Pharmaceutical Tablets 8

Comprehensive Summaries of Uppsala Dissertations from 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

SOFIA MATTSSON

ACTA UNIVERSITATIS UPSALIENSIS UPPSALA 2000 Dissertation for the Degree of Doctor of Philosophy (Faculty of Pharmacy) in Pharmaceutics presented at Uppsala University in 2000

ABSTRACT

In this thesis, the strength-enhancing mechanisms of dry binders in direct compression were studied. The systems investigated were binary mixtures containing various compounds and binders. Among the binders used were a series of different molecular weights of polyethylene glycol. The proposed simplified tablet model describing the fracture path in a tablet during strength testing offers an explanation for the increase in tablet strength caused by the binder. The model and results in this thesis indicate that fractures will usually propagate around the tablet particles and through the interparticulate voids during tablet strength testing. One important characteristic of the binder is its ability to be effectively and evenly distributed through the interparticulate voids in a compound tablet. Characteristics such as high plasticity, low elasticity and a small particle size were associated with a more even distribution and a consequent pronounced effect on pore structure and marked improvement in tablet strength. The strength of tablets containing less plastic binders was governed more by the compactibility of the binder. The tablet porosity, bonding mechanisms and volume reduction mechanisms of the compound also influenced the effect of the binder. For example, the plasticity and particle size of the binder had the most significant effects on tablet strength when the tablet porosity of the compound was relatively low. A combination of the plasticity and the compactibility of the binder determined the strength of tablets when the tablet of a compound was more porous. The positive effect of a binder on pore structure and tablet strength resulted in an increase in the disintegration time. Although addition of a superdisintegrant generally improved the disintegration time, the effect was decreased when the formulation included more deformable binders. The choice of a suitable binder for a tablet formulation requires extensive knowledge of the relative importance of binder properties for enhancing the strength of the 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 thesis enables 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 0282-7484 ISBN 91-554-4857-7 Contents

Papers discussed 7

Pharmaceutical tablets 8

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

Mechanical strength of tablets 13 Measurements of mechanical strength 13 Theoretical models of mechanical strength 14 Bond summation concept Fracture mechanics concept Percolation theory Effect of particle and powder properties on mechanical strength 15 Effect 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 18 Distribution of binders - comparison between direct compression and wet granulation 19 Effect of binders on mechanical strength of directly compressed tablets 19 Commonly used binders in direct compression 20 Polyethylene glycol 21

Aims of the thesis 21

Materials and methods 22 Preparation of test materials 22 Model compounds Binder materials Superdisintegrant Choice of model compounds 23 Characterisation of materials 24 Density External surface area Amorphous content Preparation of mixtures 24 Compaction of tablets 25 6

Characterisation of compaction behaviour 25 Deformation properties Fragmentation properties Characterisation of tablets 26 Tensile strength Examination of fracture surfaces Porosity Pore size distribution Degree of binder saturation Disintegration

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

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

Tablet model describing the effect of binder addition on tablet strength and pore structure 43 Fracture characteristics 43 Relation between binder saturation and tablet strength 47 Qualitative assessment of the strength of interactions in tablets 48

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

Conclusions 53

Acknowledgements 55

References 57 7

Papers discussed

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

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

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

III Mattsson, S., Nyström, C., 2000. Evaluation of critical binder properties affecting the compactibility of binary mixtures. Drug Dev. Ind. Pharm., accepted for publication.

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

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

Reprints were made with permission from the journals. 8

Pharmaceutical tablets

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

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

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

The uniaxial compaction of a pharmaceutical powder results in an anisotropic and heterogeneous tablet with variations in such properties as density, porosity and mechanical strength throughout the tablet (Train, 1956; Kandeil et al., 1977; Nyström et al., 1993). The tablet porosity of most materials is about 5 to 30%. This means that even 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 and bonding characteristics of a certain material. In the first model, a tablet is described as powder particles dispersed in air, so that the tablet then contains a network of pores. The validity of this model is supported by the applicability of methods such as surface area measurement by air permeametry and measurement with mercury intrusion, since these methods are based on a medium flowing through or penetrating the tablet. As a consequence of this model, the interparticulate bonds are considered weaker than the intraparticulate bonds. In the second model, a tablet is regarded as individual units of air dispersed through a solid continuous phase. The first model appears to be most suitable for commonly used tableting materials (Nyström et al., 1993; Alderborn, 1996). The applicability of this model is further supported by scanning electron microscope photomicrographs, since individual particles can be discerned in tablets after compaction (Hardman and Lilley, 1970; Down, 1983). 9

Compaction of pharmaceutical powders

When pressure is applied to a powder bed, the bulk volume of the powder is reduced and the amount of air is decreased. During this process, energy is consumed. As the particles are moved into closer proximity to each other during the volume reduction process, bonds may be established between the particles. The formation of bonds is associated 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 term compression is often used to describe the process of volume reduction and the term compaction is used to describe the whole process, including the subsequent establishment of bonds. The strength of a tablet composed of a certain material can be used as a measure of the compactibility of that material. Volume reduction takes place by various mechanisms and different types of bonds may be established between the particles 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 are rearranged under low compaction pressures to form a closer packing structure. Particles with a regular shape appear to undergo rearrangement more easily than those of irregular shape (York, 1978). As the pressure increases, further rearrangement is prevented and subsequent volume reduction is accomplished by plastic and elastic deformation and/or fragmentation of the tablet particles (e.g. Train, 1956; Duberg and Nyström, 1986). Brittle particles are likely to undergo fragmentation, i.e. breakage of the original particles into smaller units. Plastic deformation is an irreversible process resulting in a permanent change of the particle shape, whereas after elastic deformation the particles resume their original shape, i.e. this is a reversible process.

The degree of volume reduction that a pharmaceutical powder bed undergoes depends on the mechanical properties of the powder and the type of volume reduction mechanisms involved. Particle size and speed of compression will in turn influence the mechanical 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 at which a transition from brittle to ductile behaviour occurs as the particles become smaller (Robert and Rowe, 1987b; Roberts et al., 1989). Brittle materials which undergo extensive fragmentation generally result in tablets of relatively high porosity because of the large number of bonding points that are created which prevent further volume reduction. A ductile material, on the other hand, will often result in tablets of low porosity because the high degree of plastic deformation enables the particles to move very close to each other. The deformation of surface asperities will play a special role in this context. 10

Methods for characterisation of volume reduction mechanisms

Both fragmentation and deformation can occur in different stages of the volume reduction process (Duberg and Nyström, 1986). One mechanism often predominates, however, and various techniques are available for characterisation of the dominating volume reduction mechanism. As mentioned above, the mechanical properties of a material have some influence on its volume reduction behaviour. These properties can be obtained by measuring the hardness and Young’s modulus of a material in order to assess its plasticity and elasticity (Roberts and Rowe, 1987a). Attempts have also been made 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 as a 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 a function of applied pressure (e.g. the Heckel, Kawakita and Cooper-Eaton equations) have been developed in an effort to quantitatively describe the volume reduction behaviour of a powder (Heckel, 1961a,b; Paronen and Illka, 1996). The applicability of these equations depends on the pressure or porosity range studied.

When measuring the change in porosity during compression and decompression and applying the Heckel equation, the resistance to deformation may be obtained by using the reciprocal of the slope of the linear part of the Heckel plot (Heckel, 1961a,b). This value is defined as the yield pressure of the material (Hersey and Rees, 1971). When the measurements are made in-die, i.e. during one compression cycle, this yield pressure value 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 tablet after ejection, thus allowing for elastic expansion to take place. Therefore, the obtained yield 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 the influence of the elastic component (Fell and Newton, 1971a; Paronen and Juslin, 1983). Consequently, a small difference between these yield pressure values indicates a low degree of elastic deformation (Fell and Newton, 1971a; Paronen, 1986). The extent of elastic deformation of the powder bed during compression can also be assessed by measuring the relative difference in porosity (Duberg and Nyström, 1986) or tablet height (Armstrong and Haines-Nutt, 1972) during and after compression.

It appears that some experimental variables can affect the outcome of Heckel plots, and limitations to their use for prediction of compaction behaviour have been proposed (Rue and Rees, 1978; York, 1979; Sonnergaard, 1999). For example, compression speed and particle size can affect volume reduction behaviour (Rue and Rees, 1978). There also appear to be limitations to the Heckel function at high compaction pressures or low tablet porosity (Paronen and Illka, 1996). Determination of the volume reduction behaviour of a material is generally performed in bulk and does not take changes in surface properties (e.g. deformation of asperities) into account. The deformation of asperities can affect the performance of the powder when compressed and the 11

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

Other methods for characterising the volume reduction behaviour of a material have been presented in the literature. These include scanning electron microscopy (Hardman and Lilley, 1970; de Boer et al., 1978; Krycer et al., 1982), the use of ratios from axial and radial tensile strength measurements (Duberg and Nyström, 1982), and measurement of surface area changes during compaction using permeametry (Alderborn et 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 are mainly 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 dry powders by direct compression are considered to be distance attraction forces, solid bridges and mechanical interlocking (Führer, 1977).

