An Overview of DisintegrantsPrint
The ability of an active ingredient to be absorbed by the body depends on its bioavailability, which is affected by the active ingredients solubility and absorbency as it passes the gastrointestinal membrane and is subjected to the gastrointestinal fluid. The ability to be absorbed depends on several physical and chemical composition of the drug. That said, the rate in which drugs dissolves depends on the tablet’s disintegration.
A drug for example, has a slow dissolution rate when it is capped inside a non-disintegrating shell due to the fact that only a part of the drug is exposed to the fluid. In order for tablets to pass the disintegration requirements, an official test is undertaken for every batch manufactured.
One important medium added to the formulation of tablets or capsules are the disintegrants which are added to ensure the breakup of the tablet when it comes into contact with liquid or fluid matter. The process where the basic matters are combined and merged before the drug dissolves is known as the “disintegration process” and the vehicle or medium which is used to break it up is called as disintegrant.
The purpose of adding the disintegrants in the formulation is to increase the surface area of the capsule and to soften the binding matter that keeps the capsule together.
Figure.16. Schematic Representation Of Tablet Disintegration And Subsequent Drug Dissolution
Tablet Disintegrants Methods
Tablets break down depending on the following method:
- Through the Capillary Action/Wicking
- Through Swelling/Distension
- Caused by the Heat/ Air Expansion
- Caused by Disintegrating Forces
- Caused by Deformity of the Tablet
- Caused by the Release of Gas Materials
- Triggered by enzymatic action
A. Through the Capillary Action/Wicking
The first step in the process of disintegration is through the capillary action. When a tablet is placed into an ideal liquid medium, the medium will quickly penetrate the tablet and replace the air inside the tablet matter and weaken the tablet resulting to the breakage of the matter. The level of water absorbed by the tablet depends on its “hydrophilicity” as well as on its tableting conditions. This type of disintegrant will find the porous surfaces and low surface tension ideal as it helps to create a network of hydrophilicity around the drug matter.
B. Through Swelling/Distension
The most popular and widely accepted method of tablet disintegration is swelling. Some tablets with high porosity have poor disintegration due to the fact that it lacks enough swelling force. This is not the case when swelling provided is sufficient especially for tablets with low porosity. Some tablets do have high packing fraction which can hinder the penetration of the fluid inside causing the disintegration process to slow down.
C. Caused by the Heat/ Air Expansion
Another method includes the disintegration through heat or air expansion. When tablets that have exothermic properties are wetted, it releases stress caused by the sudden expansion of the air capillary which starts the disintegration process. The application process is limited only and should not be used as a way to describe or explain the actions of other recent or modern agents.
D. Caused by Disintegrating Forces
Another method of which disintegration is also observed is through non-swellable disintegrants. In a theory proposed by Guyot-Hermann, the “particle repulsion theory” is based on the effects that non-swelling matters can also cause the tablet’s disintegration. The electric repulsive forces between the matters is the driving vehicle for the disintegration although water is needed in order to achieve the break up. Scientists discover that repulsion is only secondary to wicking.
E. Caused by Deformity of the Tablet
One research by Hess proves that during tablet compression, the disintegrant particles are deformed and yet will still form their normal pattern when it comes into contact with any aqueous liquid. In certain instances, the swelling capacity of the starch material greatly improved when the particles are deformed during the compression process causing the tablet to break. The use of starch as a tool is one of the recent development and is still undergoing further studies.
Figure.18. Disintegration By Deformation And Re
F. Caused by Release of Gas Materials
Another method of disintegration is done through the release of gas materials, specifically carbon dioxide caused by the wetting of substances such as bicarbonate and carbonate with that of citric (or tartaric) acid. The pressure results to the disintegration inside the tablet. This type of method is done by a chemist when one needs a rapid dissolving tablet or a fast-disintegrating tablet. Due to the high sensitivity level of these chemical compounds, small changes such as change in humidity level or sudden or sharp drop in temperature levels can readily cause reactions. Due to its sensitivity to even minute changes, these disintegrants are handled inside a strict and controlled environment especially during the tablet manufacturing process. The compounds are mixed together with the rest after the compression or can be added to the formulation.
