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CONTENTS
PAPERS DISCUSSED 8
INTRODUCTION 9
PREPARATION OF GRANULES BY WET GRANULATION 10
Drying of granules 11
The influence of drying conditions on structural and functional
properties of granules 11
Contraction of granules during drying 11
Other factors influencing structural properties of granules 12
PREPARATION OF PARTICLES BY SPRAY DRYING 12
Amorphous solids 13
Definitions 13
Pharmaceutically advantageous properties of amorphous material 14
The glass transition temperature 14
Amorphous materials and water 14
Crystallisation of amorphous materials 15
Stabilisation of amorphous materials 15
COMPRESSIBILITY AND COMPACTABILITY OF POWDERS 16
Tabletting of granulated materials 17
Tabletting of amorphous materials 18
CONCLUDING REMARKS CONCERNING
THE PERTINENT LITERATURE 19
AIMS OF THE THESIS 20
MATERIALS 20
EXPERIMENTAL SECTION 22
Particle preparation 22
Preparation of pellets 22
Drying of pellets 22
Assessment of the porosity, contraction, densification and
degree of liquid saturation of pellets during drying 22
Drying of pellets under different conditions 23
Preparation of spray-dried particles 23
Characterisation of the prepared particles 24
Morphology 24
Circularity 24
Apparent particle density 24
Assessment of pellet porosity 25
Surface area of powders 25
Moisture content 25
Crystallinity 25
Heat-induced transformations 25
Moisture-induced isothermal transformations 26
Long-term stability 26
Preparation of tablets 27
Determination of porosity, tensile strength and surface area of tablets 27 Calculation of compression parameters 27
Heckel parameter 27
Kawakita parameters 28
Elastic recovery 28
INFLUENCE OF CONTRACTION AND DENSIFICATION DURING CONVECTIVE DRYING ON THE POROSITY,
COMPRESSION SHEAR STRENGTH AND TABLET-FORMING
ABILITY OF MICROCRYSTALLINE CELLULOSE PELLETS 28
The importance of the composition of the agglomeration liquid on
contraction and densification during drying 28
The degree of liquid saturation during drying 30
Modulation of densification, porosity, compression shear strength and tablet forming ability of mcc pellets with the drying rate 33
Drying under different conditions 33
The effect of drying rate on densification, porosity and the shape of pellets 34 The effect of porosity and drying rate
on the compression shear strength of pellets 35
The effect of pellet porosity and drying rate on tablet tensile strength 36 MODULATION OF SOLID-STATE STABILITY
AND TABLETTING BEHAVIOUR OF AMORPHOUS LACTOSE
BY CO-SPRAY DRYING WITH POLYMERS 37 Properties of the spray-dried amorphous composite particles
containing lactose and different polymers 37
Morphology 37
Crystallinity 38
Apparent particle density 38
The effect of the content and molecular weight of PVP on
the physical stability of amorphous lactose 38
Resistance to transformations induced by heat and moisture 38
The effect on the relationship between critical RH for crystallisation
and storage time 41
The effect of incorporation of stabilising polymers and a surfactant
on the tabletting behaviour of amorphous lactose 42
Compression behaviour 42
SUMMARY AND CONCLUSIONS 46 ACKNOWLEDGEMENTS 49
PAPERS DISCUSSED
This thesis is based on the following papers, which will be referred to by their Roman numerals in the text.
I Berggren, J. and Alderborn, G., 2001. Drying behaviour of two sets of
microcrystalline cellulose pellets. Int. J. Pharm. 219, 113-126. Reproduced with permission. © 2001 Elsevier Science.
II Berggren, J. and Alderborn, G., 2001. Effect of drying rate on porosity and
tabletting behaviour of cellulose pellets. Int. J. Pharm. 227, 81-96. Reproduced with permission. © 2001 Elsevier Science.
III Berggren, J. and Alderborn, G., 2003. Effect of polymer content and molecular
weight on the morphology and heat- and moisture-induced transformations of spray-dried composite particles of amorphous lactose and
poly(vinylpyrrolidone). Pharm. Res. Accepted for publication.Reproduced with permission. © 2003 Plenum Publishing Corp. Kluwer Academic.
IV Berggren, J. and Alderborn, G., 2003. Long-term stabilisation potential of
poly(vinylpyrrolidone) for amorphous lactose in spray-dried composites. Submitted.
V Berggren, J. and Alderborn, G., 2003. Compression behaviour and tablet
INTRODUCTION
The tablet is today the dominating pharmaceutical dosage form, for many reasons, and not least because it offers a convenient and safe way for the patient to administer a drug. The manufacturing procedure facilitates accurate dosing of the drug and tablets can be mass-produced with robust production procedures at relatively low manufacturing costs. Drug release from tablets can be modified to meet biopharmaceutical and
pharmacological requirements. Furthermore, tablets are generally more stable than other dosage forms such as liquid preparations.
The production of tablets involves different processing steps including operations where particles are engineered with the intention of optimising functional properties such as the technical performance during tabletting and drug release properties. The
manufacturing of tablets requires certain qualities of the powder, low segregation tendency, good flowability and compactability being examples. It is also important that the materials constituting a tablet, i.e. drug and excipients, are chemically and
physically stable during processing and storage. The concept of engineering materials to improve their functionality is applied within many disciplines and knowledge of relationships between structure and functional properties will clearly lead to a more rational approach to engineer materials. The term structure, used here, covers a wide range of features, from those on a macroscale, visible to the eye, down to those on a nanoscale, corresponding to interatomic distances.
In the production of pharmaceutical tablets it is common to prepare particles with the aid of a liquid that is subsequently removed by drying. In this context, the most common particle preparation method is wet granulation, in which fine particles (often drug and excipient) are aggregated under convective mixing and by addition of an agglomeration liquid. Liquid bridges will be created that hold the fine particles together and, when the liquid is removed by drying, cohered aggregated particles remain. Another frequently used particle preparation technique is precipitation from a liquid, e.g. crystallisation and spray drying, where the material is dissolved or suspended in a liquid, which then is removed by drying.
Preparation of pharmaceutical particles using procedures of the kind described above will subject the materials to different processing stresses (Fig. 1), such as exposure to liquids, mechanical stress and heat. These stresses may significantly affect and change particle structural properties (i.e., physical and solid-state properties), with
consequences on properties like tabletting behaviour, drug release and stability. Stresses occurring during the removal of a liquid by drying may, for instance, produce
amorphous materials and influence on the porosity of granules, with subsequent effects on the dosage form. Thus, obtaining mechanistic knowledge regarding relationships between processing stresses, structural and functional properties of particles is of obvious interest to be able to predict and optimise functionality of solid dosage forms. In this context, there is a need for increased understanding of relationships between stresses during the removal of a liquid by drying and structural properties of particles critical for functional behaviour, and an awareness of how these stresses can be used to engineer particles with desired pharmaceutical properties.
Processing stresses
e.g. temperature, pressure, mechanical stress, radiation, exposure to liquids, gases, vapours
Particle preparation e.g. crystallisation, precipitation, milling, spray drying, size enlargement, drying, coating of particles Tablet manufacturing
e.g. mixing, filling, compression
PREPARATION OF GRANULES BY WET GRANULATION
Figure 1. Processing stresses involved during particle preparation and tablet
manufacturing (modified from York (1992)).