The term distance attraction forces includes van der Waals forces, hydrogen bonds and electrostatic forces. The common feature is that these bonds act between surfaces that are separated by some distance. Van der Waals forces can occur over distances up to 100 to 1000 Å and the strength of the van der Waals forces is dependent on the distance between the attracting molecules, ions or particles and the medium surrounding them (Israelachvili, 1992). Hydrogen bonds occur primarily through electrostatic interaction and may occur both intramolecularly and intermolecularly (Israelachvili, 1992). Microcrystalline cellulose is an example of a material where hydrogen bonds are considered important for the tablet strength (Reier and Shangraw, 1966). Electrostatic forces may arise from triboelectric charging during mixing and compaction. However, electrostatic forces are neutralised relatively quickly over time and are not considered to be 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 between particles. The molecules or ions in the solid bridge are assumed to be arranged and bonded in the same manner as those inside each particle. Certain prerequisites are considered to facilitate the development of solid bridges, e.g. a simple chemical structure, a certain degree of plastic deformation and the concentration of high stress levels at interparticulate contact points (Führer, 1977; Adolfsson et al., 1997). Because of their structure, solid bridges are regarded as relatively strong bonds and materials bonding with such bonds, e.g. sodium chloride, form relatively strong tablets on compaction. However, tablets containing these strong bonds are also associated with an extended disintegration time (Führer, 1977). The ability to bond with solid bridges has been shown to increase with an increase in particle size and compaction pressure 12

(Adolfsson et al., 1997). It has also been proposed that amorphous materials are more likely to bond with solid bridges (Fürher, 1977; Sebhatu et al., 1997) and that the presence 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 a tablet. This is possible because of particle irregularities and roughness on the surface of the particles (Fürher, 1977).

Methods for characterisation of bonding mechanisms

Several methods for determining the dominating bonding mechanisms in tablets have been proposed. The results generally conclude that the dominating bond type in pharmaceutical 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 and Nyström, 1990; Olsson et al., 1996; Adolfsson et al., 1997), the tablet strength of various compounds decreased. However, this reduction in tablet strength was comparatively less for tablets made from some materials, e.g. sodium chloride. The remaining tablet strength of sodium chloride is attributed to solid bridges, since these are able to be developed even though magnesium stearate or liquid surrounded the sodium chloride particles. The proportion of solid bridges in a tablet can thus be calculated.

Another approach to estimating the dominating bonding mechanisms has been to calculate the surface specific tablet strength (Nyström et al., 1993; Adolfsson et al., 1999). The rationale behind such an approach is the assumed proportionality between tablet surface area and the surface area participating in bonding. The surface specific tablet 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 distance attraction forces. The results are in agreement with other methods for estimating bond types (Karehill and Nyström, 1990; Olsson et al., 1996; Adolfsson et al., 1997). The concept of surface specific tablet strength was developed further by also taking the estimated average distance between the particles into consideration (Adolfsson et al., 1999). However, the results were generally not affected by this procedure. A study by Olsson and Nyström (2000b) considered features of the internal tablet structure that were important for tablet strength and assessed bond types by establishing an interaction factor that reflected the dominating bond type. Although both these latter approaches (Adolfsson et al., 1999; Olsson and Nyström, 2000b) were able to differentiate between dominating bond types, they were not able to fully account for effects of particle size and compaction pressure. 13

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 compaction behaviour of a material (Davies and Newton, 1996). The mechanical strength of a tablet can be characterised by the force necessary to break the tablet. When a tablet is subjected to such a force, the response can be interpreted on the basis of the bond summation or fracture mechanics concepts. In the bond summation concept, the bonds holding the particles together and the breakage of these bonds during strength testing are emphasised. In the fracture mechanics concept, focus is on the propagation of cracks in the tablet during strength testing. Although the aim of both concepts is to describe the mechanical strength of a tablet, the discrepancy between the theoretical and the measured mechanical strength may vary between them. The two concepts are discussed briefly 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. the breaking strength, diametral compression, axial tensile strength and bending tests. However, the results vary according to the method applied. This may be attributed to variations in the stress conditions induced by the test and also to the heterogeneity and anisotropic nature of tablets, with variations in, for example, the interparticulate bond and pore distribution (Newton et al., 1992). Furthermore, the mode of failure and the dimensions of the tablet have to be taken into consideration. Consequently, the strength values obtained may be considered to represent specimen properties rather than material properties (Newton et al., 1992; 1993)

The most common strength test in pharmaceutical applications is the diametral compression test, which is used to calculate the radial tensile strength of a tablet (Fell and Newton, 1970a). In order to calculate the radial tensile strength, the stress conditions 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 tablet rather than the strength of the weakest plane in the tablet.

Another method for determining mechanical strength is to measure the axial tensile strength. The force necessary to break the tablet is obtained by pulling the tablet parallel to the applied force during the formation of the tablet and this force is then used to calculate the axial tensile strength (Nyström et al., 1978). During axial tensile strength measurements, the fracture will occur through the weakest plane in the tablet. Consequently, this method allows detection of capping tendencies in a tablet. 14

Theoretical models of mechanical strength

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

Bond summation concept The mechanical strength of a tablet has traditionally in the pharmaceutical literature been regarded to depend on the dominating bonding mechanism between the particles and 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 bond structure. The strength of a given plane within a tablet is described by the sum of all attraction forces between the particles in that plane. It is assumed that all interparticulate bonds in the failure plane break more or less simultaneously. Such a simplification has been criticised by proponents of the fracture mechanics concept. Several expressions originating from Rumpf (1962) have been proposed in order to describe the mechanical strength 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 process and the variety of factors affecting the bond formation process.

Considering the importance of the bonding surface area for the mechanical strength, it would be desirable to measure the actual surface area participating in bonding. However, direct measurements of the bonding surface area are difficult. Instead, more indirect methods have been applied, for example to measure the surface area of the powder 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 of studies using these methods suggest that the surface area participating in bonding is very small compared with the total surface area (Nyström and Karehill, 1986). It has been proposed that the external tablet surface area obtained by air permeametry holds the best proportionality to the bonding surface area (Alderborn et al., 1985a). Other techniques, such as gas adsorption and mercury porosimetry, also take into account the contribution of an eventual intraparticulate surface area, which does not participate in interparticulate bonding.

Fracture mechanics concept The application of fracture mechanics has also been studied in relation to the mechanical strength of pharmaceutical tablets (e.g. Mashadi and Newton, 1987; York et al., 1990; Rowe and Roberts, 1994; Al-Nasassrah et al., 1998). The fracture mechanics concept stresses the importance of defects and flaws in the tablet, which can be considered as starting points for the fracture, and the subsequent propagation of the fracture. 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 brittle fracture generally propagates rapidly, whereas a ductile fracture is characterised as being preceded by plastic deformation (Amidon, 1995). The crack in the tablet grows and 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 15

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

Percolation theory In the percolation theory, the tablet is seen as consisting of clusters of particles which form a network. This theory has been used to describe the formation of the tablet and the 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 relative density of a tablet and the percolation theory relates changes in tablet properties, such as mechanical strength, to the appearance of percolation thresholds. The percolation theory has been applied to describe the compaction of both single components and binary mixtures (Blattner et al., 1990; Leuenberger and Leu, 1992; Picker, 1999; Kuentz and Leuenberger, 2000). For example, property changes associated with a change in the composition 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 large number of interparticulate contact points, which in turn provide a large number of possible bonding zones. Consequently, tablets made of these materials can have a high mechanical strength. Extensive elastic deformation, on the other hand, may cause a pronounced decrease in the mechanical strength of the tablet, due to breakage of interparticulate bonds when the compaction pressure is released. Plastic deformation is considered beneficial to the mechanical strength since it enables the particles to move very close to each other, thereby creating a large surface area over which bonds may be established. As the distance between the particles is decreased during compaction of plastic materials, particle interactions are also favoured.

Several studies have investigated the effect of the size of the particles of powdered material on the mechanical strength of the tablet; a reduction in particle size is generally associated 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 increase in the surface area available for interparticulate attractions, as the particles become smaller. For example, a linear relationship between specific surface area and the mechanical strength of tablets has been suggested for different types of lactose (Vromans et al., 1985; de Boer et al., 1986). In these studies, proportionality between specific 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 area and 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 mechanical strength of the tablet has been reported for e.g. sodium chloride (Alderborn and 16

Nyström, 1982a). This is attributed to an increased ability to bond with solid bridges as the 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 solid bridges (e.g. Adolfsson et al., 1997). For materials with a high fragmentation tendency, such as dibasic calcium phosphate dihydrate and saccharose, the mechanical strength of the 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. Milling the powder prior to compaction can induce changes in the shape and roughness. More irregular 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 of irregularly shaped particles increases the number of possible bonding points (Alderborn et al., 1988). Furthermore, an irregular shape and high surface roughness of the particles would favour plastic deformation, because of a higher degree of surface asperities and crystal defects in such particles (Wong and Pilpel, 1990). The mechanical strength of tablets of materials with a high fragmentation tendency has been shown to be less affected by particle shape and surface texture (Alderborn and Nyström, 1982b; Wong and Pilpel, 1990).

