Current Status of Tablet Disintegrants:A Review
Mr. Uddhav S. Bagul
Despite increasing interest in controlled-release drug delivery systems, the most common tablets are those intended to be swallowed whole and to disintegrate and release their medicaments rapidly in the gastrointestinal tract (GIT).
The proper choice of disintegrant or superdisintegrant and its consistency of performance are of critical importance to the formulation development of such tablets.
Drug release from a solid dosage form can be enhanced by addition of suitable disintegrants. In more recent years, increasing attention has been paid to formulating fast dissolving and/or disintegrating tablets that are swallowed, but also orally disintegrating tablets that are intended to dissolve and/or disintegrate rapidly in the mouth. (1-3) Therefore, the purpose of writing this review on Current Status of Disintegrants was to compile the existing literature on various disintegrants.
Disintegrants are substances or mixture of substances added the drug formulation that facilitate the breakup or disintegration of tablet or capsule content into smaller particles that dissolve more rapidly than in the absence of disintegrants (4,5) . Superdisintegrants are generally used at a low level in the solid dosage form, typically 1 – 10 % by weight relative to the total weight of the dosage unit. Examples of superdisintegrants are crosscarmelose, crosspovidone, sodium starch glycolate which represent example of a crosslinked cellulose, crosslinked polymer and a crosslinked starch respectively.
Tablet disintegration has received considerable attention as an essential step in obtaining fast drug release. The emphasis on the availability of drug highlights the importance of the relatively rapid disintegration of a tablet as a criterion for ensuring uninhibited drug dissolution behavior. Number of factors affects the disintegration behavior of tablets. The development of fast dissolving or disintegrating tablets provides an opportunity to take an account of tablet disintegrants. Recently new materials termed as superdisintegrant have been developed to improve the disintegration processes. Selecting appropriate formulation excipients and manufacturing technology can obtain the design feature of fast disintegrating tablet. The disintegrants have the major function to appose the efficiency of the tablet binder and the physical forces that act under compression to form the tablet. The stronger the binder, the more effective must be the disintegrating agents in order for the tablet to release its medication. Ideally, it should cause the tablet to disrupt, not only into the granules from which it was compressed, but also into powder particles from which the granulation was prepared.
Method of Addition of Disintegrants:
The requirement placed on the tablet disintegrant should be clearly defined. The ideal disintegrant has-
1. Poor solubility
2. Poor gel formation
3. Good hydration capacity
4. Good molding and flow properties
5. No tendency to form complexes with the drugs
Disintegrants are essentially added to tablet granulation for causing the compressed tablet to break or disintegrate when placed in aqueous environment.
There are two methods of incorporating disintegrating agents into the tablet:
I.Internal Addition (Intragranular)
II.External Addition (Extragranular)
III.Partly Internal and External
In external addition method, the disintegrant is added to the sized granulation with mixing prior to compression. In Internal addition method, the disintegrant is mixed with other powders before wetting the powder mixtures with the granulating fluid. Thus the disintegrant is incorporated within the granules. When these methods are used, part of disintegrant can be added internally and part externally. This provides immediate disruption of the tablet into previously compressed granules while the disintegrating agent within the granules produces further erosion of the granules to the original powder particles. The two step method usually produces better and more complete disintegration than the usual method of adding the disintegrant to the granulation surface only.
Disintegrant is a substance or mixture of substances added to tablets to facilitate its break up or disintegration. The active constituents must be released from the tablet as efficiently as possible to allow its rapid action. The mechanism by which the tablets are broken into small pieces and then produces a homogeneous suspension is based on :
i. Capillary action
ii. High swellability
iii.Capillary action and high swellability
iv. Chemical reaction (Acid base reaction)
The most popular disintegrants are corn starch, soluble starch etc. which have been well dried and powdered. Starches have great affinity for water and swells when moistened, thus facilitating the rupture of the tablet matrix, its disintegrating action in tablets is due to capillary action because of spherical shape of starch increases the porosity of tablet thus promoting capillary action. Some other materials are reported to be effective as disintegrants. These substances have high swellability with water and rupture the tablets into small particles for example. Gums, celluloses.
Another mechanism for the disintegration of tablet is inclusion of citric acid and tartaric acid along with the sodium bicarbonate, sodium carbonate, potassium bicarbonate or calcium carbonate. These react in contact with water to liberate carbon dioxide that disrupts the tablet.
FACTORS AFFECTING ACTION OF DISINTEGRANTS (6,7)
- Percentage of disintegrants present in the tablets.
