INTRODUCTION:

Oral dosing remains the preferred mode of administration for many types of medication owing to its simplicity, versatility, convenience, and patient acceptability^.(1) But difficulty in swallowing of some oral solid dosage forms such as tablets and capsules is common among all age groups.⁽²⁾Due to fear of choking, many pediatric, geriatric, bed ridden , nauseous and non compliant patients are unwilling to take these solid preparations.^(3,4)Inconvenience in swallowing conventional dosage forms is also seen in travelling patients who do not have ready access to water and in various physiological and neurological conditions like dysphagia, motion sickness (kinetosis), persistent nausea, sudden episodes of coughing during the common cold, allergic conditions, bronchitis and hand tremors .^{(5, 6)}This leads to non compliance and ineffective therapy.⁽⁷⁾In order to solve the above problem and to improve patient acceptance orodispersible tablets (ODT) were developed.⁽⁸⁾ODTs are also called as Mouth dissolving tablets, quick-disintegrating tablets, Orally disintegrating tablets , fast-disintegrating tablets, fast dissolving tablets, rapid-dissolving tablets, porous tablets, and rapimelts.⁽⁹⁾

United States Food and Drug Administration (FDA) defined ODT as “A solid dosage form containing medicinal substance or active ingredient which disintegrates rapidly usually within a matter of seconds when placed upon the tongue.”⁽¹⁰⁾The disintegration time for ODTs generally ranges from several seconds to about a minute. Now these fast disintegrating or ODT tablets are official to European pharmacopoeia. The term ‘Orodispersible Tablet’ as appears in European Pharmacopoeia is defined as ‘‘uncovered tablet for Buccal cavity, where it disperses before ingestion’’.⁽¹¹⁾European Pharmacopoeia also specifies that the ODTs should disintegrate within 3 minutes when subjected to conventional disintegration test used for tablets and capsules.⁽¹²⁾ The Mouth dissolving tablets disperse or disintegrate upon contact with the saliva in less than 60 seconds and quickly release their components without mastication or water, forming a solution or suspension which is easy to swallow.^(13,14) Use of superdisintegrants provide instantaneous disintegration of the tablet after putting it on the tongue ,there by releasing the drug into the saliva.⁽¹⁵⁾As the saliva passes down into the stomach, some drug is absorbed into the systemic circulation from the mouth, pharynx and esophagus or it can be swallowed as a solution to be absorbed from the gastrointestinal tract thereby exerting rapid onset of action.⁽¹⁶⁾

Advantages^(17-26)

· Do not require water for oral administration. Hence, convenient for the patients do not have easy access of water.

· Ease of administration of drugs to the patients who cannot swallow.

· Ideal for pediatric and geriatric patients.

· Rapid onset of action due to rapid dissolution and absorption of drug.

· Drugs which undergo pre-gastric absorption bypass the first pass metabolism in the liver. Hence, bioavailability is improved resulting in reduced dosage, improved clinical performance by reducing side effects.

· Provides a pleasant mouth feel.

· Bitter taste of some drugs can be masked by the use of flavor and sweetener to produce good mouth feel. This helps to change the perception of medication as bitter pill, particularly for pediatric patients.

· Provides benefits of a liquid medication in the form of solid preparation.

· Durable and sufficient strength to withstand the rigors of the manufacturing process and manufacturing handling.

· Provide new business opportunity like product differentiation, product promotion, patent life extension and life cycle management.

· Allows the manufacture of tablet using conventional processing and packaging equipments.

· Safely administrable to patients on water intake restriction.

· Prescribed as unit dosage. Hence, these are free of need of measuring (An essential drawback in liquid preparation).

Disadvantages ^{(22, 27, 28)}

· Due to the insufficient mechanical strength, mouth dissolving tablets should be handled carefully.

· Mouth dissolving tablets are hygroscopic in nature. Hence, should be kept in dry place.

· If not formulated properly, the tablets may leave unpleasant taste and or grittiness in the mouth.

· Due to lack of physical resistance in standard blister packs, mouth dissolving tablet requires special packaging for proper stabilization and safety of the stable product.

· ODTs have limited ability to incorporate higher concentrations of active drug.

· Patients who concurrently take anticholinergic medications may not be the best candidates for ODT. Similarly patients with Sjogren's syndrome or dryness of the mouth due to decreased saliva production may not be good candidates for these tablet formulations.

Challenges in formulating ODT ⁽^{22, 29-31)}

· Mechanical strength and disintegration time

ODTs are formulated to obtain disintegration time usually less than a minute. In order to allow ODTs to disintegrate in the oral cavity, they are made of either very porous and soft-molded matrices or compressed into tablets with very low compression force, which makes the tablets friable and/or brittle, difficult to handle, and often requiring specialized peel-off blister packing .

