An Overview of DisintegrantsPrint
The ability of the active ingredient in a drug to be absorbed by the body depends on its bioavailability. This, in turn, is a function of the solubility of the active ingredient in the gastrointestinal fluids as the drug passes through the intestines. The ability to dissolve depends on the physical form and chemical composition of the drug. Nonetheless, the rate at which drugs dissolve in the biofluids of the body is influenced by the tablet’s disintegration. For most tablets, it is necessary to overcome the cohesive forces that bind together the particles within the tablet that were introduced as a result of the tablet pressing process. This is made difficult in some cases through the introduction of materials that are added before the tabletting process with the aim of binding the particles together. For some tablets disintegration is even more difficult as the active ingredients are capped inside a non-disintegrating shell. The shell protects the bulk of the materials from being exposed to the gastric fluids. To ensure that tablets disintegrate at a sufficiently fast rate within the body, formal disintegration tests can be routinely carried out on each batch that is manufactured.
A disintegrant is an excipient that is incorporated into the formulation of tablets or capsules to promote their disintegration when they come into contact with liquid or fluid matter. Several types of disintegrant have been routinely used for many years and may be distinguished according to their mode of action: (a) those that enhance the action of capillary forces that promote the absorption of water (by wicking) (b) those that swell on contact with water and (c) those that release gases leading directly to disintegration of the tablet. The general purpose of incorporating one or more disintegrants in the product formulation is to increase the surface area of the product and soften the binding matter that holds together the solid particles that make up the product. The net effect is that a tablet when exposed to aqueous media disintegrates first into granules, and then into fine particles. The rate of dissolution in the media increases as the particle size reduces and is greatest when the tablets or capsules reduced to fine particles, as shown schematically in Figure. 1. Rapid dissolution increases the rate of absorption of the active ingredient by the body, producing the desired therapeutic action. Note that tablets that are labelled as chewable generally do not require a disintegrant to be incorporated in the formulation.
Figure.1. Schematic representation of tablet disintegration and subsequent drug dissolution
Tablet Disintegrants Methods
Tablets disintegrate by:
- capillary action and wicking
- swelling or distension
- as the result of expansion caused by heating entrapped air
- disintegrating forces
- deformation of the tablet
- the release of gaseous materials
- being triggered by enzymatic action
Each of these mechanisms and examples of disintegrant materials is described below.
Capillary action and wicking
There is a general consensus that water uptake into the tablet by capillary action is the necessary first step in the disintegration process. When a porous tablet is placed in an aqueous liquid, the liquid will quickly penetrate the pores of the solid by capillary forces. The pores act as a wick that draws liquid into the solid. Such liquid absorption can lead to breakage of the solid matter of the tablet by weakening the forces that hold together the solid particles.
The amount of aqueous liquid that is absorbed depends on the ‘hydrophilicity’ of the solid material, sometimes referred to as its ‘wettability’. Typically between 5 and 20% by weight is incorporated into the material before tabletting. Such levels do not significantly change the pore structure of the material. Absorption of water also depends on the pore size distribution of the solid material which in turn is dependent on the particle size distribution in the tablet starting material, and on the manner in which the disintegrant is added (e.g., whether it is added before or after the solid granulation process). It is also possible that the tabletting conditions can affect the water uptake, since the density and porosity may to some extent depend on the force used to compress the tablet. Water will be drawn into large pores more slowly than small pores, and to increase the rate of disintegration an disintegrant may be incorporated into a table that promotes a low surface tension of the liquid (i.e., increases the hydrophilicity of the solid), thereby encouraging liquid to be absorbed around the particles of drug matter.
Swelling and Distension
Tablets may swell as a consequence of liquid becoming absorbed in the pores of the solid material through capillary action and wicking. If absorption of liquid is low, the rate of swelling will be low. If liquid is absorbed, it can exert considerable forces within the pores, especially within small hydrophilic pores, causing particles of either active agent or excipient to swell and fracture. Forces may be great enough in solids of high packing density for stresses to penetrate throughout the material causing severe disintegration.
The incorporation of a disintegrant that will swell on contact with water is one of the most practiced methods of promoting disintegration in tablets.
