriatric patients and psychiatric patients.

· No need or little water is required to swallow the dosage form which is highly convenient feature for patients who are travelling and do not have access to water.

· Free of risk of suffocation due to physical obstruction when swallowed, thus offering improved safety.

· Rapid disintegration and absorption of drug very fast, which will produce quick onset of action.

· Quick absorption from the gastro intestinal tract improves bioavailability and reduces unwanted effects caused by the drugs and also improves patient compliance.

· Drug and dosage form stability.

· The chewable tablets have available in the market for some time, but they are not consider as the novel fast dissolving tablets. Patients for whom difficult to chew or painful can use these novel tablets easily. Fast dissolving tablets can be used easily in children who have lost their primary teeth.

Disadvantages of FDT:⁷

· Fast dissolving tablets common problem is mechanical strength when compare to conventional or traditional tablets. Many FDT products are very lightweight and fragile requiring them to be packed individually. Patients should be advised not to push these tablets through the film, but instead of pushing the film, peel the film back to release the tablet.

· The fast dissolving tablets are more susceptible to degradation due to temperature and humidity, some of the novel fast dissolving tablet formulations is dispensed and packed in conventional stock bottle. The Pharmacists are advised to take care when dispensing of such formulations to ensure that they should not exposed to high levels of moisture or humidity.

· It freely water absorbs vapour from the atmosphere so must be save in dry place.

· Some time it retains the mouth feeling.

· ODT requires special packaging for safety product.

· Usually have inadequate mechanical strength. Hence, wisely handling is required.

Limitations of OTS⁸:

· Insufficient mechanical strength. Hence, it needs careful packaging and handling.

· If formulated tablets are not prepared perfectly, it may appear disagreeable taste and grittiness in mouth.⁹

· Specific packing is required for moisture sensitive and light sensitive drugs.

· Precautions to be taken while administering proximately after eliminate from pack.

· Light sensitive drug, ODTs may not be appropriate as no selection for film coating^{10, 11}.

Significance¹²:

· Fast disintegration of tablet effects in quick dissipation and quick immersion which deliver rapid onset of action. FDT must produce property like excellent mouth feel by the use of flavours and sweeteners in Orodispersible tablets.

· Suitable for delivering moderately low molecular weight and greatly permeable drugs.

· Fast disintegration of tablets requires minimum number of ingredients and so it is cost effective dosage form.

· Novel drug delivery systems do not require sterilisation procedures, so less expensive to manufacture FDTs.

· Rapid dissolution and absorption of the drug, which produce quick onset of action^.[13]

· Bioavailability of drug is increased certain medicines are immersed since mouth, pharynx and oesophagus as the saliva permits depressed into the stomach. ^{[14, 15]}

Ideal properties of ODT^{16, 17}:

· Orodispersible tablet should be disperse or break down in the saliva contained by a seconds.

· It should not need any liquid to show its action^{18, 19}.

· Well-suited with taste masking and Have need of an attractive mouth feel.

· The excipients must have high wet ability, and the tablet structure should have a highly porous network.

· Be flexible and affable to existing treating and wrapping equipment.

· They should not require water or other liquid at the time of administration.

· Mask or overcome unacceptable taste of drug.

· They should produce pleasant feel in the mouth.

· They should have negligible or no residue in oral cavity after administration.

· FDTs should have less sensitivity against environmental conditions like Moisture, temperature etc.

· Mentally ill, disabled and uncooperative patients FDT are ease of administration.

· Should be portable without fragility concern.

· FDTs should be manufactured by using conventional tablet processing and Packing equipments are at low cost.

Developmental challenges in fast dissolving drug delivery.

1. Taste of the active ingredient²⁰:

Some drugs posses relatively no taste, and simply by adding a suitable flavour can hide any unpleasant taste or sensation. However, the most of the drugs require taste masking agents if they are to be incorporated into fast dissolving formulations. Different methods are existing to achieve this, including simple wet granulation or roller compression with other excipients to minimize the surface area of the drug. Spray drying can also be employed to shroud the drug.

If further taste masking is required, the resultant particle can be sealed or coated with a suitable coating material (like HPMC, MC, EC, methacrylate and PVP). The choice of coating material will be selected properly to determine the mechanism of taste masking. In addition, the quantity of coating applied, what method used to apply, and other excipients are used in the coating will affect the quality of taste masking.

Cyclodextrins (cyclic linked oligosaccharides) are widely employed for taste masking. Cyclodextrins have been shown to prove to measure of taste masking by entrapping the drug molecules within the cyclic structure long enough to render initial dissolution. Other taste masking methods are also used namely coating methods including electrochemical, hot melt and super critical fluids. Encapsulation by using coacervation method has also been employed to encapsulate certain drugs.

2. Dose:

Presently three challenges to development of fast dissolving dosage forms: 1) Taste masking of active substance, 2) mouth feel or grittiness and 3) tablet size. These challenges are not unrelated because most drugs will require taste masking depending on the degree of bitterness relative to the dose of the drug, which will in turn affect the final tablet size. As mentioned previously, drug may require coating, which will result in an increase in the particle size and thereby increase the weight of the tablet. The extent to which this increase will affect the mouth feel and tablet size will depend on the dose of the drug and the amount of coating material required masking its taste.

