DIS-INTEGRATION OF TABLETS

1.5.4 Disintegrants

What will you gain?

1.5.4.1 Introduction

1.5.4.2 Mechanism of tablet disintegrants

1.5.4.3 Methods of addition of disintegrants

1.5.4.4 Types of disintegrants

1.5.4.5 Factors affecting disintegration

1.5.4.1 Introduction

Bioavailability of a drug depends in absorption of the drug, which is affected by solubility of the drug in gastrointestinal fluid and permeability of the drug across gastrointestinal membrane. The drugs solubility mainly depends on physical - chemical characteristics of the drug. However, the rate of drug dissolution is greatly influenced by disintegration of the tablet.

The drug will dissolve at a slower rate from a nondisintegrating tablet due to exposure of limited surface area to the fluid. The disintegration test is an official test and hence a batch of tablet must meet the stated requirements of disintegration.

Disintegrants, an important excipient of the tablet formulation, are always added to tablet to induce breakup of tablet when it comes in contact with aqueous fluid and this process of desegregation of constituent particles before the drug dissolution occurs, is known as disintegration process and excipients which induce this process are known as disintegrants.

The objectives behind addition of disintegrants are to increase surface area of the tablet fragments and to overcome cohesive forces that keep particles together in a tablet.

Figure.16. Schematic Representation Of Tablet Disintegration And Subsequent Drug Dissolution

1.5.4.2 Mechanism of tablet disintegrants (16,29,33-39)

Disintegration by capillary action is always the first step. When we put the tablet into suitable aqueous medium, the medium penetrates into 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 tablet depends upon 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.

By Swelling

Perhaps the most widely accepted general mechanism of action for tablet disintegration is swelling Tablets with high porosity show poor disintegration due to lack of adequate swelling force. On the other hand, sufficient swelling force is exerted in the tablet with low porosity. It is worthwhile to note that if the packing fraction is very high, fluid is unable to penetrate in the tablet and disintegration is again slows down.

Figure.17. Disintegration Of Tablet By Wicking And Swelling

Because of heat of wetting (air expansion)

When disintegrants with exothermic properties gets wetted, localized stress is generated due to capillary air expansion, which helps in disintegration of tablet. This explanation, however, is limited to only a few types of disintegrants and can not describe the action of most modern disintegrating agents.

Due to disintegrating particle/particle repulsive forces

Another mechanism of disintegration attempts to explain the swelling of tablet made with 'non-swellable' disintegrants. Guyot-Hermann has proposed a particle repulsion theory based on the observation that nonswelling particle also cause disintegration of tablets. the electric repulsive forces between particles are the mechanism of disintegration and water is required for it. Researchers found that repulsion is secondary to wicking.

Due to deformation

Hess had proved that during tablet compression, disintegranted particles get deformed and these deformed particles get into their 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. This increase in size of the deformed particles produces a break up of the tablet. This may be a mechanism of starch and has only recently begun to be studied

Figure.18. Disintegration By Deformation And Repulsion

Due to release of gases

Carbon dioxide released within tablets on wetting due to interaction between bicarbonate and carbonate with citric acid or tartaric acid. The tablet disintegrates due to generation of pressure within the tablet. This effervescent mixture is used when pharmacist needs to formulate very rapidly dissolving tablets or fast disintegrating tablet. As these disintegrants are highly sensitive to small changes in humidity level and temperature, strict control of environment is required during manufacturing of the tablets. The effervescent blend is either added immediately prior to compression or can be added in to two separate fraction of formulation.

By enzymatic reaction

Here, enzymes presents in the body act as disintegrants. These enzymes destroy the binding action of binder and helps in disintegration

1.5.4.3 Methods of addition of disintegrants

The method of addition of disintegrants is also a crucial part. Disintegrating agent can be added either prior to granulation (intragranular) or prior to compression (after granulation i.e. extragranular) or at the both processing steps. Extragranular fraction of disintegrant (usually, 50% of total disintegrant requires) facilitates breakup of tablets to granules and the intragranular addition of disintegrants produces further erosion of the granules to fine particles.

1.5.4.4 Types of disintegrants (34,40-42)

Starch

Starch was the first disintegrating agent widely used in tablet manufacturing. Before 1906 potato starch and corn starch were used as disintegrants in tablet formulation. However, native starches have certain limitations and have been replaced by certain modified starches with specialized characteristics.

The mechanism of action of starch is wicking and restoration of deformed starch particles on contact with aqueous fluid and in doing so release of certain amount of stress which is responsible for disruption of hydrogen bonding formed during compression.

Lowenthal & Wood proved that the rupture of the surface of a tablet employing starch as disintegrant occurs where starch agglomerates were found. The conditions best suited for rapid tablet disintegration are sufficient number of starch agglomerates, low compressive pressure and the presence of water.

The concentration of starch used is also very crucial part. If it is below the optimum concentration then there are insufficient channels for capillary action and if it is above optimum concentration then it will be difficult to compress the tablet.

Pregelatinized starch

Pregelatinized starch is produced by the hydrolyzing and rupturing of the starch grain. It is a directly compressible disintegrants and its optimum concentration is 5-10%. The main mechanism of action of Pregelatinized starch is through swelling.

Modified starch

To have a high swelling properties and faster disintegration, starch is modified by carboxy methylation followed by cross linking, which is available in market as cross linked starch. One of them is SODIUM STARCH GLYCOLATE. Even low substituted carboxymethyl starches are also marketed as ExplotabO and Primojel(r).

