Comprehensive Summaries of Uppsala Dissertationsfrom the Faculty of Pharmacy 238

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Pharmaceutical Binders and Their Function in Directly

Compressed Tablets

Mechanistic Studies on the Effect of Dry Binders on Mechanical Strength, Pore Structure and Disintegration of Tablets

BY

SOFIA MATTSSON

ACTA UNIVERSITATIS UPSALIENSISUPPSALA 2000

Dissertation for the Degree of Doctor of Philosophy (Faculty of Pharmacy) inPharmaceutics presented at Uppsala University in 2000

ABSTRACT

In this thesis, the strength-enhancing mechanisms of dry binders in direct compressionwere studied. The systems investigated were binary mixtures containing variouscompounds and binders. Among the binders used were a series of different molecularweights of polyethylene glycol. The proposed simplified tablet model describing thefracture path in a tablet during strength testing offers an explanation for the increase intablet strength caused by the binder. The model and results in this thesis indicate thatfractures will usually propagate around the tablet particles and through theinterparticulate voids during tablet strength testing.

One important characteristic of the binder is its ability to be effectively and evenlydistributed through the interparticulate voids in a compound tablet. Characteristics suchas high plasticity, low elasticity and a small particle size were associated with a moreeven distribution and a consequent pronounced effect on pore structure and markedimprovement in tablet strength. The strength of tablets containing less plastic binderswas governed more by the compactibility of the binder. The tablet porosity, bondingmechanisms and volume reduction mechanisms of the compound also influenced theeffect of the binder. For example, the plasticity and particle size of the binder had themost significant effects on tablet strength when the tablet porosity of the compound wasrelatively low. A combination of the plasticity and the compactibility of the binderdetermined the strength of tablets when the tablet of a compound was more porous. Thepositive effect of a binder on pore structure and tablet strength resulted in an increase inthe disintegration time. Although addition of a superdisintegrant generally improved thedisintegration time, the effect was decreased when the formulation included moredeformable binders.

The choice of a suitable binder for a tablet formulation requires extensiveknowledge of the relative importance of binder properties for enhancing the strength ofthe tablet and also of the interactions between the various materials constituting a tablet.Thus, the increased knowledge of the functionality of a binder obtained in this thesisenables a more rational approach to tablet formulation.

Sofia Mattsson, Department of Pharmacy, Division of Pharmaceutics,Uppsala Biomedical Centre, Box 580, SE-75123 Uppsala, Sweden

© Sofia Mattsson 2000

ISSN 0282-7484ISBN 91-554-4857-7

Contents

Papers discussed 7

Pharmaceutical tablets 8

Compaction of pharmaceutical powders 9Volume reduction mechanisms 9Methods for characterisation of volume reduction mechanisms 10Bonding mechanisms 11Methods for characterisation of bonding mechanisms 12

Mechanical strength of tablets 13Measurements of mechanical strength 13Theoretical models of mechanical strength 14

Bond summation conceptFracture mechanics conceptPercolation theory

Effect of particle and powder properties on mechanical strength 15Effect of compaction process and environment on mechanical strength 16

Pore structure of tablets 17

Disintegration of tablets 18

Binders as strength-enhancing materials in pharmaceutical tablets 18Distribution of binders - comparison between direct compressionand wet granulation 19Effect of binders on mechanical strength of directly compressed tablets 19Commonly used binders in direct compression 20Polyethylene glycol 21

Aims of the thesis 21

Materials and methods 22Preparation of test materials 22

Model compoundsBinder materialsSuperdisintegrant

Choice of model compounds 23Characterisation of materials 24

DensityExternal surface areaAmorphous content

Preparation of mixtures 24Compaction of tablets 25

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Characterisation of compaction behaviour 25Deformation propertiesFragmentation properties

Characterisation of tablets 26Tensile strengthExamination of fracture surfacesPorosityPore size distributionDegree of binder saturationDisintegration

Effect of binders on tablet pore structure 28Effect of binder deformability and particle size on tablet porosity 28Effect of amount of binder and compaction pressure on tablet porosity 31Effect of compound properties on tablet porosity 32Effect of binder addition on pore size distribution 32

Effect of binders on tablet strength 35Effect of binder deformability and particle size on tablet strength 36Effect of amount of binder and compaction pressure on tablet strength 39Effect of compound properties on tablet strength 40

Tablet model describing the effect of binder addition on tablet strengthand pore structure 43

Fracture characteristics 43Relation between binder saturation and tablet strength 47Qualitative assessment of the strength of interactions in tablets 48

Effect of binders on tablet disintegration 50Relation between tablet strength/porosity and disintegration properties 50Binder properties of importance for optimal function of superdisintegrants 50

Conclusions 53

Acknowledgements 55

References 57

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Papers discussed

This thesis is based on the following papers, which will be referred to by their Romannumerals in the text.

I Olsson, H., Mattsson, S., Nyström, C., 1998. Evaluation of the effect of additionof polyethylene glycols of differing molecular weights on the mechanical strengthof sodium chloride and sodium bicarbonate tablets. Int. J. Pharm. 171, 31-44.

II Mattsson, S., Nyström, C., 2000. Evaluation of strength-enhancing factors of aductile binder in direct compression of sodium bicarbonate and calcium carbonatepowders. Eur. J. Pharm. Sci. 10, 53-66.

III Mattsson, S., Nyström, C., 2000. Evaluation of critical binder properties affectingthe compactibility of binary mixtures. Drug Dev. Ind. Pharm., accepted forpublication.

IV Mattsson, S., Nyström, C. The use of mercury porosimetry in assessing the effectof different binders on the pore structure and bonding properties of tablets.Manuscript.

V Mattsson, S., Bredenberg, S., Nyström, C. Formulation of high tensile strengthrapidly disintegrating tablets – evaluation of the effect of some binder properties.Submitted.

Reprints were made with permission from the journals.

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Pharmaceutical tablets

The most commonly used dosage form for pharmaceutical preparations is currently thetablet, available in various forms and administered orally. The advantages of this dosageform are manifold: tablets are cost effective to manufacture, convenient to dispense andstore, and easy for the patient to administer, and they provide a versatile means ofdelivering the drug. Release of drug from the tablet can be controlled by altering thedesign and content of the formulation. Also, since this is a dry dosage form, tabletsprovide a supportive environment for drug stability and generally have a relatively longshelf life.

Tablets are manufactured by applying pressure to a powder bed, which compresses thepowder into a coherent compact. The powder may consist of either primary particles oraggregated primary particles (i.e. granules). When these are compressed, bonds areestablished between the particles or granules, thus conferring a certain mechanicalstrength to the compact.

The properties of the tablet (e.g. mechanical strength, disintegration time and drugrelease characteristics) are affected by both the properties of the constituent materialsand the manufacturing process. Excipients such as diluents, binders and lubricants aregenerally needed in a formulation in order to facilitate the manufacturing process, butalso to ensure that the resulting tablets have the desired properties. For instance, tabletsshould be sufficiently strong to withstand handling during manufacturing and usage, butshould also disintegrate and release the drug in a predictable and reproducible manner.It is thus important to choose the appropriate excipient and manufacturing process whendeveloping a new tablet formulation.

The uniaxial compaction of a pharmaceutical powder results in an anisotropic andheterogeneous tablet with variations in such properties as density, porosity andmechanical strength throughout the tablet (Train, 1956; Kandeil et al., 1977; Nyströmet al., 1993). The tablet porosity of most materials is about 5 to 30%. This means thateven at relatively high compaction pressures, tablets will rarely be non-porous.

Two models have been suggested in an effort to describe the distribution of air in tablets(Nyström et al., 1993). The most appropriate model depends on the compaction andbonding characteristics of a certain material. In the first model, a tablet is described aspowder particles dispersed in air, so that the tablet then contains a network of pores. Thevalidity of this model is supported by the applicability of methods such as surface areameasurement by air permeametry and measurement with mercury intrusion, since thesemethods are based on a medium flowing through or penetrating the tablet. As aconsequence of this model, the interparticulate bonds are considered weaker than theintraparticulate bonds. In the second model, a tablet is regarded as individual units of airdispersed through a solid continuous phase. The first model appears to be most suitablefor commonly used tableting materials (Nyström et al., 1993; Alderborn, 1996). Theapplicability of this model is further supported by scanning electron microscopephotomicrographs, since individual particles can be discerned in tablets aftercompaction (Hardman and Lilley, 1970; Down, 1983).

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Compaction of pharmaceutical powders

When pressure is applied to a powder bed, the bulk volume of the powder is reducedand the amount of air is decreased. During this process, energy is consumed. As theparticles are moved into closer proximity to each other during the volume reductionprocess, bonds may be established between the particles. The formation of bonds isassociated with a reduction in the energy of the system as energy is released (Coffin-Beach and Hollenbeck, 1983; Rowlings et al., 1995). In the literature, the termcompression is often used to describe the process of volume reduction and the termcompaction is used to describe the whole process, including the subsequentestablishment of bonds. The strength of a tablet composed of a certain material can beused as a measure of the compactibility of that material. Volume reduction takes placeby various mechanisms and different types of bonds may be established between theparticles depending on the pressure applied and the properties of the powder.

Volume reduction mechanisms

The first thing that happens when a powder is compressed is that the particles arerearranged under low compaction pressures to form a closer packing structure. Particleswith a regular shape appear to undergo rearrangement more easily than those ofirregular shape (York, 1978). As the pressure increases, further rearrangement isprevented and subsequent volume reduction is accomplished by plastic and elasticdeformation and/or fragmentation of the tablet particles (e.g. Train, 1956; Duberg andNyström, 1986). Brittle particles are likely to undergo fragmentation, i.e. breakage ofthe original particles into smaller units. Plastic deformation is an irreversible processresulting in a permanent change of the particle shape, whereas after elastic deformationthe particles resume their original shape, i.e. this is a reversible process.

The degree of volume reduction that a pharmaceutical powder bed undergoes dependson the mechanical properties of the powder and the type of volume reductionmechanisms involved. Particle size and speed of compression will in turn influence themechanical properties of the material (Roberts and Rowe, 1987a). For example,reduction in particle size has been related to a decreased tendency to fragment (e.g.Alderborn and Nyström, 1985). Some materials appear to have a critical particle size atwhich a transition from brittle to ductile behaviour occurs as the particles becomesmaller (Robert and Rowe, 1987b; Roberts et al., 1989). Brittle materials which undergoextensive fragmentation generally result in tablets of relatively high porosity because ofthe large number of bonding points that are created which prevent further volumereduction. A ductile material, on the other hand, will often result in tablets of lowporosity because the high degree of plastic deformation enables the particles to movevery close to each other. The deformation of surface asperities will play a special role inthis context.

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Methods for characterisation of volume reduction mechanisms

Both fragmentation and deformation can occur in different stages of the volumereduction process (Duberg and Nyström, 1986). One mechanism often predominates,however, and various techniques are available for characterisation of the dominatingvolume reduction mechanism. As mentioned above, the mechanical properties of amaterial have some influence on its volume reduction behaviour. These properties canbe obtained by measuring the hardness and Young’s modulus of a material in order toassess its plasticity and elasticity (Roberts and Rowe, 1987a). Attempts have also beenmade to obtain mechanical properties by extrapolating tablet measurements of e.g.elasticity and brittleness to corresponding values for a tablet of zero porosity (e.g.Mashadi and Newton, 1987). Furthermore, a brittle fracture index has been proposed asa method of assessing the brittleness of a material (Hiestand and Smith, 1984).Mechanical properties have also been investigated using single particle measurements(Duncan-Hewitt, 1993).

Several mathematical equations based on the measurements of porosity changes as afunction of applied pressure (e.g. the Heckel, Kawakita and Cooper-Eaton equations)have been developed in an effort to quantitatively describe the volume reductionbehaviour of a powder (Heckel, 1961a,b; Paronen and Illka, 1996). The applicability ofthese equations depends on the pressure or porosity range studied.

When measuring the change in porosity during compression and decompression andapplying the Heckel equation, the resistance to deformation may be obtained by usingthe reciprocal of the slope of the linear part of the Heckel plot (Heckel, 1961a,b). Thisvalue is defined as the yield pressure of the material (Hersey and Rees, 1971). When themeasurements are made in-die, i.e. during one compression cycle, this yield pressurevalue is considered to reflect both plastic and elastic deformation (Duberg and Nyström,1986; Paronen, 1986). Out-of-die measurements are based on the porosity of the tabletafter ejection, thus allowing for elastic expansion to take place. Therefore, the obtainedyield pressure is regarded as a reflection of the extent of plastic deformation (Paronen,1986). Yield pressure values obtained in-die are generally lower because of theinfluence of the elastic component (Fell and Newton, 1971a; Paronen and Juslin, 1983).Consequently, a small difference between these yield pressure values indicates a lowdegree of elastic deformation (Fell and Newton, 1971a; Paronen, 1986). The extent ofelastic deformation of the powder bed during compression can also be assessed bymeasuring the relative difference in porosity (Duberg and Nyström, 1986) or tabletheight (Armstrong and Haines-Nutt, 1972) during and after compression.

It appears that some experimental variables can affect the outcome of Heckel plots, andlimitations to their use for prediction of compaction behaviour have been proposed (Rueand Rees, 1978; York, 1979; Sonnergaard, 1999). For example, compression speed andparticle size can affect volume reduction behaviour (Rue and Rees, 1978). There alsoappear to be limitations to the Heckel function at high compaction pressures or lowtablet porosity (Paronen and Illka, 1996). Determination of the volume reductionbehaviour of a material is generally performed in bulk and does not take changes insurface properties (e.g. deformation of asperities) into account. The deformation ofasperities can affect the performance of the powder when compressed and the

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possibility of forming interparticulate bonds (e.g. Bowden and Tabor, 1950; Train,1956; Olsson and Nyström, 2000a). Nonetheless, Heckel plots have been foundvaluable as a means of comparing materials with differing volume reduction behaviours,as long as the experimental conditions are kept constant (York, 1979; Duberg andNyström, 1986).