Caused by the Heat/ Air Expansion
Some tablets contain materials that react with water exothermically. In other words, heat is generated within the pores of the solid on account of a reaction between the absorbed water and the solid material. The generated heat can cause a rapid rise in internal temperature and expansion of the air trapped within the pores both of which can start the disintegration process. This method of disintegration is limited to only certain materials and was attributed as one of the modes of action of starch. It does not describe the action of most modern disintegrants.
Caused by Disintegrating Forces
A further method of disintegration is observed in the case of non-swellable starch-based disintegrants. The “particle repulsion theory” proposed by Guyot-Hermann is based on the notion there are electrical repulsive forces between similarly charged particles, and that these effect particle disintegration. The fact that water needs to be present to achieve the breakup suggest that such repulsive forces are only secondary to water absorption or wicking in terms of promoting material disintegration.
Deformation of the tablet
Research by Hess has shown that during tablet compression, particles of starch disintegrant are deformed under stress and will revert to their normal structure when the material is brought into contact with any aqueous liquid. Hess showed that the swelling capacity of starch material is greatly improved when the particles are deformed during the compression process. The effect is not fully understood and needs to be evaluated with further research.
Figure.18. Disintegration By Deformation And Repulsion
Caused by Release of Gas Materials
Effervescent tablets that release carbon dioxide when introduced into water are the basis for another type of disintegrant. The simplest is a mixture of solid chemical comounds such as citric or tartaric acid and a carbonate or bicarbonate. The release of gas when water is absorbed by the tablet leads to rapid disintegration within the tablet. Such gas-producing disintegration is favoured when a rapid dissolving tablet or a fast-disintegrating tablet is required. The problem with using such materials is that they are highly sensitive to environmental conditions such as temperature and humidity. For this reason gas-producing disintegrants are handled in a strictly controlled environment, and are introduced into the product mixture usually immediately prior to compression in the tablet manufacturing process.
Triggered by Enzymatic Action
Small amounts of enzymes may be added to the product. Alternatively the enzymes found inside the body may attack excipients such as starch or other binder materials, thereby promoting disintegration.
|Cellulase||Cellulose and it's derivative|
Adding disintegrant to the product formulation
The procedure of adding disintegrant to a formulation can have a profound influence on its effectiveness. Disintegrants can be added:
- Intragranular – the disintegrant is added before the granulation process
- Extragranular – the disintegrant is added after granulation and before the compression process
- Disintegrant can also be added at both the intragranular and extragranular stages.
When a wet granulation process is employed, the addition of disintegrant extragranular promotes more rapid disintegration than that added intragranular. Having said that, there appears to be a general view that adding some disintegrant in both steps provides the best results.
Starch, in the form of potato and corn starch, has been a common and widely used disintegrating agent, since the beginning of the 20th Century. Natural starches have some limitations as tablet disintegrants, however, and these have stimulated the discovery of modified starches that have more appropriate qualities. Starches function by promoting wicking of water and, to a lesser extent, by their particles becoming deformed during compression and restored on absorption of water (reportedly due to the hydration of hydroxyl groups within the starch molecule).
Starch is a polymer (polysaccharide) of high molecular weight. The starch molecules naturally arrange themesleves into crystalline agglomerates or granules of different sizes that are visible under an optical microscope. According to Lowenthal & Wood, large agglomerates are required for starch to be an effective disintegrant. Starches also perform best if a low compression pressure is employed for the tablet making. The concentration of starch in the formulation is also important. If the concentration is low the starch will create an insufficient number of channels for wicking of water or body fluid. On the other hand, if the concentration is too high, the material will be too difficult to compress into a tablet.
Pregelatinized starch is formed by the rupturing and hydrolyzing of the starch grains. It is widely used as a disintegrant in tablets and capsules, at concentrations of between 5 and 10% by weight. It is highly compressible and easily digested in the gut.
Starch can be chemically modified by carboxymethylation to increase cross-linking between molecules. Such modified starch yields a higher degree of swelling when it absorbs water, leading to faster disintegration of the tablet. Sodium starch glycolate is an example of a such a starch derivative that can absorb 20 times its weight in water. It is commonly manufactured from potato starch, compares favourably with other modified starches and is widely used as a disintegrant under the brand names Primojel and Explotab.