G. Triggered by Enzymatic Action
Under this method, the disintegrant itself are the enzymes found inside the body. The enzymes found in the body attacks the binder resulting to the disintegration process.
|Cellulase||Cellulose and it's derivative|
Procedures of Adding Disintegrants
The way disintegrants are added to the formulation is an essential process. There are several ways that disintegrants are added:
- Intragranular – added before the granulation process
- Extragranular – added before the compression process
- During both intragranular and extragranular processing
During the extragranular process, it takes about 50% to start the breakup of the tablet whereas in the intragranular process, the addition of the disintegrants results to the granules being turned into fine particles.
Starch. Starch is a common and widely used disintegrating agent, even before the discovery of potato and corn starch as disintegrants as well in 1906. One problem with the use of starch is that natural or native varieties have certain restrictions or limitations resulting to the discovery and eventual use of modified starches that have the qualities necessary.
Starch uses wicking and restoration of deformed particles as method of disintegration. When the starch particle comes in contact with any liquid matter, stress is also released resulting to the disruption of the hydrogen compound bond during compression.
According to Lowenthal & Wood, in order for starch to successfully break the tablet surface, one needs plenty of starch agglomerates. The three best conditions for the tablet to rapidly disintegrate is through low compression pressure, presence of water or any liquid and high number of starch agglomerates.
One important thing to consider when using starch as disintegrant is the concentration level to be added to the tablet. If the concentration level is low, then success is not achieved as there are insufficient channels to perform wicking. Too much concentration on the other hand would result to difficulty in compressing the tablet.
Pregelatinized starch is another type which makes use of swelling to break up the tablet. It is formed by the rupturing and hydrolyzing of the starch grain. Concentration percentage is at 5-10% with the disintegrants directly compressible.
When starch is modified by the chemical carboxy methylation and is cross linked, a higher swelling occurs resulting to faster disintegration of the tablet. This type of starch is marketed in the industry as cross-linked starch, an example of which is the sodium starch glycolate. Other low version of modified starch available is labelled under the Primojel and Explotab.
Modified starches swell extensively with optimum concentration levels of 4-6% including minimum gelling. When the starch reaches its limit, it produces a sticky and gelatinous matter that helps in increasing the disintegration process as it helps the tablet resist breaking up. Due to their high swelling capacity, modified starches are highly efficient even if there is only low concentration.
List Of Disintegrants
|Disintegrants||Concentration in Granules (%W/W)||Special Comments|
|Starch USP||5-20||Higher amount is required, poorly compressible|
|Avicel(r)(PH 101, PH 102)||10-20||Lubricant properties and directly compressible|
|Solka floc(r)||5-15||Purified wood cellulose|
|Alginic acid||1-5||Acts by swelling|
|Alginic acid||1-5||Acts by swelling|
|Na alginate||2.5-10||Acts by swelling|
|Explotab(r)||2-8||Sodium starch glycolate, superdisintegrant.|
|Amberlite(r) (IPR 88)||0.5-5||Ion exchange resin|
|Methyl cellulose, Na CMC, HPMC||5-10|
|Carbon dioxide||Created insitu in effervescent tablet|
Cellulose and Its By-Products
NaCMC or Sodium carboxy methylcellulose and Carmellose sodium are two chemical compounds that are highly hydrophilic, attracting water than other compounds and are water soluble. That said, when the compounds are modified through internal crosslinking it becomes water insoluble, example of which is the crosscarmellose. Crosslinked cellulose increases their volume by as much as 4-8 times when it comes into contact with liquid matter.
Due to its insolubility and usage of wicking, Microcrystalline cellulose is one of the ideal disintegrants. The humidity breaks down the hydrogen compound that bonds the other properties in the cellulose. The cellulose is also a great binder and can cause statics when exposed to excessive humidity level. In order to prevent granulation separation, the cellulose is partially dry to remove excess moisture.
Hydrophilic Colloidal Substance – Alginates
Alginates are an example of hydrophilic colloidal substances that has a higher sorption ability. The alginic acids are water insoluble and is slightly acidic when reacting to other compound, making its use only for neutral or acidic granulation. Alginates can be used together with multivitamins, ascorbic acid and even together with acid salts of those organic bases which is not the case with MCC or starch derivatives.
This type of derivatives has the highest water absorption capacity than other available disintegrants such as sodium and starch. It also has the predisposition of adsorbing other drugs.
