Disintegrants in Solid Dosage Forms

The dynamic approach to tablet disintegration, which is based on the measurement of the force that develops inside the compact upon water entrance, is basically taken up.

The combined measurements of force development and water uptake, simultaneously effected on the same compact, provide a novel parameter that is proposed to quantify and compare the efficiency of disintegrants.

The new parameter, which is based on the “force-equivalent” concept, expresses the capability of a disintegrant of transforming water uptaken into swelling (or disintegrating) force. A few examples, that illustrate the usefulness of this parameter for disintegrant characterization, are given.

In parallel to the quantification of swelling (or disintegrating) efficiency inside compacts, attention is also being paid to the characterization of swelling disintegrants as pure materials.

In particular the case of the so-called limited swelling materials, for which the quantification of intrinsic swelling (particle volume increase in swelling media) is critical, is considered.

The applicability of an instrumental method, which is based on the employment of a Coulter Counter, is discussed alternatively to microscopic methods.

Disintegrant characterization may also be considered in view of new possible exploitations of the swelling properties of polymers in controlling drug release.     

Disintegrating Agents in Hard Gelatin Capsules. Part II: Swelling Efficiency

Abstract

The wicking and swelling properties of pure disintegrants were investigated from plugs prepared under conditions similar to those used in encapsulation of powder mixtures into hard gelatin capsules. Pure AcDiSol exhibited the greatest wicking and swelling action followed by Primojel, Polyplasdone-XL 10 and corn starch. The swelling properties of pure disintegrants correlated best with the swelling of formulation mixtures and the efficiency of these materials in enhancing the dissolution of hydrochlorothiazide. A change in the penetrating liquid from dilute acid to water altered the liquid uptake and swelling of AcDiSol and Primojel but not those of Polyplasdone-XL 10 and corn starch. The extent of swelling per unit volume of liquid absorbed, defined as the swelling efficiency, varied with time and type of disintegrant. The swelling efficiencies of pure AcDiSol and corn starch were unaffected by the nature of the penetrating liquid while Primojel and Polyplasdone-XL 10 exhibited greater efficiencies in water than in dilute acid. All disintegrants lost part of their efficiency when incorporated in capsule formulations, especially in very hydrophilic matrices. The rate of wicking action could be a limiting step in the rate and extent of swelling of a disintegrant and hence hinder its efficacy in hard gelatin capsules.     

The Effect of Recompression on the Swelling Kinetics of Wet Massed Tablets,Containing ‘Super’ Disintegrants

Abstract

The effect of recompression on the swelling force kinetics of tablets employing a wet massed Avicel matrix and those containing extra-granular super disintegrants has been investigated. Explotab, unlike the Ac-Di-Sol and Polyplasdone XL systems, was found to give a high initial compact swelling force at low tablet porosities, but the rework process reduced the maximal swelling forces for all systems. However, the measured maximal swelling forces did not correlate with tablet disintegration time.

The rate of fluid penetration into the compacts was found to be controlled by tablet porosity but the penetration rates for all disintegrant systems were essentially identical. However the penetration rates for reworked compacts were significantly lower than those for tablets produced by first compression possibly due to the effects of increased lubricant distribution and relubrication causing poorer wettability.

Tablet disintegration times were found to correlate with a fluid penetration kinetic function involving lag time and time for 50% tablet swelling. Also, the retention of disintegration efficiency following rework correlated with the retention of the rate of fluid penetration. It is concluded that lubricants can play an important role in the efficiency of compact disintegration following tablet rework.     

Comparative Study of Disintegrating Agents in Tiaramide Hydrochloride Tablets

Abstract

The water sorption properties of some commonly used disintegrants (i.e., starch, sodium starch glycolate, croscarmellose sodium, crospovidone and alginic acid) were studied to correlate the disintegration and physical mechanical properties of tiaramide hydrochloride tablets containing 5% of these disintegrants. With the exception of alginic acid, disintegration time of tablets decreased with the increase in water sorption properties of the disintegrants.When exposed to high humidity (100% RH at 35°C), tablets containing two high water-sorbing disintegrants, e.g., croscarmellose sodium and crospovidone, exhibited a marked decrease in hardness. When these tablets were dried after exposure to humidity, the hardness remained lower than the initial values. It is possible that high water affinity of the disintegrants disrupts the interparticulate bonds inside the tablets. However, such a decrease in interparticulate bond may not be observed if the disintegrant also acts as a binder in the presence of water. For example, the hardness of tablets containing another high water-sorbing disintegrant, sodium starch glycolate, increased when these tablets dried after exposure to high humidity. Unlike croscarmellose sodium and crospovidone, sodium starch glycolate also increased the disintegration time if tablets were previously exposed to high humidity. Studies of the moisture absorption and drying cycle may be very important in evaluating environmental effects of tablets containing high watersorbing disintegrants.     

