Disintegrants in Solid Dosage Forms

Abstract

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.     

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.     

Disintegrating Force and Tablet Properties

The development of a disintegrating force inside the tablet due to the liquid/solid contact depends on a proper wetting of the material and occur according to saturation kinetics.

The aim of the present work is the evaluation of such a force development in relation to the characteristics of the tablet in particular to the compression force.

For this purpose, the disintegrating force of different tablets formulations has been measured by means of a previously described apparatus.

The results obtained show that a new evaluation of a compact disintegration characteristics may be obtained through the determination of such parameters as the maximum force developed (y₀) and the time of the half maximum force development (b).     

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

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     

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     

Controlled Release from Glycerol Palmito-Stearate Matrices Prepared by Dry-Heat Granulation and Compression at Elevated Temperature

Diprophylline release from glycerol palmito-stearate “precirol” matrices containing different direct compression (DC) excipients, with variable dissolving/disintegrating ability, is investigated. The matrices are formed by employing dry-heat granulation and compression at elevated temperature.

Greater drug release prolongation is achieved with the dissolving DC excipients than with the swelling ones. The release is described on the basis of two biexponential first order models and the Weibull function as well.

The effect of compression conditions (temperature and pressure) on the drug release is found to be related to the compaction behaviour of the DC excipients, i.e. plastic deformation or fragmentation.     

Disintegration Mechanisms of Tablets Containing Starches. Hypothesis About the Particle-Particle Repulsive Force

The disintegration of a tablet immersed in a liquid appears to be essentially a mechanical phenomenon: penetration of liquid then destruction of compressed structure

For a number of authors, the starch granule swelling is the mechanical force which destroys the tablet.

Indeed, a study on a series of experimental carboxymethylstraches indicates that those that do not swell, show the same disintegration time to those that do swell.

We can also notice that the carboxymethylstarches wich swell much less in a gastric medium, produce even shorter disintegration times in this medium.

The destruction of the cohesion forces between the constitutive elements of the tablet under the action of water may be ascribed to the creation of a repulsive force when the elements of the tablet enter into contact with water, or to a simple annihilation of the hydrogen bonds or of the capillary cohesion forces.

The hydrophilic nature of starch seems to be determinant: water penetrates into the tablet owing to hydrophilic porosity under the action of an important hydrostatic pressure.     

Evaluation of sorghum starch as a tablet excipient

The suitability of sorghum starch as a binder and disintegrant at various concentrations in diverse tablet formulations have been investigated. Sodium bicarbonate and calcium carbonate were used as soluble and insoluble inorganic medicinal substances in various tablet formulations.

The effect of sorghum starch on the physical properties of the tablets were compared with those formulated with maize starch using the same concentrations of binder and disintegrant under the same experimental conditions.

The observations show that sorghum starch can be used as binder and disintegrant in tablet formulations. The indication is that the starch exhibit about twice the disintegrant power and about the same binding efficacy compared to maize starch.     

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

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.     

Methods for the Determination of the Carbon Dioxide Evolved from Effervescent Systems

Different methods for determining the carbon dioxide evolved from effervescent systems are described. In addition, a comparison between some of them is carried out when a stoechiometric mixture of L-tartaric acid and sodium bicarbonate reacts.

The methods compared are: gravimetric, volumetric and gasometric.

The gravimetric methods can be direct or indirect. The direct ones are based on taking in the carbon dioxide by a sorbent substance. The increase of weight after the absorption represents the CO₂ evolved. In the indirect gravimetric methods the amount of carbon dioxide is determined by substraction of the weight of the sample after and before the effervescent reaction.

The volumetric methods are based on an acid-base titration. In the method used, the carbon dioxide released reacts with barium hydroxide. The excess of barium hydroxide is titrated with oxalic acid. It is possible to calculate then the carbon dioxide produced in the reaction from the volume of oxalic acid used.

In the gasometric methods the volume of gas is directly determined by the displacement of a solution when the gas is released.

The gasometric method seems to be the most efficient among the studied ones.     

Dissolution Study of Prolonged Release Morphine Tablets Using Hydrophilic Matrices

This study presents the results of “in vitro” dissolution of prolonged release morphine tablets using hydroxypropylmethylcellulose. Tablets with four different doses were elaborated and the liberation from these formulated tablets was compared with that of the only commercial pharmaceutical preparation of this type registered in the Spanish Pharmaceutical Market.

The results of the dissolution tests show that the drug was gradually released in all cases and tablets had released from 60 to 90% of its contents after 8 hours.

In the comparative study, the commercial tablets showed the fastest release. In both cases the release rate was lower when artificial intestinal fluids were used as the dissolution medium.     

Research Papers: Preparation of Indobufen Pellets by Using Centrifugal Rotary Fluidized Bed Equipment Without Starting Seeds

ABSTRACT

Pellets containing Indobufen as model drug were prepared by using the centrifugal-rotary fluidized bed equipment without employing non-pareil seeds.

The influence of different amounts of spheronization enhancer (microcrystalline cellulose) and of different fillers (lactose, mannitol, calcium carbonate) on both processing and physical properties of the pellets were evaluated.

