A Comprehensive Review on Fast Dissolving Tablets: Formulation Technique and Evaluation Parameter

1.1 Overview of Fast-Dissolving Tablets¹

Orally disintegrating tablets (ODTs) and fast dissolving tablets (FDTs) are solid oral dose forms that dissolve quickly in the mouth, typically in a matter of seconds to a minute, without the need for water. An ODT is "a solid dosage form containing medicinal substances which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue," according to the U.S. Food and Drug Administration (FDA). These tablets are especially helpful in settings when water is not easily accessible and for patients who have trouble swallowing traditional tablets or capsules, such as pediatric, elderly, or mental patients. Many methods, including lyophilization, direct compression, spray drying, and sublimation, are used to create FDTs. FDTs include benefits such better bioavailability, quicker start of action, and more patient compliance in addition to being simple to administer.

Superdisintegrants like sodium starch glycolate, croscarmellose sodium, and crospovidone, which facilitate rapid tablet breakup upon contact with saliva, are the main means of achieving this rapid disintegration. In addition to being easy to administer, FDTs offer benefits like improved bioavailability, faster onset of action, and increased patient compliance.

 The most common dosage forms are tablets and capsules, but one significant disadvantage of these forms is "dysphagia," or difficulty swallowing, which is linked to a number of conditions like:

1. Parkinsonism 
2. Motion sickness 
3. Unconsciousness 
4. Elderly patients 
5. Children 
6. Mentally disabled persons 
7. Unavailability of water

1.2  The Development of Fast-Dissolving Tablets (FDTs)²

By creating a convenient dosage form for administration and improving patient compliance, recent developments in innovative drug delivery systems (NDDS) seek to improve the safety and toxicity of pharmacological compounds. One such strategy is the creation of oral disintegrating pills, which enhance patient compliance and are helpful for dysphagic, elderly, and pediatric patients. Without the need for water, this dose form quickly dissolves or disintegrates in the oral cavity in a matter of seconds. Faster medication release has been thought to be limited by tablet disintegration. The pharmaceutical industry has extensively investigated the use of natural gums and mucilage as thickeners, stabilizers, gelling agents, emulsifiers, granulating agents, binder, suspending agents, film formers, disintegrants, and sustain release matrices.

2. Advantages and Challenges of FDTs²

Figure 1 Advantages of FDTs

1. Easy administration to patients who are unable to swallow, such as the elderly, stroke victims, bedridden patients, individuals with renal failure, and patients who refuse to swallow, such as pediatric, geriatric, and psychiatric patients  
2. The dose form does not require water to be swallowed, which is a very practical advantage for patients who are traveling and do not have instant access to water. 
3. The medicine will dissolve and absorb quickly, resulting in a quick commencement of effect. Because saliva travels down into the stomach, certain pills are absorbed from the mouth, throat, and esophagus. The drug's bioavailability is greatly enhanced in these situations.
4. A pleasant mouthfeel aids in altering the impression of medication as a bitter tablet, especially in children who are impacted. 
5. By avoiding the possibility of choking or suffocating due to physical obstruction, oral administration of traditional formulations improves safety for patients who are unable to swallow, including the elderly, bedridden patients, patients with renal failure, and patients with swallowing difficulties, including pediatric, geriatric, and psychiatric patients. 
6. Quick medication intervention. 
7. Pre-gastric absorption of medication from the mouth, throat, and esophagus as saliva goes down allows for increased bioavailability and fast absorption. 
8. Easy to administer and compliant for patients who are bedridden or incapacitated, as well as for travelers and busy persons who don't always have access to water. 
9. A medication's pleasant mouthfeel can assist patients, particularly young ones, perceive it as a sour tablet. By avoiding the possibility of choking or suffocation from physical obstruction, oral administration of conventional formulations improves safety.