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

Because of the effect of the above-mentioned particle and powder properties on mechanical strength, it is obvious that a thorough characterisation of these properties is essential 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 the mechanical strength of the resulting tablet (Davies and Newton, 1996). A material which undergoes time-dependent plastic or elastic deformation is referred to as a viscous or viscoelastic material. For such a material, a change in the compression speed significantly affects the deformation of the material (e.g. Roberts and Rowe, 1985; Armstrong and Palfrey, 1989). The effect of compression speed has been evaluated by calculating the strain rate sensitivity, which is the relative difference between yield pressure values at a high and low compression speed (Roberts and Rowe, 1985). For a material known to deform by plastic flow, the volume reduction generally decreases as the compression speed increases, thus allowing a shorter time for plastic deformation and a subsequent decrease in mechanical strength of tablets (David and Augsburger, 1977; Armstrong and Palfrey, 1989; Cook and Summers, 1990). A fragmenting material, on the other hand, has been shown to be less affected by variations in 17

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

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

Pore structure of tablets

The pore structure of a tablet can be expressed in terms of porosity and pore size distribution and is influenced by the mode of volume reduction during compaction and the compaction pressure applied. Increasing the compaction pressure brings the particles closer to each other, resulting in a reduction in tablet porosity. Tablet properties such as mechanical strength and disintegration are in turn affected by the pore structure. However, the relationship between mechanical strength and pore structure appears to be ambiguous. For example, a linear relationship between porosity and the logarithm of the strength of tablets has been reported (Ryshkewitch, 1953). This suggests that tablets of low porosity will have high mechanical strength. Further, the total pore surface area has been suggested to be directly proportional to the breaking force of lactose tablets, i.e. an increase in the total pore surface area resulted in an increase in tablet strength (Vromans et al., 1985; de Boer et al., 1986). However, in another study this relationship could not be established for lactose or for other materials (Juppo, 1996). An increase in tablet strength was instead proposed to be related to a decrease in the volume of large pores and 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 tablet strength, linear relationships are seldom obtained, probably partly because of the influence of the whole pore size distribution.

The porosity of tablets made of plastically deforming materials has been shown to increase with increased compression speed (Armstrong and Palfrey, 1989; Cook and Summers, 1990). This is consistent with a decrease in the time available for plastic deformation as the compression speed increases. Also, a decrease in particle size of the powdered material has been shown to increase tablet porosity (McKenna and McCafferty, 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 mercury porosimetry (e.g. Stanley-Wood and Johansson, 1980; Juppo, 1996; Westermarck et al., 1998). These techniques are complementary, in that mercury porosimetry can be used to measure larger pores (the lower size limit is about 0.003 µm in diameter) while gas adsorption allows measurement of smaller pores. 18

Disintegration of tablets

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

Many tablet formulations have inadequate disintegration properties. Therefore, disintegrants, which swell extensively in contact with water (so-called superdisintegrants), are often added to a formulation in order to facilitate the rupture of bonds during disintegration (Shangraw et al., 1980). It has been proposed that the efficacy of disintegrants is dependent on tablet porosity. A relatively low porosity was shown to be most effective for the action of a disintegrant since the swelling of the disintegrant particles 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 to measure the disintegrating force developed after penetration of water and the subsequent 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 mechanical strength of a tablet. In direct compression, it is generally considered that a binder should have a high compactibility to ensure the mechanical strength of the tablet mixture. Alternatively, amorphous binders which undergo pronounced plastic deformation have been suggested to provide an effective means of creating a large surface area available for bonding (Nyström et al., 1993). However, the mechanisms behind the strength enhancing effect of a binder are not yet fully understood. The rational choice of a suitable binder in a formulation requires extensive knowledge of which properties of a binder are important for the strength enhancing effect. Only then would it be possible to predict the function of a binder in a formulation. Increased knowledge of the functionality of a binder would enable a more rational approach to tablet formulation. Furthermore, the extensive use of powder mixtures renders knowledge of how different materials interact with each other important.

The development of direct compression as an alternative method to wet granulation has stimulated 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 in order to obtain a mixture with improved compaction behaviour and functionality as a binder (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 poorly compressible drug is included in the formulation.

Distribution of binders - comparison between direct compression and wet granulation

In direct compression, the binder is added in its dry state, whereas a liquid is employed in wet granulation. Besides the common aim of enhancing the bonding properties between particles or granules, the binder in wet granulation also aims at improving the binding between powder particles during agglomeration. Addition of a binder in its liquid state would probably facilitate its distribution; it can be more difficult to obtain a homogeneous distribution with a dry binder. Therefore, binders added as dry powders are generally less effective than when added as solutions (Nyström et al., 1982). The binders used in wet granulation are generally polymeric materials, which are amorphous or semi-crystalline, e.g. polyvinylpyrrolidone and gelatin. These binders are considered plastically deformable, which is probably an important attribute for their effective distribution. In direct compression, however, focus has mainly been on using a binder with 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 surface properties of the coarse compound particles as they are covered by the small binder particles. It was proposed that this surface coverage increased the surface area available for interparticulate bonding, thus increasing the number of bonds and also possibly creating stronger bonds, with a subsequently increased mechanical strength (Nyström et al., 1982; Duberg and Nyström, 1985; Nyström and Glazer, 1985). Addition of a binder which increases elasticity can decrease tablet strength because of the breakage of bonds as the compaction pressure is released (Nyström et al., 1982). The addition of a second component, such as a binder, to a compound has also been reported to affect and modify the volume reduction behaviour of the compound (Wells and Langridge, 1981; Yu et al., 1989; Larhrib and Wells, 1998). However, others have observed that volume reduction of the materials constituting as binary mixture occurred independently of each other (Humbert-Droz et al., 1983).

In a binary mixture consisting of components A and B, three types of bonds may occur after compaction: A-A, A-B and B-B. The relative importance of these bonds was used to explain the behaviour of a binary mixture (Leuenberger, 1982). A quantitative expression based on compressibility and compactibility parameters of pure materials has been used to estimate and predict the behaviour of mixtures (Leuenberger, 1982; Jetzer, 1986). Jetzer (1986) concluded that the compaction characteristics of mixtures were principally governed by the behaviour of the individual materials and that interactions were most likely to occur with mixtures of components with dissimilar compaction mechanisms. 20

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

In some cases, the combination of two materials has resulted in a tablet strength that is higher than the tablet strength of the individual materials (Newton et al., 1977; Cook and Summers, 1985; Vromans and Lerk, 1988; Garr and Rubinstein, 1991; Gren and Nyström, 1996; Larhrib and Wells, 1997; 1998). It was suggested that this high mechanical strength occurs because the bonds between different particles are stronger than those between the same type of particles (Newton et al., 1977). Furthermore, in relation to fracture mechanics, it was proposed that the addition of a plastically deforming 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 unexpectedly high tablet strength is caused by increased densification of the mixture compared with the pure materials (Vromans and Lerk, 1988).

Although the studies cited above do not consider binders specifically, but rather the mixing of two components in general, the results may be applicable in understanding the functionality of a dry binder. The results imply that if the correct combination of materials 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 direct compression because of its good bonding properties. MCC is also claimed to have disintegrating and lubricating properties. The high compactibility of MCC has been attributed to a relatively high propensity for plastic deformation, which enables large surfaces to come close to each other and a large number of bonds, mainly intermolecular 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 also been suggested (Karehill and Nyström, 1990). A silicified form of MCC has been shown to exhibit improved flow properties and compactibility compared to regular MCC (Allen, 1996). This modified form of MCC is chemically and physically very similar to regular MCC (Tobyn et al., 1998).

Other commonly used binders in direct compression include starches and their derivatives, such as pregelatinised and granulated starches. The common feature of many filler-binders in direct compression is that they undergo plastic deformation during compaction. One exception is dibasic calcium phosphate dihydrate, which fragments 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 that lubricants have practically no effect on the bonding properties of dibasic calcium phosphate dihydrate. Lactose is also used in direct compression but, compared to other filler-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 general structural formula HOCH2(CH2OCH2)mCH2OH, where m represents the average number of oxyethylene groups. PEG is used in the pharmaceutical industry as an excipient in suppositories, ointments, suspensions, emulsions and capsules (Wade and Weller, 1994). In tableting, PEG is used as a lubricant, a plasticizer in wet granulation, a binder to enhance the effectiveness of other binders and in film coating (Wade and Weller, 1994). Solid state characterisation has shown PEG to contain both ordered and disordered regions (Craig and Newton, 1991). Characterisation of different molecular weights of PEG indicates that it is a ductile plastically deformable material with a moderate mechanical strength and that the mechanical properties are related to the average 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 that when PEG is combined with dibasic calcium phosphate dihydrate, a mixture with good tableting characteristics that has potential as an excipient in direct compression is obtained (Larhrib and Wells, 1997; 1998).

Although PEG is not normally considered as a dry binder in direct compression, it was chosen as a model for a binder in this thesis because the range of molecular weights available 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 direct compression in order to gain further knowledge of the strength-enhancing mechanisms involved in their use. The papers constituting this thesis had the following detailed aims:

• To evaluate material properties of both the binder and the model compound in order to establish which properties have the most impact on the compactibility of pharmaceutical powders (papers I-V). • To investigate the effects of binders on the mechanical strength and pore structure of tablets consisting of binary mixtures and especially to evaluate the effectiveness of a ductile binder in direct compression (papers I-IV). • To study the formation of fractures in tablets and to relate fracture properties to the mechanical strength of tablets of binary mixtures (papers I-III). • To utilise non-porous test materials to further evaluate some concepts of determining dominating bond types in tablets (paper IV). 22

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

Materials and methods

Preparation of test materials

Model compounds The 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 calcium phosphate dihydrate (DCP; 90-180 µm). The different size fractions were obtained by dry sieving (Retsch, Germany). The term compound is used throughout this thesis for materials that are not used as binders. The compounds used are summarised in Table 1.