Aside from the ones mentioned above, other disintegrants include those that produce gases, hydrous aluminum silicate and surfactants. Those gas producing agents are added to tablets that are soluble, dispersible and effervescent.
Other derivatives includes Polyplasdone XL10 and Polyplasdone XL which can cause the disintegrant process through swelling, deformation and wicking. The XL does not decrease the tablet’s hardness although it improves the dissolution of the tablet as well as increase rapid disintegration. The Polyplasdone is developed with small particle size making it ideal for a smooth mouth feel when taken, the tablet also dissolves quickly. Tablets that are labelled as chewable no longer need additional disintegrants.
The demand for faster and more rapid disintegrating formulation is demanded every day and as such, pharmacists look for ways of formulating disintegrants resulting to what the industry called “superdisintegrants”. These derivatives are developed to have greater efficiency even at a low concentration level. They are also effective intragranularly. That said, one disadvantage is that they are “hygroscopic” or moisture absorbent/adsorbent which can affect drugs that are moisture-sensitive.
Superdisintegrants causes the particles to swell, the built up pressure causes the tablet to break as a result. The rapid absorption of the liquid matter also increases the volume causing disintegration.
Figure.19. Mechanism of superdisintegrants by swelling
List Of Superdisintegrants
|Superdisintegrant||Example of||Mechanism of Action||Special Comment|
-Swells 4-8 folds in < 10 seconds.
-Swelling and wicking both.
-Swells in two dimensions.
-Direct compression or granulation
|Crosslinked PVP||Swells very little and returns to original size after compression but act by capillary action||Water insoluble and spongy in nature so get porous tablet|
Sodium starch glycolate
|Crosslinked starch||Swells 7-12 folds inSwells in three dimensions and high level serve as sustain release matrix|
Alginic acid NF
|Crosslinked alginic acid||Rapid swelling in aqueous medium or wicking action||Promote disintegration in both dry or wet granulation|
|Natural super disintegrant||Does not contain any starch or sugar. Used in nutritional products.|
|Calcium silicate||Wicking action||
-Optimum concentration is between 20-40%
Causes that Influence Disintegration
Fillers affect the speed and the process of the tablet’s disintegration due to their solubility and compression features. Fillers that are soluble can cause increase in the viscosity level of the introduced liquid matter reducing the strength of the disintegrating agents. As they are water soluble, they will liquefy instead of disintegrate. Insoluble ones can cause increased disintegration provided that sufficient amount of disintegrants are introduced.
In a study conducted by Chebli and Cartilier, they proved that tablets that are made with water soluble fillers such as spray dried lactose will disintegrate slowly due to the fact that it has no solid surface area where the disintegrating process can be used with the exemption of the tablets that were created with crystalline lactose monohydrate.
Most lubricants are water repellent or what are known as “hydrophobic”. Once the formula is mixed together, lubricants are added to protect the surface area and at the same time these can also cause the tablet’s disintegration.
If the tablet has little to no disintegrants, the use of lubricants can have a negative effect especially on the uptake of water and can even affect highly concentrated swelling disintegrants. That said, if there is strong formulation mixed in the table, the disintegration time is not affected with the exception of sodium starch glycolate which is unaffected even when exposed to hydrophobic lubricants.
Effect of Surfactants
|Sodium lauryl sulfate||"Good-various drugs
Poor - various drugs"
|Polysorbate 40 & 60||Poor|
|Poly ethylene glycol||Poor|
(Good - decrease in disintegration time, Poor - increase in disintegration time)
The chemical compound sodium lauryl sulphate can increase water absorption of starch and also affect the liquid penetration for tablets. Surfactants for one, can help reduce the hydrophobic level of drugs as the higher the hydrophobicity the longer the disintegration time. It should be noted that they are only effective within a certain range.
The disintegration time of water soluble tablets remains almost the same with the introduction of nonionic surfactants; however when surfactants are added water penetration speed level increases especially for granules that are made with slightly soluble materials.
- Disintegrants are added to tablet to induce breakup when it comes in contact with aqueous fluid.
- Disintegration by capillary action or by swelling is the major mechanism for disintegrants.
- Disintegrant can be added intragranular or extragranular or at both stages.
- Superdisintegrants have greater efficiency at low concentration and hence, their demand is increasing day by day.