A New Computer-Aided Apparatus for Simultaneous Measurements of Water Uptake and Swelling Force in Tablets

Abstract

Water uptake and disintegrating force development have frequently been related to tablet disintegration properties.

Water penetration into compressed tablets has been studied by many authors using modified Enslin apparatus. Meanwhile, in previous papers by our group, a great deal of attention has been paid to the measurements of disintegrating force and to the kinetics of force development.

Given the fact that water penetration and swelling force development are related to each other, a new apparatus was set up which allows simultaneous measurements of water penetration and force development. It consists of a modified apparatus for force measurements, integrated with a modified Enslin apparatus. Both force and water uptake data were collected by a computer and stored for subsequent analysis.

Fitting of both water penetration and force development curves was performed with a commercially available software package for non-linear regression analysis.

This enables an examination of the relationships between force development and water penetration on the basis of homogeneous rate parameters. The apparatus was validated on a model tablet formulation based on dicalcium phosphate dihydrate with carboxymethylstarch.

Besides application in fast disintegrating tablets, this approach could be useful to study the behaviour of swelling-controlled release systems, in which the release mechanism (swelling force) is triggered by water penetration.     

The Effect of Recompression on Disintegrant Efficiency in Tablets Prepared by wet Granulation

Abstract

The efficiency of three modern disintegrants, Explotab, Ac-Di-Sol and Polyplasdone XL, has been investigated following rework of a wet massed, slowly eroding, tablet formulation. When the disintegrants were placed extra-granularly it was found that only Explotab retained good efficiency following rework. All disintegrants placed intra-granularly had rework efficiencies that were essentially the same as the control (no disintegrant). However, the addition of 2% extra-granular disintegrant prior to the second compression restored tablet disintegration behaviour for Polyplasdone XL and partially for Ac-Di-Sol.

Two of the factors potentially affecting the reworkability of disintegrants (comminution and regranulation) were also investigated. Regranulation caused Ac-Di-Sol and Explotab to significantly lose disintegrant efficiency. However milling alone caused no reduction in efficiency of any disintegrant.     

The Influence of the Swelling Characteristics of Starch and Starch Derivates on the Disintegration of Powders,Packed in Hard Gelatin Capsules

Abstract

Starch and starch derivates are frequently used in tablets to improve the disintegration. Their disintegrating action has mainly been attributed to the swelling of the particles when they are immersed in an aqueous solution. It has been assumed that tablet disintegration would be related to the ratio between the pore diameter and the linear growth of the disintegrant particles. The present work investigates the relationship between disintegrant swelling, pore diameter and drug release rate for loosely packed powderbeds in hard gelatin capsules.     

The Effect of Recompression on the Dissolution of Wet Massed Tablets Containing ‘Super’ Disintegrants

The effect of recompression on the disintegration, and dissolution of tablets employing ‘super’ disintegrants within a wet-massed Avicel matrix is reported. Differences were found in the disintegration times of tablets containing intra-granular or extra-granular disintegrants (Polyplasdone XL, Explotab and Ac-di-sol), both between disintegrant type and within the same disintegrant system following rework.

In the case oE extra-granular disintegrant, reworked compacts dissolved faster than the first compression tablets, irrespective of disintegrant type. Thus, milling and dispersion of the drug during rework appear to dominate over the effects of impaired disintegration when ‘super’ disintegrants are present. The control compacts (no disintegrant), however, dissolved less quickly following rework, indicating that dissolution was controlled by disintegration.

Tablets with intra-granular Polyplasdone XL and Ac-di-sol dissolved less quickly following rework. Both disintegrants have poor intra-granular rework efficiencies. However, for Explotab, which has better rework intra-granular efficiency, reworked tablets dissolved faster than first compression compacts.     