The preparation reproducibility was also investigated. The use of 30% w/w of microcrystalline cellulose was essential to produce a good quality pellets; the incorporation of filler decreased the qualitative characteristics of the pellets.

The water feeding rate proved to be an important parameter for the pellet growth.

Therefore, the results showed that this technology based on the rotary fluidized bed is a promising and alternative method in producing pellets.     

The Effect of Molecular Structure on the Function of Sodium Starch Glycolate in wet Granulated Systems

The effect of variation in the degree of cross-linkage and extent of substitution on the disintegrant properties of sodium starch glycolate in wet granulated systems has been examined. The rates of mixing shear were evaluated for their effect on the ability of the disintegrants to function after granulation. In addition, the effect of varying the intragranular and extra-granular concentration of the disintegrants was investigated. The results indicate that increased rates of mixing shear adversely effect sodium starch glycolates. In addition, the current commercial specifications for a marketed sodium starch glycolate seem to be optimal in this segard. It also seems evident that a mixture of disintegrant within and around the granule is desirable in wet granulated systems.

Previous papers have discussed the importance of raw materials specifications in defining the fitness for use of many pharmaceutical excipients (1-6). We have recently initiated a study concerning the effect of variation of degree of cross-linkage and extent of substitution on the disintegrant action of sodium starch glycolate in direct compression systems. Further details of this study will be provided in a paper focussed on standard raw materials tests for disintegrants and their relative differences in direct compression systems (7).     

Statistical Optimization of a Controlled Release Formulation Obtained by a Double Compression Process: Application of an Hadamard Matrix and a Factorial Design

A formulation containing an antiinflammatory agent (diclofenac sodium), two inert matrices (ethylcellulose and polyvinyl chloride) and two lubricants (magnesium stearate and talc) was optimized by a double compression process

In a first stage, preliminary trials were performed in order to study the effect of lubricants added before and after precompression

An Hadamard matrix H(8) was applied to estimate the main effects of four parameters: applied force at the upper punch (UPF) during precompression, particle size range after grinding, UPF during the final compression and concentration of ethylcellulose added before the final compression

Following the Hadamard matrix, a factorial design 2² was built. The complete linear models were fitted by regression for each response reflecting the compression behaviour and dissolution kinetics

In an optimal point, the validation was carried out with the area under the dissolution curve, being the major response to be optimized

The dissolution curves were well fitted by the Weibull distribution     

Crystal Engineering and Particle Design for the Powder Compaction Process

The historical background to the subject of crystal engineering of pharmaceuticals is briefly reviewed with reference to materials as diverse as insulin and direct compression tablet excipients. In the light of the limited scientific and practical information available on the topic two questions are posed -

Is it possible to prepare 'designer' materials with preferred processing, specifically compressive, properties giving optimised product characteristics?

How can such materials be efficiently manufactured?

In order to consider these questions, several important elements of data-base requirements are regarded as essential. These include knowledge of the crystalline phases of pharmaceutical solids, full understanding of the fundamental mechanical constants and moduli of particulate solids, and the relationships describing the influence of crystallographic structure on the mechanical properties of crystals and powders. At the same time the effects of preparation, pretreatment and processing effects on crystal structure, crystallinity and thermodynamic properties of powdered solids must be established.

The topics of material based compaction problems, property groupings of pharmaceutical powders with particular emphasis on crystal structure and mechanical properties are discussed. The review then considers recent and current research work examining the compaction behaviour of modified or engineered materials, prepared using alternative crystallisation conditions and the incorporation of low level additives. Specific examples include modern direct compression excipients, 'spherical' drug particle production and high purity lubricant (magnesium stearate) powders.

In conclusion, the future potential of the concepts of crystal engineering and particle design is considered in terms of predicting mechanical and processing properties from fundamental molecular and structural information.     

A Combination Disintegration-Dissolution Apparatus for Fast-Disintegrating

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.     

Validation of solid dosage forms the FDA view

In May 1987 the United States Food and Drug Administration published the final version of a guideline for process validation for pharmaceutical manufacturing. The document incorporated the comments from the pharmaceutical industry gathered after the publication of three draft versions in 1983, 1984 and 1986.

The presentation will cover the current definition of process validation as well as terms such as “worse case” and “installation qualification”.

The stages of process validation will be discussed including the written plan (protocol): records to be maintained; suitability of raw materials; equipment performance qualification; the number of runs required; and acceptance criteria.

Specifics for solid dosage forms will be presented along with details on batch record in instructions and establishment of acceptable range limits.

Circumstances and requirements for revalidation will be discussed as well as the validation of current finished dosage forms by retrospective validation.     

Tie Effect of Disintegrants and Processing on the Bioavailability of Frusemide from Compressed Tabllts

Batches of frusemide tablets were produced using Explotab, polyplasdone XL, Amberlite IRP88, maize atarch, and Elcesan P100 as disintegrants. Bioavailability atudies were carried out on a double blind basis.

The bioavailability differences between formulations was shown to be significant. Explotab rendered the fruseulide far more bioevailable than the other four disintegrants.