Fundamental aspect of super disintegrants: A concise review

ABSTRACT

Super disintegrants (SDTs) are the class of compounds which primarily aid in the solid dosage forms for the rapid disintegration. This class of disintegrants have been shown to be effective at excipient concentrations as low as 1 to 10% when compared to traditional disintegrant starches, which may need concentrations as high as 20%. To date there have been three primary classes of modified starch used as SDTs in the formulation of solid dosage forms: sodium starch glycolate (SSG), croscarmellose sodium (CCS), and synthesized polymer crospovidone (XP). The inclusion of the right super disintegrant is a prerequisite to get optimal bioavailability in tablets and capsules which need rapid disintegration. Super disintegrants are used to improve the efficacy of solid dosage forms. This is achieved by decreasing the disintegration time which in turn enhances the drug dissolution rate.

Keywords: super disintegrants, croscarmellose sodium, sodium starch glycolate, crospovidone, swelling, concentration, mechanism, incompatibilities.

INTRODUCTION

Disintegrating agents are substances routinely included in the tablet formulations to aid in the break-up of the compacted mass into the primary particles to facilitate the dissolution or release of the active ingredients when it is put into a fluid environment. They endorse moisture penetration and dispersion of the tablet matrix. The major function of disintegrants is to oppose the efficiency of the tablet binder and physical forces that act under compression to structure the tablet[1]

Recently new materials termed as “super disintegrants” have been developed to improve the disintegration processes[2,3] Super disintegrants are another version of super-absorbing materials with tailor-made swelling properties. These materials are not planned to absorb significant amounts of water or aqueous fluids but planned to swell very fast. Super disintegrants are used as a structural weakener for the disintegrable solid dosage forms. They are physically dispersed within the matrix of the dosage form and will expand when the dosage form is exposed to the wet environment [4]

These newer substances are more effective at lower concentrations with greater disintegrating efficiency and mechanical strength[5].Their particles are generally small and porous, which allow for rapid tablet disintegration in the mouth without an objectionable mouth-feel from either large particles or gelling. The particles are also compressible which improves tablet hardness and its friability[4]. Effective super disintegrants provide improved compressibility, compatibility and have no negative impact on the mechanical strength of formulations containing high-dose drugs [2]. Generally, one gram of super disintegrant absorbs 10-40 g of water or aqueous medium. After absorption, swelling pressure and isotropic swelling of the super disintegrants particles create stress concentrated areas where a gradient of mechanical properties will exist due to which whole structure will break apart as shown in below[4].

USES OF SUPERDISINTEGRANTS IN FORMULATION

Most medicines today usually contain one of three of the main disintegrant types: Sodium starch glycolate (SSG) croscarmellose sodium (CCS), or crospovidone (XP). All three disintegrants have a similar market share, although China and India use more SSG compared to the more developed markets. The world's three leading suppliers of SSG, all based in Europe (Netherlands, Germany and France)[15].

SELECTION OF SUPERDISINTRIGATION[6]

Since superdisintegrant is used as an excipient in the tablet formulation, it has to meet certain criteria other than its swelling properties. The requirement placed on the tablet disintegrant should be clearly defined. The ideal disintegrant should have:

1. Poor solubility. 
2. Poor gel formation. 
3. Good hydration capacity. 
4. Good moulding and flow properties. 
5. No tendency to form complexes with the drugs. 
6. Good mouth feel. 
7. It should also be compatible with the other excipients and have desirable tableting properties.

MECHANISM OF SUPERDISINTEGRANTS[2,3,7,8,9]

Superdisintegrants are used to improve the efficacy of solid dosage forms. This is achieved by various mechanisms. The mechanism by which the tablets are broken into small pieces and then produces a homogeneous suspension is based on:

• Swelling 
• Wicking (Porosity and capillary action) 
• Particle repulsive forces
• Deformation recovery 
• Heat of wetting 
• Chemical reaction (Acid-Base reaction) 
• Enzymatic reaction

Swelling

Although water penetration is a necessary first step for disintegration, swelling is probably the most widely accepted mechanism of action for tablet disintegrants. Particles of disintegrants swell on coming in contact with suitable medium and a swelling force develops which leads to break-up of the matrix. 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.

Wicking (Porosity and capillary action)

Effective disintegrants that do not swell are believed to impart their disintegrating action through porosity and capillary action. Tablet porosity provides pathways for the penetration of fluid into tablets. 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.