Carboxymethylstarches in Wet Granulation

Abstract

Commercialized carboxymethystarches (CMS) are both carboxyme-thylated and cross linked potato starch.

The influence of carboxymethylation and cross linkage on the disintegrating properties of starch are studied.

Tablets are made with acetaminophen as drug, Emcompress as diluant, Magnesium stearat as lubricant, and potato starch or its derivatives as disintegrants.

Tablets are prepared by direct compression or by wet granulation with the disintegrant intervening only in internal phasis.

Five disintegrants were studied, with two different concentrations:

native potato starch

potato starch simply cross linked

potato starch simply carboxymethylated

two potato starches both cross linked and carboxymethylated at two different degrees

Compressibility of powders blending and grain for compression are discussed.

The hardness, the tablet disintegration and the rate of drug dissolution are studied.

The results showed that the simply carboxymethylated starch has a totally different behaviour after direct compression or wet granulation. The poor results after wet granulation could be imputed to the bursting of starch granules during grain drying. Since it has lost its granular structure, the carboxymethylated starch will only allow a poor disintegration and a slow dissolution of the drug.

A very similar behaviour of native and simply cross linked starch: the results of which are bad for tablets either prepared by wet granulation or direct compression.

A very similar behaviour of the starches both carboxymethylated and cross linked, allowing a very good disponibility, either with tablets prepared by direct compression or wet granulation. These experiments prove :

the need for an sufficient cross linkage for CMS in a wet granulation process     

Evaluation of Fast Disintegrants in Terfenadine Tablets Containing a Gas-Evolving Disintegrant

Abstract

Effects of four fast disintegrants on the dissolution of terfenadine tablets containing the gas-evolving disintegrant, CaC0₃, were evaluated. In addition, effects of presence of starch along with the fast disintegrants on the dissolution of the tablets were examined. Dissolution data were treated to give dissolution parameters which reflected efficiency of the disintegrant combinations. The four fast disintegrants improved disintegration/dissolution of the original formulation. The relative efficiency of improvement was in the order crospovidone < Ac-Di-Sol < Primojel < low substituted hydroxypropylcellulose. The presence of starch advertently affected the role of the fast disintegrants. Scanning electron microscope studies revealed that starch covered the drug-containing granules and other particles of the tablet. pH changes during dissolution of representative tablets in 0.1 N HCl solutions were determined at specific time intervals. The progressive decrease in rates of acid consumption as a function of the amount of starch, along with the SEM studies, suggested that a barrier existed around the tablet particles. The barrier was generated by the swelled starch grains and was responsible for the loss of the dissolution-improving capacity of the fast disintegrants. Furthermore, the barrier interfered with the diffusion of the hydronium ions and therefore, impaired the function of the disintegrant combination.     

Formulation and Processing Factors Affecting the Disintegration of Hard-Shell Gelatin Capsules

Abstract

The effectiveness of disintegrants (Starch, Sodium Starch Glycolate, Microcrystalline Cell u lose, cross-linked cellulose, cross-linked Polyvinylpyrollidone) and the influence of excipients such as the lubricant (Magnesium Stearate), glidant (Talc), insoluble and soluble compressible fillers (Calcium Phosphate, Dextrose), as well as processing factors such as the blending sequence of additives, and effects of light compaction (powder-slugs) on the disintegration of hard shell gelatin capsules were examined. It was found generally that wicking and swelling type disintegrants were most effective at de-aggregating the encapsulated powder mass especially when Magnesium Stearate was present. The incorporation of Talc to the premix (filler, disintegrant, lubricant) appeared to reduce disintegration times due to abrasion of the hydrophobic lubricant film. Tamped powder fills (slugs) took twice as long to disintegrate as loosely filled capsules, but differences became negligible when disintegrants were included.     