Other methods for characterising the volume reduction behaviour of a material havebeen presented in the literature. These include scanning electron microscopy (Hardmanand Lilley, 1970; de Boer et al., 1978; Krycer et al., 1982), the use of ratios from axialand radial tensile strength measurements (Duberg and Nyström, 1982), andmeasurement of surface area changes during compaction using permeametry (Alderbornet al., 1985a,b), gas adsorption (Hardman and Lilley, 1973; Armstrong and Haines-Nutt,1974; Alderborn et al., 1985a) and mercury porosimetry techniques (Vromans et al.,1985; Vromans et al., 1986). The techniques for measuring surface area changes aremainly used to estimate the tendency of a material to fragment under pressure.

Bonding mechanisms

The dominating bonding types which adhere particles together in a tablet made of drypowders by direct compression are considered to be distance attraction forces, solidbridges and mechanical interlocking (Führer, 1977).

The term distance attraction forces includes van der Waals forces, hydrogen bonds andelectrostatic forces. The common feature is that these bonds act between surfaces thatare separated by some distance. Van der Waals forces can occur over distances up to100 to 1000 Å and the strength of the van der Waals forces is dependent on the distancebetween the attracting molecules, ions or particles and the medium surrounding them(Israelachvili, 1992). Hydrogen bonds occur primarily through electrostatic interactionand may occur both intramolecularly and intermolecularly (Israelachvili, 1992).Microcrystalline cellulose is an example of a material where hydrogen bonds areconsidered important for the tablet strength (Reier and Shangraw, 1966). Electrostaticforces may arise from triboelectric charging during mixing and compaction. However,electrostatic forces are neutralised relatively quickly over time and are not considered tobe of significance in tablets of pharmaceutical materials (Nyström et al., 1993).

Solid bridges can be formed where there is particle-particle contact at an atomic level.These bridges can be considered as a continuous phase of powder material betweenparticles. The molecules or ions in the solid bridge are assumed to be arranged andbonded in the same manner as those inside each particle. Certain prerequisites areconsidered to facilitate the development of solid bridges, e.g. a simple chemicalstructure, a certain degree of plastic deformation and the concentration of high stresslevels at interparticulate contact points (Führer, 1977; Adolfsson et al., 1997). Becauseof their structure, solid bridges are regarded as relatively strong bonds and materialsbonding with such bonds, e.g. sodium chloride, form relatively strong tablets oncompaction. However, tablets containing these strong bonds are also associated with anextended disintegration time (Führer, 1977). The ability to bond with solid bridges hasbeen shown to increase with an increase in particle size and compaction pressure

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(Adolfsson et al., 1997). It has also been proposed that amorphous materials are morelikely to bond with solid bridges (Fürher, 1977; Sebhatu et al., 1997) and that thepresence of moisture in a tablet increases the likelihood of solid bridges developing(Sebhatu et al., 1997).

Mechanical interlocking describes the hooking and twisting together of particles in atablet. This is possible because of particle irregularities and roughness on the surface ofthe particles (Fürher, 1977).

Methods for characterisation of bonding mechanisms

Several methods for determining the dominating bonding mechanisms in tablets havebeen proposed. The results generally conclude that the dominating bond type inpharmaceutical tablets is distance attraction forces, and especially van der Waals forces(e.g. Luangtana-Anan and Fell, 1990; Karehill and Nyström, 1990).

When distance attraction forces in tablets were filtered out using magnesium stearate(Nyström et al., 1993) or liquids with different dielectric constants (Karehill andNyström, 1990; Olsson et al., 1996; Adolfsson et al., 1997), the tablet strength ofvarious compounds decreased. However, this reduction in tablet strength wascomparatively less for tablets made from some materials, e.g. sodium chloride. Theremaining tablet strength of sodium chloride is attributed to solid bridges, since theseare able to be developed even though magnesium stearate or liquid surrounded thesodium chloride particles. The proportion of solid bridges in a tablet can thus becalculated.

Another approach to estimating the dominating bonding mechanisms has been tocalculate the surface specific tablet strength (Nyström et al., 1993; Adolfsson et al.,1999). The rationale behind such an approach is the assumed proportionality betweentablet surface area and the surface area participating in bonding. The surface specifictablet strength would then give a high value for materials bonding with strong bonds,i.e. solid bridges, and a low value for materials predominantly bonding with distanceattraction forces. The results are in agreement with other methods for estimating bondtypes (Karehill and Nyström, 1990; Olsson et al., 1996; Adolfsson et al., 1997). Theconcept of surface specific tablet strength was developed further by also taking theestimated average distance between the particles into consideration (Adolfsson et al.,1999). However, the results were generally not affected by this procedure. A study byOlsson and Nyström (2000b) considered features of the internal tablet structure thatwere important for tablet strength and assessed bond types by establishing an interactionfactor that reflected the dominating bond type. Although both these latter approaches(Adolfsson et al., 1999; Olsson and Nyström, 2000b) were able to differentiate betweendominating bond types, they were not able to fully account for effects of particle sizeand compaction pressure.

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Mechanical strength of tablets

The mechanical strength of pharmaceutical tablets is frequently assessed as an in-process control during manufacturing and as a means to understand the compactionbehaviour of a material (Davies and Newton, 1996). The mechanical strength of a tabletcan be characterised by the force necessary to break the tablet. When a tablet issubjected to such a force, the response can be interpreted on the basis of the bondsummation or fracture mechanics concepts. In the bond summation concept, the bondsholding the particles together and the breakage of these bonds during strength testingare emphasised. In the fracture mechanics concept, focus is on the propagation of cracksin the tablet during strength testing. Although the aim of both concepts is to describe themechanical strength of a tablet, the discrepancy between the theoretical and themeasured mechanical strength may vary between them. The two concepts are discussedbriefly under the section dealing with theoretical models of mechanical strength.

Measurements of mechanical strength

There are several methods for measuring the mechanical strength of tablets, e.g. thebreaking strength, diametral compression, axial tensile strength and bending tests.However, the results vary according to the method applied. This may be attributed tovariations in the stress conditions induced by the test and also to the heterogeneity andanisotropic nature of tablets, with variations in, for example, the interparticulate bondand pore distribution (Newton et al., 1992). Furthermore, the mode of failure and thedimensions of the tablet have to be taken into consideration. Consequently, the strengthvalues obtained may be considered to represent specimen properties rather than materialproperties (Newton et al., 1992; 1993)

The most common strength test in pharmaceutical applications is the diametralcompression test, which is used to calculate the radial tensile strength of a tablet (Felland Newton, 1970a). In order to calculate the radial tensile strength, the stressconditions have to be such that the tablet fails in tension; most materials are, in fact,weakest in tension (Newton et al., 1992). During radial tensile strength measurements,the fracture occurs through a predetermined diametral cross section of the tablet.Therefore, the radial tensile strength is likely to reflect the average strength of tabletrather than the strength of the weakest plane in the tablet.

Another method for determining mechanical strength is to measure the axial tensilestrength. The force necessary to break the tablet is obtained by pulling the tablet parallelto the applied force during the formation of the tablet and this force is then used tocalculate the axial tensile strength (Nyström et al., 1978). During axial tensile strengthmeasurements, the fracture will occur through the weakest plane in the tablet.Consequently, this method allows detection of capping tendencies in a tablet.

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Theoretical models of mechanical strength

Different theoretical models for describing the mechanical strength of tablets have beenproposed in the pharmaceutical literature, some of which are reviewed below.

Bond summation conceptThe mechanical strength of a tablet has traditionally in the pharmaceutical literaturebeen regarded to depend on the dominating bonding mechanism between the particlesand the surface area over which these bonds act (e.g. Nyström et al., 1993). This so-called bond summation concept is based on the theories proposed by Rumpf (1962),where the agglomerate strength is considered to depend on the interparticulate bondstructure. The strength of a given plane within a tablet is described by the sum of allattraction forces between the particles in that plane. It is assumed that all interparticulatebonds in the failure plane break more or less simultaneously. Such a simplification hasbeen criticised by proponents of the fracture mechanics concept. Several expressionsoriginating from Rumpf (1962) have been proposed in order to describe the mechanicalstrength of both single components and mixtures in a more quantitative manner(Leuenberger, 1982; Jetzer, 1986; Eriksson and Alderborn, 1995). Such approaches are,however, somewhat complicated considering the complexity of the compaction processand the variety of factors affecting the bond formation process.

Considering the importance of the bonding surface area for the mechanical strength, itwould be desirable to measure the actual surface area participating in bonding.However, direct measurements of the bonding surface area are difficult. Instead, moreindirect methods have been applied, for example to measure the surface area of thepowder and compare it with the surface area of the tablet (Hardman and Lilley, 1973;Stanley-Wood and Johansson, 1978; Nyström and Karehill, 1986). The results ofstudies using these methods suggest that the surface area participating in bonding isvery small compared with the total surface area (Nyström and Karehill, 1986). It hasbeen proposed that the external tablet surface area obtained by air permeametry holdsthe best proportionality to the bonding surface area (Alderborn et al., 1985a). Othertechniques, such as gas adsorption and mercury porosimetry, also take into account thecontribution of an eventual intraparticulate surface area, which does not participate ininterparticulate bonding.

Fracture mechanics conceptThe application of fracture mechanics has also been studied in relation to themechanical strength of pharmaceutical tablets (e.g. Mashadi and Newton, 1987; Yorket al., 1990; Rowe and Roberts, 1994; Al-Nasassrah et al., 1998). The fracturemechanics concept stresses the importance of defects and flaws in the tablet, which canbe considered as starting points for the fracture, and the subsequent propagation of thefracture. The propagation of fracture is considered a kinematic process (Mullier et al.,1987; Kendall, 1988). A fracture may be regarded as either brittle or ductile. A brittlefracture generally propagates rapidly, whereas a ductile fracture is characterised asbeing preceded by plastic deformation (Amidon, 1995). The crack in the tablet growsand the fracture develops when the stress in the tablet has been raised to a critical value,referred to as the critical stress intensity factor, which describes the resistance of a

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material to fracture. The size and shape of the pores in a tablet can be assumed to be ofimportance for the propagation of the fracture. However, it may be difficult toaccurately estimate the size of the flaw where fracture is initiated.

Percolation theoryIn the percolation theory, the tablet is seen as consisting of clusters of particles whichform a network. This theory has been used to describe the formation of the tablet andthe distribution of pores and particles within it (Leuenberger and Leu, 1992; Picker,1999). A number of tablet properties are directly or indirectly related to the relativedensity of a tablet and the percolation theory relates changes in tablet properties, such asmechanical strength, to the appearance of percolation thresholds. The percolation theoryhas been applied to describe the compaction of both single components and binarymixtures (Blattner et al., 1990; Leuenberger and Leu, 1992; Picker, 1999; Kuentz andLeuenberger, 2000). For example, property changes associated with a change in thecomposition of a binary mixture were interpreted using this theory (Blattner et al.,1990).

Effect of particle and powder properties on mechanical strength

Extensive fragmentation during compaction of a brittle material may result in a largenumber of interparticulate contact points, which in turn provide a large number ofpossible bonding zones. Consequently, tablets made of these materials can have a highmechanical strength. Extensive elastic deformation, on the other hand, may cause apronounced decrease in the mechanical strength of the tablet, due to breakage ofinterparticulate bonds when the compaction pressure is released. Plastic deformation isconsidered beneficial to the mechanical strength since it enables the particles to movevery close to each other, thereby creating a large surface area over which bonds may beestablished. As the distance between the particles is decreased during compaction ofplastic materials, particle interactions are also favoured.

Several studies have investigated the effect of the size of the particles of powderedmaterial on the mechanical strength of the tablet; a reduction in particle size is generallyassociated with an increase in mechanical strength (Shotton and Ganderton, 1961;Hersey et al., 1967; Alderborn and Nyström, 1982a; McKenna and McCafferty, 1982;Alderborn et al., 1988). The increase in mechanical strength is attributed to an increasein the surface area available for interparticulate attractions, as the particles becomesmaller. For example, a linear relationship between specific surface area and themechanical strength of tablets has been suggested for different types of lactose(Vromans et al., 1985; de Boer et al., 1986). In these studies, proportionality betweenspecific tablet surface area and the surface area available for bonding was assumed.However, it has been pointed out that such a general relationship between surface areaand mechanical strength may be affected by particle size (Eriksson and Alderborn,1995).

An increase in the particle size of the powder resulting in an increase in the mechanicalstrength of the tablet has been reported for e.g. sodium chloride (Alderborn and

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Nyström, 1982a). This is attributed to an increased ability to bond with solid bridges asthe particle size increases. During the compaction of coarse particulate sodium chloride,the pressure applied will be concentrated at a relatively small number of contact points.Thus, large stresses will be created there, which will facilitate the formation of solidbridges (e.g. Adolfsson et al., 1997). For materials with a high fragmentation tendency,such as dibasic calcium phosphate dihydrate and saccharose, the mechanical strength ofthe tablet seems to be almost independent of particle size (Alderborn and Nyström,1982a).

