Mouth Dissolving Tablets: A Comprehensive Review on Technologies, Research, Patents, and Marketed Products.

The oral route is the most effective route, despite all the other advanced drug delivery systems. This is due to enhanced patient compliance and convenience for the administrator. Tablets are a frequently prescribed oral dose type that have properties like their firmness, convenience of production, and accessibility. Along with these advantages, tablets have some major disadvantages, such as difficulty in swallowing for geriatric and pediatric patients and conditions like dysphagia. Hence, mouth-dissolving tablets were developed.

Mouth dissolving tablets are defined as “The solid dosage forms that rapidly disintegrate and dissolve into saliva in the oral cavity, resulting in solution without the need for water for administration”. The technology involved in mouth-dissolving tablets makes the tablets disintegrate in the mouth without chewing, and additional water intake has drawn a greater deal of attention. Mouth dissolving tablets are also known as: fast melting tablets, rapid dissolve tablets, rapid melt tablets, fast dispersing tablets, freeze-dried wafers, and quick disintegrating tablets. These were approved by the Food and Drug Administration and classified as orally disintegrating tablets.  The term Oro-dispersible tablet for MDT was recognized by the European pharmacopoeia, which means that, tablet dissolves and disintegrates in less than 3 minutes in the mouth before swallowing. A tablet disintegrates into smaller granules and melts in the mouth, resulting in a hard, solid, to gel-like structure. This allows easy swallowing by the patients. The disintegration time for the mouth-dissolving tablets varies from about seconds to minutes. Mouh dissolving tablets have gained popularity due to their Self-administration capabilities, absence of need for water, and rapid disintegration and dissolution.

ADVANTAGES^1,2   

• Improve stability
• Ease of administration to patients who are unable to swallow. Ideal for the elderly, pediatrics, geriatric, and psychiatric patients, and people with renal illness.
• Enhance mouth feel and taste masking: The mouth-feel properties of fast-dissolving tablets contribute to the positive shift in the perception of drugs. This is particularly in children, where FDTs can improve the taste of bitter medication.
• Does not require water for administration, especially while travelling.
• No risk of suffocation and choking during mouth dissolving tablets uptake, and helpful in some cases, like motion sickness during coughing, etc.
• Cost-effective
• No chewing needed
• Good chemical stability as a conventional oral solid dosage form
• Benefits of liquid medication in the form of solid medication
• No specific packaging is required. Can be packed in push-through blisters.
• It has a good mouth feel property that helps to take the medication easily, the bitter pill in pediatric patients

DISADVANTAGES^1,2:

• Oral dissolving tablets are hygroscopic in nature, so they must be kept in a dry place.
• ODT requires special packaging for proper stabilization and safety of the stable product.
• Brittleness: FDTs can be extremely brittle, especially when molded and compressed at low force. This brittleness, advanced peel-off blister packaging, and posting challenges in production.
• The tablets often do not have enough mechanical strength, and careful handling is required as a result.
• If the pills are not prepared properly, they may have a poor taste and feel gritty in the mouth.

FORMULATION ACCEPTS OF MDTs^3,4:

Ingredients used in the formulation of MDTs must allow quick release of the drug, resulting in faster dissolution. This includes both active pharmaceutical ingredient (drug) and excipient (additives).

1. Selection of Drug Candidate: While selecting an appropriate drug candidate for developing an MDT, several candidates must be considered. The ultimate   characteristics of a drug for dissolution in the mouth include:

1. Free from bitter taste
2. Dose lower than 20 mg
3. Good solubility in water and saliva
4. Partially unionized at the oral cavity Ph
5. Small to moderate molecular weight
6. Ability to permeate at oral mucosal tissue
7. Ability to diffuse and partition in the epithelium of upper GIT (log > 1 or preferably > 2)

There are no particular limitations for the active pharmaceutical ingredient. Researchers have formulated mouth dissolving films with different drug categories such as analgesics, anti-allergics, anxiolytics, anti-bacterial agents, cardiovascular agents, neuroleptics, etc.

The characteristics that may render unsuitable of drug delivery as MDTs are:

1. Short half-life
2. Unacceptable taste
3. Require controlled or sustained release 
4. Combination with anticholinergics

2. Selection of excipients: Excipients used in MDTs should contain at least one disintegrant, a lubricant, a diluent, a sweetener, a flavoring agent, etc. The excipients used are:

1. Superdisintegrants: Superdisintegrants are added to the tablets to aid in the breakup of compacted mass when it is kept in a fluid environment. Super disintegration increases the rate of disintegration and hence dissolution. Superdisintegrant addition is a common method for preparing MDTs because of its simplicity and affordability. Although superdisintegrants primarily affect the rate of disintegration, using them at high levels can also affect tablet hardness, friability, and mouth feel, so the right amount of Superdisintegrant is to be added to achieve MDTs. Selecting the right Superdisintegrant is very important. There are different factors to be considered while selecting a Superdisintegrant.