In the production of pharmaceutical tablets it is common to agglomerate fine particles with the intention to improve technical and biopharmaceutical properties. Aggregates are, in general, more porous than the primary particles of which they consist. The most frequent procedure for the preparation of aggregates or granules in this context is wet granulation, where an agglomeration liquid is added during agitation that will contribute to the formation of liquid bridges and, consequently, to hold the fine particles together. Water, alcohols or mixtures of water and an alcohol are frequently used as
agglomeration liquids, often in combination with a polymeric binder. The size-enlargement process involves nucleation of particles followed by coalescence of agglomerated particles (Kristensen, 1988). It is also generally believed that the liquid saturation of the granules, i.e. the ratio of the volume of agglomeration liquid to the volume of the intragranular pores, increases during the granulation procedure in parallel with granule growth (Kristensen et al., 1984). The wet-massing procedure can be combined with an extrusion-spheronisation process to obtain spherical granules, often denoted pellets (Vervaet et al., 1995). Pellets have excellent flowability and the shape and smooth surface texture facilitate coating with a polymer film for controlled drug delivery (Vervaet et al., 1995). Capsules may be filled with pellets or the pellets may be tabletted to form so-called multiple unit pellet systems. The preparation of pellets by extrusion-spheronisation requires a critical balance between plasticity and brittleness of the wet mass. Excipents that give the wet mass the required properties are, therefore, added to the formulation. Microcrystalline cellulose (mcc) has been found to be a particularly useful pelletisation aid in this respect because it is able to “hold” water in a way crucial for the process (Fielden et al., 1988). In addition, it has been suggested that the extrusion process results in complete filling of the pore space between the primary particles with liquid, irrespective of the liquid content (Jerwanska et al., 1995).
Drying of granules
After the size-enlargement process the agglomeration liquid is subsequently removed by drying, and cohered granules remain. Common drying methods in pharmaceutical industries are convective methods like tray drying and fluid-bed drying. The use of microwave and vaccum drying has also been reported for pharmaceutical granulations (van Scoik et al., 1991). During the first stage of convective drying the rate of evaporation per unit area of the drying surface is independent of time, with the
evaporation rate being close to that from an open dish containing liquid. This first stage of drying is called the constant rate period (Brinker and Scherer, 1990). During this period the rate of heat transfer and the rate of mass transfer are balanced (van Scoik et al., 1991) and the rate of drying depends on factors such as the air temperature, the rate of air flow, the latent heat of vaporization and the relative humidity of the drying gas (van Scoik et al., 1991). The constant rate period continues until a critical point is reached, after which the drying rate reduces progressively, i.e. drying proceeds at a falling rate. When this period begins the rates of heat and mass transfer are no longer balanced, because the surfaces of the granules are no longer kept completely wetted and the liquid front descends into the pores of the granules (van Scoik et al., 1991). Hence, the drying rate hereon also depends on the movement of liquid inside the granules. The drying progresses until a critical liquid content is reached after which no more liquid can be removed under the given drying conditions.
The influence of drying conditions on structural and functional properties of granules It has been demonstrated that changes in structural and functional properties of granulated particles may be related to the drying conditions and the choice of drying method. It has been suggested, for example, that drying in a microwave oven gives rise to more porous granules with a lower fracture strength than drying in a convective dryer (Bataille et al., 1993). However, in contradiction, it has also been observed that
microwave drying may give granules of similar structure as conventional tray drying (Mandal, 1995). Furthermore, several articles have communicated differences in granule properties depending on the type of convective dryer used. Static bed drying has been reported to give granules of a higher strength, faster drug dissolution (Dyer et al., 1994), higher friability and bulk density (Remon and Schwartz, 1987) compared to granules dried in a fluid-bed dryer. The effect of the drying method as such on the tabletting properties of granules and pellets has also been communicated in the literature (Chatrath and Staniforth, 1990). In addition, it has been shown that freeze-drying may give extremely porous granules, (Kleinebudde, 1994; Habib and Shangraw, 1997; Habib et al., 2002) with a significantly increased deformability and tablet-forming ability, compared with other drying methods (Habib and Shangraw, 1997). It should also be pointed out in this context that the drying of solids, e.g. the removal of crystal water (Hüttenrauch and Keiner, 1979) and spray drying (Corrigan et al., 1984), may result in solid-state transformations and in the production of amorphous materials, which will be discussed further below.
Contraction of granules during drying
It has been recognised that pharmaceutical granules containing cellulose may contract and densify considerably during the drying process (Kleinebudde, 1994). However, the phenomenon of granule contraction has received limited attention in the pharmaceutical
literature. There are, however, a large number of reports in the ceramics literature (Scherer, 1990) since contraction and cracking during drying of ceramics have been identified as critical factors for their structure and functionality. The contraction of a wet plastic body is thought to be driven by a compressive force developed due to gradients in, e.g., capillary and osmotic pressure in the liquid in the pores, which drags particles in the material together during drying (Newitt and Coleman, 1952; Scherer, 1990; Hasatani et al., 1993). Hence, the material will densify, i.e. the porosity decreases during the drying process. Most of the contraction is believed to occur during the constant rate period of drying and the volume of contraction of ceramics generally equates the volume of water removed by drying (Scherer, 1990). In addition, it has also been suggested that an increased drying rate increases the degree of contraction (Hasatani et al., 1993). Thus, contraction of granules during drying may be an important feature for the structure, e.g. porosity, and functional behaviour of the dry granules.
Other factors influencing structural properties of granules
The processing conditions during the wet massing procedure can markedly affect the properties of granules. It is widely considered that granules are densified during the wet granulation procedure and variables such as the intensity of the mechanical treatment (Holm et al., 1983; Jaegerskou et al., 1984) can affect the degree of densification during the process and thus the resultant granule porosity. Furthermore, the conditions and the equipment settings during extrusion-spheronisation, such as the diameter of the perforations, the thickness of extrusion screen and the extrusion and spheronisation speed may affect, for instance, pellet shape, size and bulk density (Vervaet et al., 1995). Bataille and co-workers (1993) reported a decreased intragranular porosity of pellets produced with an increased spheronisation speed.
The size of the primary particles constituting the granules (Hunter and Ganderton, 1972; Chalmers and Elworthy 1976) and the amount of agglomeration liquid (Jaegerskou et al., 1984; Tapper and Lindberg, 1986) have been reported to affect granule porosity as well. Furthermore, it has been suggested that densification of granules during wet granulation is influenced by the surface tension of the agglomeration liquid (Wells and Walker, 1983; Ritala et al., 1988) and it has been shown that the porosity and pore structure of granules can be significantly changed by varying the ratio of ethanol and water in the agglomeration liquid (Millili and Schwartz, 1990; Johansson et al., 1995).