Binder materials The following binder materials were used in the studies: polyethylene glycol (PEG) 3000, PEG 6000, PEG 10000, PEG 20000, microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), pregelatinised starch (PGS), polyvinylpyrrolidone (PVP), α-lactose monohydrate (crystalline lactose), partially crystalline lactose and amorphous lactose. The binder particles were generally <20 µm in size and the various size 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 air classification. 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 as supplied. Partially crystalline lactose was prepared by freeze drying crystalline lactose (Virtis, Gardiner, USA) which was then ground in a mortar with a pestle for five minutes. Amorphous lactose was prepared by spray drying crystalline lactose (Niro Atomiser, A/S Niro, Denmark). The binders used are summarised in Table 1.

Superdisintegrant In paper V, crosslinked carboxymethyl cellulose sodium (Ac-Di-Sol) was used as superdisintegrant.

All powders were stored at 40% relative humidity (RH) (saturated chrome trioxide in water) (Nyqvist, 1983), except partially crystalline and amorphous lactose, which were stored at 0% RH (phosphorus pentoxide), and all were stored at room temperature for at least 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 Binder Size fractionb (µm) (µm) I Sodium chloride 355-500 PEG 3000 <20 125-180 PEG 6000 <20 Sodium bicarbonate 125-180 PEG 10000 <20 PEG 20000 <20 II Sodium bicarbonate raw material PEG 3000 <20 Calcium carbonate raw material 20-40 40-60 PEG 20000 <20 20-40 40-60 MCC raw material III Sodium bicarbonate 45-63 PEG 3000 <20 MCC raw material SMCC <20 PVP <20 PGS <20 IV Sodium chloride 355-500 PEG 3000 <20 Sodium bicarbonate 125-180 PEG 20000 <20 PGS <20 V Sodium chloride 355-500 PEG 3000 <20 Mannitol 250-425 MCC raw material DCP 90-180 Crystalline lactose <20 Partially crystalline lactose as prepared Amorphous lactose as prepared a) Obtained by dry sieving. b) Obtained by air classification (SMCC, PVP, PGS and crystalline lactose) or milling followed by air classification (PEG). MCC was used as supplied and partially crystalline and amorphous lactose as prepared.

Choice of model compounds

The main compounds used throughout this thesis are relatively coarse particulate sodium chloride and sodium bicarbonate. These compounds usually undergo plastic deformation during compaction with only a limited tendency for fragmentation (Duberg and Nyström, 1986). Sodium bicarbonate is representative of materials with poor bonding properties; additional excipients are often required in order to form tablets with sufficient strength. Sodium chloride, on the other hand, is representative of materials bonding with solid bridges, and forms tablets with relatively high strength (e.g. Karehill and Nyström, 1990). Thus, sodium chloride and sodium bicarbonate were assumed to be suitable models for the study of interactions between compounds and binders. 24

Characterisation of materials

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

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

Amorphous content In paper V, the degree of disorder of the different forms of lactose was investigated using 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 the miniature humidity chamber technique (Angberg et al., 1992). The experimental temperature was 25 °C and a saturated salt solution was used to obtain 57% RH. When DSC was used, the samples were scanned over a temperature range of 30-250 °C at a rate of 10 °C/minute. In both cases, the area under the recrystallisation peak was integrated and normalised for sample weight. The degree of disorder in the sample was calculated from these normalised values, assuming amorphous lactose as the amorphous standard (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 the studies. In papers I, II and III, the amount of binder added was chosen to correspond to the amount estimated to form a monoparticulate layer on the surface of the compound particles (Nyström et al., 1982). The coating capacity of a binder particle was assumed to correspond to its projected surface area, i.e. one-quarter of the external surface area of the binder particle (Allen, 1997). In papers II and III, the amount of binder used in some mixtures also reflected the amount theoretically required to fill the voids between the compound particles with binder, an estimation based on the porosity and dimensions of a tablet made of the pure compound and the density of the binder. This simplified calculation does not take into account the effect the binder has on the compound particles, 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. In paper IV, the amount of binder varied between 5 and 20% w/w. In paper V a constant amount (20% w/w) of binder was used and a superdisintegrant (4% w/w) was also included 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. The upper punch pressures were obtained by keeping the distance between the punches constant (3.0 mm at zero pressure) and varying the amount of powder in the die. The powder was weighed on an analytical balance and manually filled into the die. The surfaces of the die and punches were lubricated with magnesium stearate powder prior to each compaction.

In paper II, double-layer tablets containing compound in the first layer and binder in the second 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 die while the lower punch was lowered. Binder was added onto the first layer and the lower punch was adjusted to achieve a compaction pressure of 200 MPa for the double-layer tablet (Karehill et al., 1990).

Characterisation of compaction behaviour

Deformation properties Tablets were compressed at a maximum pressure of 150 MPa (papers II and III) or 200 MPa (papers I and V) and the deformability of the materials was characterised by recording the height of the tablets every millisecond during the compression cycle as a function of pressure (in-die measurements). Tablet porosity was calculated and used in the Heckel equation (Heckel, 1961a,b). The reciprocal of the slope of the linear part of the in-die Heckel plot was used to calculate the apparent yield pressure (Duberg and Nyström, 1986). In paper V, out-of-die measurements were also made, i.e. the materials were compressed at different maximum compaction pressures and the porosity was calculated from the tablet dimensions after compaction. An out-of-die yield pressure was calculated from the reciprocal of the slope of the linear part of the corresponding Heckel plot (Paronen, 1986).

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

Fragmentation properties In order to estimate the fragmentation propensity of the materials, tablets were compacted at different compaction pressures in a specially constructed die using an instrumented single punch press (Korsch EK0, Germany) (papers II and V). The specific surface area of the tablets was determined using Blaine permeametry. The degree of particle fragmentation during compaction was evaluated by plotting the tablet specific surface area as a function of compaction pressure. The slope was then used as a measure 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 and amorphous lactose which were stored at 0% RH, and all were stored at room temperature for at least 48 hours before characterisation.

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

Strength was also characterised using a diametral compression test (Holland C50, UK or M39K, Lloyd Instruments, UK) and the radial tensile strength was calculated (Fell and Newton, 1970a) (papers III-V).

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

Examination of fracture surfaces Photomicrographs of the fracture surfaces of tablets were taken using a scanning electron microscope (SEM).

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

Pore size distribution Tablet pore size distribution was assessed using mercury porosimetry (AutoPore III, Micromeritics, USA) and the relationship between the intruded volume of mercury and the intrusion pressure was analysed. The intrusion pressures were between 0.01 and 413 MPa (paper II) and 0.01 and 379 MPa (paper IV). The pore sizes corresponding to the intrusion pressures were calculated assuming cylindrical pores and a surface tension of mercury of 485 mN/m. The mercury-powder contact angles were measured using a contact anglometer (Model 1501, Micromeritics, USA). The mercury contact angles of the mixtures were calculated from the contact angles of the pure powders and the proportion by volume of respective material constituting the mixture. Other parameters obtained with mercury porosimetry were total pore surface area and average pore diameter.

For comparison of intra- and interparticulate pores, the pore size distribution of the powders was also determined (AutoPore III, Micromeritics, USA) (paper IV). In these 27

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

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

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

V DBS(%) = b ×100 + Vb Vv

= + + Vt Vc Vb Vv

Vt is the total volume of a tablet containing a binary mixture, calculated from the dimensions 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 particle density of compound and binder was used to calculate Vc and Vb.

Disintegration The 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 in order to evaluate the influence of pore structure on the mechanical strength of tablets. In all cases, a fine particulate binder was added to a coarse particulate compound and the effect on the pore structure (such as porosity and pore size distribution) of the resultant tablets was compared with that in pure compound tablets. The magnitude of the effect of the different binders on pore structure differed substantially. This was attributed to the effects of various properties of the binder and the compound as discussed in the following sections.

Effect of binder deformability and particle size on tablet porosity

The binders used throughout this thesis had different mechanical properties, e.g. the mechanical strength and deformability varied. The deformability of the binders was characterised by their yield pressure (in die and in some cases also out of die), minimum porosity during compression and elastic recovery after compression (Table 2). The results varied slightly among the individual studies because the deformability was determined at different compaction pressures. Nonetheless, the binders could be differentiated regarding their ability to deform during compaction.

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

Binders Yield Yield Minimum Elastic Fragmentation pressure pressure porosity during recoveryc tendencyd a a b (in die) (out of die) compression (%) ((cm2/g) . MPa-1) (MPa) (MPa) (%) 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 9.3-11 201 SMCC 81 * 7.3 12 * PVP 47 * 0.3 11 * PGS 76 * 4.1 19 * Crystalline lactose 190 277 11 5.2 79 Partially crystalline lactose 168 282 8.2 6.7 81 Amorphous 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 the solid 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 rather similar but the elastic recovery increased with increasing molecular weight. Since the determination of apparent yield pressure was made in die, and therefore reflects both elastic and plastic deformation, it was concluded that an increase in molecular weight of PEG 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 the pure PEG tablets (determined after 48 h, thus allowing for elastic relaxation) when the molecular weight of PEG increased (Al-Angari et al., 1985; Blattner et al., 1986; Lin and Cham, 1995; Larhrib et al., 1997). Some of the other binders used were classified as being 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 rather extensive 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 of tablets without binder (Fig. 1). The ability of the fine binder particles to partly fill the voids between the compound particles is proposed to be the reason for the reduction in porosity. The smaller and more deformable binder particles are more mobile than the larger and less deformable compound particles. Application of a pressure to the powder bed therefore results in increased rearrangement and deformation of the binder particles and forces the binder into the voids. The deformability and particle size of a binder determine its void-filling capacity.