Evaluations of the Mechanism of Disintegrant Action

The disintegrant properties of eight tablet disintegrants (a cation exchange resin, cross-linked carboxymethyl cellulose, sodium starch glycolate, U.S.P., Crospovidone, U.S.P., corn starch, an insoluble anionic cellulose polymer, a modified food starch, and a soybean cellulose derivative) have been evaluated. Three techniques were applied to some or all of the materials. Water uptake rates and capacities were determined for all disintegrants in bulk powders. Disintegration times of tablets formulated with varying concentrations of the different disintegrants in a matrix comprising 75% unmilled dibasic calcium phosphate dihydrate and 25% anhydrous lactose were measured. For four disintegrants, a novel computer assisted cinsphotomicrographic technique was applied to investigate the interaction of water with individual disintegrant particles, both in terms of swelling rate and maximum water capacity

Comparative evaluation of tablet disintegrants and studies of the mechanism of disintegrant action have quite properly attracted the attention of a number of pharmaceutical scientists. (1-16) However, it is clear that at present there is no concensus concerning a general theory rationalizing disintegrant action and at least five separate mechanism have been proposed (1, 2, 4)

In the present paper, the disintegrant action of eight disintegrants has been studied using three separate approaches. Firstly, the rate and capacity of the bulk powders to take up water and to swell as a result has been evaluated using an apparatus similar to that used by Nogami and coworkers (5). Secondly, the disintegration times of tablets containing varying concentrations of disintegrant and compressed using a matrix of 75% unmilled dibasic calcium phosphate dihydrate and 25% anhydrous lactose were determined in a manner similar to that described by Rudnic and his associates (6). Thirdly, the authors are able to report - apparently for the first time - the use of a new method for evaluating the rate and extent of swelling of individual units in an assembly of disintegrant particles. This method exploits a cinephotomicrographic technique in which groups of disintegrant particles are photographed under a microscope by a high speed movie camera with the resultant film being analyzed by a special computer technique which allows the size of both individual and all particles, in any given visual field, to be followed over the very short period of time which elapses during the interaction of the disintegrant particles with water. The results presented in this paper demonstrate that a combination of the three methods described above and, in particular, the computer assisted cinemicrophotographic technique allow considerable insight to be gained of the disintegration process     

Chitin and Chitosan as Disintegrants in Paracetamol Tablets

Abstract

Chitin and chitosan as disintegrants in paracetamol tablets were evaluated and compared to four commonly used disintegrants. Tablets containing chitosan showed faster disintegration, greater dissolution and was slightly softer than those containing chitin. An increment in concentration of these polymers caused markedly faster disintegration and better dissolution while an increase in compressional force showed opposite effects. Aging slightly altered the disintegration and dissolution. Tablets containing 7% of chitosan disintegrated within one minute which was much faster than those containing corn starch and microcrystalline cellulose but slightly slower than those containing sodium starch glycolate and croscamellose sodium. However, their dissolution profiles were non-significantly different from those of the latter ones.

Crystallinity, degree of acetylation, chain length and particle size were attributed to the efficiency of chitin and chitosan. Moisture sorption and water uptake were found to be the major mechanisms of disintegration while dissolution related to the swelling capacity.     

Evaluation of Different Fast Melting Disintegrants by Means of a Central Composite Design

Fast-disintegration technologies have encountered increased interest from industries in the past decades. In order to orientate the formulators to the choice of the best disintegrating agent, the most common disintegrants were selected and their ability to quickly disintegrate direct compressed tablets was evaluated. For this study, a central composite design was used. The main factors included were the concentration of disintegrant (X₁) and the compression force (X₂). These factors were studied for tablets containing either Zeparox® or Pearlitol 200® as soluble diluents and six different disintegrants: L-HPC® LH11 and LH31, Lycatab PGS®, Vivasol®, Kollidon CL®, and Explotab®. Their micromeritics properties were previously determined. The response variables were disintegration time (Y₁), tensile strength (Y₂), and porosity (Y₃). Whatever the diluent, the longest disintegration time is obtained with Vivasol® as the disintegrant, while Kollidon CL® leads to the shortest disintegration times. Exception for Lycatab PGS® and L-HPC LH11®, formulations with Pearlitol 200® disintegrate faster. Almost the same results are obtained with porosity: no relevant effect of disintegrant concentration is observed, since porosity is mainly correlated to the compression force. In particular, highest values are obtained with Zeparox® as the diluent when compared to Pearlitol 200® and, as the type of disintegrant is concerned, no difference is observed. Tensile strength models have been all statistically validated and are all highly dependent on the compression force. Lycatab PGS® concentration does not affect disintegration time, mainly increased by the increase of compression pressure. When Pearlitol 200® is used with Vivasol®, disintegration time is more influenced by the disintegrant concentration than by the compression pressure, an increase in concentration leading to a significant and relevant increase of the disintegration time. With Zeparox®, the interaction between the two controlled variables is more complex: there is no effect of compression force on the disintegration time for a small amount of disintegrant, but a significant increase for higher concentrations. With Kollidon CL®, the main factor influencing the disintegration time is the compression force, rather than the disintegrant concentration. Increasing both the compression force and the disintegrant concentration leads to an increase of the disintegration time.For lower Kollidon CL® percentages, the compression pressure increases dramatically the tablet disintegration. With the Explotab®, whatever the increase of compression force, the disintegrant concentration leads to an increase of the disintegration time. According to Student's t-test, only the compression force significantly and strongly influences the disintegration time when Pearlitol 200® is used. A slight interaction and some trends nevertheless appear: above 150 MPa, increasing the disintegrant concentration leads to a shortened disintegration time, below this limit the opposite effect is observed.     