PREPARATION OF PARTICLES BY SPRAY DRYING
Spray drying is a particle preparation technique that is widely used within the food, chemical, biochemical and pharmaceutical industries (Broadhead et al., 1992) for different applications. During spray drying, a solution or suspension is atomized and converted to solid particles by rapid evaporation in a one step process. Spray drying encompasses four consecutive stages: (i) atomization of the feed solution into a spray; (ii) spray-air contact; (iii) convective drying of the spray; and (iv) separation of the dried product from the drying gas (Broadhead et al., 1992). There are many different types of spray driers, however they generally consist of a feed solution delivery system, an atomizer, a heated air supply, a drying chamber, a solid-gas separator and a product
collection system (Corrigan, 1995). The atomizing process provides a large drying surface area for heat and mass transfer, which promotes rapid drying. The actual drying time of a droplet is in fact only a fraction of a second, with the consequence that amorphous or partially amorphous materials may be produced (Corrigan, 1995). However, the temperature of the solid particles is kept low by the evaporative cooling, making spray drying suitable for heat-sensitive materials, e.g. proteins (Forbes et al., 1998). Spray-dried particles also tend to be spherical and have a narrow particle size distribution (Broadhead et al.; 1992, Aulton, 2002). The spherical shape facilitates filling of such particles into capsules or dies in tablet presses. They may also be hollow and sometimes with open pores which arise from the drying process (Broadhead et al., 1992; Meenan et al., 1997; Aulton, 2002; Eissens et al., 2002). By changing the spray drying conditions it is possible to alter and control properties such as particle shape, particle size distribution, bulk and particle density, flowability, solid-state properties and moisture content (Broadhead et al., 1992; Corrigan, 1995), making it a suitable method for preparation of pharmaceutical particles. The use of spray drying for a wide range of pharmaceutical applications, such as tablet excipient production (Gunsel and Lachman, 1963; Fell and Newton, 1971; Eissens et al., 2002.), microencapsulation (Voellmy et al., 1977), enhancement of dissolution rate (Corrigan et al., 1984) and dry powder aerosol formulation (Dunbar et al., 1998; Forbes et al., 1998) have been reported. Spray-dried lactose was the first direct compression excipient introduced and, in this context, is probably the most well known example (Gunsel and Lachman, 1963).
Amorphous solids
Definitions
The terms “disordered”, “non-crystalline”, “activated” or “glass” are sometimes in the literature also used to denote amorphous material. Furthermore, “glass” is often used to describe an amorphous material that is below the glass transition temperature, whilst “super-cooled liquid” or “rubber” is used when it is above the glass transition temperature (Hancock and Zografi, 1997). Solid materials may be crystalline, amorphous or partially amorphous. In amorphous solid materials the position of the molecules relative to one another is random as in liquids, and there is a lack of the three-dimensional long-range order typical for crystalline materials (Hancock and Zografi, 1997). Nevertheless, these materials exhibit short-range order over a few molecular dimensions. An amorphous material has quite different properties in relation to the crystalline counterpart, e.g., it has a higher internal energy, increased molecular
mobility and larger free volume. Free volume is the empty space in a material that is not occupied by molecules, and since it is greater in the amorphous state than in the crystalline state, because of the differences in molecular packing, the amorphous form of a solid has a lower density (Hüttenrauch, 1978).
Amorphous solids may be formed by rapid precipitation from a solution, e.g.
lyophilisation (Shamblin et al., 1996; Craig et al., 1999), spray drying (Corrigan et al., 1984; Elamin et al., 1995); mechanical treatment of crystals, e.g. milling (Hüttenrauch, 1978; Elamin et al., 1994; Willart et al., 2001), compaction (Hüttenrauch, 1978; Ek et al., 1995); supercooling from a melt (Mosharaff and Nyström, 1999) and the removal of crystal solvents (Hüttenrauch and Keiner, 1979; Willart et al., 2002).
Most pharmaceutical materials in solid dosage forms are crystalline and often is a lot of effort made to ensure that the active ingredient is highly crystalline for reasons of stability. However, amorphous or partially amorphous drugs and excipients may be found in formulations, for instance because many tablet excipients, such as binders, fillers and film forming agents are amorphous or partially amorphous.
Pharmaceutically advantageous properties of amorphous material
Amorphous materials have certain properties that can be of advantage in drug formulation. It might for example be beneficial to render a sparingly soluble drug amorphous, since it will have a lower energetic barrier to overcome when entering a solution than the crystalline counterpart. This can result in increased solubility (Hancock and Parks, 2000), dissolution rate (Corrigan et al., 1984) and bioavailability (Fukuoka et al., 1987). It has also been shown that amorphous sugars provide stability to proteins in spray-dried or freeze-dried formulations (Suzuki et al., 1998) and that the tabletting properties of a material can be significantly improved if it is made amorphous (Hüttenrauch and Keiner, 1976; Vromans et al., 1986; Sebhatu and Alderborn, 1999). The glass transition temperature
The glass transition temperature (Tg) is a characteristic property of an amorphous
material. At Tg a significant change is observed in the molecular mobility and the free
volume. The amorphous material undergoes a change from a rigid glassy state with high viscosity to a more flexible rubbery state with a much lower viscosity (Hancock and Zografi, 1997). The molecular mobility of an amorphous material is significantly higher above Tg resulting in a higher reactivity and propensity to crystallise. However, it has
been reported that amorphous solids exhibit marked molecular mobility even well below the glass transition temperature (Hancock et al., 1995). The Tg of an amorphous
material can be determined with differential scanning calorimetry by heating the material and observing any change in the heat capacity. The Tg is associated with a
change in heat capacity and sometimes also with a relaxation endotherm, (Hancock et al., 1995) which may arise from a mismatch between heating and cooling rates or as a consequence of the amorphous material not being in a state of equilibrium, enabling it to relax over time (Craig et al., 1999). The Tg is a dynamic property of a material and
can depend on, for instance, the heating rate and the moisture content. Amorphous materials and water
It is generally considered that water can interact with crystalline solids by adsorption of water vapour to the solid-air interface, crystal hydrate formation, deliquescence and capillary condensation (Ahlneck and Zografi, 1990). However, amorphous solids absorb water into the structure with the consequence that a significant quantity of water can be taken up by the material. The amount of water that can be absorbed is related to the total mass of solid rather than the surface area available for sorption, such as for crystalline materials (Ahlneck and Zografi, 1990). The water that is absorbed into the amorphous material increases the free volume and reduces the degree of bonding between molecules in the solid, resulting in an increased molecular mobility (Oksanen and
Crystallisation of amorphous materials
A clear disadvantage of low molecular weight amorphous materials is that they are thermodynamically and physically unstable. Moisture and heat may increase the molecular mobility to such an extent that a conversion to the crystalline state spontaneously occurs under certain conditions. Thus, an amorphous material is less stable than the crystalline form of the same chemical entity.
The crystallisation of amorphous materials involves the formation of nuclei and crystal growth from the nuclei produced (Schmitt et al., 1999). Crystallisation kinetics may be evaluated for amorphous substances with the Johnson-Mehl-Avrami (JMA) theory, which describes the exponential growth of the crystalline fraction of a sample over time. Its use has been reported for the determination of isothermal crystallisation kinetics of amorphous lactose in the presence and absence of seed crystals (Schmitt et al., 1999). It has been suggested that the rate of crystallisation of an amorphous material is highest
somewhere between the Tg and the melting temperature (Jolley, 1970). However, it is
also believed that amorphous materials can exhibit sufficient molecular mobility (Hancock et al., 1995) to crystallise at temperatures even below the Tg (Yoshioka et al.,
1994).