Particle shape and surface roughness affect the mechanical strength of a tablet. Millingthe powder prior to compaction can induce changes in the shape and roughness. Moreirregular particles generally contribute to higher mechanical strength of the tablet(Shotton and Obiorah, 1973; Alderborn and Nyström, 1982b; Alderborn et al., 1988;Wong and Pilpel, 1990). It has been suggested that an increased proportion ofirregularly shaped particles increases the number of possible bonding points (Alderbornet al., 1988). Furthermore, an irregular shape and high surface roughness of the particleswould favour plastic deformation, because of a higher degree of surface asperities andcrystal defects in such particles (Wong and Pilpel, 1990). The mechanical strength oftablets of materials with a high fragmentation tendency has been shown to be lessaffected by particle shape and surface texture (Alderborn and Nyström, 1982b; Wongand Pilpel, 1990).

Milling of the particles prior to compaction may further change the surfacecharacteristics, by rendering the surfaces more disordered or amorphous. Such changesin the solid state structure may increase the deformability and thus improve the abilityof forming interparticulate bonds (Hüttenrauch, 1977).

Because of the effect of the above-mentioned particle and powder properties onmechanical strength, it is obvious that a thorough characterisation of these properties isessential in studies of the compaction behaviour of a material.

Effect of compaction process and environment on mechanical strength

The compaction pressure and speed, and the tablet dimensions, can affect themechanical strength of the resulting tablet (Davies and Newton, 1996). A materialwhich undergoes time-dependent plastic or elastic deformation is referred to as aviscous or viscoelastic material. For such a material, a change in the compression speedsignificantly affects the deformation of the material (e.g. Roberts and Rowe, 1985;Armstrong and Palfrey, 1989). The effect of compression speed has been evaluated bycalculating the strain rate sensitivity, which is the relative difference between yieldpressure values at a high and low compression speed (Roberts and Rowe, 1985). For amaterial known to deform by plastic flow, the volume reduction generally decreases asthe compression speed increases, thus allowing a shorter time for plastic deformationand a subsequent decrease in mechanical strength of tablets (David and Augsburger,1977; Armstrong and Palfrey, 1989; Cook and Summers, 1990). A fragmentingmaterial, on the other hand, has been shown to be less affected by variations in

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compression speed (Roberts and Rowe, 1985; Armstrong and Palfrey, 1989; Cook andSummers, 1990).

The relative humidity and temperature can affect the compaction process as well as themechanical strength. The mechanical strength of a tablet can also be influenced by thetime that elapses between compaction and strength characterisation. For example, in astudy of the postcompressional changes of fine particulate sodium chloride tablets, itwas suggested that moisture facilitated the bond formation process (Eriksson andAlderborn, 1994).

Pore structure of tablets

The pore structure of a tablet can be expressed in terms of porosity and pore sizedistribution and is influenced by the mode of volume reduction during compaction andthe compaction pressure applied. Increasing the compaction pressure brings the particlescloser to each other, resulting in a reduction in tablet porosity. Tablet properties such asmechanical strength and disintegration are in turn affected by the pore structure.However, the relationship between mechanical strength and pore structure appears to beambiguous. For example, a linear relationship between porosity and the logarithm of thestrength of tablets has been reported (Ryshkewitch, 1953). This suggests that tablets oflow porosity will have high mechanical strength. Further, the total pore surface area hasbeen suggested to be directly proportional to the breaking force of lactose tablets, i.e. anincrease in the total pore surface area resulted in an increase in tablet strength (Vromanset al., 1985; de Boer et al., 1986). However, in another study this relationship could notbe established for lactose or for other materials (Juppo, 1996). An increase in tabletstrength was instead proposed to be related to a decrease in the volume of large poresand to a shift in the pore size distribution towards smaller pore diameter (Juppo, 1996).Although it is reasonable to assume that a low porosity is beneficial to a high tabletstrength, linear relationships are seldom obtained, probably partly because of theinfluence of the whole pore size distribution.

The porosity of tablets made of plastically deforming materials has been shown toincrease with increased compression speed (Armstrong and Palfrey, 1989; Cook andSummers, 1990). This is consistent with a decrease in the time available for plasticdeformation as the compression speed increases. Also, a decrease in particle size of thepowdered material has been shown to increase tablet porosity (McKenna andMcCafferty, 1982; de Boer et al., 1986).

The pore size distribution of a tablet may be assessed by methods such as gas adsorption(e.g. Stanley-Wood and Johansson, 1980; Westermarck et al., 1998) or mercuryporosimetry (e.g. Stanley-Wood and Johansson, 1980; Juppo, 1996; Westermarck et al.,1998). These techniques are complementary, in that mercury porosimetry can be used tomeasure larger pores (the lower size limit is about 0.003 µm in diameter) while gasadsorption allows measurement of smaller pores.

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Disintegration of tablets

The disintegration time of a tablet can be affected by the pore structure and bondingstructure within the tablet. A high porosity and the presence of large pores facilitaterapid water penetration into the tablet with a subsequent rupture of bonds, followed bydisintegration of the tablet (Shangraw et al., 1980). The Washburn equation andnumerous subsequent expressions have been used to quantify factors, such as viscosityof the penetrating liquid and average pore size, which influence the penetration of waterinto tablets (Washburn, 1921; Groves and Alkan, 1979). It has also been proposed thatthe disintegrating medium may weaken the intermolecular bonds thus facilitating thedisintegration of tablets (Ferrari et al., 1996).

Many tablet formulations have inadequate disintegration properties. Therefore,disintegrants, which swell extensively in contact with water (so-called super-disintegrants), are often added to a formulation in order to facilitate the rupture of bondsduring disintegration (Shangraw et al., 1980). It has been proposed that the efficacy ofdisintegrants is dependent on tablet porosity. A relatively low porosity was shown to bemost effective for the action of a disintegrant since the swelling of the disintegrantparticles would then exert more impact on the surrounding particles (Khan and Rhodes,1975a; Shangraw et al., 1980; Ferrari et al., 1995). Attempts have also been made tomeasure the disintegrating force developed after penetration of water and thesubsequent swelling of the disintegrant particles (Caramella et al., 1986).

Binders as strength-enhancing materials in pharmaceutical tablets

A binder is a material that is added to a formulation in order to improve the mechanicalstrength of a tablet. In direct compression, it is generally considered that a binder shouldhave a high compactibility to ensure the mechanical strength of the tablet mixture.Alternatively, amorphous binders which undergo pronounced plastic deformation havebeen suggested to provide an effective means of creating a large surface area availablefor bonding (Nyström et al., 1993). However, the mechanisms behind the strengthenhancing effect of a binder are not yet fully understood. The rational choice of asuitable binder in a formulation requires extensive knowledge of which properties of abinder are important for the strength enhancing effect. Only then would it be possible topredict the function of a binder in a formulation. Increased knowledge of thefunctionality of a binder would enable a more rational approach to tablet formulation.Furthermore, the extensive use of powder mixtures renders knowledge of how differentmaterials interact with each other important.

The development of direct compression as an alternative method to wet granulation hasstimulated efforts to modify and improve the binders used in direct compression(commonly referred to as filler-binders) (e.g. Shangraw, 1986; Bolhuis and Chowhan,1996; Armstrong, 1997). Several attempts have been made to combine two materials inorder to obtain a mixture with improved compaction behaviour and functionality as abinder (e.g. Wells and Langridge, 1981; Larhrib and Wells, 1997; 1998). The role of the

19

binders in direct compression is especially important when a high dose of a poorlycompressible drug is included in the formulation.

Distribution of binders - comparison between direct compression and wetgranulation

In direct compression, the binder is added in its dry state, whereas a liquid is employedin wet granulation. Besides the common aim of enhancing the bonding propertiesbetween particles or granules, the binder in wet granulation also aims at improving thebinding between powder particles during agglomeration. Addition of a binder in itsliquid state would probably facilitate its distribution; it can be more difficult to obtain ahomogeneous distribution with a dry binder. Therefore, binders added as dry powdersare generally less effective than when added as solutions (Nyström et al., 1982). Thebinders used in wet granulation are generally polymeric materials, which are amorphousor semi-crystalline, e.g. polyvinylpyrrolidone and gelatin. These binders are consideredplastically deformable, which is probably an important attribute for their effectivedistribution. In direct compression, however, focus has mainly been on using a binderwith a high compactibility.

Effect of binders on mechanical strength of directly compressed tablets

The addition of a binder to a compound has been suggested to change the surfaceproperties of the coarse compound particles as they are covered by the small binderparticles. It was proposed that this surface coverage increased the surface area availablefor interparticulate bonding, thus increasing the number of bonds and also possiblycreating stronger bonds, with a subsequently increased mechanical strength (Nyströmet al., 1982; Duberg and Nyström, 1985; Nyström and Glazer, 1985). Addition of abinder which increases elasticity can decrease tablet strength because of the breakage ofbonds as the compaction pressure is released (Nyström et al., 1982). The addition of asecond component, such as a binder, to a compound has also been reported to affect andmodify the volume reduction behaviour of the compound (Wells and Langridge, 1981;Yu et al., 1989; Larhrib and Wells, 1998). However, others have observed that volumereduction of the materials constituting as binary mixture occurred independently of eachother (Humbert-Droz et al., 1983).

In a binary mixture consisting of components A and B, three types of bonds may occurafter compaction: A-A, A-B and B-B. The relative importance of these bonds was usedto explain the behaviour of a binary mixture (Leuenberger, 1982). A quantitativeexpression based on compressibility and compactibility parameters of pure materialshas been used to estimate and predict the behaviour of mixtures (Leuenberger, 1982;Jetzer, 1986). Jetzer (1986) concluded that the compaction characteristics of mixtureswere principally governed by the behaviour of the individual materials and thatinteractions were most likely to occur with mixtures of components with dissimilarcompaction mechanisms.

20

Some studies have indicated that the strength of a tablet made from two components canbe linearly related to the composition of the materials constituting the mixture (Fell andNewton, 1970b; Sheikh-Salem et al., 1988; Riepma et al., 1990). The strength of tabletsmade from the mixture can then be predicted from the strengths of tablets of theindividual materials. However, non-linear relationships between tablet strength andcomposition have also been observed (e.g. Fell and Newton, 1971b; Newton et al.,1977; Wells and Langridge, 1981). A general relationship between tablet strength andcomposition is thus difficult to obtain. The type of relationship obtained appears todepend on the materials constituting the mixture.

In some cases, the combination of two materials has resulted in a tablet strength that ishigher than the tablet strength of the individual materials (Newton et al., 1977; Cookand Summers, 1985; Vromans and Lerk, 1988; Garr and Rubinstein, 1991; Gren andNyström, 1996; Larhrib and Wells, 1997; 1998). It was suggested that this highmechanical strength occurs because the bonds between different particles are strongerthan those between the same type of particles (Newton et al., 1977). Furthermore, inrelation to fracture mechanics, it was proposed that the addition of a plasticallydeforming material can act as a crack stopper which will prevent crack propagation(Gordon, 1973; Newton et al., 1977). It has also been suggested that the unexpectedlyhigh tablet strength is caused by increased densification of the mixture compared withthe pure materials (Vromans and Lerk, 1988).

Although the studies cited above do not consider binders specifically, but rather themixing of two components in general, the results may be applicable in understandingthe functionality of a dry binder. The results imply that if the correct combination ofmaterials is chosen, a tablet of a desired mechanical strength can be obtained.

Commonly used binders in direct compression

Microcrystalline cellulose (MCC) is commonly used as a filler-binder in directcompression because of its good bonding properties. MCC is also claimed to havedisintegrating and lubricating properties. The high compactibility of MCC has beenattributed to a relatively high propensity for plastic deformation, which enables largesurfaces to come close to each other and a large number of bonds, mainlyintermolecular forces, to be established between the particles (Reier and Shangraw,1966; Lamberson and Raynor, 1976; Karehill and Nyström, 1990; Nyström et al.,1993). The contribution of mechanical interlocking to the mechanical strength has alsobeen suggested (Karehill and Nyström, 1990). A silicified form of MCC has beenshown to exhibit improved flow properties and compactibility compared to regularMCC (Allen, 1996). This modified form of MCC is chemically and physically verysimilar to regular MCC (Tobyn et al., 1998).

Other commonly used binders in direct compression include starches and theirderivatives, such as pregelatinised and granulated starches. The common feature ofmany filler-binders in direct compression is that they undergo plastic deformationduring compaction. One exception is dibasic calcium phosphate dihydrate, whichfragments quite extensively. Because of its brittle nature, the bonding properties of this

21

compound are moderate compared to other filler-binders, but the advantage is thatlubricants have practically no effect on the bonding properties of dibasic calciumphosphate dihydrate. Lactose is also used in direct compression but, compared to otherfiller-binders, lactose exhibits relatively poor bonding properties. By modifying lactose,for example by spray drying, a material with enhanced bonding properties is obtained(Bolhuis and Chowhan, 1996).

Polyethylene glycol

Polyethylene glycols (PEGs) are a series of water-soluble polymers with the generalstructural formula HOCH2(CH2OCH2)mCH2OH, where m represents the averagenumber of oxyethylene groups. PEG is used in the pharmaceutical industry as anexcipient in suppositories, ointments, suspensions, emulsions and capsules (Wade andWeller, 1994). In tableting, PEG is used as a lubricant, a plasticizer in wet granulation, abinder to enhance the effectiveness of other binders and in film coating (Wade andWeller, 1994). Solid state characterisation has shown PEG to contain both ordered anddisordered regions (Craig and Newton, 1991). Characterisation of different molecularweights of PEG indicates that it is a ductile plastically deformable material with amoderate mechanical strength and that the mechanical properties are related to theaverage molecular weight (Al-Angari et al., 1985; Blattner et al., 1986; Lin and Cham,1995; Larhrib et al., 1997; Al-Nasassrah et al., 1998). Some studies have shown thatwhen PEG is combined with dibasic calcium phosphate dihydrate, a mixture with goodtableting characteristics that has potential as an excipient in direct compression isobtained (Larhrib and Wells, 1997; 1998).