· Taste masking

Taste governs patient compliance. The amount of taste masking materials used in the dosage forms should be kept as low as possible to avoid excessive increase in tablet size. The taste-masking technology used should also be compatible with ODT formulations. Various techniques available for masking bitter taste of drugs include taste masking with ingredients such as flavors, sweeteners and amino acids; taste masking by polymer coating , conventional granulation, ion-exchange resins, spray congealing with lipids, formation of inclusion complexes with cyclodextrins, the freeze-drying process, making multiple emulsions, with gelatin, gelatinized starch, liposomes, lecithins or lecithin-like substances, surfactants, salts, or polymeric membranes.

· Mouth feel

ODT should not disintegrate into larger particles in the oral cavity and should leave minimal or no residue in mouth after oral administration. Moreover addition of fillers like mannitol, flavors and cooling agents like menthol improves the mouth feel.

· Hygroscopicity

Several fast dissolving dosage forms cannot maintain physical integrity under normal conditions of temperature and humidity due to hygroscopicity. Hence, they need specialized product packaging for protection from humidity.

· Amount of drug

ODTs are limited by the amount of drug that can be incorporated into each unit dose. For lyophilized dosage forms, the drug dose must be less than 400 mg for insoluble drugs and 60 mg for soluble drugs.⁽²⁸⁾

· Aqueous solubility

Water-soluble drugs form eutectic mixtures, resulting in freezing-point depression and formation of a glassy solid that may collapse upon drying because of loss of supporting structure during the sublimation process. Such collapse can be prevented by using various matrix-forming excipients such as mannitol that can induce crystallinity and impart rigidity to the amorphous composite.

· Size of tablet

The ease of administration of a tablet depends on its size. Sugihara et al. reported that the size of tablet that was easiest to swallow was 7–8 mm, but the size easiest to handle was one larger than 8 mm.

Formulation of ODT

The ingredients that are used in the formulation of ODTs should allow quick release of the drug, resulting in faster dissolution. Disintegration and solubilization of a directly compressed tablet depend on single or combined effects of disintegrants, water‐soluble excipients and effervescent agents. Excipients balance the properties of the actives in ODTs. Thorough understanding of the chemistry of these excipients prevents interaction with the actives.⁽³²⁾Taste‐masking is of critical importance in the formulation of an acceptable ODT. Many oral suspensions, syrups, and chewable tablets simply contain flavors, sugars and other sweeteners to overwhelm or complement the bitter taste of the drug.⁽³³⁾

Drug⁽^{34, 35)}

For an ideal ODT technology, the drug properties should not significantly affect the tablet property. 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. The ODT technology should be versatile enough to accommodate unique properties of each drug.