3. Fast-dissolving pill drawbacks: [3–4] 

1. Because fast-dissolving tablets are hygroscopic—that is, they collect moisture from the atmosphere—they must be stored in a dry environment.
2. The mechanical strength of the tablets is typically insufficient. Because of this, handling must be done carefully.
3. If improperly developed, the tablets may leave the mouth with an unpleasant taste and/or grittiness.
4. It is challenging to synthesize medications with comparatively greater dosages into fast-dissolving tablets, such as 500 mg of ciprofloxacin, 900 mg of clozapine, 800 mg of thioridazine, etc.
5. These tablet formulations might not be suitable for people who have dry mouth as a result of decreased salivation.
6. Fast-dissolving pills might not be the ideal option for patients who also use anticholinergic drugs.
7. Fast-dissolving tablets are highly absorbent, soft, molded, or packed in a tablet with low compression, making them difficult to handle because they are breakable and friable.
8. For protection during storage and shipping, it requires specific packaging.
9. Fast-dissolving tablets should not be used for medications that need frequent dosing, regulated or sustained release, or a short half-life.. 

4. Criteria for fast dissolving tablets 

Fast-dissolving tablets (FDTs) are designed to disintegrate and dissolve rapidly in the moth without need of water. The key criteria for formulating FDTs include: 

1. Disintegration Time 
2. Mechanical strength
3. Uniformity of dose
4. Taste masking 
5. Drug compatibility 
6. Wettability 
7. Manufacturability

5.  CHALLENGES IN FORMULATING FDTs:  ¹³

FDTs are either crushed into tablets with a very low compression force or have an extremely porous, softmolded matrix to enable oral disintegration. Because of this, the tablets are sometimes brittle and/or friable, challenging to handle, and often need special peel-off blister packaging, which can raise the price. The only technologies capable of producing tablets sturdy and hard enough to fit in multiple-dose bottles are the wow tab and Durasolv.

5.1 Hygroscopicity ¹⁵ 

Due to their hygroscopic nature, a number of FDTs are unable to retain their physical integrity in typical humidity and temperature circumstances. They therefore require humidity protection, necessitating the use of specialist product packaging. 

Quantity of medication: The drug dose for lyophilized dosage forms must be less than 60 mg for soluble pharmaceuticals and less than 400 mg for insoluble drugs.

5.2 Amount of Drug¹⁸ 

The quantity of drugs that can be included in each unit dose limits the amount of Drug18 ODTS technology.

The dosage in lyophilized form must be less than 60 mg for poorly dissolving pharmaceuticals and less than 400 mg for insoluble substances. When making oral films and wafers that disintegrate quickly, this feature poses a unique challenge. 

5.3 Solubility in water ¹⁵  

Water-soluble medications create eutectic mixtures, which induce a freezing-point depression and a glassy solid that may crumble when it dries due to the sublimation process' loss of supporting structure. 

5.4 Water solubility¹⁵  

Water-soluble drugs form eutectic mixtu.res, which result in freezing-point depression and the formation of a glassy solid that may collapse upon drying because of loss of supporting structure during the sublimation process. Size of tablet: It has been reported that the easiest size of tablet to swallow is 7-8 mm while the easiest size to handle was larger than 8 mm. Therefore, the tablet size that is both easy to take and easy to handle is difficult to achieve.

5.5 Tablet size 

The tablet's dimensions dictate It's simple to take. According to reports, tablets that are between 7 and 8 mm in length are the easiest to handle, while those that are longer than 8 mm are the easiest to ingest.

5.6 Mouth Feel¹⁸ 

FDTs shouldn't shatter in the mouth. bigger particles. The particles that are created when the FDTs break down ought to be as little as feasible. Additionally, adding flavors and cooling ingredients like menthol improves the texture. Additionally, adding flavors and cooling ingredients like menthol improves the texture. In the oral canal, mouth feel-FDTs shouldn't break up into bigger particles. The texture is further improved by incorporating flavors and cooling components like menthol. 

6. Mechanism of action of disintegrants ^(2,19,20) 

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

1. By capillary action 
2. By swelling 
3. Because of heat of wetting 
4. Due to release of gases 
5. By enzymatic action 
6. Due to disintegrating particle/ particle repulsive forces 
7. Due to deformation.

