Disintegrant
A disintegrant is an additive that promotes disintegration, which is the breakage of a tablet into small fragments when in contact with a liquid medium. Disintegrants and superdisintegrant excipients are essential components used in the pharmaceutical industry to enhance the dissolution and bioavailability of active pharmaceutical ingredients (APIs). These excipients facilitate the disintegration and rapid breakup of tablets or capsules, which ultimately increases their rate of absorption in the body.
Advantages of Disintegrant
Capillary action
This type of disintegrant can maintain the pore structure of the compressed tablet in the tablet, form a capillary channel that is easy to wet and present a lower interfacial tension in an aqueous medium. When the tablet is placed in water, water can quickly enter the inside of the tablet with the capillary tube, so that the entire tablet is wetted and disintegrated. Starch and its derivatives, and cellulose derivatives all belong to this type of disintegrant.
This type of disintegrant is generally added both internally and externally. The external addition method is conducive to the rapid disintegration of the tablet into particles, while the internal addition method is conducive to the finer dispersion of the particles and can improve the hardness of the agent.
Swelling effect
In addition to capillary action, some disintegrants themselves can swell with water to cause the tablet to disintegrate. For example, the starch derivative sodium carboxymethyl starch can swell in cold water, and the swelling effect of its granules is very significant, causing the tablet to disintegrate rapidly.
Gas production
Disintegrants that produce gas are mainly used for tablets that need to disintegrate or dissolve quickly, such as effervescent tablets, foam tablets, etc. In the effervescent disintegrant, citric acid or tartaric acid plus sodium carbonate or sodium bicarbonate is commonly used. When it meets water, carbon dioxide gas is generated, and the tablet disintegrates with the help of gas expansion.
Enzymatic hydrolysis
Some enzymes have an effect on certain excipients in the tablet. When they are formulated in the same tablet, they can quickly disintegrate in contact with water. For example, when the starch slurry is used as a binder, amylase can be added to dry granules, and the compressed tablets formulated by this way can disintegrate quickly once in contact with water. Commonly used adhesives and their corresponding enzymes are starch and amylase, cellulose and cellulose, gum and hemicellulose, gelatin and protease, sucrose and invertase, alginates and carrageenase, etc.
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Excipients Used as Disintegrants and Superdisintegrants
There are several excipients used as disintegrants and superdisintegrants in the pharmaceutical industry, including:
Starches
This is the most commonly used disintegrant in the industry. It includes corn starch, potato starch, and modified starches such as pregelatinized starch, sodium starch glycolate, and starch 1500.
Cellulose-based excipients
These include microcrystalline cellulose, croscarmellose sodium, sodium carboxymethyl cellulose, and hydroxypropyl methylcellulose.
Natural gums
These include guar gum, xanthan gum, and locust bean gum.
Ion exchange resins
These include polacrilin potassium and Amberlite IRP69.
Calcium silicates
These include dicalcium phosphate and tricalcium phosphate.
Others
These include sodium alginate, cross-linked polyvinylpyrrolidone, and chitosan.
The chemical structure of disintegrants and superdisintegrants varies widely depending on the excipient used. Starches, for example, are polysaccharides made up of glucose molecules linked together by alpha 1-4 glycosidic bonds. Modified starches have been chemically modified to improve their functionality. Sodium starch glycolate, for instance, is a cross-linked sodium carboxymethyl ether of starch, while starch 1500 is a pre-gelatinized maize starch that has been modified with sodium sulfate.
Cellulose-based excipients are also polysaccharides, but they are made up of glucose molecules linked together by beta 1-4 glycosidic bonds. Microcrystalline cellulose, for example, is a partially depolymerized cellulose that has been mechanically processed to produce small, crystalline particles. Croscarmellose sodium, on the other hand, is a cross-linked sodium carboxymethyl cellulose.
Natural gums, such as guar gum, xanthan gum, and locust bean gum, are polysaccharides that are obtained from plant sources. They are long chains of sugar molecules linked together by glycosidic bonds. These gums have the ability to absorb water and swell, which helps to facilitate the breakup of the tablet or capsule.
Ion exchange resins, such as polacrilin potassium and Amberlite IRP69, are synthetic polymers that contain functional groups that can exchange ions. They work by absorbing water and swelling, which disrupts the tablet or capsule structure and promotes rapid disintegration.