- Types of substances present in the tablets.
- Combination of disintegrants.
- Presence of surfactants.
- Hardness of the tablets.
- Nature of Drug substances.
- Mixing and Screening.
DISINTEGANTS USED IN TABLETTING
Starch is the oldest and probably the most widely used disintegrant in the pharmaceutical industry. Regular cornstarch USP, has certain limitation and has been replaced to some extent by modified starches with specialized characteristics to serve specific functions. The mode of action of starch is that the disintegrant forms pathways throughout the tablet matrix that enable water to draw into the structure by capillary action, thus leading to disruption of tablet. Other concept relates to swelling of starch grains on exposure to water, a phenomenon that physically ruptures the particle – particle bonding in tablet matrix.
Choudhary et al (8) reported that pregelatinized starch is a modified starch prepared from potato starch and is used in piroxicam dispersible tablets. Different proportion of drug and disintegrants as in the ratio 1: 1,1: 3, 1:9, were used to prepare dispersion. All the tablets disintegrated within 3 minutes. The possible mechanism responsible for increased dissolution rate from this tablet is rapid disintegration due to superior swelling capacity of pregelatinised starch.
2. Sodium Starch Glycolate ( Explotab and Primogel)
These are modified starches with dramatic disintegrating properties and are available as explotab and primogel which are low substituted carboxy methyl starches. Explotab consisting of granules that absorb water rapidly and swell. The mechanism by which this action takes place involve rapid absorption of water leading to an enormous increase in volume of granules result in rapid and uniform disintegration. The natural predried starches swell in water to the extent of 10-20 percent and the modified starches increase in volume by 200-300 percent in water. This modified starch is that the disintegration time may be independent of compression force. (9)
The primogel and other disintegrants such as cross carmellose sodium, cross povidone and potato starch were used as super disintegrant and the effect of these on the dissolution rate of sparfloxacin tablet has been studied by choudhary et al. (10)
The tablets formulated by using these disintegrants were disintegrated within two minutes. The higher dissolution rates observed with superdisintegrants may be due to rapid disintegration and fine dispersion of particles formed after disintegration. Sallem et al (11) had studied the effect of four disintegrants on the dissolution of Terfenamide tablet containing the gas evolving disintegrant , CaCo3 . The four disintegrants improved disintegration and dissolution of the original formulation and their relative efficiency of improvement was in order of cross povidone> Ac-di-sol> Primogel> low substituted HPC. The fast disintegrants used were characterized by good hydration capacity. Cross povidone and primogel are known for their strong hydration capacities compared to the other fast disintegrants.
The sodium starch glycolate was incorporated as a super disintegrant in the enteric coated antigen micro spheres and was studied by Zhang et al. (12) The significantly faster antigen release rate and reduced time need for breaking the film due to the swelling force generated by incorporation of sodium starch glycolate in the beads. Sodium starch glycolate has outstanding water wicking capacity and good swelling property as observed in case of enteric coated antigen micro spheres.
Zhao N and Augsburger LL (13) have investigated the efficiency of superdisintegrants in promoting tablet disintegration and drug dissolution under varied media pH. Significant reductions in the rate and extent of water uptake and swelling were observed for both sodium starch glycolate (Primojel) and croscarmellose sodium (Ac-Di-Sol) in an acidic medium (0.1 N HCl)
3. Cross-linked polyvinyl Pyrrolidone (Cross Povidone)
Kornblurn et al (14) has reported the cross linked polyvinyl pyrrolidone and evaluated as tablet disintegrants and compared to starch USP and alginic acid. The capillary activity of cross povidone for water is responsible for its tablet disintegration property. Cross linked PVP has maximum moisture absorption and hydration capacity and can be considered for the selection of new disintegrant. They possess apparent binding property resulting in low percent of tablet friability, where it is employed as disintegrant even in low concentration 0.5 to 5 percent.
Alesandro et al (15) formulated fast dissolving composition of ibuprofen tablet by using 0.5 – 10 % linear polyvinyl pyrrolidone with respect to ibuprofen. The tablet was completely in solution in 10 minutes.
Alginates are hydrophilic colloidal substances extracted from certain species of Kelp. Chemically they are available as alginic acid or salt of salt of alginic acid. Alginic acid is a polymer derived from seaweeds comprising D-mannuronic and L-glucoronic units. Its affinity for water absorption and high sorption capacity make it an excellent disintegrant. It can be successfully used with ascorbic acid, multivitamins formulation.