1. Through capillary action 

The initial step is always disintegration through capillary action. The intermolecular bond is weakened and the tablet is broken up into tiny particles when it is submerged in the proper aqueous medium. The medium enters the tablet and replaces the air adsorbed on the particles. The hydrophilicity of the medicine or excipient and the tableting conditions impact how much water tablets absorb. 

2. Through swelling 

Swelling Superdisintegrants that function through this mechanism operate on the basis of "swell" and "burst." When the superdisintegrants come into touch with water or saliva, the aqueous phase applies more adhesive force to the superdisintegrants than to other excipients and drugs, which causes the tablet to expand, thrust, or break apart. Superdisintegrants swell quickly when they come into contact with water, including cross-linked polymers like crospovidone (PVPP) and croscarmellose sodium (CCS). The tablet matrix is compressed by this swelling, which causes it to break apart and disintegrate. 

Figure 2 Swelling mechanism

3. Due of the wetting's heat 

Capillary air expansion creates localized stress when exothermic disintegrants are wetted, which facilitates tablet breakdown. However, this hypothesis only applies to a small number of disintegrants and does not account for the behaviour of most contemporary disintegrating agents.

4. Due of the gasses' release 

When certain super disintegrants come into contact with water, such as sodium bicarbonate, they produce gas. The tablet disintegrates as a result of the internal pressure created by this gas production.

5. By enzymatic action 

Through an enzymatic process the body's enzymes function as disintegrants. These enzymes aid in breakdown by interfering with the binder's ability to bind. In reality, the tablet ruptures due to expansion, pressure exerted radially or externally, or the rapid absorption of water, which greatly increases the number of granules and encourages disintegration.

6. Due to disintegrating particle/particle repulsive forces 

This perspective holds that tablets containing "non-swellable" disintegrants are the source of the swelling. Tablet disintegration is the outcome of particles rejecting one another due to the electric repulsive force. Biological enzymes are used as disintegrants in this method. Salivary enzymes can readily break down the binder in the pill. These binders are catalyzed and the pill dissolves when they come into contact with saliva. Additionally, this technique releases the drug as granules by combining the swelling and rupture. Binder starch is broken down by amylase. Carragenase breaks down alginate, hemicellulose breaks down gums, and invertase breaks down sucrose. 

7. Due to deformation

Certain disintegrants contain a high degree of flexibility. Upon exposure to water, they distort and produce channels within the tablet, enabling water penetration and dissolution. Because starch grains are "elastic," they can bend under pressure and then revert to their original shape when the pressure is released. Because tableting permanently distorts the grains, "energy rich" starch granules are more capable of swelling than starch grains that have not undergone pressure-induced distortion. 

7. Ideal properties of Fast Dissolving tablets:¹¹ 

• It should dissolve or disintegrate in the mouth in a matter of seconds and doesn't require water to consume.
• Have a high drug loading; 
• Work well with other excipients and flavor masking 
• Have a pleasant mouthfeel; 
• After oral delivery, leave little to no residue in the mouth;
• Show little reactivity to environmental factors like temperature and humidity 

8.  Super disintegrants (synthetic, natural, co-processed) ^(5,21)

Super disintegrants the fundamental strategy for creating MDTs is the use of disintegrants. Disintegrants are crucial to the dissolution and disintegration of MDT. To guarantee rapid disintegration and high dissolution rates, it is crucial to select an appropriate disintegrant at the ideal concentration. Super disintegrants offer rapid disintegration because of the formulation's combined impact of swelling and water absorption. Super disintegrants expand, increasing the carrier's wetted surface. This increases the system's wettability and dispersibility, which improves disintegration and dissolution. The critical concentration of the disintegrant can be used to determine the ideal concentration of the super disintegrants.

8.1 Types of super disintegrants  

1. Natural super disintegrants  
2. Synthetic super disintegrants  
3. Co-processed super disintegrants  

1. Natural super disintegrants  

Mucilage from Ispaghula husks (Plantago ovata)  

The dried seeds of the plant known as Plantago ovata are included in ispaghula husk, together with the mucilage found inside the seeds' skin. Plantagoovata mucilage serves a variety of purposes, including binding, dissolving, and preserving qualities.  Compared to other super disintegrants, mucilage has a very high percentage of swelling index (around 89±2.2% v/v), making it a super disintegrating agent utilized in the formulation of fast-dissolving tablets.  