3. Hygroscopy²¹:

Several fast dissolving dosage forms are hygroscopic in their nature and cannot maintain physical integrity of tablets under normal conditions of temperature and humidity. Hence they need protection from temperature and humidity that calls for specialized product package.

4. Friability⁵:

In order to prepare the fast dissolving tablets to disintegrating rapidly in the mouth, they are FDTs are prepared by porous or soft moulded matrices are used and then compressed into tablets by using low compressional force, then compressed tablets become friable and brittle which are difficult to handle, often require specialized peel-off blister packing.

Techniques used in the method of preparation of fast dissolving Tablets:

There are different techniques used in the preparation of fast dissolving tablet include;

1. Freeze drying or lyophilisation

2. Sublimation

3. Direct compression

4. Tablet moulding

5. Spray drying

6. Mass extrusion

1. Freeze drying or lyophilisation:

Freeze drying is the process in which the water is sublimed from the fast dissolving tablets after it is frozen. Freeze drying technique employed to create an amorphous porous structure to tablet and there by dissolve rapidly. Commonly used excipients employed in manufacturing of fast dissolving tablets by using Freeze-drying materials. The list of materials used in Freeze drying technique is mentioned below.

The manufacturing of fast dissolving tablets using this technique follows a typical procedure is mentioned here. The active medicament is dissolved or dispersed in an aqueous medium of a carrier/polymer.

The active medicament along with excipients blend fixes the dose by weight and poured in the wells of the preformed blister packs. The trays containing the blister packs are passed through freezing tunnel containing liquid nitrogen to freeze the drug solution present in blister packs. Then the frozen blister packs are collected and placed in refrigerated cabinets to continue the freeze drying process. After freeze drying process the aluminium foil backing is applied on a blister packs using sealing machine. Finally the blisters are suitably packed and shipped.

This technique creates an amorphous porous structure to drug sample that can dissolve rapidly. Lyophilisation is a part of pharmaceutical technology which allows for drying of heat penetrating drugs and biologically at low temperature under the situations that allow the removal of water by means of sublimation.^{[22, 23]}

The major disadvantages of lyophilization technique are it is more expensive and time consuming process and fragility makes conventional packaging unsuitable for these products and poor stability under stressed conditions.

Table 1: List of polymers and their applications with examples.

Name of Excipients	Uses	Examples
Polymer	Strength and rigidity	Gelatin, alginate and dextrin
Polysaccharides	Crystallinity, hardness and palatability	Mannitol and sorbitol
Collapse protectants	Prevents shrinking	Glycerin
Flocculating agents	Uniform dispersion	Xanthan gum and acacia
Preservatives	Prevent microbial and fungal growth	Parabens
Permeation enhancer	Transmucosal permeability Enhancer	Sodium lauryl sulphate
pH adjusters	Chemical stability	Citric acid and sodium hydroxide
Flavors and sweeteners	Patient compliance	------
Water	Porous unit formation	-------

Fig 1: Lyophilization Technology. Patented Technology Based on This Process is Zydis Technology.

2. Sublimation^{24, 25}:

Sublimation has been used to produce mouth dissolving tablet with high porosity.

Fig 2: illustration of sublimation system for the preparation of MDTs

3. Direct compression²⁶:

In preparation of oral disintegrating tablet it is most preferential technique due to its advantages.

· Easiest method to manufacture the tablets.

· Predictable equipment and commonly obtainable excipients are usage.

· A limited no. of treating steps is involved.

· Cost effective.

Direct compression represents the simplest and most common method and cost effective tablet manufactured by using this technique. This technique applied to preparation of fast dissolving tablets because of the availability of different excipients especially superdisintegrants and sugar based excipients. Direct compression method is used for preparation of FDT by using directly compressible vehicles or excipients. So this method is the most commonly used for preparing fast dissolving tablets. Directly compressible excipients are very coarse and granular in nature, free flowing in nature and give a coarse dispersion in the mouth with decreased mouth feel and compliance. It is very difficult to prepare fast dissolving tablets with drugs having very low bulk density, higher dose and poor flow property using this technique.

(a) Superdisintegrants^27-31:

In many orally disintegrating tablet technologies based on direct compression, the addition of different superdisintegrants. This technique contains coated crystals and micro granules along with the disintegrants. In this technology, two types of granules are used; a disintegrating agent (e.g. Modified cellulose, CCS), which has a high swelling force, and a swelling agent (e.g. starch), which has a low swelling force.

Other techniques like effervescent tablets in which disintegration is aided by evolution or release of carbon dioxide. Saliva activates the effervescent agent, causing the tablet to disintegrate. Care should be observed because effervescent excipients and final product require higher protection against humidity conditions.

(b) Sugar Based Excipients³²:

This is another approach used to manufacturing the fast dissolving tablets by direct compression method. In this method use of sugar based excipients especially as bulking agents. The sugar based substances are like dextrose, fructose, lactilol, lactose, maltilol, maltose, mannitol, sorbitol, starch hydrolysate, polydextrose and xylitol, which produce high aqueous solubility and also imparts sweetness, and hence improve taste of tablets and produce a pleasing mouth feel.

These excipients under defined manufacturing conditions gives a highly porous structure and friable exterior structure which helps in faster disintegration of fast dissolving tablets, they also provide a satisfactory mouth feel and so suitable for use in preparation of harder fast dissolving tablets by direct compression at low pressure.