Table 1: Drugs promising to be incorporated in orodispersible tablets⁽²¹⁾

SR. NO	CLASS OF DRUG	EXAMPLES
1	Analgesics and Anti-inflammatory Agents	Indomethacin, Aspirin, Diclofenac sodium, Ketoprofen, Ibuprofen, Mefenamic acid, Dexamethasone, Hydrocortisone, Prednisolone, Azulene, Phenacetin, Isopropylantipyrin, Acetaminophen, Benzydamine hydrochloride, Phenylbutazone, Flufenamic acid, Sodium salicylate, Choline salicylate, Sasapyrine, Clofezone , Etodolac, Naproxen, Oxyphenbutazone, Piroxicam
2	Anti-coagulants	Dicoumarol, Dipyridamole, Nicoumalone, Phenindione.
3	Anti-arrhythmic Agents	Amiodarone, Disopyramide, Flecainide Acetate, Quinidine Sulphate.
4	Anti-bacterial Agents	Ciprofloxacin, Tetracycline, Erythromycin, Rifampicin, Penicillin, Doxycycline, Nalidixic acid, Trimethoprim, Sulphacetamide, Sulphadiazine.
5	Anti-fungal Agents	Amphotericin, Butoconazole Nitrate, Clotrimazole, Econazole Nitrate, Fluconazole, Fiucytosine, Griseofulvin, Itraconazole, Ketoconazole, Miconazole, Natamycin, Nystatin, Terbinafine, Terconazole, Tioconazole, Undecenoic Acid
6	Anti-depressants	Trimipramine maleate, Nortriptyline · HCl, Trazodone · HCl, Amoxapine, Mianserin · HCl
7	Hypoglycemic agents	Glibenclamide, Glipizide, Tolbutamide, Tolazamide, Gliclazide, Chlorpropamide
8	Anti-hypertensive Agents	Amlodipine, Carvedilol, Benidipine, Darodipine, Dilitazem,Diazoxide, Felodipine, Guanabenz Acetate, Indoramin, Isradipine, Minoxidil, Nicardipine, Nifedipine, Nimodipine, Phenoxybenzamine, Prazosin, Reserpine, Terazosin
9	Anthelmintics	Albendazole, Mebendazole, Thiabendazole, Livermectin, Praziquantel, Pyrantel embonate, Dichlorophen
10	Anti-malarials	Amodiaquine, Chloroquine, Chlorproguanil, Halofantrine, Mefloquine, Proguanil, Pyrimethamine, Quinine
11	Anti-gout Agents	Allopurinol, Probenecid, Sulphinpyrazone
12	β-blockers	Acebutolol, Atenolol, Labetalol, Metoptolol, Oxprenolol, Pindolol, Propranolol
13	Anti-protozoal Agents	Clioquinol, Diloxanide, Dinitolmide, Furzolidone, Metronidazole, Nimorazole, Nitrofurazone, Omidazole, tinidazole,benznidazole
14	Anti-epileptics	Beclamide, Carbamazepine, Clonazepam, Ethotoin, Methoin, Methsuximide, Methylphenobarbitone, Oxcarbazepine, Paramethadione, Phenacemide, Phenobarbitone, Phenytoin, Phensuximide, Primidone, Sulthiame, Valproic Acid
15	Anti-migraine Agents	Dihydroergotamine, Ergotamine, Methysergide, Pizotifen,Sumatriptan
16	Anti-thyroid Agents	Carbimazole, Propylthiouracil
17	Anti-neoplastic Agents and Immunosuppressants	Aminoglutethimide, Chlorambucil, Cyclosporin, Estramustine, Etoposide, Melphalan, 5-MP,Methotrexate, Mitomycin, Mitotane, Procarbazine, Tamoxifen.
18	Diuretics	Acetazolarnide, Amiloride, Bendrofluazide, Bumetanide, Chlorothiazide, Chlorthalidone, Ethacrynic Acid,Frusemide, Metolazone, Spironolactone, Triamterene
19	Lipid regulating Agents	Bezafibrate, Clofibrate, Fenofibrate, Gemfibrozil, Probucol
20	Corticosteroids	Beclomethasone, Betamethasone, Budesonide, Cortisone, Desoxymethasone, Dexamethasone, Fludrocortisone, Flunisolide, Flucortolone, Fluticasone Propionate, Hydrocortisone, Methylprednisolone, Prednisolone, Prednisone, Triamcinolone
21	Oral Vaccines	Influenza, Tuberculosis, Meningitis, Hepatitis, Whooping Cough, Polio, Tetanus, Diphtheria, Malaria, Cholera, Herpes, Typhoid, Measles, Lyme Disease.
22	Nitrates and Other Anti-anginal Agents	Amyl Nitrate, Glyceryl Trinitrate, Isosorbide Dinitrate, Isosorbide Mononitrate, Pentaerythritol Tetranitrate
23	Gastro-intestinal Agents	Bisacodyl, Cimetidine, Cisapride, Diphenoxylate, Domperidone, Famotidine, Loperamide, Mesalazine, Nizatidine, Omeprazole, Ondansetron, Ranitidine ,granisetron · HCl
24	Anti-parkinsonian Agents	Bromocriptine Mesylate, Lysuride Maleate
25	Antiulcer agents	Ranitidine, Sulpiride, Cetraxate hydrochloride, Gefarnate, Irsogladine maleate, Cimetidine, Lanitidine hydrochloride, Famotidine, Nizatidine or Roxatidine acetate hydrochloride

The ideal characteristics of a drug for ODTs

· The drug should be partially unionized at oral pH.

· Drug should permeate through the oral mucosal tissue.

· Small to moderate molecular weight.

· Dug should have good stability in water and saliva.

· No bitter taste.

· Dose should be as low as possible

· Ability to diffuse and partition into the epithelium of the upper GIT.

Unsuitable for

· Drugs with short half-life.

· Drugs requiring frequent dosing.

· Drugs with very bitter or otherwise unacceptable taste because taste masking cannot be achieved.

· Drugs which require controlled or sustained release.

Superdisintegrants

Disintegrating agents overcome the cohesive strength imparted during compression, thus aiding in the break-up of the tablet and increasing the surface area for dissolution.⁽³⁶⁾ Several newer agents have been developed which are more effective at lower concentrations with greater disintegrating efficiency and mechanical strength. These agents are called ‘Superdisintegrants’. On contact with water the superdisintegrants swell, hydrate, change volume or form and produce a disruptive change in the tablet.⁽³⁷⁾Effective superdisintegrants provide improved compressibility, compatibility and have no negative impact on the mechanical strength of formulations containing high-dose drugs.^(38,39)

Methods of Incorporating Disintegrants into Tablets ^{(40, 41)}

There are three methods of incorporating disintegrating agents into the tablet as described below:

· Intragranular - In Internal addition method, the disintegrant is mixed with other powders before wetting the powder mixtures with the granulating fluid. Thus the disintegrant is incorporated within the granules.

· Extragranular - In external addition method, the disintegrant is added to the dry granulation with mixing prior to compression.

· Partly intragranular and extragranular - In this method, part of the disintegrant is added internally and part externally. This results in immediate disruption of the tablet into granules while the disintegrating agent within the granules produces additional erosion of the granules into smaller particles.