Stabilisation of amorphous materials
Amorphous solids have unique properties that, clearly, can be of advantage in drug formulation. However, the underlying tendency of such materials to crystallise needs to be circumvented if they are intended to be used in pharmaceutical preparations because any phase-transformation during processing and storage may cause severe changes in functional properties such as the dissolution and bioavailability. Ensuring that the materials do not crystallise can be achieved by storage at a temperature significantly below Tg and by avoiding exposure to substances that depress Tg, e.g. water. However,
for practical reasons, this strategy may not always be possible. Interest to modulate the solid-state reactivity of amorphous substances by other means has therefore arisen. A challenging alternative in this context is to co-process the amorphous material with a small amount of a water-soluble polymer with a high glass transition temperature to produce a more stable composite material (Fig. 2). In this context, a composite
amorphous material is defined as one in which the compounds form a solid solution and which consists mainly of a low molecular weight substance with a smaller fraction of a polymer. The most frequently used preparation methods for composite materials are freeze drying (Shamblin et al., 1996; Shamblin et al., 1998; Taylor and Zografi, 1998; Shamblin and Zografi, 1999; Zeng et al., 2001) and precipitation from organic solvents (Yoshioka et al., 1995; Matsumoto and Zografi, 1999). It has also been demonstrated that spray drying can be a feasible method for the preparation of such materials
(Corrigan and Holohan, 1984; Corrigan et al., 1985; Takeuchi et al., 2000a; Takeuchi et al., 2000b), while other methods may fail to solidify the materials in the amorphous form (Corrigan and Crean, 2002).
Polymers that have been recognised as stabilising agents for amorphous materials include poly(vinylpyrrolidone) (PVP) (Corrigan and Holohan, 1984; Corrigan et al., 1985; Yoshioka et al., 1995; Shamblin and Zografi, 1999; Takeuchi et al., 2000a),
hydroxypropylcellulose (Takeuchi et al., 2000a), methacrylate polymers (Kotiyan and Vavia, 2001) and sodium alginate (Takeuchi et al., 2000a; Takeuchi et al., 2000b).
Figure 2. Schematic illustration showing inhibition of crystallisation of an
amorphous material by incorporation of a stabilising polymer.
The stability of composites has been evaluated in terms of their resistance to
transformations induced by heat- and moisture, such as the glass transition temperature, crystallisation temperature, crystallisation under high relative humidities and also by enthalpy relaxation measurements (Shamblin and Zografi, 1998). The mechanism of stabilisation is believed to be related to a general increase in Tg of the system, which can
be predicted by assumptions of perfect volume additivity at Tg (Gordon and Taylor,
1952) or based on thermodynamic considerations (Couchman and Karasz, 1978).
Hence, incorporation of a polymer with a low Tg may promote crystallisation, which has
been shown to be the case for spray-dried lactose/polyethylene systems (Chidavaenzi et al.; 2001, Corrigan et al., 2002). However, it has been reported that stability may be significantly improved despite almost unchanged Tg of the system, which has led to the
assumption that other factors than just a general increase in Tg, such as specific
interactions (Yoshioka et al., 1995; Shamblin et al., 1996; Matsumoto and Zografi, 1999; Shamblin and Zografi, 1999), are also of importance for the enhanced stability.
COMPRESSIBILITY AND COMPACTABILITY OF POWDERS
Critical characteristics of pharmaceutical tablets are an adequate mechanical strength to withstand stresses during processing and transportation, and release of the active in a preordained manner. Tablets are usually prepared by uniaxial compression using eccentric presses or rotary tabletting machines. When a particle bed in a die is subjected to an external load its volume is reduced and the interparticulate porosity is decreased. The term compressibility is often used to describe the volume reduction ability of a material, whilst the compactability is the ability of a material to form a tablet of a specified mechanical strength (Leuenberger, 1982). The mechanism of volume
reduction involves an initial rearrangement of the particles, followed by fragmentation and deformation (Duberg and Nyström, 1986). The dominating volume reduction mechanism during the compression event depends on the properties of the material. In addition, the sequence of volume reduction mechanisms has been suggested to be different for granules than for non-porous particles (van der Zwan and Siskens, 1982; Johansson, 1999), which will be discussed below. During compression, the particles will be brought together into such close proximity that interparticulate bonds can be created, resulting in a tablet of a certain strength. It has been suggested that the
mechanical strength is governed by the interparticulate bonding mechanism and the area over which these bonds interact (Nyström et al., 1993).
The strength of tablets is commonly determined by diametral compression testing and subsequent calculation of the radial tensile strength (Fell and Newton, 1970). The prerequisite for the calculation of the radial tensile strength is that the tablet fails in tension during testing. Factors affecting the strength of tablets have been discussed considerably in the literature and it has been suggested that properties of the materials, such as the particle size and shape (Alderborn and Nyström, 1982ab; Alderborn et al., 1988), plastic deformation (Roberts and Rowe, 1987; Hiestand, 1991), the
fragmentation propensity, elastic deformation (Nyström et al., 1993), the moisture content (Sebhatu et al., 1997) and processing factors like the applied load and the time of loading (Roberts and Rowe, 1987) have an effect upon the mechanical strength of tablets. Several models that describe the strength of tablets have been proposed in the literature. These models are generally based on two different theoretical approaches, i.e., bond summation (Rumpf, 1962) or kinematic crack propagation (Mullier et al., 1987; Kendall, 1988).
Tabletting of granulated materials
Granules are often prepared with the intention of improving tabletting properties such as the compactability of a material. Granules are generally porous, therefore tablets of granulated particles contain both inter and intragranular pores. It has been proposed that the volume reduction process of granules (van der Zwan and Siskens, 1982) includes four successive stages: (i) particle rearrangement and the filling of intergranular pores, (ii) fragmentation and plastic deformation of the granules, (iii) filling of the
intragranular pores with primary particles, i.e., the densification of the granule, and (iv) fragmentation and plastic deformation of the primary particles. It is believed that microcrystalline cellulose granules fragment to a limited extent during compression (Johansson et al., 1995) and experiments have revealed that the incorporation of a hard material into such granules did not change the fragmentation propensity (Nicklasson et al., 1999a).
The intragranular porosity has been found to have a significant influence on tablet strength, irrespective of the granule composition (Millili and Schwartz, 1990; Wikberg and Alderborn, 1991; Wikberg and Alderborn, 1993; Johansson et al., 1995; Nicklasson et al., 1999b). Furthermore, it has been suggested that increased intragranular porosity increases the propensity of the granules to fragment facilitating the formation of stronger tablets (Wikberg and Alderborn, 1991). For granules less prone to fragment it has been proposed that the intragranular porosity is critical for the compressibility of the
granules and for the structure and tensile strength of the tablets formed. An increased intragranular porosity increased the degree of deformation, resulting in formation of a closer intergranular pore structure during compression and, therefore, stronger tablets (Johansson et al., 1995). The compression shear strength of granules during confined compression has also been found to be related to the intragranular porosity (Nicklasson and Alderborn, 2000).
The size and shape of the granules may also influence the tabletting behaviour, e.g. decreasing the granule size has been claimed to facilitate the formation of stronger tablets (Li and Peck, 1990; Riepma et al., 1993). However, for mcc granules it has also been shown that the compactability was independent of granule size at moderate applied pressures and slightly higher for larger granules at a higher applied pressure (Johansson et al., 1998). In addition, it has been found that irregularly shaped granules form stronger tablets than spherical ones of similar intragranular porosity (Johansson and Alderborn, 2001).
The properties of the primary particles comprising a granule may also affect the tabletting behaviour, examples being granule deformability, mode of deformability and compactability (Nicklasson et al., 1999a; Nicklasson and Alderborn, 1999). In this context, polymeric binders are frequently incorporated into granules to improve the granule and tablet strength, and factors such as type, amount and distribution of the binder (Wikberg and Alderborn, 1993) may influence the strength. The addition of materials, like lubricants and surface-active agents (Femi-Oyewo and Spring, 1982), have been reported to decrease tablet strength. However, the reduction in strength caused by a lubricant is related to the degree of fragmentation that takes place (Nyström et al., 1993).