Pure sodium bicarbonate

10 Pure sodium chloride

Tablet porosity (%) porosity Tablet 5

0 0 5000 10000 15000 20000 Molecular weight of PEG

Figure 1. Tablet porosity as a function of molecular weight of PEG added to sodium chloride (125-180 µm) () and sodium bicarbonate (125-180 µm) (). Mixtures contain 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.

Addition of a binder characterised by a low yield pressure value and low elastic recovery, i.e. high plastic deformability, (e.g. PEG 3000) to sodium bicabonate gave tablets with the lowest porosity (Fig. 2). High binder plasticity is indicative of an 30

a) b) 20 Pure sodium bicarbonate 20 Pure sodium bicarbonate MCC PGS 15 SMCC 15 SMCC PGS MCC PVP 10 10 PVP

5 PEG 3000 5 PEG 3000 Tablet porosity of the mixture (%) Tablet porosity of the mixture (%) 0 0 0 20 40 60 80 100 0 5 10 15 20 Yield pressure of the binder (MPa) Elastic recovery of the binder (%)

Figure 2. Porosity of tablets containing sodium bicarbonate and 21.5% (w/w) of the binders as a function of (a) yield pressure and (b) elastic recovery of the pure binders. A dotted line is drawn as a guide to indicate deviations from the expected behaviour of the binders. Confidence intervals for p = 0.05 are shown. Tablets compacted at 200 MPa. increased capacity to fill the interparticulate voids in a compound tablet. The results suggest that both elastic recovery and yield pressure are important parameters that should be taken into account in order to fully understand the effect of deformability of the binder on tablet porosity.

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

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

a b Binders Size fraction (µm) External surface area (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. 31 m µ µ + 20 Sodium bicarbonate 20 m

15 15 PEG 20000 (40-60 20000 (40-60 PEG PEG 20000 (20-40 20000 (20-40 PEG PEG 20000 (<20 µ 20000 (<20 PEG PEG 20000 (40-60 µ 20000 (40-60 PEG Sodium bicarbonate Sodium

10 10 bicarbonate+ Sodium µm) 20000 (20-40 PEG Sodium bicarbonate+ Sodium µm) 20000 (<20 PEG Sodium bicarbonate+ Sodium µm) 3000 (40-60 PEG Sodium bicarbonate+ Sodium µm) 3000 (20-40 PEG PEG 3000 (40-60 µm) 3000 (40-60 PEG PEG 3000 (20-40 µm) 3000 (20-40 PEG PEG 3000 (<20 µm) 3000 (<20 PEG Sodium bicarbonate+ Sodium µm) 3000 (<20 PEG 5 5

0 0 1234567 1234567 Figure 3. The effect of different particle sizes of (a) PEG 3000 and (b) PEG 20000 on porosity 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.

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

Tablet porosity (%) porosity Tablet 5

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

Figure 4. Tablet porosity as a function of amount of binder added to sodium bicarbonate. 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 in porosity as the particles were brought into closer proximity to each other (paper I). It appeared that the effect of the binder on tablet porosity was generally more pronounced when the compaction pressure was low. This was especially noticeable when a binder with a lower plasticity (PEG 20000) was added to a compound where a high compaction pressure resulted in dense tablets (sodium chloride).

Effect of compound properties on tablet porosity

When comparing sodium chloride and sodium bicarbonate, two materials with similar volume 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 chloride tablets probably impaired the effective localisation of the binder in the voids. Increasing the amount of binder did not further reduce the porosity of tablets containing sodium chloride, in contrast to observations with sodium bicarbonate (Fig. 4). Also, when a compound tablet is not particularly porous to start with, a high plastic deformability and small particle size become more crucial for the decrease in tablet porosity. The importance of these properties was confirmed for mixtures containing sodium chloride and PEG or PGS (paper IV). These binders represent materials with pronounced differences in plastic and elastic behaviour (Table 2).

Fragmenting materials are much less affected by addition of a second component, e.g. a binder or lubricant, than plastically deforming materials (de Boer et al., 1978; Nyström et al., 1982; Duberg and Nyström, 1985; Nyström and Glazer, 1985). New, uncoated surfaces 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 the decrease in porosity upon addition of PEG 3000 was much smaller than when PEG 3000 was added to the mainly plastically deforming sodium bicarbonate (paper II). In addition, mercury porosimetry revealed that the pores in a calcium carbonate tablet were smaller than in a sodium bicarbonate tablet, making it more difficult for the binder to be evenly distributed.

Effect of binder addition on pore size distribution

When a binder was added, the pore size distribution was shifted towards smaller pores and the distribution generally became narrower compared to the distribution in a pure compound tablet (paper IV). This is indicative of filling of the voids in a compound tablet, thereby creating pores that are generally more uniform in size. The effect on pore size distribution was most pronounced in tablets of mixtures containing sodium bicarbonate 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 that the materials were virtually non-porous, thus the contribution of intraparticulate pores on tablet porosity was assumed to be insignificant. 33

0.25

+PGS 0.2

0.15

0.1 Sodium bicarbonate +PEG 20000 dV/dlogd (ml/g*µm) dV/dlogd

0.05 +PEG 3000

0 0.001 0.01 0.1 1 10 100 Pore diameter (µm)

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

0.1 +5% PEG 3000

0.075

Sodium bicarbonate +10% PEG 3000 0.05

+20% PEG 3000

dV/dlogd (ml/g*µm) 0.025

0 0.001 0.01 0.1 1 10 100 Pore diameter (µm) Figure 6. Pore size distribution of tablets made of pure sodium bicarbonate and mixtures containing different amounts (% w/w) of PEG 3000. Sodium bicarbonate (x) and mixtures containing 5% (), 10% (∆) and 20% () of PEG 3000. Tablets compacted at 200 MPa.

If the pore size distribution of tablets containing pure sodium bicarbonate, pure PEG 3000 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 obtained results. In the tablet containing a mixture, most of the large pores between the compound particles have disappeared and the interparticulate pores were mainly between 0.1 and 1 µm in diameter, whereas the pores in the tablet containing pure binder 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 µm was smaller than expected from the theoretical distribution. Therefore, the pore structure 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 to significantly contribute to the pore structure of the tablet.

0.08

Sodium bicarbonate 0.06

PEG 3000 0.04

0.02

0 0.001 0.01 0.1 1 10 100 0.06

Theoretical distribution dV/dlogd (ml/(g*µm)) dV/dlogd of the mixture 0.04

Experimental distribution of the mixture

0.02

0 0.001 0.01 0.1 1 10 100 Pore diameter (µm) Figure 7. Upper graph: pore size distribution of tablets made of pure sodium bicarbonate (x) and pure PEG 3000 (). Lower graph: pore size distribution of tablets made of a mixture of sodium bicarbonate and 20% (w/w) PEG 3000; experimental distribution () and theoretical distribution derived from the additive effect of the pure materials based on the composition of the mixture (------). 35

It is therefore suggested that, due to extensive deformation and shearing during compaction, the binder mainly exists as small aggregates or lumps of primary particles or even as primary particles when located between the compound particles. Most of the pores in tablets composed of the mixture were thus mainly located between compound particles and binder phase and were found to a smaller extent within the binder phase. A lower tendency for the binder to undergo plastic deformation may indicate a greater probability for binder particles to form larger aggregates and an increased probability of finding 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 both the binder and the compound and these will be dealt with in the following sections. The strength of tablets composed of some mixtures was higher than that of tablets made of the individual materials, referred to as a synergistic effect. This effect was especially apparent 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 and Summers, 1985; Vromans and Lerk, 1988; Garr and Rubinstein, 1991; Gren and Nyström, 1996; Larhrib and Wells, 1997; 1998).

1 Axial tensile strength (MPa)

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

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

While binders may be differentiated according to their deformability, they are also able to be classified according to their compactibility (i.e. the mechanical strength of a tablet 36

made of pure binder; Table 4). The compactibility of cellulose (MCC and SMCC) was relatively high, whereas that of PGS was low. While the compactibility of the different molecular weights of PEG was comparatively low, it generally increased with an increase 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 was obtained between the individual studies, which may have been the result of batch to batch variations. However, these variations do not affect the general interpretation of the results.