Mechanism of action of Superdisintegrants

Superdisintegrants improve the efficacy of solid dosage forms. The mechanism by which the tablets are broken into small pieces and then produces a homogeneous suspension is based on

· Swelling

Disintegrant particles (ex. starch) swell on coming in contact with suitable medium and a swelling force develops which leads to break-up of the matrix. Tablets with high porosity show poor disintegration due to lack of adequate swelling force whereas tablet with low porosity exerts sufficient swelling force. ⁽⁴²⁾

Compressed Tablet		Superdisintegrant
		Drug

		Other Excipients
Swelling of the superdisintegrant

Break up of the tablet matrix

Fig 1: Disintegration of tablet by swelling

· Porosity and capillary action (Wicking)

Tablet porosity provides pathways for the penetration of fluid into tablets. Water uptake by tablet depends upon hydrophilicity of the drug excipient and on tabletting conditions. Liquid is drawn up or “wicked” into these pathways through capillary action and rupture the interparticulate bonds causing the tablet to break apart. E.g. Crospovidone, Croscarmellose. ⁽⁴³

Fig.2: Disintegration of tablet by wicking

· Deformation recovery

The shape of disintegrant particles is distorted during compression and the particles return to their pre-compression shape upon wetting, thereby this increase in size of the deformed particles causing the tablet to break apart. ⁽⁴⁴⁾

· Particle repulsive forces

According to Guyot-Hermann’s particle-particle repulsion theory, water penetrates into tablet through hydrophilic pores and a continuous starch network is created that can convey water from one particle to the next, imparting a significant hydrostatic pressure. The water then penetrates between starch grains, thereby breaking hydrogen bonds and other forces holding the tablet together.⁽⁴⁴⁾

· By Enzymatic Reaction

Enzymes like amylase, protease, cellulase, invertase present in the body also act as disintegrants. Due to swelling, pressure is exerted in the outer direction that causes the tablet to burst or the accelerated absorption of water leads to an enormous increase in the volume of granules to promote disintegration.^{(43, 39)}

· Chemical reaction (Acid-Base reaction)

Interaction of tartaric acid and citric acid (acids) with alkali metal carbonates or bicarbonates (bases) in presence of water leads to liberation of carbon dioxide resulting in breakup of the tablet matrix. Due to the liberation of carbon dioxide gas, the dissolution of active pharmaceutical ingredients in water as well as taste masking effect is enhanced.⁽³⁹⁾

· Heat of wetting

When disintegrants with exothermic properties get wetted, localized stress is created due to capillary air expansion, which aids 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.⁽⁴⁵⁾

Types of Superdisintegrants - The Superdisintegrants can be classified into two categories on the basis of their availability:

· Natural Superdisintegrants

· Synthetic Superdisintegrants

Natural Superdisintegrants

Natural gums and mucilages have been widely explored as disintegrants. Mucilages are secondary plant metabolites, but due to the high concentration of hydroxyl groups in the polysaccharide, mucilages have a high water-binding capacity and this ability of mucilage to hydrate offers a mechanism for plants to resist drought. Mucilage mainly consists of polysaccharides, proteins and uranides. Dried up mucilage or the concentrated mucilage is called as gum. The main difference between them is that gum dissolves in water whereas mucilage does not dissolve in water. ^{(39, 43)}

Advantages of natural superdisintegrants

These are natural in origin and are preferred over synthetic substances because

· They are comparatively cheaper

· Abundantly available

· Eco‐friendly

· Bio-acceptable

· Non-irritating

· Non-toxic in nature

Disadvantages of natural superdisintegrants

· Natural superdisintegrants are susceptible to microbial contamination. Hence, need addition of preservatives.

Examples of natural superdisintegrants include Plantago ovata seed mucilage, Lepidium sativum mucilage, Gum Karaya, Guar gum, Gellan gum, Xanthan gum, Cassia fistula gum, Fenugreek seed mucilage, Mango peel pectin, Agar and treated agar, Soy polysaccharide, chitin and chitosan, Hibiscus rosa-sinensis Linn. mucilage, Cucurbita maxima pulp powder, pregelatinized Starch, Locust Bean gum, Aegle marmelos gum, Ficus indica fruit mucilage, Mangifera indica gum and dehydrated banana powder etc.^(23,42)

Synthetic Superdisintegrants

Synthetic superdisintegrants are frequently used in tablet formulations to improve the rate and extent of tablet disintegration, thereby increasing the rate of drug dissolution. The most widely used synthetic superdisintegrants include croscarmellose sodium (Ac-Di-Sol) sodium starch glycolate (Primogel and Explotab) and crospovidone (Polyplasdone XL).^{(39, 43)}

Advantages of Synthetic Superdisintegrants

· Effective in lower concentrations than starch.

· Less effect on compressibility and flow ability.

· More effective intragranularly.

Table 2: Few works carried out using natural superdisintegrants

SR.NO	NATURAL SUPERDISINTEGRANT	DRUG	METHOD	REFERENCE
1	Ocimum americanum Lynn. Seed mucilage	Propranolol HCl	Wet granulation	46
2	Plantago ovata mucilage	Prochlorperazine maleate	Direct compression	47
3	locust bean gum	Ofloxacin	direct compression	48
4	Potato starch	Ibuprofen	Wet granulation	49
5	Plantago ovata husk Cassia tora; Cassia nodosa	Nimesulide	Granulation	50
6	Lallemantia reylenne seeds	Nimesulide	Direct compression	51
7	Calcium cross-linked Cassia fistula gum	Metoclopramide HCl	Direct compression	52
8	Hordeum vulgare seed husk	Diclofenac sodium	Wet granulation	20

Table 3: List of synthetic superdisintegrants.