The direct compression method was used to identify the compression of a single crystalline compound (i.e. sodium chloride, potassium chloride, potassium bromide, etc.) into a compact form without the addition of other substances. Current use of the direct compression is to define the process by which tablets are compressed directly from the powder blends of active ingredients with suitable excipients³³.

In the flow chart the benefits or advantage of the direct compression over other methods is described in the form of steps involved.

4. Tablet moulding^{34, 35}:

Tablets are prepared by solid dispersions method. The process of moulding in tablet manufacturing involves generally two types:

a) Solvent method:

In Solvent moulding powder blend is moistening with hydro alcoholic solvent which compressed at a least pressure via moulding plates. Removal of moisture through air drying.

b) Heat method:

the heat method involves preparation of a drug suspension. That is prepared by using drug, sugars and agar solution and packed into blister packaging.

5. Spray drying:

The spray drying techniques is used to achieve highly porous along with fine granules that help in preparation of tablets by direct compression. By these techniques achieved oral dissolving tablets have a lower disintegration time as 20 seconds. It is different with active component and compacted into tablet. Freeze dryer and drum dryer are a type of spray drying^{36, 37}.

6. Mass extrusion:

In this technology both drug and excipients are liquefy and prepared a soft blend by using suitable solvents i.e. methanol, water soluble polyethylene glycol etc. in this technique the liquefied drug and excipients are outcome with the help of a syringe or a extruder which extrude the drug product in a cylindrical form^{38, 39}.

Super Disintegrates Used in ODTs⁴⁰:

Now a day’s, demand for more rapidly disintegrating formulation is improved. So, pharmacist needs to formulate disintegrate i.e. mouth dissolving tablet are more efficient at little awareness and have a greater disintegrating effectiveness and the majority in efficient intragranularly .

Types of Super Disintegrates Used:

· Cross povidone

· Microcrystalline cellulose

· Sodium starch glycolate

· Sodium carboxy methyl cellulose

· Pregelatinzed starch

· Calcium carboxy methyl cellulose

Factors considered for selection of super disintegrates:

There are several for the selection of super disintegrating tablet;

· Compatibility

· Mouth sense

· Disintegration

Selection of super-disintegrates^{41, 42}:

The ideal Super-disintegrants should have:

· Poor solubility.

· Lowly gel formation.

· Good hydration ability.

· Good moulding and good flow properties

· No propensity to form complexes with the drugs.

· Good mouth sensation.

New Orally Disintegrating Dosage Forms:

Oral films and wafers:

Oral films and wafers are the novel technologies used in the manufacturing of orally disintegrating dosage forms. They are thin elegant films or strips of edible water-soluble polymers of various sizes and shapes like square, rectangle or disc. The strips may be flexible or brittle in their nature, opaque or transparent in physical appearance. They are designed to provide rapid disintegration on the tongue without need of water. The fast dissolving films having the advantage of a large specific surface area required for disintegration. One or combination of the following processes like hot-melt extrusion method, solid dispersion extrusion method and rolling and solvent casting method are used to manufacture these films. A major limitation of these dosage forms is low drug loading capacity and limited taste masking option.

Table 3: A list of Patented Technologies using manufacturing techniques and description^{4, 5, 7}:

Technology	Basis for technology	Company
Zydis	Lyophilization	R. P. Scherer Inc.
Quicksolv	Lyophilization	Janseen Pharmaceutical
Lyoc	Lyophilization	Farmlyoc
Flashtab	Multiparticulate Compressed Tablets	Ethypharm
Orasolv, Durasolv	Compressed Tablets	Cima Labs Inc.
Rapitab	Compressed Tablets	Schwarz Pharma
Wowtab	Compressed Molded Tablets	Yamanouchi PharmaTechnologies, Inc.
Fastmelt	Molding	Élan Corp.
Ziplets	Molding	Eurand
Flashdose	Cotton-candy process	Fuisz Technology Ltd.

ZYDIS (R.P. Scherer, Inc.)^43-45:

Zydis, the best fast dissolving tablet preparations, and which was the first marketed new technology fast dissolving tablet. The tablet after placing on the tongue in mouth tablet dissolves within few seconds. A Zydis tablet is prepared by lyophilizing or freeze drying technique the drug and gelatine is used as matrix systems. The Zydis product is very lightweight and fragile, and this product must be dispensed in a special type of blister pack. Patients should be given direction for such products not to push the tablets through the foil film, instead of pushing just peel the film back to release the tablet from blister pack. The Zydis fast dissolving tablet formulation is made to dissolve on the tongue in within 2 to 3 sec. The Zydis fast dissolving formulation is also self preserving because the final water concentration in the freeze dried product is very low content to developing for microbial growth. The Zydis formulation contains flavours and sweeteners are used to optimize the taste of the dosage form.

In addition, it utilizes microencapsulation with specialized polymers or complexation with ion exchange resins to mask the bitter tasting drug. The combination of lyophilization and taste masking creates a product that is both pleasing to the eye and also to the senses of taste and touch. A major advantage of the Zydis fast dissolving tablet formulation is bioavailability is increased and onset of action is also increased when compared to traditional or conventional tablets. Because of its rapid dispersion and dissolution in saliva in the oral cavity from this formulation. Any pregastric absorption avoids first pass metabolism and can be an advantage in drugs that undergo a great deal of hepatic metabolism. However, if the amount of drug swallowed varies, there is the potential for decrease in the bioavailability (due to incomplete absorption and first-pass metabolism). Suppose the claiming increased in bioavailability is debatable, it is clear that the major advantage of the Zydis fast dissolving tablet formulation is convenience.