A Comparative Evaluation of the Properties of some Tablet Disintegrants

The subject of the study is a cooperative evaluation of the properties of different disintegrants: starches (corn, maize, potatoe, rice) and derivatives (STARX 1500, carboxymethylstarches as PRIMOJEL or EXPLOTAB); celluloses (AVICEL, ELCEMA) and derive ted products as methylcellulose (METHOCEL), carboxymethylcellu-lose (sodium salt, NYMCEL, AC DI SOL), low substituted hydroxy-propylcellulose (L-HPC); macromolecules (Alginic acid, AMBERLITE IRP 88, ESMA SPRENG, Pectins, a.s.o.); finely divided solids (AEROSIL, VEEGUM). To realise this comparative study, different methods of evaluation of disintegrants physical properties are choosen, and wettability (contact angle), water uptake and swelling of the products measured. The disintegrants are also included in a calcium phosphate based tablet formula, and the disintegration is studied. The mechanism of action of the disintegrants is shortly discussed, and an approximate price/efficiency ratio given.

The results of the work permit a better choice of an appropriated disintegrant.

Purpose of tablets formulation is now Co obtain very short disintegrating times so that to that liberation of drug can begin without delay as soon as tha tablet is in contact with gastric juice.

Therefore, it is now iaportant to look for the sure efficient disiutugrauts, and so, many Materials are avalaible from industry.

Purpose of present study was to compare some physical properties of these different disintegranta.     

The Effect of Recompression on the Swelling Kinetics of Wet Massed Tablets, Containing 'Super' Disintegrants

The effect of recompression on the swelling force kinetics of tablets employing a wet massed Avicel matrix and those containing extra-granular super disintegrants has been investigated. Explotab, unlike the Ac-Di-Sol and Polyplasdone XL systems, was found to give a high initial compact swelling force at low tablet porosities, but the rework process reduced the maximal swelling forces for all systems. However, the measured maximal swelling forces did not correlate with tablet disintegration time.

The rate of fluid penetration into the compacts was found to be controlled by tablet porosity but the penetration rates for all disintegrant systems were essentially identical. However the penetration rates for reworked compacts were significantly lower than those for tablets produced by first compression possibly due to the effects of increased lubricant distribution and relubrication causing poorer wettability.

Tablet disintegration times were found to correlate with a fluid penetration kinetic function involving lag time and time for 50% tablet swelling. Also, the retention of disintegration efficiency following rework correlated with the retention of the rate of fluid penetration. It is concluded that lubricants can play an important role in the efficiency of compact disintegration following tablet rework.     