Although PEG is not normally considered as a dry binder in direct compression, it waschosen as a model for a binder in this thesis because the range of molecular weightsavailable provided a model with a wide variation in mechanical properties.

Aims of the thesis

The main objective of this thesis was to investigate the function of dry binders in directcompression in order to gain further knowledge of the strength-enhancing mechanismsinvolved in their use. The papers constituting this thesis had the following detailedaims:

• To evaluate material properties of both the binder and the model compound in orderto establish which properties have the most impact on the compactibility ofpharmaceutical powders (papers I-V).

• To investigate the effects of binders on the mechanical strength and pore structure oftablets consisting of binary mixtures and especially to evaluate the effectiveness of aductile binder in direct compression (papers I-IV).

• To study the formation of fractures in tablets and to relate fracture properties to themechanical strength of tablets of binary mixtures (papers I-III).

• To utilise non-porous test materials to further evaluate some concepts ofdetermining dominating bond types in tablets (paper IV).

22

• To evaluate which binder properties are associated with rapid disintegration andhigh mechanical strength of tablets, the effects of binder ductility and tablet porosityon tablet disintegration and, especially, the effects of binder properties on thefunctionality of superdisintegrants (paper V).

Materials and methods

Preparation of test materials

Model compoundsThe following compounds and size fractions were used in the studies: sodium chloride(125-180 µm, 355-500 µm), sodium bicarbonate (raw material, 45-63 µm, 125-180 µm),calcium carbonate (raw material), mannitol (250-425 µm) and dibasic calciumphosphate dihydrate (DCP; 90-180 µm). The different size fractions were obtained bydry sieving (Retsch, Germany). The term compound is used throughout this thesis formaterials that are not used as binders. The compounds used are summarised in Table 1.

Binder materialsThe following binder materials were used in the studies: polyethylene glycol (PEG)3000, PEG 6000, PEG 10000, PEG 20000, microcrystalline cellulose (MCC), silicifiedmicrocrystalline cellulose (SMCC), pregelatinised starch (PGS), polyvinylpyrrolidone(PVP), α-lactose monohydrate (crystalline lactose), partially crystalline lactose andamorphous lactose. The binder particles were generally <20 µm in size and the varioussize fractions used usually were obtained by either air classification (100 MZR, Alpine,Germany) or milling in a pin disc mill (63C or 160Z, Alpine, Germany) followed by airclassification. In paper II, additional size fractions of PEG were used, 20-40 µm and 40-60 µm, and these were obtained by milling and air classification. MCC was used assupplied. Partially crystalline lactose was prepared by freeze drying crystalline lactose(Virtis, Gardiner, USA) which was then ground in a mortar with a pestle for fiveminutes. Amorphous lactose was prepared by spray drying crystalline lactose (NiroAtomiser, A/S Niro, Denmark). The binders used are summarised in Table 1.

SuperdisintegrantIn paper V, crosslinked carboxymethyl cellulose sodium (Ac-Di-Sol) was used assuperdisintegrant.

All powders were stored at 40% relative humidity (RH) (saturated chrome trioxide inwater) (Nyqvist, 1983), except partially crystalline and amorphous lactose, which werestored at 0% RH (phosphorus pentoxide), and all were stored at room temperature for atleast 48 hours before characterisation, mixing and compaction.

23

Table 1. Compounds and binders used in the studies and their respective size fractions.

Paper Compound Size fractiona

(µm)Binder Size fractionb

(µm)I Sodium chloride

Sodium bicarbonate

355-500125-180125-180

PEG 3000PEG 6000PEG 10000PEG 20000

<20<20<20<20

II Sodium bicarbonateCalcium carbonate

raw materialraw material

PEG 3000

PEG 20000

MCC

<2020-4040-60<2020-4040-60raw material

III Sodium bicarbonate 45-63 PEG 3000MCCSMCCPVPPGS

<20raw material<20<20<20

IV Sodium chlorideSodium bicarbonate

355-500125-180

PEG 3000PEG 20000PGS

<20<20<20

V Sodium chlorideMannitolDCP

355-500250-42590-180

PEG 3000MCCCrystalline lactosePartially crystalline lactoseAmorphous lactose

<20raw material<20as preparedas prepared

a) Obtained by dry sieving.b) Obtained by air classification (SMCC, PVP, PGS and crystalline lactose) or milling followed by airclassification (PEG). MCC was used as supplied and partially crystalline and amorphous lactose asprepared.

Choice of model compounds

The main compounds used throughout this thesis are relatively coarse particulatesodium chloride and sodium bicarbonate. These compounds usually undergo plasticdeformation during compaction with only a limited tendency for fragmentation (Dubergand Nyström, 1986). Sodium bicarbonate is representative of materials with poorbonding properties; additional excipients are often required in order to form tablets withsufficient strength. Sodium chloride, on the other hand, is representative of materialsbonding with solid bridges, and forms tablets with relatively high strength (e.g. Karehilland Nyström, 1990). Thus, sodium chloride and sodium bicarbonate were assumed to besuitable models for the study of interactions between compounds and binders.

24

Characterisation of materials

DensityThe apparent particle density (B.S. 2955, 1958) of the pure materials and mixtures wasdetermined using a helium pycnometer (AccuPyc 1330 Pycnometer, Micromeritics,USA).

External surface areaThe external surface area of the compounds was determined using Friedrichpermeametry (Eriksson et al., 1990). Blaine permeametry was used to determine theexternal surface area of the binders.

Amorphous contentIn paper V, the degree of disorder of the different forms of lactose was investigatedusing microcalorimetry (2277 Thermal Activity Monitor, Thermometric AB, Sweden)and differential scanning calorimetry (DSC, Mettler DSC 20 TC10A/TC15,Switzerland). The microcalorimetry measurements were performed according to theminiature humidity chamber technique (Angberg et al., 1992). The experimentaltemperature was 25 °C and a saturated salt solution was used to obtain 57% RH. WhenDSC was used, the samples were scanned over a temperature range of 30-250 °C at arate of 10 °C/minute. In both cases, the area under the recrystallisation peak wasintegrated and normalised for sample weight. The degree of disorder in the sample wascalculated from these normalised values, assuming amorphous lactose as the amorphousstandard (Sebhatu et al., 1994).

Preparation of mixtures

In all cases, compound and binder were mixed in a Turbula mixer (W.A. Bachhofen,Switzerland) at 120 r.p.m. for 100 minutes. The amount of binder varied among thestudies. In papers I, II and III, the amount of binder added was chosen to correspond tothe amount estimated to form a monoparticulate layer on the surface of the compoundparticles (Nyström et al., 1982). The coating capacity of a binder particle was assumedto correspond to its projected surface area, i.e. one-quarter of the external surface areaof the binder particle (Allen, 1997). In papers II and III, the amount of binder used insome mixtures also reflected the amount theoretically required to fill the voids betweenthe compound particles with binder, an estimation based on the porosity and dimensionsof a tablet made of the pure compound and the density of the binder. This simplifiedcalculation does not take into account the effect the binder has on the compoundparticles, e.g. packing structure and fragmentation propensity. Including other additions,the amount of binder in papers II and III was generally between 5 and 30% w/w. Inpaper IV, the amount of binder varied between 5 and 20% w/w. In paper V a constantamount (20% w/w) of binder was used and a superdisintegrant (4% w/w) was alsoincluded in some of the mixtures.

25

Compaction of tablets

Tablets were compacted in an instrumented single punch press (Korsch, EK0, Germany)at different maximum upper punch pressures using 1.13 cm flat-faced punches. Theupper punch pressures were obtained by keeping the distance between the punchesconstant (3.0 mm at zero pressure) and varying the amount of powder in the die. Thepowder was weighed on an analytical balance and manually filled into the die. Thesurfaces of the die and punches were lubricated with magnesium stearate powder priorto each compaction.

In paper II, double-layer tablets containing compound in the first layer and binder in thesecond layer were prepared using an instrumented single punch press (Korsch, EK0,Germany). The first layer was compacted at 200 MPa and the tablet was left in the diewhile the lower punch was lowered. Binder was added onto the first layer and the lowerpunch was adjusted to achieve a compaction pressure of 200 MPa for the double-layertablet (Karehill et al., 1990).

Characterisation of compaction behaviour

Deformation propertiesTablets were compressed at a maximum pressure of 150 MPa (papers II and III) or200 MPa (papers I and V) and the deformability of the materials was characterised byrecording the height of the tablets every millisecond during the compression cycle as afunction of pressure (in-die measurements). Tablet porosity was calculated and used inthe Heckel equation (Heckel, 1961a,b). The reciprocal of the slope of the linear part ofthe in-die Heckel plot was used to calculate the apparent yield pressure (Duberg andNyström, 1986). In paper V, out-of-die measurements were also made, i.e. the materialswere compressed at different maximum compaction pressures and the porosity wascalculated from the tablet dimensions after compaction. An out-of-die yield pressurewas calculated from the reciprocal of the slope of the linear part of the correspondingHeckel plot (Paronen, 1986).

The elastic recovery of the tablets was calculated as the relative difference betweenminimum (during compaction) and maximum (after 48 hours of storage) tablet heights(Armstrong and Haines-Nutt, 1972).

Fragmentation propertiesIn order to estimate the fragmentation propensity of the materials, tablets werecompacted at different compaction pressures in a specially constructed die using aninstrumented single punch press (Korsch EK0, Germany) (papers II and V). Thespecific surface area of the tablets was determined using Blaine permeametry. Thedegree of particle fragmentation during compaction was evaluated by plotting the tabletspecific surface area as a function of compaction pressure. The slope was then used as ameasure of the degree of fragmentation (Alderborn et al., 1985b).

26

Characterisation of tablets

All tablets were stored at 40% RH, except tablets containing partially crystalline andamorphous lactose which were stored at 0% RH, and all were stored at roomtemperature for at least 48 hours before characterisation.

Tensile strengthAxial tensile strength was determined using a material tester (M39K, LloydInstruments, UK) where the tablet was fixed between two metal adapters with anethylcyanoacrylate adhesive (papers I-IV). The axial force necessary to fracture thetablet was recorded by pulling the tablet in a direction parallel to the direction of thecompaction force and the axial tensile strength was calculated (Nyström et al., 1978).

Strength was also characterised using a diametral compression test (Holland C50, UK orM39K, Lloyd Instruments, UK) and the radial tensile strength was calculated (Fell andNewton, 1970a) (papers III-V).

In paper III, the isotropy ratio, i.e. axial/radial tensile strength, was calculated (Nyströmet al., 1978; Alderborn and Nyström, 1984).

Examination of fracture surfacesPhotomicrographs of the fracture surfaces of tablets were taken using a scanningelectron microscope (SEM).

PorosityTablet porosity was calculated from the apparent particle density of the material ormixture and the dimensions and weight of the tablet (papers I-V). In paper IV, tabletporosity was also obtained from mercury intrusion measurements (AutoPore III,Micromeritics, USA).

Pore size distributionTablet pore size distribution was assessed using mercury porosimetry (AutoPore III,Micromeritics, USA) and the relationship between the intruded volume of mercury andthe intrusion pressure was analysed. The intrusion pressures were between 0.01 and413 MPa (paper II) and 0.01 and 379 MPa (paper IV). The pore sizes corresponding tothe intrusion pressures were calculated assuming cylindrical pores and a surface tensionof mercury of 485 mN/m. The mercury-powder contact angles were measured using acontact anglometer (Model 1501, Micromeritics, USA). The mercury contact angles ofthe mixtures were calculated from the contact angles of the pure powders and theproportion by volume of respective material constituting the mixture. Other parametersobtained with mercury porosimetry were total pore surface area and average porediameter.

For comparison of intra- and interparticulate pores, the pore size distribution of thepowders was also determined (AutoPore III, Micromeritics, USA) (paper IV). In these

27

cases, the intrusion pressures were between 0.04 and 241 MPa. Otherwise theconditions were as stated above for the tablets.

The pore size distributions were expressed as the log differential intrusion volumesversus pore diameter (logarithmic-scale). The derivative of the cumulative logarithmiccurve has been used for reasons of comparison (Dees and Polderman, 1981).

Degree of binder saturationThe degree of binder saturation (DBS) was calculated in order to estimate the actualvoid fraction in a tablet that is filled with binder:

DBS(%) = Vb

Vb + Vv

×100

Vt = Vc + Vb + Vv

Vt is the total volume of a tablet containing a binary mixture, calculated from thedimensions of the tablet, Vc and Vb are the volumes of compound and binder,respectively, and Vv is the volume of the void (air) in the tablet. The apparent particledensity of compound and binder was used to calculate Vc and Vb.

DisintegrationThe time taken for the tablets to disintegrate was measured in deionised water (37 °C)according to the USP XXII disintegration test (without discs) (Pharmatest PTZ-E,Germany).

28

Effect of binders on tablet pore structure

In papers I-IV, the effect of a dry binder on the tablet pore structure was investigated inorder to evaluate the influence of pore structure on the mechanical strength of tablets. Inall cases, a fine particulate binder was added to a coarse particulate compound and theeffect on the pore structure (such as porosity and pore size distribution) of the resultanttablets was compared with that in pure compound tablets. The magnitude of the effectof the different binders on pore structure differed substantially. This was attributed tothe effects of various properties of the binder and the compound as discussed in thefollowing sections.