There are few disadvantages to the Zydis technology. The process of freeze drying is a relatively expensive for manufacturing process of Zydis fast dissolving tablet formulation. The Zydis formulation has stability problem at higher temperatures and humidities. Zydis fast dissolving tablet formulation readily absorbs the water and is very sensitive to degradation at humidities more than 65%. If there is any pinhole or minor damage to the package, the patient may find the lyophilized product has collapsed due to absorption of moisture. As with most other drugs, patients should be advised to avoid storing the Zydis technology in the medicine cabinet in the bathroom. Patients should use their Zydis formulation within six months of opening the laminated foil pouch and immediately after opening its individual blister packaging.

ORASOLV (Cima Labs, Inc.) ^{4, 5, 7}:

Orasolv was Cima's first fast-dissolving dosage form. The Orasolv technology tablets when compare to Zydis formulation, disperses in the saliva with the aid of almost imperceptible effervescence. The Orasolv technology is best described as a fast dissolving tablet. In which the Orasolv tablet matrix is dissolves in less than 1 min, leaving coated drug particles. The taste masking is also associated with the Orasolv formulation is twofold. The unpleasant flavour of a drug is not only controlled by sweeteners or flavours. By using both substances sweeteners and flavours the drug particles are coated. This technology is frequently used to develop over the counter formulations. The major disadvantage of the Orasolv fast dissolving formulations is mechanical strength of the tablet formulation. The Orasolv tablet has the appearance of a traditional or conventional compressed tablet. However, the Orasolv tablets are prepared by lightly compressed, and there by produce a weaker and more brittle tablets when compared with conventional tablets. So for the above reason, Cima fast-dissolving dosage forms are developed and designed a special handling and packaging system for Orasolv. An advantage that goes along with the low degree of compression pressure is used for Orasolv fast dissolving dosage form. Lyophilization and high degrees of compression, as used in Orasolv primary competitors, may disrupt such a taste masking approach.

DURASOLV (Cima Labs, Inc.)^{5, 7}:

Durasolv is Cima's second generation of fast dissolving tablet formulation. Durasolv are formulated similar to Orasolv, Durasolv has much higher mechanical strength than its (came before the current version or method) predecessor due use of high compression pressure during tablet compression. The Durasolv product is thus produced in a faster and more cost effective manner. Durasolv is so durable that it can be packaged in either traditional blister packaging or vials. The novel Durasolv formulation, NuLev, is actually dispensed in a conventional stock bottle. Pharmacists are advised to take care when dispensing such Durasolv fast dissolving tablet formulations from stock bottles to ensure that they are not exposed to high levels of moisture or humidity. Excess handling of tablets can introduce enough moisture to initiate dissolution of the tablet matrix. The disadvantage of Durasolv fast dissolving tablet is that the technology is not compatible or suitable with higher doses of active ingredients, because during high pressure applied during compression. Orasolv fast dissolving tablet maintain the structural integrity of any taste masking tablets may be compromised with high drug doses. Therefore, the Durasolv technology is best suited for formulations including relatively small doses of active compound.

WOWTAB (Yamanouchi Pharma Technologies, Inc.)⁴⁴:

The WOWTAB fast dissolving tablet formulation has been on the Japanese market for a number of years. It has recently been introduced into the U.S market. The WOWTAB technology utilizes sugar and sugar based excipients like Mannitol. When combined the two different types of saccharides are to obtain a tablet formulation with adequate hardness and fast dissolution rate. Due to its significant hardness, the WOWTAB formulation is a little bit more stable to the environmental condition when compare to Zydis or Orasolv. WOWTAB fast dissolving tablet formulations are suitable for conventional bottle and blister packaging. The taste masking technology is also used in the WOWTAB is proprietary, but claims to offer superior mouth feel due to the patented SMOOTHMELT action. The WOWTAB product dissolves quickly within 15 sec or less. The WOW in WOWTAB signifies the tablet is to be given without water. Two WOWTAB formulations currently available in the U.S. markets are Benadryl Allergy and Sinus FASTMELT and Children's Benadryl Allergy and Cold FASTMELT.

Other Technologies:

Flash Dose, Flashtab, and OraQuick are three formulations on the worldwide market. Biovail Corporation recently announced the filing of an NDA for a Flash Dose version of zolpidem tartrate. These technologies are similar to Zydis, WOWTAB, Orasolv and Durasolv in that they dissolve or disperse on the tongue within a minute. However, each also has unique characteristics to differentiate itself from the competition.

FLASHDOSE (Fuisz Technologies, Ltd.)⁴⁴:

Fuisz Technologies has three oral fast dissolving drug delivery systems that are related to fast and rapid dissolution. The first two generations are quick dissolving tablets, Soft Chew and EZ Chew, they require some chewing. However, these paved the way for Fuisz's most recent development of FlashDose. The FlashDose technology employed as a unique spinning mechanism to produce floss like crystalline structure and FlashDose formulation looks like cotton candy. This crystalline sugar can then incorporate into active drug and be compressed into a tablet. This formulation procedure has been patented by Fuisz and is known as Shear form. The final product has a more surface area for dissolution process. It disperses and dissolves quickly once placed onto the surface of tongue. During formulation just changing the temperature and other conditions, the characteristics of the product can be changed or altered. Instead of getting floss like material, small spheres of saccharides can be produced to carry the drug molecules. The process of making microspheres has been patented by Fuisz, and patented product is known as CEFORM1 and serves as an alternative method of taste masking.