• The pill should dissolve in the mouth as soon as it comes into contact with saliva
• It should provide the patient with a satisfying mouth feel
• Small particle size should be used for patient compliance
• It should be compressed to create less fragile tablets
• It should have good flow, since it improves the flow characteristics of the total blend.

Superdisintegrants involve four different mechanisms by which a tablet is broken down into smaller particles. The mechanisms involved are:

• Swelling: Swelling is the most accepted mechanism of action for tablet disintegration. Tablets that have high porosity show poor disintegration due to a lack of sufficient swelling force. On the other hand, tablets with low porosity show sufficient swelling force and hence good disintegration.
• Porosity and capillary action: Disintegration by capillary action is always the first step. When we put a tablet into a suitable aqueous medium, the medium penetrates 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 tablets depends upon the 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.
• Due to disintegrating particle/particle repulsive forces: Another mechanism of disintegrants attempts to explain the swelling of a tablet made with ‘non-swellable’ disintegrants. Guyot-Hermann has proposed a particle repulsion theory based on the observation that non-swelling particles also cause the disintegration of tablets. The electric repulsive forces between particles are the mechanism of disintegration, and water is required for this process. Researchers found that repulsive is secondary to wicking.
• Due to deformation: Disintegrated gets deformed during tablet compression. These deformed particles get into the 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. The increase in size of deformed particles produces a breakup of the tablet. This may be a mechanism of starch and has recently begun to be studied.

Examples of superdisintegrants include carboxymethyl cellulose, sodium carboxymethyl cellulose, sodium starch glycolate, crospovidone, microcrystalline cellulose, and modified corn starch.

2. Binder: It helps to maintain the integrity of the dosage form before administration. The examples of binders are PVP, PVA, HPMC, etc.
3. Lubricants: Lubricant helps to reduce friction. The examples of lubricants are stearic acid, magnesium stearate, magnesium lauryl sulfate, talc, polyethylene glycol, liquid paraffin, colloidal silicon dioxide, etc.
4. Fillers: Fillers enhance the bulk of the dosage form. The examples of fillers are calcium carbonate, magnesium carbonate, calcium sulfate, calcium phosphate, aluminum hydroxide, magnesium trisilicate, xylitol, etc.
5. Emulsifying agents: Emulsifying agents are useful in stabilizing the immiscible blends and enhancing bioavailability. The examples of emulsifying agents are propylene glycol esters, lecithin, alkyl sulfates, sucrose esters, etc.
6. Coloring agents: Coloring agents enhance the appearance and organoleptic properties of the dosage form. The examples of coloring agents are sunset yellow, red iron oxide, Amaranth, etc. 
7. Flavoring agents: Flavoring agents are used to mask unpleasant taste. Flavoring agents include artificial sweeteners like aspartame, dextrose, maltose, mannitol, sorbitol, vanilla, oils, fruit essence, etc.

PRE FORMULATION STUDIES^5,6:

1. Bulk Density: Bulk density is measured by pouring the powder (passed through a standard sieve number # 20)   into a measuring cylinder, and the initial weight is noted, which is called bulk volume. From this bulk density is calculated from the formula mentioned below.

D_b =MVb

Where M is the mass of powder

V_b is the bulk volume of the powder.

 It is expressed in g/ml.

2. Tapped Density: Tapped density is the ratio of the total mass of the powder to the tapped volume of the powder. The total mass of the powder was measured, and the tapped volume of the powder was measured by tapping the powder 750 times. Tapping was continued until the difference between successive volumes was less than 2%. If it is more than 2% tapping is continued for 1250 times, and the tapped volume is noted. It is expressed in g/ml.

Dt = MVt

Where M is the mass of powder

V_t is the tapped volume of the powder.

3. Angle of Repose: The angle of repose is measured by the friction forces in a loose powder. It is defined as the maximum angle possible between the surface of the pile of powder and the horizontal plane.

The powder was allowed to flow through the funnel. The angle of repose was calculated by measuring the height and radius of the pile of powder.

tan (θ) = hr

θ = tan^-1 hr

Where θ is the angle of repose.

    h is the height in cms 

    r is the radius in cms.

Table 1: Relationship between angle of repose and powder flow

4. Carr’s index (or) % Compressibility: It indicates powder flow properties. It is expressed in percentage and is given by

I =Dt-DbDt

 Where, D_t is the tapped density of the powder

              D_b is the bulk density of the powder

Table 2: Relationship between % compressibility and flow ability

5. Hausner ratio: The Hausner ratio is an indirect index of ease of powder flow. It is calculated by the following formula.