Effect of binder deformability and particle size on tablet porosity

The binders used throughout this thesis had different mechanical properties, e.g. themechanical strength and deformability varied. The deformability of the binders wascharacterised by their yield pressure (in die and in some cases also out of die), minimumporosity during compression and elastic recovery after compression (Table 2). Theresults varied slightly among the individual studies because the deformability wasdetermined at different compaction pressures. Nonetheless, the binders could bedifferentiated regarding their ability to deform during compaction.

Table 2. Characterisation of deformability determined at a compaction pressure of 150or 200 MPa (data from papers I, II, III and V) and fragmentation tendency (data frompaper V) of the binders.

Binders Yieldpressure(in die)a

(MPa)

Yieldpressure(out of die)a

(MPa)

Minimumporosity duringcompressionb

(%)

Elasticrecoveryc

(%)

Fragmentationtendencyd

((cm2/g) . MPa-1)

PEG 3000 29-35 52 -0.4-(-1.3) 5.7-8.4 *PEG 6000 37 * -0.7 7.7 *PEG 10000 32 * -1.2 9.4 *PEG 20000 22-25 * -1.8-(-2.0) 12-14 *MCC 77-88 138 4.9-6.7 9.3-11 201SMCC 81 * 7.3 12 *PVP 47 * 0.3 11 *PGS 76 * 4.1 19 *Crystalline lactose 190 277 11 5.2 79Partially crystallinelactose 168 282 8.2 6.7 81Amorphous lactose 182 212 11 4.8 1.8* Not determined.a) Obtained from the reciprocal of the slope of the linear part of an in-die or out-of-die Heckel plot.b) Apparently negative minimum porosity was obtained in some cases because of densification of thesolid structure (Pedersen and Kristensen, 1994; Adolfsson and Nyström, 1996).c) Defined as the relative difference between minimum and maximum tablet height.d) Expressed as the slope of the tablet surface area-compaction pressure plot.

29

Among the different qualities of PEG, the apparent yield pressure values were rathersimilar but the elastic recovery increased with increasing molecular weight. Since thedetermination of apparent yield pressure was made in die, and therefore reflects bothelastic and plastic deformation, it was concluded that an increase in molecular weight ofPEG results in a less plastic and more elastic material (Blattner et al., 1986;Al-Nasassrah et al., 1998). This was also reflected in an increase in tablet porosity of thepure PEG tablets (determined after 48 h, thus allowing for elastic relaxation) when themolecular weight of PEG increased (Al-Angari et al., 1985; Blattner et al., 1986; Linand Cham, 1995; Larhrib et al., 1997). Some of the other binders used were classified asbeing of intermediate (e.g. PVP) or moderate (e.g. MCC, SMCC and PGS)deformability, compared to the PEGs. In addition, MCC seemed to undergo a ratherextensive fragmentation because of its aggregated structure (Table 2) (Nyström et al.,1993; Ek et al., 1994; Adolfsson et al., 1997).

The porosity of tablets containing both compound and binder was lower than that oftablets without binder (Fig. 1). The ability of the fine binder particles to partly fill thevoids between the compound particles is proposed to be the reason for the reduction inporosity. The smaller and more deformable binder particles are more mobile than thelarger and less deformable compound particles. Application of a pressure to the powderbed therefore results in increased rearrangement and deformation of the binder particlesand forces the binder into the voids. The deformability and particle size of a binderdetermine its void-filling capacity.

Addition of a binder characterised by a low yield pressure value and low elasticrecovery, i.e. high plastic deformability, (e.g. PEG 3000) to sodium bicabonate gavetablets with the lowest porosity (Fig. 2). High binder plasticity is indicative of an

200001500010000500000

5

10

15

20

Molecular weight of PEG

Tab

let p

oros

ity (%

)

Pure sodium bicarbonate

Pure sodium chloride

Figure 1. Tablet porosity as a function of molecular weight of PEG added to sodiumchloride (125-180 µm) (�) and sodium bicarbonate (125-180 µm) (�). Mixturescontain an amount of binder corresponding to a surface area ratio of unity.Confidence intervals for p = 0.05 are shown. Tablets compacted at 200 MPa.

30

increased capacity to fill the interparticulate voids in a compound tablet. The resultssuggest that both elastic recovery and yield pressure are important parameters thatshould be taken into account in order to fully understand the effect of deformability ofthe binder on tablet porosity.

The effect of binder particle size on tablet porosity was studied using PEG 3000 andPEG 20000 (Table 3). The greatest reduction in tablet porosity was obtained with thefinest size fraction (Fig. 3). It is proposed that this effect is the result of a more even andeffective distribution of the smaller binder particles in the compound tablet. Althoughthe overall effect on tablet porosity was more pronounced with the more plastic PEG3000, the effect on tablet porosity of particle size was more pronounced with PEG20000. Since this material is regarded as more elastic and less plastic than PEG 3000, adecrease in particle size might be expected to have a relatively greater impact on tabletporosity (Fig. 3).

Table 3. Characterisation of the external surface area of the various size fractions ofPEG used in paper II. Standard deviation in parentheses.

Binders Size fractiona (µm) External surface areab (cm2/g)

PEG 3000 <20 15975 (1501)20-40 3653 (118)40-60 2295 (31)

PEG 20000 <20 3370 (27)20-40 2342 (32)40-60 1486 (41)

a) Obtained by milling and air classification.b) Determined using Blaine permeametry.

Figure 2. Porosity of tablets containing sodium bicarbonate and 21.5% (w/w) of thebinders as a function of (a) yield pressure and (b) elastic recovery of the pure binders. Adotted line is drawn as a guide to indicate deviations from the expected behaviour of thebinders. Confidence intervals for p = 0.05 are shown. Tablets compacted at 200 MPa.

1008060402000

5

10

15

20

Yield pressure of the binder (MPa)

Tabl

et p

oros

ity o

f the

mix

ture

(%)

a)

PEG 3000

PVP

PGS

MCCSMCC

Pure sodium bicarbonate

201510500

5

10

15

20

Elastic recovery of the binder (%)

Tabl

et p

oros

ity o

f the

mix

ture

(%)

b)

PEG 3000

MCCSMCC

PGS

PVP

Pure sodium bicarbonate

31

Effect of amount of binder and compaction pressure on tablet porosityIncreasing the amount of binder added to a compound resulted in a gradual decrease intablet porosity as more of the interparticulate voids were filled with binder. This wasshown in paper III, where a range of different binders with various properties was addedto sodium bicarbonate (Fig. 4 and Table 2). For example, addition of the binders mostprone to undergo plastic deformation (PEG 3000 and PVP) gave the most pronouncedeffect of amount of binder on tablet porosity. The results in paper II, in which differentamounts of binder were also studied, showed concordance with these observations.

1 2 3 4 5 6 70

5

10

15

20 Sodium bicarbonate

PEG

300

0 (<

20 µ

m)

PEG

300

0 (2

0-40

µm

)

PEG

300

0 (4

0-60

µm

)

Sodi

um b

icar

bona

te+

PEG

300

0 (<

20 µ

m)

Sodi

um b

icar

bona

te+

PEG

300

0 (2

0-40

µm

)

Sodi

um b

icar

bona

te+

PEG

300

0 (4

0-60

µm

)

1 2 3 4 5 6 70

5

10

15

20

PEG

200

00 (<

20 µ

m

PEG

200

00 (2

0-40

µ

Sodi

um b

icar

bona

te+

PEG

200

00 (<

20 µ

m)

Sodi

um b

icar

bona

te+

PEG

200

00 (2

0-40

µm

)

Sodi

um b

icar

bona

te+

PEG

200

00 (4

0-60

µm

PEG

200

00 (4

0-60

µ

Figure 3. The effect of different particle sizes of (a) PEG 3000 and (b) PEG 20000 onporosity of tablets containing pure PEG and mixtures of sodium bicarbonate and 20%(w/w) PEG. Confidence intervals for p = 0.05 are shown. Tablets compacted at 200 MPa.

1008060402000

5

10

15

20

Amount of binder added (% w/w)

Tab

let p

oros

ity (%

)

Figure 4. Tablet porosity as a function of amount of binder added to sodiumbicarbonate. PEG 3000 (�), PVP (�), MCC (�), SMCC (�) and PGS (∆).Confidence intervals for p = 0.05 are shown. Tablets compacted at 200 MPa.

32

An increase in compaction pressure during tableting resulted in a gradual decrease inporosity as the particles were brought into closer proximity to each other (paper I). Itappeared that the effect of the binder on tablet porosity was generally more pronouncedwhen the compaction pressure was low. This was especially noticeable when a binderwith a lower plasticity (PEG 20000) was added to a compound where a highcompaction pressure resulted in dense tablets (sodium chloride).

Effect of compound properties on tablet porosity

When comparing sodium chloride and sodium bicarbonate, two materials with similarvolume reduction behaviour (mainly plastic deformation) (Duberg and Nyström, 1986),the porosity of sodium bicarbonate tablets was generally more affected by the binder(Fig. 1). The lower porosity of, as well as the smaller pores in, the pure sodium chloridetablets probably impaired the effective localisation of the binder in the voids. Increasingthe amount of binder did not further reduce the porosity of tablets containing sodiumchloride, in contrast to observations with sodium bicarbonate (Fig. 4). Also, when acompound tablet is not particularly porous to start with, a high plastic deformability andsmall particle size become more crucial for the decrease in tablet porosity. Theimportance of these properties was confirmed for mixtures containing sodium chlorideand PEG or PGS (paper IV). These binders represent materials with pronounceddifferences in plastic and elastic behaviour (Table 2).

Fragmenting materials are much less affected by addition of a second component, e.g. abinder or lubricant, than plastically deforming materials (de Boer et al., 1978; Nyströmet al., 1982; Duberg and Nyström, 1985; Nyström and Glazer, 1985). New, uncoatedsurfaces are created during compaction and the distribution of the second component,e.g. a binder, will be disturbed. This was observed with calcium carbonate, where thedecrease in porosity upon addition of PEG 3000 was much smaller than when PEG3000 was added to the mainly plastically deforming sodium bicarbonate (paper II). Inaddition, mercury porosimetry revealed that the pores in a calcium carbonate tablet weresmaller than in a sodium bicarbonate tablet, making it more difficult for the binder to beevenly distributed.

Effect of binder addition on pore size distribution

When a binder was added, the pore size distribution was shifted towards smaller poresand the distribution generally became narrower compared to the distribution in a purecompound tablet (paper IV). This is indicative of filling of the voids in a compoundtablet, thereby creating pores that are generally more uniform in size. The effect on poresize distribution was most pronounced in tablets of mixtures containing sodiumbicarbonate and the highest amount (20% w/w) of the binder with the greatest plasticity,PEG 3000 (Figs. 5 and 6). Characterisation of the pure powdered materials showed thatthe materials were virtually non-porous, thus the contribution of intraparticulate poreson tablet porosity was assumed to be insignificant.

33

0

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+PGS

Figure 5. Pore size distribution of tablets made of pure sodium bicarbonate andmixtures with 20% (w/w) of binder. Sodium bicarbonate (x) and mixtures containingPEG 3000 (�), PEG 20000 (�) and PGS (∆). Tablets compacted at 200 MPa.

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Sodium bicarbonate

Figure 6. Pore size distribution of tablets made of pure sodium bicarbonate andmixtures containing different amounts (% w/w) of PEG 3000. Sodium bicarbonate (x)and mixtures containing 5% (�), 10% (∆) and 20% (�) of PEG 3000. Tabletscompacted at 200 MPa.

If the pore size distribution of tablets containing pure sodium bicarbonate, pure PEG3000 and a mixture of sodium bicarbonate and 20% (w/w) of PEG 3000 are compared,the following may be noted (Fig. 7). The theoretical pore size distribution of the mixture(obtained from the sum of the effects of the pure materials based on the composition of

34

the mixture) is included in Fig. 7 as a comparison with the experimentally obtainedresults. In the tablet containing a mixture, most of the large pores between thecompound particles have disappeared and the interparticulate pores were mainlybetween 0.1 and 1 µm in diameter, whereas the pores in the tablet containing purebinder were mainly less than 0.5 µm and to a large extent less than 0.1 µm in diameter.The pore size distribution indicated that the contribution of pores slightly below 0.1 µmwas smaller than expected from the theoretical distribution. Therefore, the porestructure in tablets of pure binder (in which most pores are around 0.1 µm in diameter)will not exist to the same degree in tablets made of the mixture and are not likely tosignificantly contribute to the pore structure of the tablet.

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Experimental distributionof the mixture

Theoretical distributionof the mixture

Figure 7. Upper graph: pore size distribution of tablets made of pure sodiumbicarbonate (x) and pure PEG 3000 (�). Lower graph: pore size distribution of tabletsmade of a mixture of sodium bicarbonate and 20% (w/w) PEG 3000; experimentaldistribution (�) and theoretical distribution derived from the additive effect of the purematerials based on the composition of the mixture (------).

35

It is therefore suggested that, due to extensive deformation and shearing duringcompaction, the binder mainly exists as small aggregates or lumps of primary particlesor even as primary particles when located between the compound particles. Most of thepores in tablets composed of the mixture were thus mainly located between compoundparticles and binder phase and were found to a smaller extent within the binder phase. Alower tendency for the binder to undergo plastic deformation may indicate a greaterprobability for binder particles to form larger aggregates and an increased probability offinding pores within the binder phase.