Tabletting of amorphous materials
It is generally accepted that the tabletting properties of a material may be changed and the compactability improved if it is made amorphous. However, the effect may depend on the type of material, e.g. relatively small differences in mechanical properties between the crystalline and the amorphous form of a drug have been reported (Hancock et al., 2002).
The concept of mechanical activation to increase the compactability of materials has been presented by Hüttenrauch and Keiner (1976), who found that the tablet strength increased with milling time and the degree of disorder. Furthermore, it has been suggested that induced disorder increased the surface reactivity and plastic
deformability, resulting in a sinter-like reaction between particles during compaction, facilitating interparticulate bonding, and tablet strength (Hüttenrauch, 1983). Commercially available spray-dried lactose is partially amorphous and the particles
consist of D-lactose monohydrate crystals glued together by amorphous lactose (Bolhuis
and Chowhan, 1996). The spray-dried quality has been reported to have a markedly
higher compactability thanD-lactose monohydrate, which has been attributed to the
amorphous part of the spray-dried lactose (Vromans et al., 1986). Rendering a material amorphous can change the volume reduction behaviour in such way that it may be more
readily deformed and less prone to fragment than the crystalline counterpart (Vromans et al., 1986; Sebhatu and Alderborn, 1999) and increased moisture content may increase the particle deformability and tablet tensile strength (Vromans et al., 1986; Sebhatu et al., 1997) owing to the increased particle contact area during compression (Sebhatu et al., 1997). Furthermore, it has been proposed that the difference in compactability between the amorphous and a crystalline form of lactose is mainly related to a difference in particle-particle adhesivity (Sebhatu and Alderborn, 1999).
Incorporation of substances such as stabilising polymers into amorphous materials has been reported to significantly change their deformability and tablet-forming ability (Takeuchi et al., 1999), in addition to which, there are also indications in the literature that the observed effect on the compactability is related to the type of polymer (Takeuchi et al., 2000a).
CONCLUDING REMARKS CONCERNING THE PERTINENT LITERATURE
The literature survey presented here indicates that the drying conditions and choice of drying method may significantly affect structural and functional properties, such as tabletting behaviour, of pharmaceutical particles. Thus, it seems plausible to control and optimise functional properties by the drying process. However, this requires a
fundamental knowledge of relationships between stresses during the drying process and particle structural properties critical for their behaviour. In this light, for the two particle types discussed here, i.e. wet-granulated particles and spray-dried particles, some important structural properties can be identified. These are discussed below. Firstly, it seems that the intragranular porosity is an important characteristic for the compression behaviour and compactability of granules. Hence, factors controlling the intragranular porosity are of considerable interest for the engineering of granules with optimal tabletting properties. It has been found that varying the ratio of ethanol and water in the agglomeration liquid may result in granules with a markedly different intragranular porosity. However no explanation has been given for these observations and the relative importance of the drying and the wet-agglomeration steps has not been addressed. One possible explanation is that differences in granule contraction during drying can explain the differences in porosity. This would imply that the drying rate, in turn, could be a factor controlling the porosity and thereby the tabletting properties of granules because it has been reported that the drying rate may influence the contraction. Secondly, it has also been recognised that amorphous materials may have advantageous functional properties, e.g., increased compactability in comparison to their crystalline counterparts, and that the dramatic evaporation that occurs during spray drying can enable the formation of amorphous material. However, the use of amorphous materials in pharmaceutical preparations is limited because of their metastable character. Thus, the incorporation of a water-soluble polymer in an amorphous substance to form an amorphous composite material represents an attractive way to increase the stability of amorphous materials. In this context, spray drying is a pharmaceutically relevant method by which to prepare such particles that seems to facilitate the formation of an intimate mix of the low molecular weight substance with the polymer. Amongst stabilising polymers, PVP is the most frequently used in the literature, however despite
this fact, the role of the molecular weight of PVP for the stability of the amorphous material is not clear (Matsumoto and Zografi, 1999; Zeng et al., 2001). Furthermore, there are some very relevant questions that need to be addressed, in terms of the effect of the incorporation of polymers in amorphous material on the long-term stability and tabletting behaviour.
The examples given above clearly show the need for greater knowledge concerning drying-related effects on particle structural characteristics decisive for the
compressibility, tablet-forming ability and the solid-state stability. This would lead to better prediction of the functional behaviour of particles and enable the drying process to be used to control pharmaceutical functional properties.
AIMS OF THE THESIS
The general objective of this thesis was to deepen the understanding of relationships between stresses arising during the drying process and structural properties of particles important for their functionality, and of the use of the drying process to engineer particles with respect to tabletting properties and solid-state stability.
Two common pharmaceutical preparation methods (i.e., wet granulation and spray drying) that involve particle formation with the aid of a liquid, subsequently removed by convective drying, were selected for the current investigation. The overall aim was consequently subdivided into the following specific aims:
x To investigate the importance of the composition of the agglomeration liquid on contraction, densification and the degree of liquid saturation of microcrystalline cellulose pellets during static convective drying (Paper I).
x To study the relative importance of the drying and wet granulation phases, and the effect of the rate of drying on the porosity, compression shear strength and tablet-forming ability of microcrystalline cellulose pellets (Papers I-II). x To investigate the effect of polymer content and molecular weight on the
morphology, resistance to transformations induced by heat and moisture, and the relationship between the critical relative humidity for crystallisation and the storage time of amorphous lactose in spray-dried composite particles with poly(vinylpyrrolidone) (Papers III-IV).
x To illustrate how the compression behaviour and tablet-forming ability of spray-dried lactose can be modulated by addition of stabilising polymers and a surfactant to the feed solution during spray drying (Paper V).
MATERIALS
All the test materials used in this thesis are pharmaceutical excipents commonly used in solid oral dosage forms.
Microcrystalline cellulose (Avicel PH101, FMC, Ireland, with an apparent particle
density of 1.58 g/cm3), ethanol (Finsprit 95% w/w, Solveco Chemicals AB, Sweden)
and deionised water were used for the preparation of the pellets in Papers I and II. Cellulose is a linear polymer consisting ofE-D-glucosopyranoside units (Fig. 3), and mcc particles are composed of fibrils, which are believed to have both paracrystalline and crystalline regions (Mathur, 1994; Bolhuis and Chowhan, 1996). Mcc has excellent binding properties and is widely used as a binder and filler in oral formulations (Bolhuis and Chowhan, 1996). It has also been found to be a valuable extrusion/spheronisation aid that is crucial for the preparation of pellets (Fielden et al., 1988).
D-lactose monohydrate (Pharmatose 200M, DMV, The Netherlands, with an apparent
particle density of 1.54 g/cm3) was used for preparation of spray-dried particles in
Papers III-V. Lactose is a naturally occurring disaccharide consisting of one galactose and one glucose unit (Fig. 3) that exists in two isomeric forms,D-andE-lactose. Lactose is widely used as a filler in tablets, capsules and lyophilised products and as a drug carrier in inhalation products (Goodhart, 1994; Bolhuis and Chowhan, 1996).
Amorphous lactose may be readily produced by, e.g., spray drying, and has often been used in the literature as a model substance for amorphous materials.