Evaluation of different fast melting disintegrants by means of a central composite design

Fast-disintegration technologies have encountered increased interest from industries in the past decades. In order to orientate the formulators to the choice of the best disintegrating agent, the most common disintegrants were selected and their ability to quickly disintegrate direct compressed tablets was evaluated. For this study, a central composite design was used. The main factors included were the concentration of disintegrant (X₁) and the compression force (X₂). These factors were studied for tablets containing either Zeparox® or Pearlitol 200® as soluble diluents and six different disintegrants: L-HPC® LH11 and LH31, Lycatab PGS®, Vivasol®, Kollidon CL®, and Explotab®. Their micromeritics properties were previously determined. The response variables were disintegration time (Y₁), tensile strength (Y₂), and porosity (Y₃). Whatever the diluent, the longest disintegration time is obtained with Vivasol® as the disintegrant, while Kollidon CL® leads to the shortest disintegration times. Exception for Lycatab PGS® and L-HPC LH11®, formulations with Pearlitol 200® disintegrate faster. Almost the same results are obtained with porosity: no relevant effect of disintegrant concentration is observed, since porosity is mainly correlated to the compression force. In particular, highest values are obtained with Zeparox® as the diluent when compared to Pearlitol 200® and, as the type of disintegrant is concerned, no difference is observed. Tensile strength models have been all statistically validated and are all highly dependent on the compression force. Lycatab PGS® concentration does not affect disintegration time, mainly increased by the increase of compression pressure. When Pearlitol 200® is used with Vivasol®, disintegration time is more influenced by the disintegrant concentration than by the compression pressure, an increase in concentration leading to a significant and relevant increase of the disintegration time. With Zeparox®, the interaction between the two controlled variables is more complex: there is no effect of compression force on the disintegration time for a small amount of disintegrant, but a significant increase for higher concentrations. With Kollidon CL®, the main factor influencing the disintegration time is the compression force, rather than the disintegrant concentration. Increasing both the compression force and the disintegrant concentration leads to an increase of the disintegration time.For lower Kollidon CL® percentages, the compression pressure increases dramatically the tablet disintegration. With the Explotab®, whatever the increase of compression force, the disintegrant concentration leads to an increase of the disintegration time. According to Student's t-test, only the compression force significantly and strongly influences the disintegration time when Pearlitol 200® is used. A slight interaction and some trends nevertheless appear: above 150 MPa, increasing the disintegrant concentration leads to a shortened disintegration time, below this limit the opposite effect is observed.     

Mprovement in Pressure-Dependent Dissolution of Trepibutone Tablets by Using Intragranular Disintegrants

In developing compressed tablets trepibutone 40mg, dissolution studies indicated that the compression pressure applied exerted strong influence on drug dissolution from the tablets. It was found that the incorporation of disintegrants in the granular formulation prevented the decrease in dissolution rate of drug from tablets by compression. Instead of the intragranular disintegrants, incorporation of a rubber powder, which does not swell at all in water and has some elastic recoveries after compression, did not improve the drug dissolution from tablets. It was concluded that the addition of disintegrants in the granular formulation resulted in little prevention of the particle aggregation during compression. The swelling of disintegrant grains in water is considered to play an important part in the deaggregation of drug particles     

A Comparative Evaluation of Some Starches as Disintegrants for Double Compressed Tablets

Abstract

The effect of different types and concentrations of some starches as disintegrants on the properties of aspirin tablets as a model for double compressed tablets was studied. The formulated tablets were evaluated using the U.S.P. official tests and some other selected nonofficial tests. These tests include: uniformity of weight, uniformity of content, disintegration, dissolution, hardness, friability and thickness. Maize starch was found to be the most suitable disintegrant for the formulation of double compressed tablets while rice starch was the worst disintegrant, in this study, as it significantly increased the hardness of tablets and showed a prolonged disintegration time as well as a poor dissolution rate. increasing the starch content of tablets resulted in a marked increase in their dissolution rate.     

A Combination Disintegration-Dissolution Apparatus for Fast-Disintegrating

Abstract

A combination disintegration-dissolution apparatus for fast disintegrating tablets is described. Preliminary investigation using sodium carboxymethyl starch as the disintegrant indicated that the apparatus was capable of detecting differences in the disintegration time both due to disintegrant concentration as well as due to the intensity of agitation used in the apparatus. No difference in the disintegration times could be observed when similar tablets were evaluated using the existing disintegration apparatus.

The combination apparatus described is simple in construction and design and can be fabricated quite easily and economically in the laboratory. Due to the anticipated increase in the availability of fast-disintegrating tablets, this apparatus will be useful to the pharmaceutical formulator as a valuable quality control tool. In addition, the apparatus is adaptable to various other agitational systems in common usage and can be used by laboratories carrying out combined disintegration and dissolution tests using automated equipment.