Hausner ratio = DtDb

Where, D_t is the tapped density.

             D_b is the bulk density. 

A lower Hausner ratio (<1.25) indicates better flow properties than a higher one (>1.25).

6. Void volume: The volume of the spaces is known as the void volume. It is given by a formula

V= V_b – V_p

Where, V_b = Bulk volume (volume before tapping)

             V_p = The volume (volume after tapping)

7. Porosity: The porosity of the powder is the ratio of void volume to the bulk volume of the packing. The porosity of powder indicates the types of packaging a powder undergoes when it is subjected to vibrations, when stored, or in a tablet machine when passed through a hopper. Porosity is calculated by using the formula:

Porosity = Vb-VpVp

Porosity is frequently expressed in percentage. It is given by:

% porosity = ( 1- VpVb

8. Identification of drug sample:  It was confirmed by melting point determination and also by FT-IR spectral analysis
9. Drug excipient Compatibility study: The compatibility of the drug with excipients was determined by FT-IR spectral analysis. This study was carried out to detect any changes in the chemical constitution of the drug after it was combined with the excipients. The samples were taken for the FT-IR study

EVALUATION TESTS FOR MOUTH DISSOLVING TABLETS^7,8:

1. Weight variation: The weight variation test is conducted to ensure uniformity in the weight of tablets within a batch. The total weight of 20 tablets from each formulation is determined and calculated. The individual weight of each tablet is determined to find out the weight variation.

Table 3: Uniformity of weight according to USP Specification

2. Hardness: Hardness or tablet crushing strength (f_c), the force required to break a tablet in a diametric compression, was measured using the Monsanto tablet hardness tester. It is expressed in kg/cm².
3. Friability test: Friability test is done to assess the ability of the tablet to withstand abrasion in packing, handling, and transport. Friability is the loss of weight of tablets due to the removal of fine particles from the surface. The Roche friabilator is used for finding the friability of the tablets. Weigh 20 tablets from each batch and then place them in the Roche friabilator. Rotate the Roche friabilator at 25 rpm for 4 minutes. Dedust the tablets and weigh again. The percentage of friability is calculated using the formula:

% Friability =  W1- W2W1

Where, W₁ = weight of tablet before test

                     W₂= weight of tablet after test

4. Disintegration test:

In – vivo disintegration test: In – vivo disintegration test is carried out on 2 or 3 tablets in the mouth, and the time taken to disintegrate the complete tablet is noted.

In – vitro disintegration test: In – vitro disintegration test is measured by dropping a tablet in the beaker containing 50 ml of Sorenson’s buffer pH 6.8. Three tablets from each formulation are randomly selected, and in vitro dispersion is carried out.

5. In – Vitro Dissolution test: In – Vitro Dissolution test is carried out using USP Type II Apparatus, i.e., paddle type at 50 rpm. 900ml phosphate buffer pH 6.8 is used as dissolution medium, maintained at 37± 0.5. Withdraw the sample of 10 ml at specific time intervals of 2 minutes and filter. The amount of drug dissolved is determined by a suitable analytical technique.
6. Wetting time: The wetting time of tablets is measured by placing the five circular tissue papers of 10 cm diameter in a petri dish containing 0.2%w/v solution (3ml). A tablet is carefully placed on tissue paper. The time required for developing blue color on the surface of the tablet is noted as wetting time.
7. Water absorption ratio: A small piece of tissue paper folded twice is placed in a small Petri dish containing 6 ml of water. Put a tablet on the paper. The time required for complete wetting is measured. The wetted tablet is then weighed. Water absorption ratio is measured by using a formula

R= 100 X Wa-WbWb

Where,

W_b is the weight of the tablet before water absorption

W_a is the weight of the tablet after water absorption

8. Uniformity of dispersion: Two tablets are placed in 100 ml of water and stirred gently for 2 minutes. The dispersion is passed through mesh 22. The tablets, uniformity will be considered passing if no residue remains on the screen.
9. Stability Studies: The optimized formulation of MDTs is subjected to a stability study as per ICH guidelines to assess their stability with respect to physical appearance.

TECHNOLOGIES USED FOR THE FORMULATION OF MOUTH-DISSOLVING TABLETS⁹:

There are several technologies used in the formulation of mouth dissolving tablets, namely (1) Conventional technologies. (2) Patented technologies.