Effect of binders on tablet strength

Addition of a binder to a compound generally resulted in an increase in tablet strength(sodium bicarbonate mixed with PEG 3000 or MCC is shown as an example of this,Fig. 8). The increase in tablet strength was influenced by properties associated with boththe binder and the compound and these will be dealt with in the following sections. Thestrength of tablets composed of some mixtures was higher than that of tablets made ofthe individual materials, referred to as a synergistic effect. This effect was especiallyapparent in tablets composed of sodium bicarbonate and PEG (Figs. 8 and 12) or PVP,as well as in tablets composed of sodium chloride and low molecular weights of PEG(Fig. 12), but it has also been reported for other systems (Newton et al., 1977; Cook andSummers, 1985; Vromans and Lerk, 1988; Garr and Rubinstein, 1991; Gren andNyström, 1996; Larhrib and Wells, 1997; 1998).

While binders may be differentiated according to their deformability, they are also ableto be classified according to their compactibility (i.e. the mechanical strength of a tablet

1008060402000

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Amount of binder (% w/w)

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Figure 8. Axial tensile strength of tablets as a function of the amount of binderadded to sodium bicarbonate. PEG 3000 (❍) and MCC (�). Confidence intervals forp = 0.05 are shown. Tablets compacted at 200 MPa.

36

made of pure binder; Table 4). The compactibility of cellulose (MCC and SMCC) wasrelatively high, whereas that of PGS was low. While the compactibility of the differentmolecular weights of PEG was comparatively low, it generally increased with anincrease in molecular weight (Blattner et al., 1986; Lin and Cham, 1995; Larhib et al.,1997). A rather large variation in the axial tensile strength of PEG 3000 tablets wasobtained between the individual studies, which may have been the result of batch tobatch variations. However, these variations do not affect the general interpretation of theresults.

Table 4. Compactibility of the binders (data from papers I-V). Axial and radial tensilestrength of tablets compacted at 200 MPa.

Binders Axial tensile strength (MPa)

Radial tensile strength (MPa)

PEG 3000 0.95-2.22 1.20-1.52PEG 6000 0.91 *PEG 10000 2.13 *PEG 20000 2.21-3.33 2.79MCC 3.10-4.12 13.3-14.4SMCC 3.30 12.9PVP 2.33 2.54PGS 1.41-1.64 2.37-2.52Crystalline lactose * 1.74Partially crystalline lactose * 2.28Amorphous lactose * 2.15* Not determined

Effect of binder deformability and particle size on tablet strength

Addition of a binder with a high propensity for plastic deformation (e.g. PEG 3000)resulted in a pronounced increase in tablet strength compared to that of the purecompound (Fig. 8). This result is associated with the pronounced effect on tablet porestructure caused by binders which undergo extensive plastic deformation. A deviationfrom the expected behaviour was observed when a plastically deforming binder wasadded to calcium carbonate. In order to obtain a synergistic increase in tablet strength itis generally required that the binder possesses a high degree of plastic deformability.However, a binder with a high compactibility (e.g. MCC) was also able to enhance thetablet strength (no synergistic effect), although the effect on tablet porosity was limited(Figs. 4 and 8). A binder with poor compactibility and moderate deformability (e.g.PGS) had only a small effect on both tablet strength and porosity.

Tablet strength was measured in both the axial and radial directions and the resultsindicated that different binder properties had varying effects on the increase in tabletstrength, depending on the direction of measurement. In paper III, a relationship wasestablished between the axial tensile strength of a tablet composed of acompound/binder mixture and the deformability parameters (apparent yield pressureand elastic recovery) of the binder (Fig. 9a,b). However, the relationship was not

37

unambiguous, and it appears that other factors, e.g. compactibility of the binder, have tobe taken into account to fully understand the effect of a binder. When measuring thetablet strength in the radial direction, the effects of yield pressure and elastic recoverywere more complex, indicating that the deformability of the binder has a greater impacton the axial tensile strength than on the radial tensile strength (Fig. 10a,b). In contrast,the compactibility of the binder appeared to have a greater impact on the radial strengthof the tablets, although the most deformable binders deviated somewhat from theexpected behaviour (Fig. 10c). The effect of compactibility of the binder was not asclear-cut when measuring in the axial direction (Fig. 9c).

Bonds rupture and flaws and defects are introducerecovery after compression, and this is often reflecThe effect of elastic recovery was best demonstratthe axial direction (Fig. 9b). The elastic recovery oremain distributed between the compound particleis probably more crucial for the axial tensile strengthe tablet, since the axial tensile strength reflects ththerefore desirable to obtain a homogeneous distri

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Figure 9. Axial tensile strength oftablets containing sodiumbicarbonate and 21.5% (w/w) of thebinders as a function of (a) yieldpressure, (b) elastic recovery and (c)axial tensile strength of the purebinders. In (a) and (b), a dotted lineis drawn as a guide to indicatedeviations from the expectedbehaviour of the binders. Confidenceintervals for p = 0.05 are shown.Tablets compacted at 200 MPa.

d into the tablet during elasticted in a decrease in tablet strength.ed when testing the tablet strength inf a binder influences its ability tos. Effective distribution of the binderth than the radial tensile strength ofe weakest plane in the tablet. It is

bution of bonds and a low incidence

38

of defects in the tablets. Furthermore, in paper IV, it was shown that the average porediameter by volume, which is greatly affected by the presence of large pores, had agreater influence on the axial than on the radial tensile strength of tablets. In contrast,since the fracturing of a tablet occurs through a predetermined diametral cross sectionduring radial tensile strength testing, homogeneous bond distribution is not as crucialand the radial tensile strength of a tablet will depend more on the compactibility of thebinder.

When different molecular weights of PEG were added to sodium bicarbonate (paper I),the effect of deformability on tablet strength was not as pronounced as when the rangeof binders was extended to include a larger variation in binder deformability. Because ofthe relatively high porosity of tablets made of pure sodium bicarbonate, a greaterdifference in the extent of plastic deformability of the binder is required in order toobserve any substantial effects of deformability on tablet strength. Instead, it was ratherthe compactibility of the pure PEGs that determined the resulting tablet strength of themixture. This will be further discussed in the section dealing with the effect ofcompound properties on tablet strength.

Figure 10. Radial tensile strength oftablets containing sodiumbicarbonate and 21.5% (w/w) of thebinders as a function of (a) yieldpressure, (b) elastic recovery and (c)radial tensile strength of the purebinders. In (c) a dotted line is drawnas a guide to indicate deviationsfrom the expected behaviour of thebinders. Confidence intervals forp = 0.05 are shown. Tabletscompacted at 200 MPa.

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39

In paper II, the effect of adding different particle sizes of PEG 3000 and 20000(Table 3) to sodium bicarbonate was studied (Fig. 11). Along with the decrease inporosity discussed above there was a continuous increase in tablet strength with adecrease in binder particle size (Figs. 3 and 11). The addition of the smallest particles ofPEG 3000 tended to result in the strongest tablets, even though tablets containing onlythe smallest size fraction (i.e. pure PEG 3000) had the lowest tensile strength. Thetensile strength of tablets containing sodium bicarbonate and PEG 20000 was moredirectly reflected by the tensile strength of the pure PEG tablets, varying with PEGparticle size. Since the higher molecular weight of PEG is more elastic, the smallerparticles would have a greater effect on the decrease in tablet porosity as well as on theincrease in tablet strength. Consequently, the effect of particle size was morepronounced with the higher molecular weight PEG than with the lower (Figs. 3 and 11).

Effect of amount of binder and compaction pressure on tablet strength

Earlier studies regarding the amount of binder have suggested that the amountcorresponding to a surface area ratio of unity, i.e. the amount required to cover thecompound particles with binder, resulted in the highest tablet strength (Nyström et al.,1982). The addition of binder in excess of this amount had less effect on tablet strength.The amount corresponding to a surface area ratio of unity was assumed to be necessaryin order to increase and change the nature of the surface area available forinterparticulate bonding and thereby increase tablet strength. In this thesis, theimportance of filling the voids in a compound tablet rather than covering the surface ofthe compound particles is emphasised. In papers II and III, the effect of adding theamount of binder corresponding to a surface area ratio of unity was compared with theeffect of adding the amount theoretically required to fill the voids in a compound tablet.

1 2 3 4 5 6 70

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te+

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00 (4

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µm

)Figure 11. The effect of different particle sizes of (a) PEG 3000 and (b) PEG 20000 onaxial tensile strength of tablets containing pure PEG and mixtures of sodium bicarbonateand 20% (w/w) PEG. Confidence intervals for p = 0.05 are shown. Tablets compacted at200 MPa.

40

The former amount was generally greater than the latter. However, because of relativelysmall differences between these amounts it was difficult to draw any consistentconclusions. Furthermore, the amount calculated to theoretically fill the interparticulatevoids was probably an underestimation of the actual amount because of the effect thebinder has on the pore structure of the compound tablet. Therefore, it is expected thatthe optimal amount would be higher than this, i.e. approaching the amountcorresponding to a surface area ratio of unity.

The gradual decrease in tablet porosity with increased amounts of binder wasaccompanied by a gradual increase in tablet strength compared with the tablet strengthof the pure compound. For example, when PEG 3000 was added to sodium bicarbonate,the highest tablet strength and lowest tablet porosity was obtained with additions of20% (w/w). Thereafter, there was a slight decrease in tablet strength, eventuallyapproaching the strength of pure PEG tablets (Fig. 8). When sodium bicarbonate wasmixed with MCC, the tablet strength increased with increasing amounts of MCC, butthe tablet strength of pure MCC remained highest (Fig. 8). Addition of other binderswith similar properties to those of MCC, e.g. SMCC and PGS, resulted in similar tabletstrength versus amount profiles, whereas binders resembling PEG 3000, e.g. PVP andhigher molecular weights of PEG, behaved in a similar manner to PEG 3000.

An increase in compaction pressure resulted in a continuous increase in the axial tensilestrength of pure sodium bicarbonate and sodium chloride tablets (paper I) (Fig. 12). Theaxial tensile strength of tablets made of pure PEG, on the other hand, reached a plateauat approximately 100 MPa, corresponding to a plateau in tablet porosity (see alsoAdolfsson and Nyström, 1996). The lack of tablet volume reduction past a certain pointwith increased compaction pressure has previously been related to the limited spaceavailable for additional plastic deformation (Adolfsson and Nyström, 1996). Thestrength of tablets composed of the mixtures, especially those containing sodiumchloride, also reached a plateau at about 100 MPa. An increase in compaction pressurehas been reported to increase the degree to which solid bridges contribute to the tabletstrength of sodium chloride (Adolfsson et al., 1997). The results in paper I suggestedthat the influence of PEG on the tensile strength of tablets made from sodium chlorideand PEG decreased as compaction pressure increased. The tablet strength was probablyinstead governed to a greater extent by the formation of solid bridges.

Effect of compound properties on tablet strength

Sodium chloride and sodium bicarbonate behaved differently depending on themolecular weight of the PEG added (paper I). The strength of tablets containing sodiumbicarbonate and PEG appeared to be determined by the compactibility rather than thedeformability of the pure PEGs, i.e. the profile of the strength of tablets of the mixturesas a function of molecular weight of the added PEGs was similar to that of pure PEGtablets (Fig. 12). However, the strength of tablets composed of sodium chloride andPEG increased with increasing plasticity and decreasing elasticity (i.e. with decreasingmolecular weight) of the PEGs rather than with increasing compactibility (Fig. 12). It issuggested that this was related to the lower porosity of pure sodium chloride tablets and

41

the slightly smaller interparticulate pores (as shown with mercury porosimetry in paperIV). These characteristics of sodium chloride tablets also meant that the general effectthe addition of PEG had on tablet strength was not as pronounced as when PEG wasadded to sodium bicarbonate, especially when the molecular weight of PEG was high(papers I and IV).

Sodium chloride particles are known to bond with solid bridges and it has been reportedthat these bridges are able to penetrate layers of magnesium stearate surrounding thesodium chloride particles (Nyström et al., 1993). It therefore seems reasonable toassume that solid bridges may also be capable of penetrating the PEG layer, thereby

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Figure 12. Axial tensile strength of tablets as a function of molecular weight of PEGadded to sodium chloride (125-180 µm) (�) and sodium bicarbonate (125-180 µm) (�).Axial tensile strength of the pure materials is also shown: PEG (∆), sodium chloride( ) and sodium bicarbonate ( ). The mixtures contained an amount of binder(w/w) corresponding to a surface area ratio of unity (sodium chloride and PEG: 7.6%PEG 3000; 11.5% PEG 6000; 14.1% PEG 10000; 20.6% PEG 20000 and sodiumbicarbonate and PEG: 11.3% PEG 3000; 16.8% PEG 6000; 17.7% PEG 10000; 29.8%PEG 20000). Confidence intervals for p = 0.05 are shown.

42

reducing the effect of the compactibility of PEG, at least when the amount of PEG isrelatively low (Fig. 12). However, when the amount of PEG added to coarse particulatesodium chloride was higher, the tablet strength was more determined by thecompactibility rather than the deformability of PEG (Fig. 13). Furthermore, the tabletporosity did not continue to decrease with increased amounts of PEG, but ratherincreased. Addition of a larger amount of binder probably prevented the formation ofsolid bridges (Nyström et al., 1982; Adolfsson et al., 1998), thus increasing theinfluence of the compactibility of PEG.