Calcium silicates, such as dicalcium phosphate and tricalcium phosphate, are inorganic compounds that are commonly used as excipients in the pharmaceutical industry. They have the ability to absorb water and swell, which helps to facilitate disintegration.
Sodium alginate is a natural polysaccharide obtained from brown algae that has been modified with sodium ions. Cross-linked polyvinylpyrrolidone is a synthetic polymer that has been cross-linked to increase its functionality, while chitosan is a natural polymer derived from chitin.
Disintegrants and superdisintegrant excipients are essential components used in the pharmaceutical industry to enhance the dissolution and bioavailability of APIs. There are several excipients used as disintegrants and superdisintegrants, including starches, cellulose-based excipients, natural gums, ion exchange resins, calcium silicates, and others. These excipients have different chemical structures and mechanisms of action, but they all work to facilitate the rapid disintegration of tablets or capsules. The use of disintegrants and superdisintegrants in pharmaceutical formulations is an important factor in improving the effectiveness of drugs and ensuring patient safety.
Materials
Porous tribasic calcium phosphate (TCP 500) and a DC grade anhydrous dibasic calcium phosphate (DCPA 150), DC grade microcrystalline cellulose (MCC 200); Magnesiumstearate (Mg-St); affeine (Caff); coarse crystalline saccharose (Sacc); gellan gum; potato fibre as well as cellulose powder with a D50 of 70μm (CP_2) /; cellulose fine powder with a D50 of 30 μm (CP_1); native potato starch; pregelatinized corn starch.
Powder Characterization
The materials were characterized regarding their particle size distribution (not shown here) water uptake speed (WUS), water uptake (WU) and swelling capacity (SC) using the setup comprising a glass vessel with a glass-sinter bottom.
The apparatus was prepared by pumping water until the glass sinter was wetted evenly. A powder sample of an average mass of 5.0 g was inserted into the vessel on top of the glass sinter followed by slight manual levelling and compression to obtain an even powder bed. The connection to the water supply was opened and data recording started simultaneously. The height of the wetted and swollen powder bed was determined as well as the height of the unwetted powder bed after a run time of 30 min. The swell capacity was calculated from the volume of the actually wetted dry powder and the volume of the swollen wet powder.
Tablet Formulations and Tablet Testing
Tableting mixtures were prepared by mixing the components in a Turbula blender for five minutes (without Mg-St) and a further three minutes after addition of Mg-St. Mixtures were compressed on a RoTab T rotary press using flat-faced 11.28-mm punches. For F1 the main compression force (MCF) was 18.5 kN. Tablets were tested regarding their breaking force, dimensions and mass on a P5 tablet testing system (Charles Ischi AG). Disintegration was measured using an apparatus with integrated end-point determination DISI-EVO ( CHARLES ISCHI AG - OSD Testing Technology ).
The water uptake capacity and the swelling capacity of the new disintegrant mixture is significantly higher than that of the cellulose and starch materials. In contrast to that the rate of water uptake is much faster for cellulose powders than for starches or the new DIS mixture. It can be observed that smaller cellulose particles effect a faster uptake.
Disintegrant Used in Disintegration Test
Disintegrants refer to excipients that promote the rapid disintegration of tablets into small particles in the gastrointestinal tract. Since the drug is compressed into a tablet by a large pressure, the porosity is small and the binding force is very strong. Even for the drug compressed into a tablet that is easily soluble in water, it takes a certain amount of time to get dissolved or disintegrated. The disintegration of the tablet is generally the first step in the dissolution of the drug. In order for tablets to quickly exert their drug effects, disintegrants are generally required to be added except for buccal tablets, sublingual tablets, implant tablets, and long-acting tablets that require slow drug release.
1. A process for the preparation of a disintegrant, suitable for use in a composition in the form of a moulded body, comprising forming by a dry granulation process a granular composition comprising a swelling clay and a water insoluble inorganic material.
2. A process for the preparation of a disintegrant, suitable for use in a composition in the form of a moulded body, comprising forming by a dry granulation process a granular composition comprising a swelling clay, a water insoluble inorganic material and a water- swellable agent which, in its anhydrous state, comprises no more than 20 per cent of the combined weight of said swelling clay, said water insoluble material and said water-swellable agent.
3. A process according to claim 1 or 2 characterised in that the dry granulation process comprises blending ingredients of the granular composition in a mixer followed by roller compaction of the mixture so produced.