Poly(vinylpyrrolidone) (PVP) with a viscosity-average molecular weight of 8200
(PVPK17) and a glass transition temperature of 140qC(Kollidon 17 PF, BASF,
Germany, with an apparent particle density of 1.18 g/cm3) and PVP with a
viscosity-average molecular weight of 1 100 000 (PVPK90) and a glass transition temperature of 176qC (Kollidon 90 F, BASF, Germany, with an apparent particle density of 1.23 g/cm3) were used for the preparation of spray-dried composite particles in Papers III-V. PVP is a linear polymer consisting of 1-vinyl-2-pyrrolidinone units (Fig. 3) which is frequently used in both solid and liquid formulations, e.g. as a binder in tablets and a viscosity-increasing agent in suspensions (Walkling, 1994).
Polysorbate 80 (Polysorbatum 80, Apoteket AB, Sweden) was used for the preparation of spray-dried composite particles in Paper V. Polysorbate 80 or polyoxyethylene sorbitan fatty acid ester is a non-ionic surfactant that is used as an emulsifying, solubilising and wetting agent in topical, oral and parenteral formulations (Leyland, 1994). O CH2OH H H H OH OH H H O O O H OH H CH2OH H H OH H n O CH2OH H OH H H OH OH H H O CH2OH H H H OH OH H OH H O N O CH CH2 n
Figure 3. Structural formula of E-D-glucosopyranoside unit (left),D-lactose (middle) and 1-vinyl-2-pyrrolidinone (right).
EXPERIMENTAL SECTION Particle preparation
Preparation of pellets
The pellets of microcrystalline cellulose in Papers I and II were prepared by an extrusion/spheronisation technique. Mixtures containing different proportions of water and ethanol were used as the agglomeration liquid. The powder was dry mixed for 1 min at 500 rpm in a high shear mixer (model QII, Donsmark Process Technology, Denmark), thereafter the agglomeration liquid was added by atomisation at a flow rate of 100 g/min, whereupon wet mixing took place for 1 min at 500 rpm. The wet powder mass was then extruded in a radial screen extruder (model E140, Nica System, Sweden) equipped with a 1.2 mm thick screen with circular openings of diameter 1.0 mm. The extrudate was spheronised for 3 min at 875 rpm on a radial plate spheroniser (model S320, Nica System, Sweden). The pellets were then immediately placed in closed containers and stored at room temperature.
Drying of pellets
A comparison between parallel changes in the volume and liquid content of the pellets during drying (Paper I), was made possible by placing pellets on microscope slides to dry by leaving the slides in the open atmosphere in the laboratory (about 20qC temperature and 40 % RH) without any forced convection. Pellets agglomerated with water were placed in wells in a specially constructed microscope slide. At set intervals, the pellets were photographed in an optical light microscope (model Vanox, Olympus, Japan) at 1.3 times magnification and weighed on an analytical balance immediately after each photograph. The pellets agglomerated with a mixture of water and ethanol were randomly placed on an ordinary microscope slide and some of them were photographed in the optical light microscope at set intervals. Drying profiles were obtained by drying an approximately equal number of pellets on a microscope slide on an analytical balance. The volume of the pellets and their liquid content were calculated
from the microscopy and weight data. The pellet volume (Vp) was calculated from the
projected area diameter of the pellets, i.e. the diameter of a circle of equal projected area to that of the pellet (Dp), by assuming a perfect spherical shape, i.e.:
Vp = S Dp3/ 6 (1)
The liquid content of the pellets was calculated as the mass of liquid divided by the mass of solid and as the volume of liquid divided by the mass of solid (Ht).
Assessment of the porosity, contraction, densification and degree of liquid saturation of pellets during drying
The initial porosity and the porosity at different times during the drying process of each individual pellet (Et) was in calculated from the following equation (Paper I):
Et (%) = (1-(VdryUedry / VtUadry)) x 100 (2)
where Vdry and Vt are the volumes of the dry pellet and the wet pellet (at time t),
by mercury pycnometry as described below) and the apparent particle density
respectively. The contraction and densification of each pellet during the drying process were calculated as follows (Papers I and II):
Contraction (%) = (1-(Vt / V0)) x 100 (3)
Densification (%) = (1-(Et / E0)) x 100 (4)
where V0 is the initial pellet volume and Vt is the pellet volume at time t. E0 and Et are
the initial pellet porosity and the pellet porosity at time t, respectively. The ratio of the pore volume occupied by the agglomeration liquid to the total volume of the pores, i.e. the degree of liquid saturation (Kristensen et al., 1984) St, was calculated for each
individual pellet at set times during the drying process using the following equation (Paper I):
St (%) = (HtUa (1- Et / Et)) x 100 (5)
where Ht is the liquid content at time t (volume liquid/mass of solid), Et is the porosity
at time t (from Eq. 1) and Ua is the apparent particle density. Drying of pellets under different conditions
In Paper II a convective static dryer was constructed with the intention of investigating the effect of the drying rate on the densification of the pellets during drying. Four different sets of pellets (agglomerated with different agglomeration liquids) were dried under six different drying conditions (21-60qC, 15-58 l/min) in the dryer and under ambient conditions as well. The weight loss on drying was determined by removing the pellets from the dryer and placing them on an analytical balance at given time intervals. Drying was continued until the weight of the pellets was constant with time. From the drying rate profiles, a drying rate constant (kD) was calculated as the gradient of the
relationship between ln mt/ m0 and the time, i.e.:
ln mt/ m0 = kDt (6)
where mt and m0 are the amount of removable liquid at time t and the total amount of
removable liquid, respectively. It has been suggested that during tray drying of a bed of granular material, the reduction in liquid content with time commonly obeys a log-lin relationship, i.e. ln mt/ m0 relates linearly to the drying time (Carstensen and Zoglio,
1982). The weight of the pellets before and after drying was determined and their liquid content calculated as the percentage mass of liquid/mass of solid. After drying, these pellets were stored in a desiccator (40% RH) for at least 10 days prior to
characterisation and tabletting. Preparation of spray-dried particles
Particles of only lactose and composite particles of lactose and different contents of PVPK17 or PVPK90 (two-component particles) were prepared by spray drying (Papers III-V). Three-component composite particles with 0.1% w/w polysorbate 80 (as a proportion of the dry mass) were also prepared (Paper V). Water solutions of the materials were spray-dried in a spray dryer (Niro Atomizer, Niro A/S, Denmark),
equipped with a rotary atomizer. The liquid feed rate was 17 ml/min (peristaltic pump, Watson Marlow 505S, Watson Marlow Ltd., England), inlet and outlet temperatures 170r5qC and 95r5qC, respectively. The particles were stored in a desiccator over P2O5
(0% RH) for at least 7 days, after which a size fraction 5-15 Pm was prepared by air classification (Alpine 100 MZR, Alpine AG, Germany). Finally, the particles were stored at room temperature and 0% RH for 7 days and then for a further 7 days at 40qC and 0% RH. Thereafter the particles were stored at room temperature and 0% RH. Particles used for the preparation of tablets were pre-stored in 33% RH until a constant weight was reached.
Characterisation of the prepared particles
Morphology
Suspensions of spray-dried particles in liquid paraffin were prepared and sonicated until complete deaggregation was achieved. The particles were then inspected in an optical light microscope (model Vanox, Olympus, Japan) at 40 times magnification (Papers III and V). Images of spray-dried particles, pellets and also of the upper surfaces of tablets formed from spray-dried particles were taken with the aid of a scanning electron microscope (Leo 1530 Gemini, Leo, UK (Papers III and V) and Philips SEM 525, The Netherlands (Paper II)).