200001500010000500000

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Molecular weight of PEG

Axi

al te

nsile

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ngth

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)

Figure 13. Axial tensile strength of tablets as a function of molecular weight of PEGadded to sodium chloride (355-500 µm). Amount of PEG (w/w) corresponding to asurface area ratio of unity (2.7% PEG 3000; 4.1% PEG 6000; 5.1% PEG 10000; 7.9%PEG 20000) (�). A higher amount of PEG (w/w), corresponding to a surface area ratiogreater than unity (the same amounts as to sodium chloride (125-180 µm) in Fig. 12)(�). Confidence intervals for p = 0.05 are shown. Tablets compacted at 300 MPa.

A similar effect was seen when PGS was added to sodium chloride (paper IV). Additionof PGS, which has pronounced elastic behaviour, probably resulted in rupture ofinterparticulate bonds and interfered with the formation of solid bridges, thus reducingthe level of interparticulate bonding. In fact, the strength of tablets of the sodiumchloride/PGS mixture was lower than that of pure sodium chloride tablets (see alsovan Veen et al., 2000). Also, tablet porosity increased upon addition of PGS, indicatingthat this binder was not able to easily fill the voids in a tablet made of sodium chloride.

Different size fractions of sodium bicarbonate were investigated in papers I-IV. Theresults indicated that, when the other conditions (e.g. amount of binder and compactionpressure) were kept essentially the same, smaller particles of sodium bicarbonategenerally resulted in increased tablet strength for both pure sodium bicarbonate and themixtures with various binders. This is consistent with previously reported relationshipsbetween the particle size of the powder and the resulting tablet strength (e.g. McKennaand McCafferty, 1982).

43

Tablet model describing the effect of binder addition on tablet strength and porestructure

As already indicated from the discussion of the effect of a binder on tablet porestructure and tablet strength, the decrease in porosity and pore diameter, the shift in poresize distribution and the increase in strength caused by the binder are all interrelated.Consequently, binders with a high ability to fill the interparticulate voids in a compoundtablet and thereby affect the pore structure are also able to substantially enhance tabletstrength.

Fracture characteristics

A simplified qualitative tablet model to describe the effect of a binder on tablet porosityand strength is proposed (Fig. 14). This model is based on a tablet being considered aspowder particles dispersed in gas (see page 8) (Nyström et al., 1993). The tablet modelconsiders the formation of fractures in a tablet during strength testing. A tablet isfrequently described as a large aggregate of particles in which the interparticulate bondsare weaker than the intraparticulate bonds. In this case the fracture is more likely tooccur around, rather than through, the individual particles that can be identified in theformed tablet (Shotton and Ganderton, 1961; Eriksson and Alderborn, 1995; Adolfssonand Nyström, 1996). However, there are also reports of fractures occurring through oracross the particles (Shotton and Ganderton, 1961; de Boer et al., 1978). The strength ofthe intra- and interparticulate bonds is thus an important factor in fracture propagation.

Scanning electron microscope (SEM) photomicrographs of the fracture surface of puresodium bicarbonate and sodium chloride tablets showed relatively intact particles,indicating that the fracture mainly occurred around the particles, i.e. through areascontaining air (Figs. 14a and 15a-c). The fracture in a tablet composed of pure bindermay be more difficult to describe in such general terms. However, SEMphotomicrographs of the fracture surface of tablets made of MCC indicated that thefracture also went around the irregularly shaped particles (Fig. 15d). The fracture in apure PEG tablet was difficult to evaluate from SEM photomicrographs (Fig. 15e). Eventhough there may be some tendency for melting of asperities during compaction of PEG(Fassihi, 1988; Larhrib et al., 1997), it is likely that, considering the low but significantporosity of PEG tablets, the fracture occurred around individual PEG particles stillexisting as discrete particles in the tablet (Fig. 14c) (Adolfsson and Nyström, 1996).

Addition of a binder to a compound resulted in a decrease in tablet porosity because thebinder particles were able to be localised in the interparticulate voids in the compoundtablet (Figs. 14b and 16). The reduction in tablet porosity increased the probability ofbonds being established between particles. By utilising different techniques, i.e. SEM,extrapolation of tensile strength to zero porosity (Ryskewitch, 1953; Mashadi andNewton, 1987) and double layer tablets (Karehill et al., 1990), it was concluded that thefracture still occurs mainly around the compound particles and thereby through theinterparticulate voids which contain binder as well as air (Figs. 14b and 16). Therefore,a fracture through the compound particles is less likely (1 in Fig. 14b). The presence of

44

32

1b

a

c

Figure 14. A qualitative tablet model showing the addition of a binder and thefracture in a tablet: (a) pure compound tablet (e.g. sodium bicarbonate), (b) tabletcomposed of a binary mixture of compound and binder and (c) pure binder tablet(e.g. PEG). The white particles represent the coarse particulate compound and thegrey particles represent the fine particulate binder. The black line indicates thefracture through the tablet. In b) 1 indicates a fracture through the compoundparticles, 2 indicates a fracture around the binder particles located between thecompound particles and 3 indicates a fracture between compound particles andbinder particles.

45

binder in the voids affects the fracture and increbroken. Thus, there is an increase in tablet strencompound tablet.

A binder with a high plasticity is able to displacthereby increasing the number of bonds that ha

(a) (b)

(c) (d)

(e)

Figure 15. SEM photomicrographsof fracture surfaces of tablets. (a)pure sodium chloride (355-500 µm)(50 MPa), (b) pure sodium chloride(355-500 µm) (200 MPa), (c) puresodium bicarbonate (125-180 µm)(200 MPa), (d) pure MCC (200MPa) and (e) pure PEG 3000 (<20µm) (200 MPa). The white barrepresents 0.1 or 1 mm.

ases the number of bonds that have to begth compared to the strength of a pure

e a greater portion of the air with binder,ve to be broken. A binder with a

46

moderate plasticity but a high compactibility affects the strength rather than the numberof interparticulate bonds. As indicated by the pore size distribution determinations(paper IV), the binder phase mainly exists as small aggregates or primary particles andit is suggested that the fracture occurs around these units located between the compoundparticles (2 in Fig. 14b). Furthermore, compaction and strength measurements of doublelayer tablets indicated that the bonds between binder and compound were relativelystrong and it is speculated that this prevents the fracture occurring between binder andcompound particles to any great extent (3 in Fig. 14b). In fracture mechanics terms, theaddition of a binder probably decreased the propensity for fracture initiation andpropagation resulting in an increase in tablet strength (Newton et al., 1977). This haspreviously been referred to as a plastically deforming material acting as a crack stopperin more brittle materials (Gordon, 1973).

(a) (b)

(c) (d)

Figure 16. SEM photomicrographs of fracture surfaces of tablets. (a) a mixtureconsisting of sodium chloride (355-500 µm) and 5% (w/w) PEG 10000 (50 MPa), (b)a mixture consisting of sodium chloride (355-500 µm) and 5% (w/w) PEG 10000(200 MPa), (c) a mixture consisting of sodium bicarbonate and 20% (w/w) MCC(200 MPa) and (d) a mixture consisting of sodium bicarbonate and 20% (w/w) PEG3000 (200 MPa). The white bar represents 0.1 or 1 mm.

47

The synergistic increase in tablet strength observed for mixtures containing sodiumbicarbonate and PEG or PVP, or sodium chloride and low molecular weight PEGs, mayalso be explained by this qualitative tablet model. In a tablet consisting of pure binder,the fracture probably propagates relatively straight through the tablet, because of thesmall particle size (Fig. 14c). However, the presence of coarse compound particles inthe tablet is likely to increase the length of the path the fracture has to take in order toavoid breaking the compound particles (Fig. 14b) and this would increase the number ofinterparticulate bonds that have to be broken. Consequently, a higher tablet strengththan that of pure binder can be obtained for a mixture.

Relation between binder saturation and tablet strength

Another way of expressing the effect the binder has on tablet porosity, i.e. the ability ofthe binder to fill the interparticulate voids in a compound tablet, is to calculate thedegree of binder saturation (DBS) (see equation on page 27) (paper III). This expressionis analogous to the degree of liquid saturation used in wet agglomeration (Kristensenet al., 1984; Jerwanska et al., 1995). The DBS is related to the deformability of thebinder (a binder with a high deformability generally resulted in a high DBS), which inturn is related to the porosity and tablet strength of the resulting tablet composed of amixture. There was no unique relationship between DBS and tablet strength because, asdiscussed above, factors other than the void-filling capacity also determine the resultingtablet strength of a mixture. However, when different amounts of a plasticallydeformable binder were added to sodium bicarbonate or sodium chloride, a relationshipbetween DBS and tablet strength was obtained, indicating the importance of the extent

1008060402000

1

2

3

Degree of binder saturation (%)

Axi

al te

nsile

stre

ngth

(MPa

)

Figure 17. Axial tensile strength of tablets as a function of degree of binder saturation.Tablets compacted at 200 MPa and containing different amounts of PEG 3000 mixedwith sodium bicarbonate (�) and sodium chloride (�).

48

of void-filling by such a binder on tablet strength (Fig. 17). The deviation seen with thehighest DBS value in tablets containing sodium chloride and PEG 3000 may beinterpreted as an unexpectedly low tablet strength because of the prevention of solidbridges (Fig. 17).

Addition of a binder probably moved the compound particles further apart from eachother compared to the positions of the particles in a pure compound tablet. In otherwords, addition of a binder increased the void available to be filled with bindercompared to the void in a pure compound tablet (paper III). Consequently, when a solidmaterial, in contrast to a liquid, is used as a binder, complete filling of the voids (i.e.100% DBS) can not be achieved. The apparent particle density (obtained with heliumpycnometry) was used to calculate the volume of binder in a tablet containing a mixture.This was based on the assumption that the binder phase, to a significant extent,consisted of small aggregates or even primary particles when located in theinterparticulate voids and that the pores in these binder aggregates only contributed to asmall extent to the composed tablet porosity. This assumption seems valid consideringthe pore size distribution determinations in paper IV.

Qualitative assessment of the strength of interactions in tablets

An attempt was made to substantiate the above-mentioned ability of a binder to preventthe formation of solid bridges by assessing the dominating bond types. The generalapplicability of mercury porosimetry for characterisation of dominating bond types intablets was also evaluated. The approach used is based on previous theoreticalapproaches to estimate bonding mechanisms (see page 12) (Adolfsson et al., 1999;Olsson and Nyström, 2000b). These two models were based on air permeametry but, inpaper IV, data obtained from mercury porosimetry were used instead. Air permeametrycould not be applied because of the limitation of the technique when using very densetablets (Alderborn et al., 1985a). However, for non-porous materials, mercuryporosimetry and air permeametry are, in principal, equivalent techniques for estimatingthe same type of surface area. In paper IV, tablet strength was adjusted for pore surfacearea and average pore diameter (Adolfsson et al., 1999) as well as for pore surface areaand solid fraction (1-porosity) (Olsson and Nyström, 2000b).

Overall, both approaches gave similar results and they were in agreement with thosepreviously obtained for sodium chloride in the sense that the adjusted tablet strength ofa material expected to bond with solid bridges in addition to distance attraction forceswill be high (Fig. 18) (Nyström et al., 1993; Adolfsson et al., 1999; Olsson andNyström, 2000b). Accordingly, the bonds in tablets made of the binders were essentiallyweak distance attraction forces. Sodium bicarbonate had an intermediate value, whichsuggests mainly distance forces. However, the contribution of solid bridges in coarseparticulate sodium bicarbonate cannot be excluded and has also been suggestedpreviously (Adolfsson et al., 1999).

Addition of a binder to sodium chloride resulted in a decrease in the adjusted tabletstrength, indicating a decreased ability to bond with solid bridges, probably because the

49

binder prevented the formation of such bonds (Adolfsson et al., 1998). This effect wasalso observed when increasing the amount of PEG 3000 in the sodium chloride tablets(Fig. 18b,c). In Fig. 18c, the adjusted tablet strength suggests a more gradual decrease inthe probability of forming solid bridges as the amount of binder increases, whereas theadjusted tablet strength in Fig. 18b indicates a more drastic effect on the addition ofeven a small amount of binder. The adjusted tablet strength was not affected as muchwhen a binder was added to sodium bicarbonate, probably because of the smallerprobability of the existence of solid bridges. The decrease in adjusted tablet strength didnot directly reflect the measured increase in tablet strength (Fig. 18). Therefore, it isreasonable to assume that although there is a decreased probability of solid bridges,addition of a binder increases bonding by distance attraction forces, thus resulting in anoverall increase in tablet strength.

The results were in agreement with previous similar attempts to assess bondingmechanisms (Adolfsson et al., 1999; Olsson and Nyström, 2000b) and it is thereforepostulated that data from mercury porosimetry can be used to qualitatively assess thestrength of interactions in tablets. Furthermore, the materials used in paper IV wereessentially non-porous and therefore intraparticulate pores were assumed not tocontribute to tablet porosity. This facilitates the interpretation of data obtained withmercury porosimetry.

Figure 18. (a) Radial tensilestrength, (b) adjusted tabletstrength according to poresurface area and pore radius and(c) adjusted tablet strengthaccording to pore surface areaand solid fraction as a function ofamount of binder. Sodiumchloride and PEG 3000 (�).Tablets compacted at 200 MPa.