Modified starches and starch derivatives swell extensively with minimal gelling, and optimum concentration levels of 4-6% by weight. When fully hydrated the starch forms a sticky and gelatinous matter that continues to aid the disintegration process as it helps to hold keep the table particles together. Due to their high swelling capacity, modified starches are highly efficient even in low concentrations.
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 derivatives
Sodium carboxy-methylcellulose (NaCMC) and carmellose sodium are two highly hydrophilic and water-soluble compounds. These compounds can be modified to increase cross-linking between the cellulose molecules thereby reducing their solubility in water. Such crosslinking of cellulose increases the volume of water absorbed by as much as 4-8 times, and an example of a widely used cross-linked cellulose is crosscarmellose sodium. It should be noted however, that there are concerns that such products may bring on allergic reactions in individuals that are gluten intolerant.
Microcrystalline cellulose (MCC) is one of the ideal disintegrants. It is a refined form of natural cellulose found in most plant materials. It is used in dehydrated form as both disintegrant and binder in pharmaceutical products.
Hydrophilic Colloidal Substance – Alginates
Alginates are an example of hydrophilic colloidal substances that have high water absorbing properties. Alginates when dissolved in water form acidic solutions which renders them useful only for neutral or acidic granulation. Unlike MCC or starch derivatives, alginates can therefore be used with multivitamins, ascorbic acid and with formulations containing organic acids.
Synthesized ion-exchange resins have clear and well-characterized molecular structures and can have a higher water absorption capacity than most other readily available disintegrants. They are also employed in pharmaceutical products as taste-masking agents.
In addition to the above listed disintegrants are those that function be releasing gases; examples include hydrous aluminium silicate and various surfactants. These are widely ised in effervescent tablets as they are soluble and dispersable.
More recent polymer materials include products such as various grades of cross-linked Polyplasdone (e.g., Polyplasdone XL10 and Polyplasdone XL) which, like starches, promote the disintegrant process through swelling, deformation and wicking. Cross-linked polymers does increase the rates of dissolution and disintegration whilst not affecting the hardness of the tablet. Polyplasdone is produced in the form of small particle size giving it a smooth feeling in the mouth.
The growing demand for faster and more rapid disintegrating formulations has stimulated pharmacists to develop what the industry is calling “superdisintegrants”. These derivatives are developed to have greater effectiveness even at low concentrations. They are also effective intragranularly. Unfortunately most superdisintegrants are hygroscopic and readily absorb moisture, which generally rules them out for drugs that are moisture-sensitive.
Superdisintegrants function principally by swelling on absorbing water.
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%
Factors that influence disintegration
Fillers affect the speed and the process of tablet disintegration. Water-soluble fillers can lead to an increase in viscosity of the absorbed fluid. The effect of this is to reduce the strength of the disintegrating agents. Fillers that are insoluble in water can cause increased disintegration provided that a sufficient quantity of disintegrants are introduced.
Most lubricants are hydrophobic, i.e., they repel water. Lubricants are often added to formulations to protect the surface of the tablet as it is formed in the tablet press. Such addition can often render the tablet more susceptible to disintegration.
If the tablet has little to no added disintegrants, the use of lubricants can have a negative influence especially on the uptake of water, and even affecting highly concentrated swelling disintegrants. In most cases, if a strong disintegrant is used in the formulation, the disintegration time is influenced little by the addition of lubricants. The performance of sodium starch glycolate, for example, is unaffected by the presence of hydrophobic lubricants.
Surfactants are added to help reduce the hydrophobicity of drugs as high hydrophobicity leads to longer disintegration times. It should be noted that they are only effective within a certain range. Note that the chemical compound sodium lauryl sulphate, which is often added as a surfactant in drug formulations, can increase water absorption of starch and also affect the liquid penetration for tablets.
The disintegration time of water-soluble tablets remains almost the same with or without the introduction of nonionic surfactants; however when surfactants are added the rate of water penetration generally increases especially for granules that are made with slightly soluble materials.
|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)
- 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.