The wicking and swelling mechanism in tablet disintegration as shown below[15]:

Particle Repulsive Forces

This is another mechanism of disintegration that attempts to explain the swelling of tablet made with non-swellable disintegrants. According to Guyot-Hermann’s particle-particle repulsion theory, water penetrates into tablet through hydrophilic pores and a continuous starch network is created that can convey water from one particle to the next, imparting a significant hydrostatic pressure. The water then penetrates between starch grains because of its affinity for starch surfaces, thereby breaking hydrogen bonds and other forces holding the tablet together. The electric repulsive forces between particles are the mechanism of disintegration and water is required for it.

Deformation Recovery

Deformation recovery theory implies that the shape of disintegrant particles is distorted during compression and the particles return to their pre-compression shape upon wetting, thereby this increase in size of the deformed particles causing the tablet to break apart. Such a phenomenon may be an important aspect of the mechanism of action of disintegrants such as Crospovidone and starch that exhibit little or no swelling.

The repulsion and deformation mechanism in tablet disintegration as shown below[15]:

Heat of wetting

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

Chemical reaction (Acid-Base reaction)

The tablet is quickly broken apart by internal liberation of CO₂ in water due to interaction between tartaric acid and citric acid (acids) with alkali metal carbonates or bicarbonates (bases) in presence of water. The tablet disintegrates due to generation of pressure within the tablet. Due to liberation in CO₂ gas, the dissolution of active pharmaceutical ingredients in water as well as taste masking effect is enhanced. As these disintegrants are highly sensitive to small changes in humidity level and temperature, strict control of environment is required during preparation of the tablets. The effervescent blend is either added immediately prior to compression or can be added in two separate fraction of formulation.

Enzymatic Reaction

Enzymes present in the body also act as disintegrants. These enzymes dearth the binding action of binder and helps in disintegration. Due to swelling, pressure is exerted in the outer direction that causes the tablet to burst or the accelerated absorption of water leads to an enormous increase in the volume of granules to promote disintegration.

Synthetic Super disintegrants

Synthetic super- disintegrants are frequently used in tablet formulations to improve the rate and extent of tablet disintegration thereby increasing the rate of drug dissolution. The most widely used synthetic super disintegrants are illustrated below.

CROSCARMELLOSE SODIUM

It is an internally cross-linked polymer of carboxymethyl cellulose sodium. It has high swelling capacity with minimal gelling resulting in rapid disintegration[10].Due to fibrous structure, croscarmellose particles also show wicking action. In tablet formulations, croscarmellose sodium may be used in both direct compression and wet-granulation processes. When used in wet granulation, the croscarmellose sodium should be added in both the wet and dry stages of the process (intra- and extra-granularly) so that the wicking and swelling ability of the disintegrant is best utilized[10,11].

Properties

The mechanism of action of CCS in a tablet starts when it swells, which is highly dependent on the penetration of a liquid into the tablets. The swelling breaks the tablet’s binding forces, causing it to disintegrate and thereby accelerating the dissolution of the active pharmaceutical ingredients (API).

It is insoluble in water, although it rapidly swells to 4-8 times its original volume on contact with water. Specific surface area- 0.81-0.83 m²/g. Swelling index- 65±1.7% v/v.

Concentration for disintegration

It is used in the range of 0.5%–5% w/w but up to 2% is sufficient in most formulation prepared by direct compression and 3% when tablets prepared by a wet-granulation process.

SODIUM STARCH GLYCOLATE 

Sodium Starch Glycolate is the sodium salt of a carboxymethyl ether of starch. These are modified starches made by crosslinking of potato starch as it gives the product with the best disintegrating properties[12].The degree of cross-linking and substitution are important factors in determining the effectiveness of these materials as super disintegrants[12].The effect of the crosslinking is to reduce both the water-soluble fraction of the polymer and the viscosity of dispersion in water.

Properties

Absorbs water rapidly, resulting in swelling up to 6%. High concentration causes gelling and loss of disintegration. Swelling index- 52±1.2% v/v.

Concentration for disintegration

It is used in the range of 2-8%. Above 8%, disintegration times may actually increase due to gelling and its subsequent viscosity producing effects.