Circularity
In Paper II, pellets were manually dispersed on microscope slides and photographed in the light microscope at two times magnification. The photographs were digitalised and the perimeter (P) and projected area (A) were determined by image analysis (NIH Image 1.61, USA, available on the Internet at www.nih.gov) The pixel resolution was 5.3-5.2 µm/pixel. A steel sphere (SKF, Sweden, with a diameter of 1 mm), with an assumed circularity of 1.00 (Eriksson et al., 1997), was used as a reference in each picture. The circularity (C) of the pellets was calculated from the following equation (Cox, 1927):
C= 4 S A / P2 (7)
Apparent particle density
The apparent particle density of the raw materials (Papers I-V) and the spray-dried particles (Papers III and V) was determined using a helium pycnometer (AccuPyc 1330, Micromeritics, USA). The density of mixtures of materials (Papers III and V) was estimated according to the following equation:
U = (w1 + w2) / ((w1 / U1) + (w2 / U2)) (8)
Assessment of pellet porosity
The porosity of the dried pellets (Papers I and II) was calculated from the apparent particle density of the microcrystalline cellulose powder and the effective particle (or pellet) density, according to:
E (%) =(1-(Ue / Ua)) x 100 (9)
where Ue and Ua are the effective particle density of the dry pellet and the apparent
particle density, respectively. The effective particle density was determined by mercury pycnometry at 101 kPa (Paper I) or 90.3 kPa (Paper II) using a mercury porosimeter (Autopore III, Micromeritics, USA). As a plateau was observed around this pressure in the graph showing the cumulative volume of mercury intruded plotted as a function of pressure, it was concluded that the intergranular pores were filled at this point. Determination of poured bulk density and voidage of poured pellet bed
Pellets (Paper II) or spray-dried particles (Paper V) were poured into a 10 ml cylinder (with an inner diameter of 10 mm) to a volume of 9 ml and the poured bulk density was calculated from the volume and weight of the pellets. The voidage of the poured pellet bed, i.e., the relative volume of the intergranular pores, was calculated from the poured bulk density and the effective particle density.
Surface area of powders
The surface area of the powders was determined by air permeametry (Paper V). The samples were poured into the sample container and compressed manually to a porosity of approximately 40% whereupon the permeability was determined using a Blaine permeameter. The surface area was calculated by the Kozeny-Carman equation, including a slip flow correction term (Alderborn et al., 1985).
Moisture content
Samples (500r5 mg) of the different materials were weighed in 5 ml glass beakers and then stored in a desiccator over P2O5until the weight change was less than 1 mg/24 h.
Thereafter, the materials were transferred to a desiccator with 33% RH and samples were periodically removed to be weighed on an analytical balance until the weight change was less than 1 mg in 24 h. The moisture content was calculated as the percentage mass of liquid/mass of dry solid (Paper V).
Crystallinity
The different spray-dried particles (Papers III and IV) were analysed with a Diffractor
D5000 (Siemens, Germany), equipped with a scintillation detector, using Cu-KD
radiation, 45 kV and 40 mA. Bragg-Brentano focusing geometry was used and the samples were scanned in steps of 0.02q from 5 to 35q (2T).
Heat-induced transformations
Heat-induced transformations, i.e. the glass transition, crystallisation, melting and heat of crystallisation were determined (Papers III-V) using a differential scanning
calorimeter (DSC 220, SSC/5200H, Seiko, Japan). The materials were placed in open aluminium DSC pans and analysed under dry nitrogen purge. The samples were heated to 20qC above their glass transition temperature, then cooled with liquid nitrogen to
20qC, and subsequently reheated to 300qC. Heating and cooling rates of 10qC/min were used. To determine the effect of absorbed moisture on Tg, the materials were placed in
coated aluminium DSC pans that were hermetically sealed and scanned according to the procedure described above. To verify that the moisture content was kept constant, the weight of the samples was monitored before and after each cycle. The calorimeter was temperature and heat calibrated with indium, tin, gallium and mercury.
The theoretical glass transition temperatures of the composite particles were calculated (Paper III) with the Gordon-Taylor equation (Gordon and Taylor, 1952). If the glass transition temperature (Tg), true density (U) and weight fraction (w) of the components
are known, the Tg of the mixture can be calculated as follows:
Tgmix= ((w1 Tg1)+(K w2Tg2)) / (w1+(K w2)) (10)
The constant K was estimated from the true densities and the glass transition temperatures of the two components:
K= (U1 Tg1) / (U2 Tg2) (11)
Moisture-induced isothermal transformations
To study moisture-induced isothermal (25qC) crystallisation of the materials, a microcalorimeter (2277 Thermal Activity Monitor, Thermometic AB, Sweden) equipped with a humidity control device (perfusion cell) was used (Papers III and IV). Dry nitrogen gas was pumped by means of a peristaltic pump into the humidity control device and mixed with different proportions of nitrogen gas saturated water to obtain different controlled relative humidities. The perfusion cell was calibrated with saturated salt solutions (NaCl, CuCl2, Mg(NO3)2 and NaI) according to a method described by
Buckton (2000). First, the material was dried with dry nitrogen gas, until no
endothermal signal was observed. Thereafter the humidity control device was set to the desired relative humidity (RH), and the heat flow was monitored. This method was used to determine the critical RH for crystallisation within 10 days, time to moisture-induced crystallisation and heat of crystallisation at different relative humidities. Moisture-induced isothermal crystallisation was investigated gravimetrically as well (Paper III). Samples (500r5 mg) of the different materials were weighed in 5 ml glass beakers and then stored in a desiccator over P2O5(0% RH) until the weight change was less than 1
mg in 24 h. Thereafter the materials were moved to desiccators (25qC) with a certain RH and the samples were periodically taken out of the desiccators and weighed on an analytical balance.
Long-term stability
In Paper IV samples were placed in desiccators (n=2) with different relative humidities and stored at 25qC for up to 6 months. After 3 and 6 months samples were taken out, placed in open aluminium DSC pans and analysed with DSC (as described above). The DSC thermograms were compared with the thermograms obtained before storage to check for the existence of a glass transition event and a crystallisation exotherm to determine whether the materials were crystalline or amorphous. For those samples that still were amorphous at the end of the six months period, Tg was also determined as a
Preparation of tablets
Tablets of pellets (Paper II) were prepared with an instrumented single punch press (Korsch EK 0, Germany) at an applied pressure of 200 MPa. Tablets of spray-dried particles (Paper V) were prepared using the same press at applied pressures of 25, 50, 75, 100, 150, 200 and 275 MPa. The press was equipped with flat-faced punches with a diameter of 11.3 mm. The particles were poured manually into the die, which was lubricated before each compaction with a 1% w/w magnesium stearate in ethanol suspension (Paper II) or magnesium stearate powder (Paper V). The weight of the material was kept constant and the upper punch pressure was controlled by adjusting the position of the lower punch (Paper II). In Paper V the upper punch pressure was controlled by adjusting the amount of material in the die and the distance between the punches was kept constant (3.00 mm).
Determination of porosity, tensile strength and surface area of tablets
After compaction, the weight and dimensions of the tablets were determined.