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Rad

ial t

ensi

le st

reng

th (M

Pa)

0 20 40 60 80 100

Amount of binder (% w/w)

a)

0

10

20

30

40

50

60

Tabl

et st

reng

th a

djus

ted

acco

rdin

g to

por

e su

rfac

ear

ea a

nd p

ore

radi

us (n

N)

0 20 40 60 80 100Amount of binder (% w/w)

b)

0

0.25

0.5

0.75

1

Tabl

et st

reng

th a

djus

ted

acco

rdin

g to

por

e su

rfac

ear

ea a

nd so

lid fr

actio

n (P

a)

0 20 40 60 80 100Amount of binder (% w/w)

c)

50

Effect of binders on tablet disintegration

Relation between tablet strength/porosity and disintegration propertiesIn paper V, the objective was to obtain high tensile strength rapidly disintegratingtablets. However, the effect of a binder on pore structure and tablet strength can oftenaffect the disintegration time negatively. Rapid disintegration of tablets not containing asuperdisintegrant was generally associated with low tablet strength (e.g. mixturescontaining crystalline lactose). Conversely, high tablet strength was associated withlonger disintegration time (e.g. mixtures containing PEG 3000, MCC or amorphouslactose). Addition of a superdisintegrant gave no correlation between tablet strength anddisintegration since, provided the superdisintegrant is effective, it is possible to obtainhigh tablet strength and a short disintegration time. Disintegration of tablets containingDCP was generally rapid, which is partly explained by the high porosity of those tabletsfacilitating a rapid water penetration. The results indicated, however, no generalrelationship between porosity and disintegration time of the different tablets studied.

Binder properties of importance for optimal function of superdisintegrants

The binders used in paper V were classified according to their volume reductionbehaviour (Table 2). MCC is thought to undergo rather extensive fragmentation becauseof its aggregated structure and plastic deformation whereas PEG undergoes plasticdeformation during compaction. Of the different types of lactose investigated, thecrystalline form responded to pressure primarily by fragmentation while the amorphousform underwent plastic deformation and very little fragmentation occurred (Table 2).Microcalorimetry and DSC also allowed differentiation between the different lactoseforms according to the amount of amorphous material present (Table 5). Thedeformability and bonding ability of the materials increased with increased amorphouscontent, thus increasing the ability of lactose to act as a binder (Vromans et al., 1986;Sebhatu et al., 1997).

The strongest lactose tablets with the longest disintegration time were generally thosecontaining the amorphous form (Fig. 19). Tablets containing PEG also had a relativelylong disintegration time, which is attributed to the low tablet porosity and the viscosity-enhancing properties of PEG (Fig. 19). In contrast to the reported ability of MCC toimprove disintegration because of its ability to draw water into the tablet (Khan andRhodes, 1975b; Bolhuis et al., 1979; Lerk et al., 1979), tablets of pure MCC andmixtures containing this binder did not disintegrate in this study (Fig. 19).

When a binder was included to increase tablet strength, addition of a superdisintegrantwas normally needed to decrease the disintegration time. However, the microstructuresurrounding the disintegrant particles influenced the disintegrating effect.

51

0

100

200

300

400

500

600

Disi

nteg

ratio

n tim

e (s

)

1

a)

0

100

200

300

400

500

600

Disi

nteg

ratio

n tim

e (s

)

1

b)

Table 5. Degrees of disorder of the different forms of lactose as obtained by twomeasurement techniques (data from paper V). Standard deviation in parentheses.

Material DSC MicrocalorimetryHeat of

crystallisation (J/g)Degree ofdisorder

(%)

Heat ofcrystallisation (J/g)

Degree ofdisorder

(%)Crystalline lactose 0 0 0 0Partially crystalline lactose 23 (4.0) 23 9.1 (2.1) 29Amorphous lactose 100 (5.5) 100 31 (5.2) 100

E CL CL+D PL PL+D AL AL+D C C+D P P+D

S CL CL+D PL PL+D AL AL+D C C+D P P+D

Figure 19. Disintegration time of tablets containing (a) sodium chloride or (b) dibasiccalcium phosphate dihydrate alone, with binder or with binder plus superdisintegrant.Disintegration times longer than 3600 s are shown as 600 s with an arrow indicatingthe extension. Confidence intervals for p = 0.05 are shown. Tablets compacted at200 MPa. AL = amorphous lactose; C = microcrystalline cellulose; CL = crystallinelactose; D = Ac-Di-Sol; E = dibasic calcium phosphate dihydrate; P = PEG 3000;PL = partially crystalline lactose; S = sodium chloride.

52

Addition of a superdisintegrant to tablets containing PEG and sodium chloride evenincreased the disintegration time, probably because of the environment created by thisductile binder (Fig. 19a). When the superdisintegrant particles swelled, the force thatwould normally have caused the bonds to break would instead have been absorbed bythe deformable structure of PEG, thus counteracting the disintegrating force. Theviscosity enhancing properties of PEG may have also counteracted the effect of thesuperdisintegrant. In contrast, in highly porous tablets, as when PEG was mixed withDCP, the negative effect of the deformable environment was reduced and thepenetration of water was facilitated, thus allowing the superdisintegrant to achieve itspurpose (Fig. 19b). Addition of the superdisintegrant had a substantial effect on thedisintegration time of tablets containing MCC (Fig. 19). The effect of thesuperdisintegrant on the disintegration time of tablets containing lactose and sodiumchloride was reduced with increasing amorphous content, as the lactose became moredeformable (Fig. 19).

-100

-50

0

50

Rel

ativ

e ch

ange

in d

isin

tegr

atio

n tim

e (%

)

0 50 100 150 200 250

Fragmentation tendency ((cm 2/g)*MPa-1)

Figure 20. Relative change in disintegration time after addition of superdisintegrantto the mixtures containing compound and binder as a function of fragmentationtendency of the binder (the slope of a graph of the specific tablet surface area vscompaction pressure). Mixtures containing sodium chloride ( ����) and dibasic calciumphosphate dihydrate ( ����). Tablets compacted at 200 MPa.

These results indicate that the dominating volume reduction mechanism of the binderinfluences the effect of the superdisintegrant (Fig. 20). When a deformable binder witha low fragmentation propensity was added to a compound such as sodium chloride toform tablets with low porosity, the effect of a superdisintegrant was insignificant.However, when these binders were added to a compound, which creates a highly poroustablet (e.g. DCP), the importance of the volume reduction mechanism of the binder wasreduced. Tablets containing binders that fragmented to a larger extent were moresusceptible to the addition of a superdisintegrant, regardless of the compound used.

53

Conclusions

This thesis has investigated the strength-enhancing mechanisms of a dry binder in directcompression. Material properties of both the binder and the compound, forming abinary mixture, were delineated in order to investigate which properties were of mostimportance for the tensile strength of the resulting tablet. The strength-enhancing effectof a dry binder was explained by proposing a simplified qualitative tablet modeldescribing the fracture which occurs in a tablet during strength testing. According tothis tablet model, the fracture mainly propagates around the particles and through theinterparticulate voids. This type of failure will occur in tablets of pure compound, purebinder and binary mixtures.

When a fine particulate polymeric binder is added to a coarse particulate compound,there is an effect on tablet characteristics such as tensile strength, pore structure anddisintegration. However, the effect on these tablet characteristics varies with theproperties of the binder and compound used.

The strength-enhancing effect of a binder appears to be closely related to its ability toreduce tablet porosity. This decrease in porosity is the result of the distribution of binderin the voids between the compound particles which increases the possibility fordevelopment of interparticulate bonds. In this case, the fracture occurs partly throughthe binder phase located in the voids, instead of mainly through air as in a purecompound tablet. Consequently, more interparticulate bonds have to be broken andthere is an increase in tablet strength. The synergistic increase in tablet strengthobserved for some binary mixtures is explained in terms of a change in the fracture pathfrom the path expected in a tablet of pure fine particulate binder, because of thepresence of coarse compound particles in a tablet of a binary mixture.

One important characteristic of the binder is thus the ability to be effectively and evenlydistributed in the interparticulate voids, thereby affecting the pore structure (e.g.porosity and pore size distribution) and tensile strength of the tablet. A pronouncedvoid-filling capacity in a binder is strongly related to greater plasticity, less elasticityand small particle size, properties exemplified by PEG and PVP. However, in somecases, the tensile strength of a tablet of a binary mixture was governed more by thecompactibility of the binder. This was especially evident when the plastic deformabilityof the binder was relatively limited, as exemplified by MCC and PGS.

It was found that the tablet porosity, bonding mechanisms and volume reductionmechanisms of the model compound influence the effect of a binder. The plasticity andparticle size of the binder are the main factors affecting tablet strength when theporosity of tablets of the compound is low (e.g. sodium chloride). The tablet strength ofa compound, which gives more porous tablets (e.g. sodium bicarbonate), is determinedby a combination of the plasticity and compactibility of the binder. A compound thathas the ability of bonding with solid bridges (e.g. sodium chloride) or has a highfragmentation propensity (e.g. calcium carbonate) is less affected by the addition of thebinder, at least when the amount of binder added is below a certain level.

54

Data obtained with mercury porosimetry were utilised to qualitatively assess thedominating bond types in tablets and the effect of a binder on the relative importance ofthese bonds. This method appears to be useful in assessing the interparticulate distancesand dominating bond types in tablets of non-porous materials. The results indicate thatthe addition of a binder reduces bonding by solid bridges, especially during compactionof sodium chloride, and instead increases bonding by distance attraction forces. Sincethe results regarding dominating bond types are in accordance with those obtainedpreviously (Adolfsson et al., 1999; Olsson and Nyström, 2000b), the applicability ofthese concepts to the estimation of dominating bond types in tablets is substantiated.

Materials with a high propensity for plastic deformation (e.g. PEG and PVP) seem to besuitable as binders in direct compression and may be an alternative to the morecommonly used MCC for increasing tablet strength. However, the effect a binder has onpore structure and tablet strength may negatively affect the disintegration of tablets andcan also decrease the functionality of a superdisintegrant. For example, tabletscontaining PEG have a relatively long disintegration time, which is attributed to the lowtablet porosity and viscosity-enhancing properties of PEG. Tablets of pure MCC ormixtures containing MCC were non-disintegrating, in direct contrast to the reportedability of MCC to enhance the disintegration time.

In order to obtain rapid disintegration of tablets, which also contain a binder to ensure ahigh tensile strength, it is necessary to add a disintegrant. However, the microstructuresurrounding the disintegrant particles may influence the disintegrating effect. Whenusing deformable binders that do not fragment to any significant extent (e.g. PEG andamorphous lactose), the disintegration time is extended and is not substantially affectedby the addition of a superdisintegrant. However, if the tablet is sufficiently porous, thenegative effect of the deformable surroundings is reduced. When less deformablebinders which are likely to fragment are used (e.g. MCC), the effect of thesuperdisintegrant is substantial, and rapidly disintegrating tablets of high tensile strengthare obtained.

One of the aims of the thesis was to classify binders with different properties accordingto their ability to enhance tablet strength. The proposed tablet model, which describesthe fracture process in a tablet during strength testing, appears to be applicable to thecharacterisation of the function of a dry binder. The applied characteristics of thebinders (i.e. deformability, particle size and compactibility) were shown to be usefulwhen evaluating the effectiveness of a binder. Although, the focus of the thesis was onbinary mixtures, and the complexity of using more than two components is understood,the results provide valuable information for facilitating the choice of a suitable binderfor a new drug formulation.

55

Acknowledgements

The studies in this thesis were carried out at the Division of Pharmaceutics,Department of Pharmacy, Faculty of Pharmacy, Uppsala University.

I would like to express my sincere gratitude to:

Professor Christer Nyström, my supervisor, for encouragement and inspiration andfor always seeing the positive things when discussing new results, making it mucheasier to carry on with the work.

Professor Göran Alderborn for interesting discussions and kind interest in my work.

Dr Christina Gustafsson, my room mate during these years for being a great friend,always willing to discuss scientific as well as non-scientific matters, and for makingour room such a cosy and pleasant place.

Dr Helena Olsson, enthusiastic co-author and great friend, and for being a good andinspiring supervisor during my 8th and 9th term studies, making me discover thefascination of powders and tablets.

Susanne Bredenberg, enthusiastic co-author and wonderful friend, for all the nicetimes in the lab and at the golf course.

The powder people, past and present: Dr Åsa Adolfsson, Gunilla Andersson, JonasBerggren, Susanne Bredenberg, Elisabet Börjesson, Leif Dahlberg, TorstenFjellström, Dr Torkel Gren, Dr Christina Gustafsson, Dr Barbro Johansson, Dr MitraMosharraf, Dr Fredrik Nicklasson, Dr Helena Olsson, Dr Tesfai Sebhatu and ÅsaTunon for being great friends, for your scientific support and for creating such apleasant atmosphere in the powder group.

Eva Nises Ahlgren for your positive and friendly attitude and for always being sohelpful regarding various matters, including the final preparation of this thesis.

All the people, past and present, at the Division of Pharmaceutics for makingGaleniken such a fun and inspiring place to work at.

Antona Wagstaff for skilful and rapid linguistic revision of the papers and thesis.

Anna Printzell and Ulrika Westin for experimentally contributing to this thesis.

All my friends for lots of fun times.

Hasse and Birgitta for being so wonderful, always caring for me.

Mormor, för att du är världens gosigaste mormor!

56

Mats, for being my big brother and for all the gourmet dinners.

Anna, for being my best friend and the best twin sister in the world. Talking to youalways makes me feel better. Next stop: New Zealand!

My parents, Gunnar and Gunvor, for being the best parents one could ever wish forand for your love and support throughout the years.

Pär, my one and only, for your love, endless support and encouragement and forenthusiastic (sometimes too enthusiastic!) scientific discussions about my work.

***

Financial support from AstraZeneca (Sweden), Pharmacia Corporation (Sweden), theKnut and Alice Wallenberg Foundation, IF Foundation for Pharmaceutical Research,the CD Carlsson Fund and the CR Leffman Scholarship Fund is gratefullyacknowledged.

57

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