FLASHTAB (Prographarm Group)⁴⁴:

The Flashtab technology is another fast dissolving oral tablet formulation. It uses most of the same excipients or additives are used in conventional compressed tablets. The disintegrating agent and swelling agent are used in combination for coating the drug particles in this formulation to produced tablet that disintegrates in the mouth in less than one minute.

ORAQUICK (KV Pharmaceutical Co., Inc.)⁴⁶:

The OraQuick fast dissolving tablet formulation utilizes a patented taste masking technology. KV Pharmaceutical claims its microsphere technology known as Micro Mask, has superior mouth feel when compare to taste masking alternatives. The taste masking process does not used any kind solvents and therefore leads to rapid and more efficient production. Also, lower heat of production than alternative fast dissolving technologies makes OraQuick appropriate used for heat sensitive drugs. OraQuick claims quick dissolution in a matter of seconds, with good taste masking.

SOLID DISPERSION:

Definition⁴⁷: Solid dispersion in the pharmaceutical field are dispersion of one or more active ingredients, generally poorly water soluble drugs, in an inert carrier or matrix at solid state which are prepared by either melting the two (fusion) or dissolving them in a solvent or a combination of approaches followed by removal of the solvent.

Methods for preparing solid dispersion:

(A) Hot melt method:

Sekiguchi and Obi⁴⁸ used a hot melt method to prepare simple eutectic mixtures. In this method the drug and carrier were melted together at a temperature above the eutectic point (melting point). The molten mixture is then cooled rapidly. The resultant solid eutectic was then milled to reduce the particle size. Cooling leads to supersaturation, but due to solidification the dispersed drug becomes trapped within the carrier matrix. Whether or not a molecular dispersion can be achieved depends on the degree of supersaturation and rate of cooling attained in the process. In other words, the process has an effect on the resultant dispersion and can be varied to optimize the product.

(B) Solvent Method:

Tachibani and Nakumara⁴⁹ were the first to use the solvent method. This process uses organic solvents to dissolve and intimately disperse the drug and carrier molecule. An important prerequisite for the manufacture of a solid dispersion using the solvent method is that both the drug and the carrier are sufficiently soluble in the solvent. The solvent can be removed by any one of a number of methods. Temperatures used for solvent evaporation usually lie in the range of 23-65 ºC. The solvent can also be removed by freeze-drying or by spray-drying.

(C) Melting solvent method^{47, 50}:

In the case where there is difficulty with thermal instability and immiscibility between the drug and the carrier, the hybrid melting solvent method can be employed. The drug is first dissolved in a small quantity of organic solvent and added to the molten carrier. The solvent is then evaporated to generate a product that is subsequently milled to produce a powder.

Dosage form development:

Solid dispersion must be developed into convenient dosage forms, such as tablets or capsules, for their clinical use and successful commercialization. Solid dispersions produced my melt method are usually hardened at very low temperatures and then pulverized with mortar and pestles. Similarly, solid dispersions produced by the solvent method are also pulverized after solvent removal and hardening. Some of the challenges in the dosage form development of such materials are difficulty of pulverization and sifting of the dispersions, which are usually soft and tacky, poor flow and mixing properties of powders thus prepared, poor compressibility, drug-carrier incompatibility, and poor stability of dosage forms.^[1]

Table 4: Drugs to be promising incorporate in FDTS^51-54:

S No	Category	Examples
1	Analgesics and Anti-inflammatory Agents.	Aloxiprin, Auranofin, Azapropazone, Benorylate, Diflunisal, Etodolac, Fenbufen, Fenoprofen Calcim, Flurbiprofen, Ibuprofen, Sulindac, Indomethacin, Ketoprofen, Meclofenamic Acid, Mefenamic Acid, Nabumetone, Naproxen, Oxaprozin, Piroxicam, Phenylbutazone.
2	Anthelmintics	Albendazole, Bephenium, Hydroxynaphthoate, Cambendazole, Dichlorophen, Iverrnectin, Oxarnniquine, Oxfendazole, Praziquantel, Embonate, Thiabendazole.
3	Anti-Arrhythmic Agents	Amiodarone, Disopyramide, Flecainide Acetate, Quinidine Sulphate.
4	Anti-Epileptics	Beclamide, Carbamazepine, Clonazepam, Ethotoin, Methoin, Phenytoin, Methsuximide, Methyl phenobarbitone, Primidone, Valproic acid.
5	Anti-bacterial Agents	Benethamine, Penicillin, Cinoxacin, Clarithromycin, Clofazimine, Cloxacillin.
6	Anti-coagulants	Dicoumarol, Dipyridamole, Nicoumalone, Phenindione.
7	Anti-Depressants	Amoxapine, Ciclazindol, Maprotiline, Mianserin, Nortriptyline, Trazodone, Trimipramine Maleate.
8	Anti-Epileptics	Beclamide, Carbamazepine, Clonazepam, Ethotoin, Methoin, Phenytoin, Paramethadione, Phensuximide, Phenobarbiton Phenacemide, Methylphenobarbitone, Oxcarbazepine.
9	Anti-Fungal Agents	Amphotericin, Butoconazole Nitrate, Clotrimazole, Econazole, Nitrate, Fluconazole, Flucytosine, Griseofulvin, Itraconazole, Ketoconazole, Miconazole, Natamycin, Nystatin, Sulconazole, Nitrate, Terbinafine, Terconazole, Tioconazole, Undecenoic acid.
10	Anti-Gout Agents	Allopurinol, Probenecid, Sulphinpyrazone.
11	Anti-Hypertensive Agents:	Amlodipine, Carvedilol, Benidipine, Darodipine, Dilitazem, Diazoxide, Felodipine, Guanabenz Acetate, Indoramin, Isradipine, Minoxidil, Nicardipine, Nifedipine, Nimodipine.
12	Anti-Malarial	Amodiaquine, Chloroquine, Chlorproguanil Halofantrine, Mefloquine, Proguanil, Pyrimethamine, Quinine Sulphate.
13	Anti-Migraine Agents	Dihydroergotamine, Mesyiate, Ergotamine Tartrate, Methysergide Maleate, Pizotifen Maleate, Sumatriptan Succinate.
14	Muscarinic Agents	Atropine, Benzhexol, Biperiden, Ethopropazine, Hyoscine, Butyl Bromide, Hyoscyarnine, Mepenzolate Bromide, Orphenadrine, Oxyphencylcimine, Tropicamide.
15	Immuno suppressants	Aminoglutethimide, Aminoglutethimide, Amsacrine, Azathiopine, Busulphan, Chlorambucil, Cyclosporine, Dacarbazine, Estramustine, Etoposide, Lomustine, Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitotane, Mitozantrone, Procarbazine, Tamoxifen Citrate, Testolactone.
16	Anti Protozoal Agents	Benznidazole, Clioquinol, Decoquinate, Di iodo hydroxyl quinoline, Diloxanide Furoate, Dinitolmide, Furzolidone, Metronidazole, Nimorazole, Nitrofurazone, Alprazolam, Barbitone, Bentazeparn, Bromazepam, Bromperidol, Brotizoiam, Butobarbitone, Carbromal, Chlordiazepoxide, Chlormethiazole, Chlorpromazine, Clobazam, Clozapine, Diazepam, Droperidol, Flunanisone, Flunitrazepam, Fluopromazine, Fluphenazine, Decanoate, Flurazepam, Haloperidol,Lorazepam, Zopiclone, Lormetazepam, Medazepam, Meprobamate, Methaqualone, Midazolam, Nitrazepam, Oxazepam, Pentobarbitone, Perphenazine, Pimozide, Prochlorperazine, Temazepam, Triazolam.
17	Cardiac Inotropic Agents.	Amrinone, Digitoxin, Digoxin, Enoximone, Lanatoside C, Medigoxin.
18	Corticosteroids	Beclomethasone, Betamethasone, Cortisone, Acetate, Desoxymethasone, Dexamethasone, Fludrocortisone, Flunisolide, Flucortolone, Hydrocortisone, Methyl prednisolone, Prednisolone, Prednisone, Triamcinolone.
19	Diuretics	Acetazolarnide, Amiloride, Bendrofluazide, Bumetanide, Chlorothiazide, Chlorthalidone, Ethacrynic Acid, Frusemide, Metolazone, Spironolactone.
20	Anti-Parkinsonism Agents	Bromocriptine Mesylate, Lysuride Maleate.
21	Gastro-Intestinal Agents	Bisacodyi, Cimetidine, Cisapride, Diphenoxylate, Domperidone, Famotidine, Loperamide, Nizatidine, Omeprazole, Ondansetron, Ranitidine, Sulphasalazine.
22	Histamine H,- Receptor Antagonists:	Acrivastine, Astemizole, Cinnarizine, Cyclizine, Cyclizine Cyproheptadine, Dimenhydrinate, Flunarizine, Loratadine, Meclozine, Oxatomide, Terfenadine, Triprolidine.
23	Lipid Regulating Agents	Bezafibrate, Clofibrate, Fenofibrate, Gemfibrozil, Probucol.
24	Local Anaesthetics	Lidocaine. Omidazole, Tinidazole.
25	Anti-Thyroid Agents.	Carbimazole, Propylthiouracil.
26	Nitrates and Other Anti-Anginal Agents:	Amyl Nitrate, Glyceryl Trinitrate, Isosorbide Dinitrate, Isosorbide Mononitrate, Pentaerythritol Tetranitrate.
27	Nutritional Agents	Beta-carotene, Vitamin A, Vitamin B 2, Vitamin D, E and K.
28	Opoid Analgesics	Codeine, Dextropropyoxyphene, Diamorphine, Dihydrocodeine, Meptazinol, Methadone, Morphine, Nalbuphine, Pentazocine.
29	Oral Vaccines: Vaccines designed to prevent or reduce the symptoms of diseases.	Influenza, Tuberculosis, Meningitis, Hepatitis, Whooping Cough, Polio, Tetanus, Diphtheria, Malaria, Cholera, Herpes, Typhoid, HIV, Aids, Measles, Lyme Disease, Travellers Diarrhoea, Hepatitis A, B And C, Otitis Media, Dengue Fever, Rabies, Para influenza, Rubella, Yellow Fever, Dysentery, Legionnaires Disease, Toxoplasmosis, Q-Fever, Haemorrhagic Fever, Argentina Haemorrhagic Fever, Caries, Chagas Disease, Urinary Tract Infection Caused By E.Coli, Pneumococcal Disease, Mumps.
30	Proteins, Peptides and Recombinant Drugs	Insulin (Hexameric/Dimeric/Monomeric Forms), Glucagon, Growth Hormone (Somatotropin), Polypeptides or Their Derivatives, (Preferably with molecular weight from 1000 To300,000), Calcitonins and Synthetic Modifications, Enkephalins, Interferons (Especially Alpha-2 Interferons for treatment of common colds).
31	Sex Hormones	Clomiphene Citrate, Danazol, Ethinyl oestradiol, Medroxy progesterone Acetate, Mestranol, Methyl testosterone, Norethisterone, Norgestrel, Oestradiol, Conjugated Oestrogens, Progesterone, Stanozolol, Stiboestrol, Testosterone, Tibolone.
32	Stimulants	Amphetamine, dexamphetamine, dexfenfluramine, fenfluramine, pemoline.
33	Neuro -Muscular Agents	Pyridostigmine.