Cellulose such as purified cellulose, methylcellulose, crosslinked sodium carboxy methylcellulose (Ac-Di-Sol) and carboxy methyl cellulose are disintegrants to some extent depending on their ability to swell on contact with water. A crosslinked form of Ac-Di-Sol has been accepted as tablet disintegrant and it is essentially water insoluble. It has high affinity for water, which results in rapid tablet disintegration. (23)
Botzolakis et al (16) have studied the wicking and swelling properties of pure disintegrants from plugs prepared under condition similar to those used in encapsulation of powder mixture into hard gelatin capsules. Use of Ac-Di-Sol exhibited the greatest wicking and swelling action followed by primogel and corn starch. The swelling property of pure disintegrant correlated best with the swelling of formulation mixtures and the efficiency of these materials in enhancing the dissolution of drug. Drug dissolution from the encapsulated dosage form can be improved significantly with the addition of disintegrating agents into the formulation. The efficiency of disintegrant employed, the nature of the matrix and the lubricant level.
Augsburger et al (17) had shown the mechanism of action of disintegrants such as Ac-Di-Sol primogel, polyplasdone –XL-10 and corn starch by rapid liquid absorption and swelling of disintegrant particles which fills the void spaces and cause the compact to disintegrate rapidly. Disintegrants, however, varied widely in their wicking and swelling properties and minimum concentration of disintegrant is necessary to produce primary particles upon disintegration and effectively improve drug dissolution. This study was thus designed to examine the behavior of disintegrant in their pure state and in hard gelatin capsule formulations. The intrinsic ability of disintegrant to absorb water and swelling was measured.
Jagdish Singh (18) included a new range of sodium carboxymethyl cellulose (Nymzel ® types –ZSB-10, ZSB-16, ZSB-18) into Lorazepam tablet formulations to improve the disintegration, dissolution and bioavilability of drug. Sodium carboxy methylcellulose containing tablet disintegrated within 30 seconds.
Bi et al (19) reported a rapidly disintegrating tablet with sufficient mechanical integrity as well as pleasant taste using cross-linked sodium carboxy methyl cellulose (Ac-Di-Sol) and tablettose. Ac-Di-Sol was one of the super disintegrant and has excellent disintegrant ability. It swells to a large extent when it comes in contact with water to disintegrate tablets and has fibrous nature that allows intraparticulate and extra particulate wicking of water even at low concentration level.
Cousin et al, (20) formulated rapidly disintegrable multiparticular tablets containing carboxymethyl cellulose as a disintegrating agent and one swelling agent consisting of modified starch or microcrystalline cellulose. The tablets were disintegrated in the mouth in less than 60 seconds.
6. Microcrystalline Cellulose (Avicel pH -101, pH - 102, pH – 105)
Avicel exhibit very good disintegrant property when present in as low as 10 percent. It functions by allowing water to enter the tablet matrix by means of capillary pores, which break the hydrogen bonding between adjacent bundles of cellulose microcrystals. Tablets with excess avicel have a tendency to stick to the tongue due to rapid capillary absorption and dehydrating the most surface. Avicel has a fast wicking rate for water, hence this and starch makes an excellent combination for effective and rapid disintegration in tablet formulation (9) To develop a rapidly disintegrating tablet, a mixture of MCC and L-HPC was in the range of 8:2 – 9:1 shown shortest disintegration time.
MCC was used as disintegrating agent in the formulation of fast releasing compressed propranol hydrochloride suppositories as reported by Malladi et al (21). The concentration of MCC Shows faster drug release from suppository and evaluated their pharmacokinetics and pharmacodynamics performance and compared the result obtained with oral administration.
Bi et al (22) and Watanabe et al (23) used microcrystalline cellulose and Low substituted hydroxy propyl cellulose (L-HPC) as disintegrants to prepare rapidly disintegrating tablets. Ratio of the MCC and L- HPC was in the range of 8: 2 – 9: 1 resulted in tablets with shortest disintegration time.
Chaudhary et al (24) had formulated and evaluated dispersible tablets of poorly soluble drugs using MCC (pH – 105) and potato starch. Higher dissolution rate were observed in tablets as compared to the dissolution rate of conventional tablets.
7. Ambrelite IPR 88 (Ion Exchange Resins)
Ion exchange resin has ability to swell in the presence of water. When used as a disintegrant care must be taken that many resins have the ability to absorb drug particles. Anionic and Cationic resins have been used to absorb substances and release them when the charge changes.(9)
Gums have been used as disintegrants because of their tendency to swell in water. They can display good binding characteristics (1 to 10 percent of tablet weight). This property can oppose the desired property of assisting disintegration and the amount of gum must be carefully titrated to determine the optimum level for the tablet. Common gums used as disintegrant include agar, locust bean, karaya, Pectin and tragacanth.