Gum made of xanthan  

Xanthan gum that's derived from Xanthomonas campestris is official in usp with excessive hydrophilicity and poor gelling tendency.  It has poor water solubility and large swelling properties for faster disintegration.

Gellan gum 

Gellan gum's strong hydrophilicity and on-the-spot swelling properties when it comes into touch with water could be the cause of the tablet's disintegration. When using gellan gum at a 4% w/w concentration, the tablet completely dissolves in 4 minutes.

Silicon dioxide, chitin, and chitosan 

Through a deacetylation reaction in an alkaline media, chitin is naturally removed from the shell wastes of shrimp, crab, lobster, krill, and squid and utilized to make chitosan. Chitosan is a well-known herbal polysaccharide with a wide range of uses in the pharmaceutical sector. 

2. Synthetic super disintegrants  

Modified starch (primojel, sodium starchglycolate)  

The sodium salt of starch's carboxymethyl ether is known as sodium starch glycolate. These modified starches are created by cross-linking potato starch to provide a product with improved disintegration qualities. 

Crospovidone, or cross-linked polyvinyl pyrrolidone  

In order to create the volume expansion and hydrostatic pressure necessary for speedy disintegration within the mouth, crospovidone quickly wicks saliva into the tablet.  

Modified celluloses (sodium croscarmellose)  

Even though it quickly grows to four to eight times its original volume when in contact with water, it is completely insoluble in water. Croscarmellose sodium has a specific surface area of 0.81-0.83 m2/g and a swelling index of 65±1.7% v/v. It can be used in both wet-granulation and direct compression tablet formulations. 

3. Co-processed super disintegrants: 

This is mainly predicated on the radical notion that two to three excipients interact at the particle level, with the goal of providing a synergy of functionality development and altering the taste of an individual's undesirable characteristics. Excipient granules with enhanced characteristics are created when excipients are co-processed.  in contrast to physical additive combinations such as enhanced compressibility and flow characteristics.   reduced susceptibility to lubricants and improved complete uniformity and dilution capacity.

9. Manufacturing Techniques⁶

Some of the methodologies which are employed for the formulation of FDTs are 

1. Disintegrant addition method 
2. Freeze-drying/Lyophilization 
3. Direct compression 
4. Sublimation 
5. Spray drying 
6. Tablet molding 
7. Mass extrusion 
8. Melt granulation 
9. Cotton candy process 

1. Disintegrant addition method 

One of the often-used methods for creating FDTs is the disintegrant addition procedure. This method is inexpensive and simple. This method involves adding various excipients and the necessary concentration of super disintegrants to the medication, which is then compacted into tablets. Super disintegrants that are frequently used include calcium silicate, gellan gum, xanthan gum, sodium starch glycolate, crospovidone, and croscarmellose. This method is used to set up oxybutynin FDTs.  

2. Freeze-drying/Lyophilization

It is a pharmaceutical process that makes it possible to dry biological materials and heat-sensitive medications at low temperatures by utilizing the valuable resource of sublimation and the vacuum's ability to remove water. The process involves dissolving or dispersing drugs in a carrier's aqueous medium, transferring them to premade blister packs, flushing them with nitrogen to prevent freezeout, and placing them inside the refrigerator to complete the process. Lyophilization techniques are characterized by their high porosity, distinct surface area, and rapid oral dissolution, which results in high medication bioavailability. The main disadvantages are the high cost, time-consuming process, fragility, and stability issues under stress conditions, rendering typical packing unnecessary for this dosage form.

3. Direct compression

It is the most straightforward method of producing tablets. Direct compression involves a small number of processing stages, widely accessible excipients, and standard equipment.

Additionally, the final weight of the pill can easily surpass that of previous production methods, and high doses can be allowed.

Advantages of   direct compression