SR.NO	SYNTHETIC SUPERDISINTEGRANT	BRAND NAME	MECHANISM OF ACTION	REFERENCE
1	Crosslinked cellulose	Croscarmellose Ac-Di-Sol Nymce ZSX Primellose Solutab Vivasol	Swelling and wicking	40
2	Cross-linked polyvinyl Pyrrolidone	Crospovidone Kollidon Polyplasdone	Swells very little and returns to original size after compression. It also acts by wicking and capillary action	40
3	Cross linked Starch	Sodium Starch Glycholate(SSG) Explotab Primogel	Swelling	40
4	Cross-linked polyacrylic	Indion 414	Swelling	53

Disadvantages of Synthetic Superdisintegrants

· More hygroscopic (may be a problem with moisture sensitive drugs)

· Some are anionic and may cause some slight in-vitro binding with cationic drugs.

· An acidic medium significantly reduces the liquid uptake rate and capacity of sodium starch glycolate and croscarmellose sodium, but not crospovidone.

· The degree of swelling of Primogel (sodium starch glycolate) and Polyplasdone XL101 (crospovidone) is minimized following wet granulation formulation.

· Finally, the medium ionic strength was found to have an adverse effect on the swelling capacity of croscarmellose.

Therefore, natural superdisintegrants serve as a better alternative to overcome the shortcomings of these superdisintegrants.

Sweetners

Wide range of sweeteners including sugar, dextrose and fructose, as well as non-nutritive sweeteners such as aspartame, sodium saccharin, sugar alcohols and sucralose are used in ODT formulations.⁽⁵⁵⁾

Fillers

Directly compressible spray dried mannitol, dextrose, fructose, maltose, starch hydrolysate, polydextrose, sorbitol, xylitol, calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulfate, pregelatinized starch, magnesium trisilicate, aluminum hydroxide etc. are used as fillers in ODTs.^{(54, 55)}

Surface active agents

Sodium doecyl sulfate, sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters (Tweens), sorbitan fatty acid esters (Spans), polyoxyethylene stearates etc., are used as surface active agents in ODTs.⁽⁵⁴⁾

Binders

To provide mechanical strength for handling and impart cohesive strength in compression binders like Polyvinyl pyrrolidone (PVP), Polyvinyl alcohol (PVA), Hydroxypropyl methyl cellulose (HPMC) etc. are added in formulation.⁽⁵⁶⁾

Colour and flavors

FDA approved colours and flavors are used in formulation. Sunset yellow, amaranth etc. are used as colours in ODT formulations. Flavors used in ODTs include flavoring aromatic oils like peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil thyme oil, oil of bitter almonds. Flavoring agents include vanilla, citrus oils and fruit essences.⁽⁵⁴⁾

Lubricants

Different hydrophilic and hydrophobic lubricants are used depending on the property of drug.⁽⁵⁴⁾

Common techniques for manufacturing of ODTs

Molding

Tablets produced by molding are solid dispersions. The physical form of the drug present in ODTs depends on whether and to what extent it is dissolved in the molten carrier or molten matrix. The disintegration time and dissolution rate of ODTs prepared using molding depend upon the dissolution or dispersion type of the drug.⁽²¹⁾

Lyophilization/Freeze drying

Lyophilization or freeze drying is used for drying of heat sensitive drugs and biological at low temperature conditions that allow removal of water by sublimation. The product obtained is highly porous, with a very high specific surface area. Hence, the liquid medium penetrates into the interior surface of the tablet thereby enhancing its disintegration resulting in improved absorption and bioavailability. ^(21,
27)

Direct compression

The disintegration and solubilization of direct-compression tablets are based on the single or combined action of disintegrants, water-soluble excipients and effervescent agents. The disintegrating efficacy is strongly affected by tablet size and hardness

· Disintegrants

Disintegrants affect the rate of disintegration and hence dissolution, which is further enhanced in the presence of water soluble excipients and effervescent agents.

· Effervescent Agents

The evolution of CO₂ as a disintegrating mechanism forms the basis of the patented Orasolv technology. Saliva activates the effervescent agent which causes the tablet to disintegrate.^{(24, 23, 57)}

· Sugar-Based Excipients

Mizumoto et al.,have classified sugar-based excipients into two types based on their mouldability and dissolution rate.⁽⁵⁸⁾

Type I saccharides (e.g., lactose, glucose, sucrose and mannitol) exhibit low mouldability but high dissolution rate and Type II saccharides (e.g., maltose, sorbitol and maltitol) exhibit high mouldability but low dissolution rate.