Blank et al (25) described pharmaceutical dosage form which disintegrates rapidly in water, within 10 seconds, having an open matrix network structure comprised of mannitol and natural gum can be used particularly for oral administration to pediatric and geriatric patient.
9. Guar Gums
It is naturally occurring gum (marketed under the trade name jaguar). It is free flowing, completely soluble, neutral polymer composed of sugar units and is approved for use in food.
It is not sensitive to pH, moisture contents or solubility of the tablet matrix. It is not always pure white and sometimes varies in color from off-white to tan tends to discolor with time in alkaline tablets. (9)
10. Gum Karaya
Karaya has the natural gum exudates from the traces of Sterculia urens belonging to family sterculiacea. Chemically the gum has an anionic polysaccharide, containing 43%. D-galacturonic acid, 13% D-galactose and 15 percent L-rhamnose. The high viscosity nature of gum limits its uses as binder and disintegrant in the development of conventional dosage form.
Mohan Babu et al (26) has been reported the modified gum karaya (Mgk) prepared from gum karaya (GK) by heat treatment can be used as disintegrant (because of low viscosity). The viscosity and volatile acetyl value of Mgk was markedly less than GK. The formulation containing Mgk absorb water readily, disintegrates and dissolves rapidly due to its low viscosity and high swelling properties.
11. Chitin and Chitosan
These are obtained from marine sources. Chitin a structural constituents in the sheels of crutacean and insect has an acylated polyamine, which is biodegradable and non toxic. It is the most abundant natural polymer after cellulose.
Chitin and Chitosan as disintegrant in paracetamol tablets were evaluated and compared with four commonly used disintegrants such as corn starch, sodium starch glycolate, methyl cellulose and cross Carmellose sodium, reported by Ritthidet et al. (27)
Tablets containing Chitosan shows faster disintegration, greater dissolution and are slightly softer than those containing Chitin. An increment in concentration of these polymers causes markedly faster disintegration and better dissolution. Tablet containing seven percent Chitosan disintegrate within one minute which was much faster than those containing sodium starch glycolate and cross carmellose sodium. Moisture sorption and water uptake was found the major mechanism of disintegration while dissolution related to swelling capacity.
Smecta is a clay mostly composed of smectile, a non fibrous Attapulgite, belonging to the family montomorillonite. Its layered leaf like structure consist of aluminium and octahydral layers sandwiched between tow tetrahydral silica layers. Smecta has a large specific area and high affinity for water. Smecta was found more adsorptive than other antdiarrheal clays, as fibrous attapulgite and kaolin.
Smecta is evaluated as disintegrant in tablet made by compression and by wet granulation using lactose, dicalcium phosphate as water soluble and water insoluble fillers. An inorganic clay, magnesium aluminum silicate (Veegum), modified starch, Ac-di-sol and cross linked PVP as a disintegrants evaluated by Bhargava etal (28). Smecta performed well as a disintegrant in tablet superior to Veegum and starch, but inferior to Ac-di-sol and cross linked PVP.
13. Gellan Gum
Gellan gum is a linear anionic polysaccharide, biodegradable polymer obtained from Pseudomonos elodea consisting of a linear tetrasaccharide repeat structure and use as a food additive.
Antony et al (29) studied the Gellan gum as a disintegrant and the efficiency of gum was compared with other conventional disintegrants such as dried corn starch, explotab, avicel (pH 102), Ac-di-sol. And Kollidon CL.
The disintegration of tablet might be due to the instantaneous swelling characteristics of gellan gum when it comes into contact with water and owing to its high hydrophilic nature. The complete disintegration of tablet was observed within 4 minutes with gellan gum concentration of 4 percent w/w and 90 percent of drug dissolved within 23 minutes. Ac-di-sol and Kollidone CL showed very similar pattern of disintegration and in vitro dissolution rates. With the same concentration tablet made with starch showed 220 minutes. From this result gellan gum has proved itself as a superior disintegrant.
14. Isapghula Husk
It is a natural substance as disintegrant. It consists of dried seeds of the plant known as plantago ovata. It contains mucilage which is present in the epidermis of the seeds. The mucilage is used as binding agent in the granulation of material for compressed tablets. Plantago ovata seeds husk has high swellability and gives uniform and slightly viscous solution hence it is used as thickening and suspending agent.