Table 4: Different Conventional and Patented technologies

Conventional technologies for mouth-dissolving tablets:

There are many conventional technologies for the formulation of MDTs. They are:

1. Freeze-drying method: Freeze-drying technology is one of the best methods for the formulation of mouth-dissolving tablets. It is also called Lyophilization. In this method, an amorphous porous structure is created that can be rapidly dissolved. Lyophilization is a process in which water is sublimed from the product after freezing. This results in preparations, which are highly porous, with a very high specific surface area, that dissolve rapidly and improve absorption and bioavailability.
2. Tablet Molding: These are of two types of molding processes. The solvent method and the heat method. The solution method involves moistening the powder blend with a hydro- alcoholic solvent, followed by compression at low pressures in molded plates to form a wetted mass (compression molding). Below, Air-drying is done to remove the solvent. The tablets manufactured in so form are low compact. Whereas in the heat molding process, a suspension is prepared that contains the drug, agar, and sugars like mannitol and lactose. This suspension is poured into the blister packaging wells, resulting in the formation of jelly, and is dried at 30 ⁰C under vacuum.
3. Direct Compression: This is a simple and the most economical method. In this method, the drug and other components are compressed without any preliminary treatment. The concentration of the disintegrant has a great impact and is inversely proportional to the disintegration time. This method can be useful for a limited number of drugs.
4. Sublimation: The principle involved in the formulation of MDTs by sublimation is the addition of a volatile salt to the tableting components. This results in a homogeneous mixture; removal of volatile salts creates pores in the tablet. This helps in rapid disintegration in the mouth. The drugs that can be formulated by using this method are camphor, Naphthalene, etc.

Patented technologies for mouth-dissolving tablets:

1. Zydus Technologies: This Technology was discovered by R P Scherer, a subsidiary of Cardinal Health. In this method, the drug is lyophilized and freeze-dried in water water-soluble matrix material like gelatin. It is a self-preserving formulation as the water concentration in the freeze-dried product is very less. This prevents microbial contamination.
2. Orasolv technologies: This was prepared by CIMA labs. Orasolv is a slightly effervescent tablet, as it can rapidly dissolve in the mouth. the active ingredients are dispersed in saliva due to the action of the effervescent agent, resulting in taste masking. The major disadvantage of this method is low mechanical strength. the formulated tablets need to be packed in a specially designed pack because they are very soft and fragile in nature.
3. Durasolv technologies: These are second-generation mouth dissolving tablets by CIMA Labs. It is similar to Orasolv technology but has a much higher mechanical strength. The product formulated using this technology is fast and cost-effective. One of the major disadvantages of this technology is compatibility problems with large doses of active ingredients. this technology is currently available in two products, namely Nulev and Zorlip.
4. Wowtab technologies: This technology was discovered by Yamanouchi. Wow means “Without water”. Wowtab technology is an intrabuccal soluble. This compressed tablet consists of granules made with saccharides of low and high mouldability. Mouldability

PATENTS ON MOUTH-DISSOLVING TABLETS¹⁰:

There is an account of some recent patents in the field of mouth-dissolving tablets, as shown in Table 5.

Table 5: Patents on mouth-dissolving tablets

Some of the marketed products of mouth dissolving tablets are illustrated in Table 6.

Table 6: Marketed products of mouth-dissolving tablets

Drugs	Product	Super- disintegrants	Manufactured By	Uses	Images
Olanzapine	Zyprexa Zydis	Crosspovidone	Eli Lilly and Company	It is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder.
Ondansetron	Zofran ODT	Crosscaramellose	Glaxo Smith Kilne (GSK)	It is used to prevent nausea and vomiting caused by cancer medicines(chemotherapy) or radiation therapy.
Alprazolam	Niravam	Crospovidone	Schwarz Pharma	It is used as a CNS Depressant and is used to treat anxiety and panic disorders
Donepezil	Aricept ODT	Crosspovidone	Eisai Inc.	It is used to treat dementia and Alzheimer’s disease.
Rizatriptan benzoate	Maxalt MLT	Crospovidone, Carboxymethylcellulose calcium,	Merck and Co.	It is used in the acute treatment of migraine with or without aura.
Aripiprazole	Abilify Discmelt	Croscarmellose sodium, Crospovidone	Otsuka America/ Bristol-Myers Squibb	It is used to treat schizophrenia, bipolar disorder, depression, and Tourette’s disorder.
Lansoprazole	Prevacid SoluTab	Crospovidone, Microcrystalline cellulose, Hydroxypropyl cellulose	Takeda Pharmaceuticals	It is used to treat duodenal and gastric ulcers, erosive esophagitis, and gastroesophageal reflux disease
Metoclopramide hydrochloride	Reglan ODT	Crospovidone, microcrystalline cellulose	Oaknet Healthcare Pvt Ltd	It is used to treat nausea, vomiting, indigestion, and heartburn.
Carbidopa levodopa	Parcopa	Crospovidone, Microcrystalline cellulose	Schwarz Pharma	It is used to treat symptoms of Parkinson's disease.
Risperidone	Risperdal M-Tab	Microcrystalline cellulose, Hypromellose,	Janssen	It is used to treat schizophrenia, bipolar disorder, and irritability.