CROSPOVIDONE (CROSS-LINKED POLYVINYL PYRROLIDONE)

Unlike other super disintegrants, which rely principally on swelling for disintegration, crospovidone use a combination of swelling and wicking. Due to its high crosslink density, crospovidone swells rapidly in water without gelling. Crospovidone particles are found to be granular and highly porous which facilitates wicking of liquid into the tablet and particles to generate rapid disintegration[1].Larger particles provide a faster disintegration than smaller particles[1].Crospovidone disintegrants are highly compressible materials as a result of their unique particle morphology[1]. Crospovidone can also be used as solubility enhancer.

Properties

It is completely insoluble in water.it disintegrates tablets mainly by swelling, with little tendency to form gels. Rapidly disperses and swells in water.  Greatest rate of swelling compared to other disintegrants. Greater surface area to volume ratio than other disintegrants. Available in micronized grades if needed for improving state of dispersion in the powder blend. Swelling index- 58±1.5% v/v.

Concentration for disintegration

It is used in the range of 2%–5% w/w. Concentration range up to3% gives better results. Crospovidone levels higher than 8% of tablet weight produces weaker tablets with a faster disintegration.

CHARACTERISTICS OF SUPERDISINTEGRANTS[9,10.11,13] 

Super disintegrants are products of simple natural or synthetic pharmaceutical products but modified in such a manner so that their swelling nature is enhanced which helps in significant water uptake and helps in disintegration upon reaching the required site.

When super disintegrants, SSG, CCS, and crospovidone, were used extra-granularly, recompression improved dissolution. However, when used intra-granularly, recompression decreased dissolution of tablets containing CCS and crospovidone but increased for SSG.

Super disintegrants	Croscarmellose sodium	Sodium starch glycolate	Crospovidone
Mechanism	Swelling and wicking both. Swells 4-8 folds in <10 seconds.	Swelling and wicking both Swells 6-10 folds in <30  seconds	Swelling and wicking both. Swells 7-12 folds in <30  seconds
Incompatibilities	Incompatible with strong acids or with soluble salts of iron and some other metals such as aluminum, mercury, and zinc.	Incompatible with ascorbic acid	Forms molecular adducts in solution with sulfathiazole, sodium salicylate, salicylic acid, phenobarbital, tannin, and other compounds
Gel Forming Tendency	Yes	Yes	No

ADVANTAGE OF SUPERDISINTEGRANTS[14]

• Effective in lower concentrations than starch. 
• Less effect on compressibility and flow ability. 
• More effective intra granularly.

However, there are a number of limitations that super disintegrants practically impose in pharmaceutical applications. For example,

• More hygroscopic (may be a problem with moisture sensitive drugs) 
• An acidic medium significantly reduces the liquid uptake rate and capacity of sodium starch glycolate and croscarmellose sodium, but not crospovidone[34,35]. 
• The degree of swelling of sodium starch glycolate and crospovidone is minimized following wet granulation formulation. Finally, the medium ionic strength was found to have an adverse effect on the swelling capacity of croscarmellose[36,37].

CONCLUSION

This article provides the valuable information about the super disintegrants types and its properties, mechanism and characterization, concentration, selection criteria and several factors to be considered while use in the formulation. Finally, selecting a super disintegrants for a formulation requires a systematic approach with careful consideration of the performance of both product and process.

ACKNOWLEDGEMENT

The authors would like to acknowledge Dr. D. P. Singh, Ex-University Professor for support and discussion relating to this article and deep gratitude for their guidance, enthusiastic encouragement, support during my Ph.D.  and grateful to our colleagues Mr. Gaurav Tripathi, Works Manager, Mr. Sanjay Chauhan, Sr. Manager, Supply Chain, and Ms. Monika Tomar, Manager-R&D, Sigachi Industries Private Limited, Telangana, India for support.

FUNDING

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CONFLICT OF INTEREST

The author declares that he does not have any financial and personal relationships with other people or any other organizations that could inappropriately influence this research work.

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15. Photo courtesy: Google.

ABBREVIATIONS

SDTs: Super disintegrants, CCS: Croscarmellose sodium, SSG: Sodium starch glycolate, XP: Crospovidone, API: Active Pharmaceutical Ingredients, R&D: Research and Development. v/v: volume/volume.

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About the Author

Dr. Ajay Kumar Singh, M.Sc. (Gold Medalist), Ph.D. is the author and founder of “Pharma Solutions by Dr. Ajay”. For more helpful articles, please visit our blog. Need Help: Ask Question