Gupta G.D. et al (30) has investigated the disintegrating property of the Isapghula husk, Cassia tora and Cassia nodosa and the formulations were evaluated for the standard of dispersible tablets and were compared with marketed products. The study shown that the natural gums used as disintegrants were effective in low (5%) concentrations.
15. Polacrillin Potassium (Tulsion 339)
Tulsion (339) is a resin consisting of highly purified crosslinked polacrillin copolymer in potassium form. It is used as a tablet disintegrant and as a taste-masking agent for various drugs. When Tulsion-339 is used as disintegrant, it swells up at very fast rate upon contact with water or gastro intestinal fluid and act as an effective tablet disintegrant. It is to be added in a dry form in the proportion of 0. 5 to 5% of the total weight of tablet, amount may vary depending upon nature of tablet.
Polacrillin Potassium is high molecular weight polymer so can't be absorbed by body tissues & is safe for human consumption. It has no any physiological action at recommended dosage & it is non-toxic.
Specific features of Tulsion-339 as a disintegrant:
- Faster rate of swelling.
- No lump formation after disintegration / dispersion.
- High compatibility. With excipitients and common therapeutic agent.
- Does not stick to punches and clays.
16. Agar (31,32)
Agar is the dried gelatinous substance obtained from Gelidium Amansii ( Gelidanceae ) and several other species of red algae like, Gracilaria ( Gracilariaceae) and Pterocadia (Gelidaceae). Agar is yellowish gray or white to nearly colorless, odorless with mucilaginous taste and is available in the form of strips, sheet flakes or coarse powder. Agar consists of two polysaccharides as agarose and agaropectin. Agarose is responsible for gel strength and Agaropectin is responsible for the viscosity of agar solutions. High gel strength of agar make it a potential candidate as a disintegrant.
Ito et al (33) investigated the use of agar powder as a disintegrating agent for the development of rapidly disintegrating oral tablets. Agar was chosen because it absorbs water and swell significantly but do not become gelatinous in water at physiological temperature.
17. Gas – Evolving disintegrants
Another approach for the disintegration of tablet is inclusion of citric acid and tartaric acid along with the sodium bicarbonate, sodium carbonate, potassium bicarbonate or calcium carbonate. These react in contact with water to liberate carbon dioxide that disrupts the tablet.
Onali et al (34) described the process of making rapidly disintegrating tablets. The tablets consisting of malic acid or effervescence base, calcium carbonate as an active ingredient (antacid) and cornstarch as a bulking agent and disintegrating agent. The tablets prepared from these ingredients disintegrated within 20 second.
Tablet disintegration has received considerable attention as an essential step in obtaining fast drug release. Disintegration remains a powerful influence and precursor for drug absorption. Disintegration of tablet or capsule is depending upon the type and quantity of disintegrants. The development of fast dissolving or disintegrating tablets provides an opportunity to take an account of tablet disintegrants. Therefore, there is a huge potential for the evaluation of new disintegrants or modification of an existing disintegrants into superdisintegrants, so as to formulate fast dissolving dosage form
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Mr. Uddhav S. Bagul * (M. Pharm. Pharmaceutics) Lecturer,
S.T.E.S.’s Smt. Kashibai Navale College of Pharmacy, Kondhwa (Bk), Pune – 411 048, Maharashtra, INDIA Phone No – 020 26906066 (o), Cell: 9822192443, Email – firstname.lastname@example.org
Mr. Nilesh S. Bagul (B. Pharm.) Quality Assurance Executive, Glenmark Pharmaceuticals Co., Verna Ind. Area, Goa, INDIA.
Ms. Minal S. Kulkarni (M. Pharm. Pharmaceutical Chemistry) Lecturer, S.T.E.S.’s, Smt. Kashibai Navale College of Pharmacy, Kondhwa (Bk), Pune – 411 048, Maharashtra, INDIA
Dr. S. D. Sawant (M. Pharm. PhD), Principal, S.T.E.S.’s, Smt. Kashibai Navale College of Pharmacy, Kondhwa (Bk), Pune, Maharashtra, INDIA
Dr. K. N. Gujar (M.Pharm PhD), Principal, STES, Sinhgad Institute of Pharmacy, Pune, Maharashtra State, INDIA
Mr. A. A. Bidkar (M. Pharm. Pharmacognosy) Lecturer, S.T.E.S.’s Smt. Kashibai Navale College of Pharmacy, Kondhwa (Bk), Pune – 411 048,Maharashtra, India