Mechanism of action of this modified starches are rapid and extensive swelling with minimum gelling. And its optimum concentration is 4-6 %. If it goes beyond its limit, then it produces viscous and gelatinous mass which increases the disintegration time by resisting the breakup of tablet. They are highly efficient at low concentration because of their greater swelling capacity.

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Cellulose and its derivatives

Sodium carboxy methylcellulose (NaCMC and CARMELLOSE sodium) has highly hydrophilic structure and is soluble in water. But when it is modified by internally crosslinking we get modified crosslinked cellulose i.e. Crosscarmellose sodium which is nearly water insoluble due to cross linking. It rapidly swells to 4-8 times its original volume when it comes in contact with water.

Microcrystalline cellulose (MCC)

MCC exhibit very good disintegrating properties because MCC is insoluble and act by wicking action. The moisture breaks the hydrogen bonding between adjacent bundles of MCC. It also serves as an excellent binder and has a tendency to develop static charges in the presence of excessive moisture content. Therefore, sometimes it causes separation in granulation. This can be partially overcome by drying the cellulose to remove the moisture.

Alginates

Alginates are hydrophilic colloidal substances which has high sorption capacity. Chemically, they are alginic acid and salts of alginic acid. Alginic acid is insoluble in water, slightly acidic in reaction. Hence, it should be used in only acidic or neutral granulation. Unlike starch and MCC, alginates do not retard flow and can be successfully used with ascorbic acid, multivitamin formulations and acid salts of organic bases.

Ion-exchange resin

Ion exchange resin (AmbreliteO IPR-88) has highest water uptake capacity than other disintegrating agents like starch and Sodium CMC. It has tendency to adsorb certain drugs.

Miscellaneous

This miscellaneous category includes disintegrants like surfactants, gas producing disintegrants and hydrous aluminium silicate. Gas producing disintegrating agents is used in soluble tablet, dispersible tablet and effervescent tablet.

PolyplasdoneOXL and PolyplasdoneOXL10 act by wicking, swelling and possibly some deformation recovery. Polyplasdone(r)XL do not reduce tablet hardness, provide rapid disintegration and improved dissolution. Polyplasdone(r) as disintegrating agent has small particle size distribution that impart a smooth mouth feel to dissolve quickly. Chewable tablet does not require addition of disintegrant.

Superdisintegrants

As day's passes, demand for faster disintegrating formulation is increased. So, pharmacist needs to formulate disintegrants i.e. Superdisintegrants which are effective at low concentration and have greater disintegrating efficiency and they are more effective intragranularly. But have one drawback that it is hygroscopic therefore not used with moisture sensitive drugs.

And this superdisintegrants act by swelling and due to swelling pressure exerted in the outer direction or radial direction, it causes tablet to burst or the accelerated absorption of water leading to an enormous increase in the volume of granules to promote disintegration.

Figure.19. Mechanism of superdisintegrants by swelling

1.5.4.5 Factors affecting disintegration

Effect of fillers (43,44)

The solubility and compression characteristics of fillers affect both rate and mechanism of disintegration of tablet. If soluble fillers are used then it may cause increase in viscosity of the penetrating fluid which tends to reduce effectiveness of strongly swelling disintegrating agents and as they are water soluble, they are likely to dissolve rather than disintegrate. Insoluble diluents produce rapid disintegration with adequate amount of disintegrants.

Chebli and cartilier proved that tablets made with spray dried lactose (water soluble filler) disintegrate more slowly due to its amorphous character and has no solid planes on which the disintegrating forces can be exerted than the tablet made with crystalline lactose mono-hydrate.

Effect of binder

As binding capacity of the binder increases, disintegrating time of tablet increases and this counteract the rapid disintegration. Even the concentration of the binder can also affect the disintegration time of tablet.

Effect of lubricants(16,34)

Mostly lubricants are hydrophobic and they are usually used in smaller size than any other ingredient in the tablet formulation. When the mixture is mixed, lubricant particles may adhere to the surface of the other particles. This hydrophobic coating inhibits the wetting and consequently tablet disintegration.

Lubricant has a strong negative effect on the water uptake if tablet contains no dis-integrates or even high concentration of slightly swelling disintegrants. On the contrary, the disintegration time is hardly affected if there is some strongly swelling disintegrants are present in the tablet. But there is one exception like sodium starch glycolate whose effect remains unaffected in the presence of hydrophobic lubricant unlike other disintegrants.

Effect of surfactants

(Good - decrease in disintegration time, Poor - increase in disintegration time)

Sodium lauryl sulphate increased absorption of water by starch or had a variable effect on water penetration in tablets. Surfactants are only effective within certain concentration ranges. Surfactants are recommended to decrease the hydrophobicity of the drugs because the more hydrophobic the tablet the greater the disintegration time.

Aoki and fukuda claimed that disintegration time of granules of water-soluble drugs did not seem to be greatly improved by the addition of nonionic surfactant during granulation , but the desired effect of a surfactant appeared when granule were made of slightly soluble drugs. The speed of water penetration was increased by the addition of a surfactant.

Key Phrases

O Disintegrants are added to tablet to induce breakup when it comes in contact with aqueous fluid.

O Disintegration by capillary action or by swelling is the major mechanism for disintegrants.

O Disintegrant can be added Intra-granular or extra-granular or at both stages.

O Superdisintegrants have greater efficiency at low concentration and hence, their demand is increasing day by day.

About the Author

Author: Dr.Mukesh Gohel

Dr. Mukesh Gohel is principal, professor at the LMCP, Ahmedabad served in academics for more than 40 years. He provides training in leading pharmaceutical industries in the areas of Design of Experiments and Quality by Design. His current areas of interest are direct compression and improvement of drug dissolution.