EVALUATION OF TABLETS:

I) Post-compression parameters^55-60:

1. Hardness.

2. Friability.

3. Weight variation.

4. Uniformity of thickness.

5. Drug content uniformity.

6. Wetting time.

7. Water absorption ratio.

8. In vitro disintegration time.

9. In vitro dissolution studies.

10. Taste or mouth feel

11. Stability Studies.

12. Clinical Studies.

Post-Compression parameters:

1. Hardness test:

Tablets require a certain amount of strength, or hardness and resistance to friability, to withstand mechanical shocks of handling in manufacture, packaging and shipping. The hardness of the tablets was determined using Monsanto Hardness tester. It is expressed in Kg/cm². Three tablets were randomly picked from each formulation and the mean and standard deviation values were calculated.

2. Friability test:

It is the phenomenon whereby tablet surfaces are damaged and/or show evidence of lamination or breakage when subjected to mechanical shock or attrition. The friability of tablets was determined by using Veego Friabilator. It is expressed in percentage (%). Twenty tablets were initially weighed (W_initial) and transferred into friabilator. The friabilator was operated at 25 rpm for 4 minutes or run up to 100 revolutions. The tablets were weighed again (W_final). The percentage friability was then calculated by,

F =

% Friability of tablets less than 1% is considered acceptable.

3. Weight variation test:

The tablets were selected randomly from each formulation and weighed individually to check for weight variation. The U.S Pharmacopoeia allows a little variation in the weight of a tablet. The following percentage deviation in weight variation is allowed.

Table 5: Percentage deviation in weight variation

Average weight of a tablet

Percentage deviation

130 mg or less

More than 130 mg and less than 324 mg

324 mg or more

±10

±7.5

±5

In all the formulations the tablet weight was more than130mg and less than 324 mg, hence 7.5% maximum difference allowed.

4. Uniformity of thickness:

The crown thickness of individual tablet may be measured with a micrometer, which permits accurate measurements and provides information on the variation between tablets. Other technique employed in production control involves placing 5 or 10 tablets in a holding tray, where their total crown thickness may be measured with a sliding caliper scale. The tablet thickness was measured using screw gauge.

5. Drug content uniformity:

Four tablets weighted and crushed in a mortar then weighed powder contain equivalent to 100mg of drug transferred in 100ml distilled water. Its concentration 1000 mcg/ml. 10ml from this stock solution taken and diluted to 100ml 0.1 N HCl or any buffer solution, it makes 100mg/ml. Then 20mg/ml solution prepared by taking 2ml from stock solution and diluted to 10ml. Absorbance measure at particular wavelength.

6. Wetting time:

The method was applied to measure tablet wetting time. A piece of tissue paper folded twice was placed in a small petri dish (i.d. = 6.5 cm) containing 10 ml of water, a tablet was placed on the paper, and the time for complete wetting was measured. Three trials for each batch were performed and standard deviation was also determined. The method was reported by Yunxia Bi et al.

Fig 3: Simple method for the measurement of wetting time of a tablet.

7. Water absorption ratio:

A piece of tissue paper folded twice was placed in a small petri dish containing 6ml of water. A tablet was put on the paper and time required for complete wetting was measured. The wetted tablet was then weighed. Water absorption ratio, R was determined using following equation.

R = 100 (W_a – W_b)/ W_b

Where,

W_b – weight of tablet before absorption

W_a – weight of tablet after absorption

Three tablets from each formulation were performed and standard deviation was also determined.

8 In vitro disintegration time:

The process of breakdown of a tablet into smaller particles is called as disintegration. The in-vitro disintegration time of a tablet was determined using disintegration test apparatus as per I.P. specifications.

I.P. Specifications: Place one tablet in each of the 6 tubes of the basket. Add a disc to each tube and run the apparatus using 0.5 % of SLS so0.1 N HCl or any buffer solution maintained at 37° ± 2°C as the immersion liquid. The assembly should be raised and lowered between 30 cycles per minute in the 0.1 N HCl or any buffer solution maintained at 37° ± 2°C. The time in seconds taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus was measured and recorded.