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

Binders Axial tensile strength Radial tensile strength (MPa) (MPa) PEG 3000 0.95-2.22 1.20-1.52 PEG 6000 0.91 * PEG 10000 2.13 * PEG 20000 2.21-3.33 2.79 MCC 3.10-4.12 13.3-14.4 SMCC 3.30 12.9 PVP 2.33 2.54 PGS 1.41-1.64 2.37-2.52 Crystalline lactose * 1.74 Partially crystalline lactose * 2.28 Amorphous 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 pure compound (Fig. 8). This result is associated with the pronounced effect on tablet pore structure caused by binders which undergo extensive plastic deformation. A deviation from the expected behaviour was observed when a plastically deforming binder was added to calcium carbonate. In order to obtain a synergistic increase in tablet strength it is 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 the tablet 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 results indicated that different binder properties had varying effects on the increase in tablet strength, depending on the direction of measurement. In paper III, a relationship was established between the axial tensile strength of a tablet composed of a compound/binder mixture and the deformability parameters (apparent yield pressure and 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 to be taken into account to fully understand the effect of a binder. When measuring the tablet strength in the radial direction, the effects of yield pressure and elastic recovery were more complex, indicating that the deformability of the binder has a greater impact on 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 strength of the tablets, although the most deformable binders deviated somewhat from the expected behaviour (Fig. 10c). The effect of compactibility of the binder was not as clear-cut when measuring in the axial direction (Fig. 9c).

a) b) 6 6

5 PEG 3000 5 MCC PVP PEG 3000 4 4 MCC PVP 3 SMCC 3

2 2 SMCC PGS 1 1 PGS Axial tensile strength (MPa) Axial tensile strength (MPa) Pure sodium bicarbonate Pure sodium bicarbonate 0 0 0 20 40 60 80 100 0 5 10 15 20 Yield pressure of the binder (MPa) Elastic recovery of the binder (%)

c) 6 Figure 9. Axial tensile strength of tablets containing sodium 5 bicarbonate and 21.5% (w/w) of the PEG 3000 MCC PVP binders as a function of (a) yield 4 pressure, (b) elastic recovery and (c) axial tensile strength of the pure 3 binders. In (a) and (b), a dotted line 2 is drawn as a guide to indicate PGS SMCC deviations from the expected 1

Axial tensile strength (MPa) behaviour of the binders. Confidence Pure sodium bicarbonate intervals for p = 0.05 are shown. 0 0 1 2 3 4 5 Tablets compacted at 200 MPa. Axial tensile strength of the binder (MPa)

Bonds rupture and flaws and defects are introduced into the tablet during elastic recovery after compression, and this is often reflected in a decrease in tablet strength. The effect of elastic recovery was best demonstrated when testing the tablet strength in the axial direction (Fig. 9b). The elastic recovery of a binder influences its ability to remain distributed between the compound particles. Effective distribution of the binder is probably more crucial for the axial tensile strength than the radial tensile strength of the tablet, since the axial tensile strength reflects the weakest plane in the tablet. It is therefore desirable to obtain a homogeneous distribution of bonds and a low incidence 38

of defects in the tablets. Furthermore, in paper IV, it was shown that the average pore diameter by volume, which is greatly affected by the presence of large pores, had a greater 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 section during radial tensile strength testing, homogeneous bond distribution is not as crucial and the radial tensile strength of a tablet will depend more on the compactibility of the binder.

a) b) 6 PVP MCC 6 MCC PVP 5 5 SMCC SMCC PEG 3000 PEG 3000 4 4

3 3 PGS

2 PGS 2 Pure sodium bicarbonate Pure sodium bicarbonate 1 1 Radial tensile strength (MPa) tensile Radial Radial tensile strength (MPa) tensile Radial

0 0 0 20 40 60 80 100 0 5 10 15 20 Yield pressure of the binder (MPa) Elastic recovery of the binder (%)

c) Figure 10. Radial tensile strength of 6 MCC PVP tablets containing sodium 5 bicarbonate and 21.5% (w/w) of the SMCC PEG 3000 binders as a function of (a) yield 4 pressure, (b) elastic recovery and (c) radial tensile strength of the pure 3 PGS binders. In (c) a dotted line is drawn

2 as a guide to indicate deviations Pure sodium bicarbonate from the expected behaviour of the 1 binders. Confidence intervals for Radial tensile strength (MPa) tensile Radial p = 0.05 are shown. Tablets 0 0 5 10 15 20 compacted at 200 MPa. Radial tensile strength of the binder (MPa)

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 range of binders was extended to include a larger variation in binder deformability. Because of the relatively high porosity of tablets made of pure sodium bicarbonate, a greater difference in the extent of plastic deformability of the binder is required in order to observe any substantial effects of deformability on tablet strength. Instead, it was rather the compactibility of the pure PEGs that determined the resulting tablet strength of the mixture. This will be further discussed in the section dealing with the effect of compound properties on tablet strength. 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 in porosity discussed above there was a continuous increase in tablet strength with a decrease in binder particle size (Figs. 3 and 11). The addition of the smallest particles of PEG 3000 tended to result in the strongest tablets, even though tablets containing only the smallest size fraction (i.e. pure PEG 3000) had the lowest tensile strength. The tensile strength of tablets containing sodium bicarbonate and PEG 20000 was more directly reflected by the tensile strength of the pure PEG tablets, varying with PEG particle size. Since the higher molecular weight of PEG is more elastic, the smaller particles would have a greater effect on the decrease in tablet porosity as well as on the increase in tablet strength. Consequently, the effect of particle size was more pronounced with the higher molecular weight PEG than with the lower (Figs. 3 and 11). - 4 ( ) 0 G 0 5 d m 5 So PE Sodiu 3 PEG PEG 20 PEG

4 Sodium bic PEG 3000 4 PEG 3000 (40 PEG 3000 (20- Sodium bicarbon PEG 3000 (40-6 Sodium bicarbonat PEG 20000 (20-40

3 PEG 3000 (<20 µm) 3 PEG 20000 (20-40 µm PEG 20000 (40-60 µm

2 2 Sodium bicarbonate+ PEG 20000 (40-60 µm)

1 1 Sodium bicarbonate Sodium bicarbonate

0 0 123 4 5 6 7 Figure 11. The effect of different particle sizes of (a) PEG 3000 and (b) PEG 20000 on axial tensile strength 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.

Effect of amount of binder and compaction pressure on tablet strength

Earlier studies regarding the amount of binder have suggested that the amount corresponding to a surface area ratio of unity, i.e. the amount required to cover the compound 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 necessary in order to increase and change the nature of the surface area available for interparticulate bonding and thereby increase tablet strength. In this thesis, the importance of filling the voids in a compound tablet rather than covering the surface of the compound particles is emphasised. In papers II and III, the effect of adding the amount of binder corresponding to a surface area ratio of unity was compared with the effect of adding the amount theoretically required to fill the voids in a compound tablet. 40

The former amount was generally greater than the latter. However, because of relatively small differences between these amounts it was difficult to draw any consistent conclusions. Furthermore, the amount calculated to theoretically fill the interparticulate voids was probably an underestimation of the actual amount because of the effect the binder has on the pore structure of the compound tablet. Therefore, it is expected that the optimal amount would be higher than this, i.e. approaching the amount corresponding to a surface area ratio of unity.

The gradual decrease in tablet porosity with increased amounts of binder was accompanied by a gradual increase in tablet strength compared with the tablet strength of 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 of 20% (w/w). Thereafter, there was a slight decrease in tablet strength, eventually approaching the strength of pure PEG tablets (Fig. 8). When sodium bicarbonate was mixed with MCC, the tablet strength increased with increasing amounts of MCC, but the tablet strength of pure MCC remained highest (Fig. 8). Addition of other binders with similar properties to those of MCC, e.g. SMCC and PGS, resulted in similar tablet strength versus amount profiles, whereas binders resembling PEG 3000, e.g. PVP and higher 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 tensile strength of pure sodium bicarbonate and sodium chloride tablets (paper I) (Fig. 12). The axial tensile strength of tablets made of pure PEG, on the other hand, reached a plateau at approximately 100 MPa, corresponding to a plateau in tablet porosity (see also Adolfsson and Nyström, 1996). The lack of tablet volume reduction past a certain point with increased compaction pressure has previously been related to the limited space available for additional plastic deformation (Adolfsson and Nyström, 1996). The strength of tablets composed of the mixtures, especially those containing sodium chloride, also reached a plateau at about 100 MPa. An increase in compaction pressure has been reported to increase the degree to which solid bridges contribute to the tablet strength of sodium chloride (Adolfsson et al., 1997). The results in paper I suggested that the influence of PEG on the tensile strength of tablets made from sodium chloride and PEG decreased as compaction pressure increased. The tablet strength was probably instead 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 the molecular weight of the PEG added (paper I). The strength of tablets containing sodium bicarbonate and PEG appeared to be determined by the compactibility rather than the deformability of the pure PEGs, i.e. the profile of the strength of tablets of the mixtures as a function of molecular weight of the added PEGs was similar to that of pure PEG tablets (Fig. 12). However, the strength of tablets composed of sodium chloride and PEG increased with increasing plasticity and decreasing elasticity (i.e. with decreasing molecular weight) of the PEGs rather than with increasing compactibility (Fig. 12). It is suggested that this was related to the lower porosity of pure sodium chloride tablets and 41

6 50 MPa 6 100 MPa

5 5

4 4

3 3

2 2

1 1 Axial tensile strength (MPa) tensile strength Axial Axial tensile strength (MPa) tensile strength Axial

0 0 20000150001000050000 20000150001000050000 Molecular weight of PEG Molecular weight of PEG

6 200 MPa 6 300 MPa

5 5

4 4

3 3

2 2

1 1 Axial tensile strength (MPa) Axial tensile strength (MPa) tensile strength Axial