4. That the roller pressure during roller compacting is in the range 8 to 25 MPa.
5. That the granules are screened to a size in the range 500 to 3000 μm.
6. A composition suitable for use as a disintegrant in a composition in the form of a moulded body, said composition being in the form of granules comprising a swelling clay, a water insoluble inorganic material and a water-swellable agent which, in its anhydrous state, comprises no more than 20 per cent of the combined weight of said swelling clay, said water insoluble inorganic material and said water-swellable agent.
7. A composition according to claim 6 characterised in that the water-swellable agent is present in an amount comprising no more than 7.5 per cent of the combined weight of said swelling clay, said water insoluble inorganic material and said water-swellable agent.
8. A composition according to claim 6 or 7 characterised in that the water-swellable agent is present in an amount comprising at least 1 per cent of the combined weight of said swelling clay, said water insoluble material and said water-swellable agent.
9. A composition according to any one of claims 6 to 8 characterised in that the swelling clay is a smectite clay.
10. A composition according to claim 9 characterised in that the smectite clay is a bentonite clay.
11. A composition according to any one of claims 6 to 10 characterised in that the water insoluble inorganic material is silica, a material containing at least 70 per cent silica by weight or an aluminosilicate.
12. A composition according to claim 11 characterised in that the water insoluble inorganic material is a crystalline aluminosilicate which is a zeolite having the empirical formula
Mz/nO ■ Al203 • xSi02 • yH20 wherein M represents a metallic cation having a valency of n, x indicates the ratio of atoms of silica to atoms of aluminium and y indicates the ratio of molecules of water to atoms of aluminium.
13. A composition according to claim 12 characterised in that the zeolite is a zeolite P, a zeolite A or a zeolite X.
14. A composition according to claim 12 or 13 characterised in that the zeolite is a zeolite P in which M is an alkali metal and x has a value in the range 1.8 to 2.66.
15. A composition according to claim 12, 13 or 14 characterised in that zeolite is a zeolite P having a water content in the range 9 to 12 per cent by weight of the zeolite.
16. A composition according to any one of claims 6 to 15 characterised in that the relative amounts of swelling clay and crystalline aluminosilicate in the granular disintegrant are in the ratio of 9 : 1 to 1 : 9 by weight clay : aluminosilicate.
17. A composition according to any one of claims 6 to 16 characterised in that the swelling clay is present in the granular disintegrant in an amount in the range 20 to less than 50 per cent by weight and the water insoluble material is present in the granular disintegrant in an amount in the range 35 to 70 per cent by weight.
18. A composition according to any one of claims 6 to 17 characterised in that the water- swellable agent has an average primary particle size of up to 600 μm.
19. A composition according to any one of claims 6 to 18 characterised in that the water- swellable agent has a water-swelling capacity of at least 5 cm3/g.
20. A composition according to any one of claims 6 to 19 characterised in that the water- swellable agent is natural cellulose, cross-linked cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, pre-gelatinised starch, cross linked starch, or cross linked polyvinyl pyrrolidone.
A Study of Water Uptake by Selected Superdisintegrants from the Sub-Molecular to the Particulate Level
Water diffusion through the matrix of three superdisintegrants, namely sodium starch glycolate (SSG), croscarmellose sodium (cCMC-Na) and crospovidone (cPVP), was studied at the sub-molecular level using Attenuated Total Reflectance (ATR)-FTIR spectroscopy and molecular dynamics simulations, and the results were correlated to water uptake studies conducted at the particulate level using Parallel Exponential Kinetics (PEK) modeling in dynamic moisture sorption studies and optical microscopy. ATR-FTIR studies indicated that water diffuses inside cPVP by a single fast acting process, while in SSG and cCMC-Na, a slow and a fast process acting simultaneously, were identified. The same pattern regarding the rate of water uptake for all superdisintegrants was found also at the particulate level by PEK modeling. Moreover, molecular dynamics simulation helped elucidate the hydrogen bonding patterns formed between water-SSG and water-cCMC-Na, mainly via their carboxylic oxygen atoms and secondarily via their hydroxyl groups, while cPVP formed hydrogen bonds only through carbonyl oxygen. Finally, cPVP chains showed significant flexibility during hydration, while cCMC-Na and SSG chains retain their conformation to some extent, explaining the extensive swelling observed also at the particulate level by optical microscopy hydration studies.