9. In vitro dissolution studies:

Dissolution rate was studied by using USP type-II apparatus (USP XXIII Dissolution Test Apparatus at 50 rmp) using 900ml of 0.1 N HCl or any buffer solution as dissolution medium. Temperature of the dissolution medium was maintained at 37 ± 0.5°C, aliquot of dissolution medium was withdrawn at every 1 min interval and filtered. The absorbance of filtered solution was measured by UV spectrophotometric method at respective wavelength and concentration of the drug was determined from standard calibration curve.

In vitro drug release studies details:

Apparatus used : USP XXIII dissolution test apparatus

Dissolution medium : Buffer Solution [0.1 N HCl]

Dissolution medium volume: 900 ml

Temperature : 37 ± 0.5°C

Speed of basket paddle : 50 rpm

Sampling intervals : 1 min

Sample withdraw : 5 ml

Absorbance measured : Particular wavelength

10. Taste or mouth feel:

Healthy human volunteers were used for evaluation of mouth feel of the tablet. One tablet was evaluated for its mouth feel. A panel of 5 members evaluate the mouth feel by time intensity method. Sample equivalent to 40 mg was held in mouth for 10 seconds and the opinion is rated by giving different score values. (0: good, 1: tasteless, 2: slightly bitter, 3: bitter, 4: awful).

11. Stability studies:

· Stability of a drug has been defined as the ability of a particular formulation, in a specific container, to remain within its physical, chemical, therapeutic and toxicological specifications.

· The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity an light and enables recommended storage conditions, re-test periods and shelf lives to be established.

ICH specifies the length of study and storage conditions:

· Short term testing 25°C ± 2°C / 60 % RH ± 5 % for 12 months

· Accelerated testing 40°C ±2 °C / 75 % RH ± 5 % for 6 months

The present study, stability studies were carried out at 25°C/ 60% and 40°C / 75 % RH for a specific time period up to 3 months for the selected formulations.

12 Clinical Studies:

In vivo studies show the actual action of FDT in the oral esophageal tract, their pharmacokinetic and therapeutic efficacy, and acceptability. The investigation using gamma-scintigraphy showed that the dissolution and buccal clearance of fast disintegrating dosage forms was rapid. The esophageal transit time and stomach emptying time were comparable to those of traditional dosage forms i.e. tablets, capsules, or liquid forms.

CHALLANGES OF ODTs:

Physical strength:

orally disintegrating tablet is allowed to disintegrate or dissolved in the oral mucosa, they very permeable and soft-moulded matrices if not compressed into tablets with very little compression force. It is hard, difficult to handle, and frequently have need of specific blister packing that might add to the cost^{[61, 62]}.

Amount of drug:

Submission of technologies used for Orally Disintegrating Tablet is taking the limited amount of drug it can be integrated in unit doses form. In case of Lyophilized dosage form, insoluble drug should be less than 400 mg and soluble drugs fewer than 60mg. ^[63]

Hygroscopicity:

Oro-dispersible dosage forms can be hygroscopic in nature. They cannot maintain physical integrity under the common conditions like: temperature and humidity. Therefore, they want safety from humidity which demands for particular product packaging⁶⁴.

Size of tablet:

The amount of give when entrancing a tablet depends on its size. It is a simplest form of tablet to ingest is 7-8 mm. the larger size of tablet is 8mm. Consequently, the size of tablet is both simple to take and simple to handle are difficult to accomplish. ^[65]

Aqueous solubility:

Water soluble drugs posture various formulation trials as they form eutectic mixtures, which consequence in freezing point dejection and the formation of a smooth solid that may disintegrate leading ventilation because defeat of ancillary structure during the division process^{66, 67}.

CONCLUSION:

Currently these tablets are achievement more importance in industry targeting paediatrics, geriatrics and all age groups The ODTs have expected advantages of more conventional oral dosage forms as they improved patient compliance; convenience, quick onset of action and bioavailability. About one of the third paediatric and geriatric population have difficulty to swallow the tablet, but orally disintegrating tablet is convenient for paediatric and geriatric populations to swallow the tablet easily without need of water. These dosage forms are shows good taste masking properties and excellent mechanical strength. These tablets are planned to be dispersed quickly in the saliva within 60 seconds. Many drugs can be added in ODT mainly unpalatable drugs. The basic approach follow by all the obtainable ODTs technologies is to maximize the porous structure of tablet matrix to accomplish rapid tablet disintegration in the oral cavity along with good taste masking properties and outstanding mechanical strength.

ACKNOWLEDGEMENTS:

The authors are thankful to Sri. Sardar Raja Singh Sir, Chairman and Mrs. Lata Gupta Madam, Director Admin, GRD (PG) Institute of Management and Technology, Dehradun, providing the facilities to carry out this research and also to publish this research work.

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Received on 13.09.2018 Accepted on 01.11.2018

Asian J. Pharm. Res. 2019; 9(1): 42-54.

DOI: 10.5958/2231-5691.2019.00008.X

Step	Direct compression	Dry granulation	Wet granulation
1	Mixed / blending of active drug and adjuvants	Mixing/blending of Active drug and adjuvants	Mixing/blending Active drug and adjuvants

2	Compression	Compression to slugs	Preparation if binder solution

3		Size reduction of slugs and sieving	Massing of binder solution of step 2 with powder mixture of step 1.
4		Mixing of granules with pharmaceutical additives.	Wet screening of damp mass
5		Compression	Drying of wet granules
6			Resifiting of dried granules and blending with pharmaceutical additives.
7			Compression

Name of Excipients

Technology