0 0 20000150001000050000 20000150001000050000 Molecular weight of PEG Molecular weight of PEG Figure 12. Axial tensile strength of tablets as a function of molecular weight of PEG added 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 sodium bicarbonate 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. the slightly smaller interparticulate pores (as shown with mercury porosimetry in paper IV). These characteristics of sodium chloride tablets also meant that the general effect the addition of PEG had on tablet strength was not as pronounced as when PEG was added 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 reported that these bridges are able to penetrate layers of magnesium stearate surrounding the sodium chloride particles (Nyström et al., 1993). It therefore seems reasonable to assume that solid bridges may also be capable of penetrating the PEG layer, thereby 42

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

1 Axial tensile strength (MPa)

0 0 5000 10000 15000 20000 Molecular weight of PEG Figure 13. Axial tensile strength of tablets as a function of molecular weight of PEG added to sodium chloride (355-500 µm). Amount of PEG (w/w) corresponding to a surface 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 ratio greater 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). Addition of PGS, which has pronounced elastic behaviour, probably resulted in rupture of interparticulate bonds and interfered with the formation of solid bridges, thus reducing the level of interparticulate bonding. In fact, the strength of tablets of the sodium chloride/PGS mixture was lower than that of pure sodium chloride tablets (see also van Veen et al., 2000). Also, tablet porosity increased upon addition of PGS, indicating that 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. The results indicated that, when the other conditions (e.g. amount of binder and compaction pressure) were kept essentially the same, smaller particles of sodium bicarbonate generally resulted in increased tablet strength for both pure sodium bicarbonate and the mixtures with various binders. This is consistent with previously reported relationships between the particle size of the powder and the resulting tablet strength (e.g. McKenna and McCafferty, 1982). 43

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

As already indicated from the discussion of the effect of a binder on tablet pore structure and tablet strength, the decrease in porosity and pore diameter, the shift in pore size 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 compound tablet and thereby affect the pore structure are also able to substantially enhance tablet strength.

Fracture characteristics

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

Scanning electron microscope (SEM) photomicrographs of the fracture surface of pure sodium bicarbonate and sodium chloride tablets showed relatively intact particles, indicating that the fracture mainly occurred around the particles, i.e. through areas containing air (Figs. 14a and 15a-c). The fracture in a tablet composed of pure binder may be more difficult to describe in such general terms. However, SEM photomicrographs of the fracture surface of tablets made of MCC indicated that the fracture also went around the irregularly shaped particles (Fig. 15d). The fracture in a pure PEG tablet was difficult to evaluate from SEM photomicrographs (Fig. 15e). Even though 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 significant porosity of PEG tablets, the fracture occurred around individual PEG particles still existing 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 the binder particles were able to be localised in the interparticulate voids in the compound tablet (Figs. 14b and 16). The reduction in tablet porosity increased the probability of bonds being established between particles. By utilising different techniques, i.e. SEM, extrapolation of tensile strength to zero porosity (Ryskewitch, 1953; Mashadi and Newton, 1987) and double layer tablets (Karehill et al., 1990), it was concluded that the fracture still occurs mainly around the compound particles and thereby through the interparticulate 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

b 1 3 2

Figure 14. A qualitative tablet model showing the addition of a binder and the fracture in a tablet: (a) pure compound tablet (e.g. sodium bicarbonate), (b) tablet composed 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 the grey particles represent the fine particulate binder. The black line indicates the fracture through the tablet. In b) 1 indicates a fracture through the compound particles, 2 indicates a fracture around the binder particles located between the compound particles and 3 indicates a fracture between compound particles and binder particles. 45

(a) (b)

Figure 15. SEM photomicrographs of fracture surfaces of tablets. (a) pure sodium chloride (355-500 µm) (50 MPa), (b) pure sodium chloride (355-500 µm) (200 MPa), (c) pure sodium bicarbonate (125-180 µm) (200 MPa), (d) pure MCC (200 MPa) and (e) pure PEG 3000 (<20 µm) (200 MPa). The white bar (e) represents 0.1 or 1 mm. binder in the voids affects the fracture and increases the number of bonds that have to be broken. Thus, there is an increase in tablet strength compared to the strength of a pure compound tablet.

A binder with a high plasticity is able to displace a greater portion of the air with binder, thereby increasing the number of bonds that have to be broken. A binder with a 46

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

(a) (b)

(c) (d) Figure 16. SEM photomicrographs of fracture surfaces of tablets. (a) a mixture consisting 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) PEG 3000 (200 MPa). The white bar represents 0.1 or 1 mm. 47

The synergistic increase in tablet strength observed for mixtures containing sodium bicarbonate and PEG or PVP, or sodium chloride and low molecular weight PEGs, may also 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 the small particle size (Fig. 14c). However, the presence of coarse compound particles in the tablet is likely to increase the length of the path the fracture has to take in order to avoid breaking the compound particles (Fig. 14b) and this would increase the number of interparticulate bonds that have to be broken. Consequently, a higher tablet strength than 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 of the binder to fill the interparticulate voids in a compound tablet, is to calculate the degree of binder saturation (DBS) (see equation on page 27) (paper III). This expression is analogous to the degree of liquid saturation used in wet agglomeration (Kristensen et al., 1984; Jerwanska et al., 1995). The DBS is related to the deformability of the binder (a binder with a high deformability generally resulted in a high DBS), which in turn is related to the porosity and tablet strength of the resulting tablet composed of a mixture. There was no unique relationship between DBS and tablet strength because, as discussed above, factors other than the void-filling capacity also determine the resulting tablet strength of a mixture. However, when different amounts of a plastically deformable binder were added to sodium bicarbonate or sodium chloride, a relationship between DBS and tablet strength was obtained, indicating the importance of the extent

1 Axial tensile strength (MPa)

0 0 20 40 60 80 100 Degree of binder saturation (%)

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 mixed with sodium bicarbonate () and sodium chloride (). 48

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

Addition of a binder probably moved the compound particles further apart from each other compared to the positions of the particles in a pure compound tablet. In other words, addition of a binder increased the void available to be filled with binder compared to the void in a pure compound tablet (paper III). Consequently, when a solid material, 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 helium pycnometry) 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 the interparticulate voids and that the pores in these binder aggregates only contributed to a small extent to the composed tablet porosity. This assumption seems valid considering the 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 prevent the formation of solid bridges by assessing the dominating bond types. The general applicability of mercury porosimetry for characterisation of dominating bond types in tablets was also evaluated. The approach used is based on previous theoretical approaches to estimate bonding mechanisms (see page 12) (Adolfsson et al., 1999; Olsson and Nyström, 2000b). These two models were based on air permeametry but, in paper IV, data obtained from mercury porosimetry were used instead. Air permeametry could not be applied because of the limitation of the technique when using very dense tablets (Alderborn et al., 1985a). However, for non-porous materials, mercury porosimetry and air permeametry are, in principal, equivalent techniques for estimating the same type of surface area. In paper IV, tablet strength was adjusted for pore surface area and average pore diameter (Adolfsson et al., 1999) as well as for pore surface area and solid fraction (1-porosity) (Olsson and Nyström, 2000b).

Overall, both approaches gave similar results and they were in agreement with those previously obtained for sodium chloride in the sense that the adjusted tablet strength of a material expected to bond with solid bridges in addition to distance attraction forces will be high (Fig. 18) (Nyström et al., 1993; Adolfsson et al., 1999; Olsson and Nyström, 2000b). Accordingly, the bonds in tablets made of the binders were essentially weak distance attraction forces. Sodium bicarbonate had an intermediate value, which suggests mainly distance forces. However, the contribution of solid bridges in coarse particulate sodium bicarbonate cannot be excluded and has also been suggested previously (Adolfsson et al., 1999).

Addition of a binder to sodium chloride resulted in a decrease in the adjusted tablet strength, 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 was also 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 in the probability of forming solid bridges as the amount of binder increases, whereas the adjusted tablet strength in Fig. 18b indicates a more drastic effect on the addition of even a small amount of binder. The adjusted tablet strength was not affected as much when a binder was added to sodium bicarbonate, probably because of the smaller probability of the existence of solid bridges. The decrease in adjusted tablet strength did not directly reflect the measured increase in tablet strength (Fig. 18). Therefore, it is reasonable 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 an overall increase in tablet strength.

a) Figure 18. (a) Radial tensile 3.0 strength, (b) adjusted tablet 2.5 strength according to pore surface area and pore radius and 2.0 (c) adjusted tablet strength 1.5 according to pore surface area and solid fraction as a function of 1.0 amount of binder. Sodium 0.5 chloride and PEG 3000 (). Tablets compacted at 200 MPa. Radial tensile strength (MPa) 0.0 0 20 40 60 80 100 Amount of binder (% w/w)

b) c) 60 1

50 0.75 40

30 0.5

20 0.25 10 Tablet strength adjusted according to pore surface area and pore radius (nN) Tablet strength adjusted according to pore surface (Pa) fraction and solid area

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

The results were in agreement with previous similar attempts to assess bonding mechanisms (Adolfsson et al., 1999; Olsson and Nyström, 2000b) and it is therefore postulated that data from mercury porosimetry can be used to qualitatively assess the strength of interactions in tablets. Furthermore, the materials used in paper IV were essentially non-porous and therefore intraparticulate pores were assumed not to contribute to tablet porosity. This facilitates the interpretation of data obtained with mercury porosimetry. 50