Cotton candy process

Flash melting and spinning results in the formation of candy floss matrix of polysaccharides or saccharides, which is partially recrystallized to improve the 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 high doses of drug and offers improved mechanical strength.⁽²¹⁾

Sublimation

· The process by which a solid changes directly to vapor without passing through the liquid phase is called as sublimation.⁽⁵⁹⁾Removal of volatile material like camphor, ammonium bicarbonate, ammonium carbonate, benzoic acid, hexamethylene tetramine, naphthalene, phthalic anhydride, urea and urethane etc, by sublimation generates a porous structure, which helps in achieving rapid disintegration when the tablet comes in contact with saliva.

Mass extrusion

The active blend is softened by using water soluble polyethylene glycol and methanol. Expulsion of softened mass through the extruder results in cylinder shaped extrudate of the product which is then cut into even segments using heated blade to form tablets. ⁽²⁹⁾

Phase transition method

Kuno et al. used a combination of two sugar alcohols (SAs) , Erythritol as the high melting point sugar alcohol (HMP-SA) and trehalose or xylitol as the low melting point sugar alcohol (LMP-SA) and ODTs were produced followed by heating of the tablets. It was concluded that tablet hardness was related to the increase in inter-particle bonds or the bonding surface area in tablets induced by the phase transition of the low melting point SA (LMP-SA).^{( 60)}

Fig 3. Steps involved in sublimation technique

Table 4: Formulations using different techniques

SR. NO	TECHNIQUES	DRUGS	EXCIPIENTS	CONCLUSION	REFERNCE
1	Lyophilization	Meloxicam Valsartan Nimesulide	Gelatin(matrix former) Glycine (Collapse protectant) Mannitol(sugar alcohol) PEG, PVP, Tween (Disintegration accelerators) Gelatin, mannitol,spray dried lactose, pregelatinized starch, xanthum gum, pectin Gelatin(matrix former) Glycine (Collapse protectant) Mannitol(sugar alcohol), PEG, PVP, Tween (Disintegration accelerators)	Meloxicam ODTs disintegrated within few seconds and showed better absorption leading to increased bioavailability. Valsartan ODTs showed improved patient compliance, rapid onset of action, and enhanced bioavailability when compared to conventional Valsartan tablets Compared to conventional formulations, Nimesulide ODTs showed improved absorption and increased	A.A. Elbary et al. ^{( 61)} Ibrahim and El-Setouhy ⁽¹³⁾ R.A. Shoukri et al. ⁽⁶²⁾
2	Sublimation	Meloxicam Nimesulide Levocetirizine HCl	Camphor Menthol Thymol Ac-Di-Sol Camphor Crospovidone colloidal SiO_2,lactose Menthol, perlitol SD 200, colloidal silicon dioxide	Meloxicam ODTs disintegrated within few seconds and showed better absorption and increased bioavailability Sublimation of camphor from tablets resulted in superior tablets as compared with the tablets prepared from granules that were exposed to vacuum. Tablets having 30% menthol rapidly dissolved within 15 seconds	A.A. Elbary et al.⁽⁶¹⁾ M Gohel et al.⁽⁶³⁾ A.K. Mahapatra et al., ⁽⁶⁴⁾
3	Molding	Valde-coxib	Polyvinyl pyrrolidone (PVP-K30)	Molded tablets containing solid dispersion of valdecoxib and PVP exhibited better dissolution profile than commercial tablets.	Modi and Tayade ⁽⁶⁵⁾
4	Wet granulation	Domperidone Diclofenac Sodium	D-mannitol , maize starch gum, Microcrystalline cellulose Microcrystalline cellulose, sodium starch glycolate, Hordeum vulgare hull, croscarmellose sodium, Alcoholic solution of PVP	The tablets disintegrated within 1 min and exhibited both enhanced structural integrity and decreased disintegration time. Tablets having Hordeum vulgare hull showed release profile comparable and even slightly better than those tablets having sodium starch glycolate and croscarmellose sodium.	Julia et al. ⁽⁶⁶⁾ Rajpurohit, et al ⁽²⁰⁾
5	Direct Compression (superdisintegrant addition method) Direct compression (Effervescent method) Direct compression (Effervescent method)	Meloxi-cam Prochlorperazine maleate Fexofenadine HCl	Sodium starch glycolate, croscarmellose sodium, crospovidone, mannitol Sodium bicarbonate, anhydrous citric acid, croscarmellose sodium, crospovidone Sodium bicarbonate, anhydrous citric acid, croscarmellose sodium, crospovidone, Sodium starch glycolate	Compared to the conventional tablets, Meloxicam ODTs containing sodium starch glycolate and croscarmellose showed three fold faster drug release Formulation containing crospovidone and effervescent mixture showed three fold faster drug release when compared to conventional formulation of Prochlorperazine maleate. Formulation containing crospovidone and effervescent mixture showed fourfold faster drug release when compared to commercial tablet.	Swamy et al.^{( 67)} Shirsand et al.⁽⁶⁸⁾ Nagendra kumar et al.⁽⁶⁹⁾

6	Direct compression (superdisintegrant addition, effervescence ) sublimation	Flutamide	Sodium starch glycolate, Sodium bicarbonate, citric acid , Camphor, mannitol, sucralose, PEG 6000	The order of increased drug dissolution was as follows: superdisintegrant addition>effervescence> sublimation	K.A. Elkhodairy et al.⁽⁷⁰⁾
7	Direct compression (superdisintegrant addition) and Sublimation	Zolmitriptan	Sodium starch glycolate, croscarmellose sodium, crospovidone, Kyron -314, camphor	Camphor acts synergistically with Kyron -314,the most effective superdisintegrant , decreasing the disintegration time to below 30 sec.	Sudarshan Singh et al.⁽⁴⁾
8	Spray drying	Drugs like antibiotic, antihistamines etc. Valdecoxib, metoclopramide	Gelatin (support matrix) Mannitol, croscarmellose, sodium starch glycolate, citric acid, sodium bicarbonate Mannitol, sodium starch glycolate, Kollidon CL, Ac-Di-Sol, MCC	Tablets manufactured from this powder disintegrated in less than 2Oseconds in an aqueous medium. Maximum drug release and minimum disintegration time were observed with Kollidon CL excipient base, showing the superiority of the spray dried excipient base technique over direct compression technique.	Allen LV⁽⁷¹⁾ D.N. Mishra et al. ⁽⁷²⁾
9	Mass extrusion	Oxybutynin or Pirenzepine	Eudragit E‒100, ethanol, L‒HPC	The tablets prepared by this method have sufficient strength and disintegrated in less than 20 secs.	N. Utoguchi et al.⁽⁷³⁾

Table 5: Orally Disintegrating Tablet technology Platforms ^{(74, 75)}

ODT Technology	Proprietary Technology	Company	Examples of commercial Products
Lyophilization	Zydis Lyoc Pharmafreeze Quicksolv	Catalent R.P.Scherer/Glaxo R.P.Scherer/Eli Lilly, R.P.Scherer /Merck and Co., Cephalon SPI Pharmaceuticals Janssen	Grazax and Claritin Zofran ODT Zyprexa Zydis Maxalt-MLT Proxalyoc and Loperamide Lyoc Risperdal
Direct Compression	AdvaTab Orasolv/ Durasolv Flashtab Pharmaburst	Eurand CIMA Labs Ethypharm SPI Pharmaceuticals	AdvaTab cetirizine Lactimal ODT Remeron Soltab Zomig-ZMT Niravam FazaClo Orapred Prevacid Solutab Ibuprofen
Sugar floss	Flashdose	Biovail	Ralivia
Molded tablet	WOWtab	Yamanouchi/Astellas	Benedryl FastMelt

Table 6: ODTs Currently Available in the market ⁽⁷⁶⁾

PRODUCT	MANUFACTURED BY	DRUG	CATEGORY	INDICATION
Zyprexa Zydis	Eli Lily and Company	Olanzapine	Atypical antipsychotics	Bipolar disorder, Schizophrenia
Zofran ODT	GlaxoSmithKline	Ondansetron	Antiemetics	Nausea, Vomiting
Zelapar	Valeant Pharmaceuticals	Selegiline	Monoamine oxidase inhibitor	adjunct therapy in Parkinson's disease
Saphris	Merck and Co.	Asenapine	Atypical antipsychotics	Schizophrenia, Bipolar disorder
Prevacid SoluTab	Takeda Pharmaceuticals	Lansoprazole	Proton pump inhibitors	Ulcers
Parcopa	Schwarz Pharma	Carbidopa/ Levodopa	DOPA Decarboxylase inhibitors	Parkinson's disease
Maxalt-MLT	Merck and Co	Rizatriptan	Serotonin agonists	Acute Migraine
Nurofen Meltlets	Reckitt Benckiser	Ibuprofen	NSAIDs	Pain, Fever, Inflammation
Alavert Quick Dissolving Tablets	Wyeth	Loratidine	Antihistamine	Allergy
Allegra ODT	Sanofi Aventis	Fexofenadine	Antihistamine	Allergic rhinitis, Urticaria
Clarinex RediTabs	Schering-Plough	Desloratadine	Antihistamine	Allergy
Calpol Fast Melts	McNeil Healthcare UK	Paracetamol	Analgesic	Pain
Benadryl Fast Melt	Pfizer	Diphenhydramine	Antihistamine	Allergy

Evaluation of ODTs

Tablet pore size

Mercury porosimeter is used to measure the pore size of tablets. A contact angle of 130⁰ was set between the mercury and the powder sample. The surface tension was set at 485 dynes/cm.Pore size calculated using the following Equation- 1:

-4γcosθ

Pore size = --------------------………Equ-1

Where, P is the pressure (psia), θ the contact angle, and γ is the surface tension of the mercury.