Effect of binders on tablet disintegration

Relation between tablet strength/porosity and disintegration properties In paper V, the objective was to obtain high tensile strength rapidly disintegrating tablets. However, the effect of a binder on pore structure and tablet strength can often affect the disintegration time negatively. Rapid disintegration of tablets not containing a superdisintegrant was generally associated with low tablet strength (e.g. mixtures containing crystalline lactose). Conversely, high tablet strength was associated with longer disintegration time (e.g. mixtures containing PEG 3000, MCC or amorphous lactose). Addition of a superdisintegrant gave no correlation between tablet strength and disintegration since, provided the superdisintegrant is effective, it is possible to obtain high tablet strength and a short disintegration time. Disintegration of tablets containing DCP was generally rapid, which is partly explained by the high porosity of those tablets facilitating a rapid water penetration. The results indicated, however, no general relationship 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 reduction behaviour (Table 2). MCC is thought to undergo rather extensive fragmentation because of its aggregated structure and plastic deformation whereas PEG undergoes plastic deformation during compaction. Of the different types of lactose investigated, the crystalline form responded to pressure primarily by fragmentation while the amorphous form underwent plastic deformation and very little fragmentation occurred (Table 2). Microcalorimetry and DSC also allowed differentiation between the different lactose forms according to the amount of amorphous material present (Table 5). The deformability and bonding ability of the materials increased with increased amorphous content, 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 those containing the amorphous form (Fig. 19). Tablets containing PEG also had a relatively long 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 to improve disintegration because of its ability to draw water into the tablet (Khan and Rhodes, 1975b; Bolhuis et al., 1979; Lerk et al., 1979), tablets of pure MCC and mixtures containing this binder did not disintegrate in this study (Fig. 19).

When a binder was included to increase tablet strength, addition of a superdisintegrant was normally needed to decrease the disintegration time. However, the microstructure surrounding the disintegrant particles influenced the disintegrating effect. 51

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

Material DSC Microcalorimetry Heat of Degree of Heat of Degree of crystallisation (J/g) disorder crystallisation (J/g) disorder (%) (%) Crystalline lactose 0 0 0 0 Partially crystalline lactose 23 (4.0) 23 9.1 (2.1) 29 Amorphous lactose 100 (5.5) 100 31 (5.2) 100

a) 600

500

400

300

200 Disintegration time (s) Disintegration 100

0 S CL CL+D PL PL+D AL1 AL+D C C+D P P+D b) 600

500

400

300

200 Disintegration time (s) Disintegration 100

0 E CL CL+D PL PL+D AL1 AL+D C C+D P P+D

Figure 19. Disintegration time of tablets containing (a) sodium chloride or (b) dibasic calcium phosphate dihydrate alone, with binder or with binder plus superdisintegrant. Disintegration times longer than 3600 s are shown as 600 s with an arrow indicating the extension. Confidence intervals for p = 0.05 are shown. Tablets compacted at 200 MPa. AL = amorphous lactose; C = microcrystalline cellulose; CL = crystalline lactose; 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 even increased the disintegration time, probably because of the environment created by this ductile binder (Fig. 19a). When the superdisintegrant particles swelled, the force that would normally have caused the bonds to break would instead have been absorbed by the deformable structure of PEG, thus counteracting the disintegrating force. The viscosity enhancing properties of PEG may have also counteracted the effect of the superdisintegrant. In contrast, in highly porous tablets, as when PEG was mixed with DCP, the negative effect of the deformable environment was reduced and the penetration of water was facilitated, thus allowing the superdisintegrant to achieve its purpose (Fig. 19b). Addition of the superdisintegrant had a substantial effect on the disintegration time of tablets containing MCC (Fig. 19). The effect of the superdisintegrant on the disintegration time of tablets containing lactose and sodium chloride was reduced with increasing amorphous content, as the lactose became more deformable (Fig. 19).

-50

-100 Relative change in disintegration time (%) time in disintegration change Relative 0 50 100 150 200 250 Fragmentation tendency ((cm2 /g)*MPa-1) Figure 20. Relative change in disintegration time after addition of superdisintegrant to the mixtures containing compound and binder as a function of fragmentation tendency of the binder (the slope of a graph of the specific tablet surface area vs compaction pressure). Mixtures containing sodium chloride ( ) and dibasic calcium phosphate dihydrate ( ). Tablets compacted at 200 MPa.

These results indicate that the dominating volume reduction mechanism of the binder influences the effect of the superdisintegrant (Fig. 20). When a deformable binder with a low fragmentation propensity was added to a compound such as sodium chloride to form tablets with low porosity, the effect of a superdisintegrant was insignificant. However, when these binders were added to a compound, which creates a highly porous tablet (e.g. DCP), the importance of the volume reduction mechanism of the binder was reduced. Tablets containing binders that fragmented to a larger extent were more susceptible 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 direct compression. Material properties of both the binder and the compound, forming a binary mixture, were delineated in order to investigate which properties were of most importance for the tensile strength of the resulting tablet. The strength-enhancing effect of a dry binder was explained by proposing a simplified qualitative tablet model describing the fracture which occurs in a tablet during strength testing. According to this tablet model, the fracture mainly propagates around the particles and through the interparticulate voids. This type of failure will occur in tablets of pure compound, pure binder 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 and disintegration. However, the effect on these tablet characteristics varies with the properties of the binder and compound used.

The strength-enhancing effect of a binder appears to be closely related to its ability to reduce tablet porosity. This decrease in porosity is the result of the distribution of binder in the voids between the compound particles which increases the possibility for development of interparticulate bonds. In this case, the fracture occurs partly through the binder phase located in the voids, instead of mainly through air as in a pure compound tablet. Consequently, more interparticulate bonds have to be broken and there is an increase in tablet strength. The synergistic increase in tablet strength observed for some binary mixtures is explained in terms of a change in the fracture path from the path expected in a tablet of pure fine particulate binder, because of the presence 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 evenly distributed in the interparticulate voids, thereby affecting the pore structure (e.g. porosity and pore size distribution) and tensile strength of the tablet. A pronounced void-filling capacity in a binder is strongly related to greater plasticity, less elasticity and small particle size, properties exemplified by PEG and PVP. However, in some cases, the tensile strength of a tablet of a binary mixture was governed more by the compactibility of the binder. This was especially evident when the plastic deformability of the binder was relatively limited, as exemplified by MCC and PGS.

It was found that the tablet porosity, bonding mechanisms and volume reduction mechanisms of the model compound influence the effect of a binder. The plasticity and particle size of the binder are the main factors affecting tablet strength when the porosity of tablets of the compound is low (e.g. sodium chloride). The tablet strength of a compound, which gives more porous tablets (e.g. sodium bicarbonate), is determined by a combination of the plasticity and compactibility of the binder. A compound that has the ability of bonding with solid bridges (e.g. sodium chloride) or has a high fragmentation propensity (e.g. calcium carbonate) is less affected by the addition of the binder, at least when the amount of binder added is below a certain level. 54

Data obtained with mercury porosimetry were utilised to qualitatively assess the dominating bond types in tablets and the effect of a binder on the relative importance of these bonds. This method appears to be useful in assessing the interparticulate distances and dominating bond types in tablets of non-porous materials. The results indicate that the addition of a binder reduces bonding by solid bridges, especially during compaction of sodium chloride, and instead increases bonding by distance attraction forces. Since the results regarding dominating bond types are in accordance with those obtained previously (Adolfsson et al., 1999; Olsson and Nyström, 2000b), the applicability of these 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 be suitable as binders in direct compression and may be an alternative to the more commonly used MCC for increasing tablet strength. However, the effect a binder has on pore structure and tablet strength may negatively affect the disintegration of tablets and can also decrease the functionality of a superdisintegrant. For example, tablets containing PEG have a relatively long disintegration time, which is attributed to the low tablet porosity and viscosity-enhancing properties of PEG. Tablets of pure MCC or mixtures containing MCC were non-disintegrating, in direct contrast to the reported ability of MCC to enhance the disintegration time.

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

One of the aims of the thesis was to classify binders with different properties according to their ability to enhance tablet strength. The proposed tablet model, which describes the fracture process in a tablet during strength testing, appears to be applicable to the characterisation of the function of a dry binder. The applied characteristics of the binders (i.e. deformability, particle size and compactibility) were shown to be useful when evaluating the effectiveness of a binder. Although, the focus of the thesis was on binary mixtures, and the complexity of using more than two components is understood, the results provide valuable information for facilitating the choice of a suitable binder for 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 and for always seeing the positive things when discussing new results, making it much easier 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 making our room such a cosy and pleasant place.

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

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

The powder people, past and present: Dr Åsa Adolfsson, Gunilla Andersson, Jonas Berggren, Susanne Bredenberg, Elisabet Börjesson, Leif Dahlberg, Torsten Fjellström, Dr Torkel Gren, Dr Christina Gustafsson, Dr Barbro Johansson, Dr Mitra Mosharraf, Dr Fredrik Nicklasson, Dr Helena Olsson, Dr Tesfai Sebhatu and Åsa Tunon for being great friends, for your scientific support and for creating such a pleasant atmosphere in the powder group.

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

All the people, past and present, at the Division of Pharmaceutics for making Galeniken 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 you always makes me feel better. Next stop: New Zealand!

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

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

***

Financial support from AstraZeneca (Sweden), Pharmacia Corporation (Sweden), the Knut and Alice Wallenberg Foundation, IF Foundation for Pharmaceutical Research, the CD Carlsson Fund and the CR Leffman Scholarship Fund is gratefully acknowledged. 57

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