Wetting time

A tablet is placed on a circular shaped filter paper of 10 cm diameter is placed in a petri dish and a mL of water soluble dye, amaranth was added to it. Wetting time is noted as the time required for the water to reach the upper surface of the tablet. ⁽⁴⁾

Fig 4: Wetting time and water absorption ratio

Water absorption ratio

A tablet was placed on a twice folded tissue paper in a small petri dish containing 6 mL of water. Wetting time is measured as the time required for complete wetting of tablet. The wetted tablet is weighed. ⁽¹¹⁾Water absorption ratio, R, was calculated by the following

Equation 2:

w_a-w_b

R=--------------……..Equ.2

w_b

Where, W_b = weight of the tablet before water absorption

W_a = weight of the tablet after water absorption

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

Disintegration test⁽¹²⁾

Disintegration time of ODT is usually measured using the disintegration test apparatus mentioned in the pharmacopoeia for conventional tablets. A time limit of 3 min is set as the disintegration time according to European pharmacopoeia. Compared to the volume of human saliva (6 mL), conventional test apparatus employs a relatively huge volume of test solution (900 mL). Hence, the results from the conventional disintegration tester do not compel with the actual disintegration rate in the mouth which usually ranges from 5 to 30 seconds. Therefore, to overcome these problems several new methods have been developed.

Disintegration test using modified dissolution apparatus

Modified dissolution apparatus has been suggested by Bi et al. This method includes 900 mL of water maintained at 37 ^ºC as dissolution fluid and a 100 rpm paddle is used as a stirring element. The tablet while it disintegrates completely passes through the screen of the sinker where in the disintegration time is noted.

Disintegration test on wire cloth

This disintegration test has been carried out by Motohiro et al. A mouth dissolving tablet was placed on a piece of wire cloth (no. 10) and water is poured drop wise onto the tablet at a rate of 4mL per minute. The time taken by the tablet to completely pass through the wire cloth is determined as the disintegration time.

Disintegration test on shaking water bath

This disintegration test was conducted by Fu et al. A mouth dissolving tablet is placed in a glass cylinder fitted with a 10 mesh sieve at its base. This set up is then transferred into a shaking water bath operated at 150 rpm wherein 1mL of purified water is used as the medium. The whole setup is maintained at 37 ^ºC temperature. The time taken by the tablet to pass through the mesh was determined as the disintegration time.

Disintegration test using texture analyzer

In this method a cylindrical flat ended probe is used to apply a constant penetration force upon the tablet while it is immersed in a defined volume of distilled water and the time is plotted against the distance, which the probe travelled into the tablet. Texture analysis software is used to generate typical time – distance profiles, thereby enables to determine the starting and end time points of disintegration.

Disintegration test using Electro force 3100

Recently an Electro force 3100 instrument has been designed by the Bose Corporation with an aim to stimulate the disintegration condition of the ODT in the human saliva. The tablet is held on a lower plate upon which a 10 mN force is applied, followed by the addition of 5mL of water maintained at 37 ^ºC on to the tablet. The disintegration time is noted.

Disintegration test with rotary shaft method

Disintegration test conducted by placing a tablet on a wire gauge, immersed in a medium and then compressed by a rotary shaft, used to provide mechanical stress upon the tablets by means of its rotation and weight. Purified water maintained at 37 ^ºC used as the medium. The tablet is then crushed by the rotary shaft, wherein the tablet disintegrates into the medium.

Dissolution test for ODTs ⁽¹²⁾

This is an important test used to determine the drug release profiles. USP Type 1 as well as USP -Type 2 apparatus can be used to determine the dissolution of ODT. USP Type 1 basket apparatus may have certain applications , but tablet fragments (or) disintegrated tablet masses get trapped on the inside top of the basket at the spindle leading to irreproducible dissolution profiles. Thus, Type-2 paddle type dissolution apparatus maintained at a speed of 50-100 rpm is generally preferred for dissolution testing of orodispersible tablets.

CONCLUSIONS:

Orodispersible tablets concept has been evolved to overcome some of the problems existing in the conventional solid dosage forms like dysphagia in pediatric and geriatric patients. ODTs can be prepared using different methods but the product performance depends upon the suitability of the drug and selection of the excipients in the delivery system. Due to its rapid absorption, these tablets show improved efficacy, bioavailability, quick onset of action and better patient compliance. Thus, these dosage forms provide enhanced commercial and therapeutic benefits leading to the development of advanced formulations by most of the pharmaceutical companies in the near future. The authors were tinted on an updated vision on formulation strategy in design and development and/or technologies for design of orodispersible tablets and excipients used there with. With an optimized dispersion time, taste and flavor, an orodispersible tablet can be better accepted over conventional tablets .More over this can furnish better marketing strategy for the formulations. This review can help the formulation scientists to conceive and work on this novel tableting technique to meet the patient compliance.

ACKNOWLEDGEMENTS:

The authors would like to thank Dr. Sudarsan Biswal (Drugs control Department, Govt. of Odisha) for his discussions on some aspects of the manuscript. We also like to acknowledge MANSAS management for providing necessary library facilities for journals and e-journals, books and internet access.

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Received on 24.06.2013 Modified on 02.07.2013

Research J. Pharm. and Tech. 6(9): September 2013; Page 941-953