Thereafter, the tablet porosity was calculated from the weight, dimensions and apparent particle density. Within 60 s of compaction, the tablets were also compressed
diametrically at 4 mm/min (Paper II) or 1 mm/min (Paper V) in a tablet-testing instrument (Holland C50, UK) and the tensile strength was calculated from the
diameter, thickness of the compact and the force required to fracture the tablet (Fell and Newton, 1970). Judging from the appearance of the fractured tablets, it was concluded that they failed in tension during testing. In addition (Paper V), tablets were formed in special dies with the instrumented single punch press at an applied pressure of 75 MPa. The permeability of the tablets was determined after compaction using a Blaine permeameter and the slip flow-corrected surface area was calculated from the modified Kozeny–Carman equation as described by Alderborn et al. (1985).
Calculation of compression parameters
Heckel parameter
Using the Heckel equation (Heckel, 1961a), a compression parameter can be derived that is generally considered to reflect the deformability of the particles in terms of a yield strength or yield pressure (Heckel, 1961b). The Heckel equation describes the relationship between the Heckel number and the applied pressure during compression, as follows:
ln (1 / e) = Pa / Py+ intercept (12)
where e is the porosity of the tablet, Pa the applied pressure and Py the yield pressure.
Heckel numbers, ln (1 / e), were determined for a series of compaction pressures between 25 and 200 MPa in Paper V. They were determined on ejected tablets, to avoid any influence of particle elastic deformation on the calculated yield pressures (Sun and Grant, 2001).
Kawakita parameters
The Kawakita equation (Lüdde and Kawakita, 1966) can be used to derive two
compression parameters. This equation describes the relationship between the degree of compression (C) of a bed of particles in a die and the applied pressure during
compression (P), as follows:
P / C = 1 / ab + P / a (13)
The compression parameter, denoted a in the equation, reflects the total degree of volume reduction of the powder at infinite applied pressure. It has been suggested that the reciprocal of the compression parameter b (i.e. 1/b) represents an indication of the stress at which particles deform or fail during confined compression (Kawakita et al., 1977; Adams and McKeown, 1996; Nicklasson and Alderborn, 2000). The degree of compression (C) was calculated from the tablet height and the height before
compression, which was itself calculated from the poured bulk density. The height of the bed of pellets in-die at pressure was estimated from the in-die displacement data after correction for punch deformation (Paper II). In Paper V the tablet height was determined “out of die”.
Elastic recovery
The elastic recovery (ER) of the particles during decompression was also determined in Paper V, using the equation:
ER (%) = ((he – hpmax ) / hpmax) x 100 (14)
where he is the height of the ejected tablet and hpmax the in-die height of the tablet at
maximum pressure (calculated from the minimum distance between the punches at zero pressure (3.00 mm) and the punch deformation at the given pressure).
INFLUENCE OF CONTRACTION AND DENSIFICATION DURING CONVECTIVE DRYING ON THE POROSITY, COMPRESSION SHEAR STRENGTH AND TABLET-FORMING ABILITY OF MICROCRYSTALLINE CELLULOSE PELLETS
The importance of the composition of the agglomeration liquid on contraction and densification during drying
Previously it has been reported (Millili and Schwartz, 1990; Johansson et al., 1995) that significant differences in the porosity of mcc granules can by obtained by varying the ratio of water and ethanol in the agglomeration liquid. Thus, to investigate (Paper I) the importance of the drying phase in relation to the wet granulation phase of such granules, mcc pellets were prepared with two different agglomeration liquids, i.e. only water (W) and a mixture of water and ethanol (W/E) (25/75% w/w), and contraction and
densification was determined during static convective drying.
Drying of a single layer of pellets on microscope slides facilitated rapid drying for both types of pellets. The initial and final liquid content was similar and the drying profiles
0 10 20 30 40 50 60 Contraction (%) 1 10 100 1000 10000 Time (min) 100/0% w/w water/ethanol 25/75% w/w water/ethanol 0 25 50 75 100 Densification (%) 1 10 100 1000 10000 Time (min) a. b.
(i.e., the liquid content as a function of time) were non-linear for both types of pellet with the rate of drying decreasing throughout the drying process. The absence of a constant drying rate period (i.e. one in which the rate of drying per unit area of surface is independent of time) may be explained in terms of a reduction in the area from which liquid was evaporated during drying, as the pellets contracted or due to differences in the drying rate of individual pellets.
Figure 4. Contraction (a) and densification (b) during drying of two mcc pellet
types prepared with different agglomeration liquids. Symbols are defined in the graph. Error bars show 95% confidence limits of arithmetic mean values.
The absolute reduction in pellet volume and the relative change in pellet volume (i.e. the contraction) (Fig. 4a) were considerably higher for the pellets agglomerated with water only. However, both pellet types contracted by a significant amount: 54% and 40% for the W and W/E pellets, respectively. The final porosity determined by mercury pycnometry on dry pellets was 7.85 and 33.8%, respectively, for the W and W/E, while the initial porosity (calculated from Eq. 2) of the wet pellets was similar for both types
0 10 20 30 40 50 60 Contraction (%) 0 20 40 60 80 100 120
Degree of liquid saturation (%)
25/75% w/w water/ethanol 100/0% w/w water/ethanol 0 10 20 30 40 50 60 70 80 90 Densification (%) 0 20 40 60 80 100 120
Degree of liquid saturation (%)
a.
b.
(57.3 and 60.0%, respectively, for the W and W/E pellets). Thus, the densification during drying was strongly influenced by the type of agglomeration liquid used (Fig. 4b).
Figure 5. Contraction (a) and densification (b) of two mcc pellet types prepared with
different agglomeration liquids as a function of degree of liquid saturation during drying. Symbols are defined in the graph. Error bars show 95% confidence limits of arithmetic mean values.
The degree of liquid saturation during drying
The mechanical treatment to which the pellets were subjected during preparation was similar and seemed to densify both sets of pellets to a maximum, i.e. to a degree of liquid saturation of approximately 100% (Fig. 5), which is consistent with previous findings on extruded cylinders (Jerwanska et al., 1995). Thus, the pores inside the pellets were completely filled with liquid at the beginning of the drying process. Consequently, the difference in the final porosity between the two types seemed to be
0 0,1 0,2 0,3 0,4 0,5
Cumulative decrease in pore volume/pellet (mm
3)
0 0,1 0,2 0,3 0,4
Cumulative volume liquid evaporated/pellet (mm 3 ) 25/75% w/w water/ethanol
100/0% w/w water/ethanol
the result of a difference in densification, due to contraction, during drying rather than a difference in the degree of densification during the pelletisation procedure. For the pellets prepared with water, the volume of contraction was approximately equal to the volume of liquid removed (Fig. 6), thus the degree of liquid saturation of the pellets was kept high for a considerable fraction of the drying process (Fig. 5). It seems that the drying front was located at the exterior of the pellets for a significant time during drying and the system strives to keep the solid pore surfaces wetted. In contrast, for the pellets prepared with water and ethanol, the volume of contraction was less than the volume of removed liquid (Fig. 6), so the degree of liquid saturation decreased whilst drying took place (Fig. 5). It seems therefore, that the drying front moved gradually towards the interior of these pellets throughout the drying process.
Figure 6. Mean cumulative decrease in pore volume as a function of mean
cumulative volume of liquid evaporated during drying for two mcc pellet types prepared with different agglomeration liquids. Symbols are defined in the graph. Error bars show 95% confidence limits of arithmetic mean values.
Each solid particle in a liquid filled granule can be described to be surrounded by a liquid film, separating the particles from each other. Removal of this film during drying leads to the particles approaching one another, i.e., as it is progressively reduced in thickness, the interparticulate separation distance and granule volume are reduced. It has been suggested that the driving force drawing the particles together, originates from pressure gradients in the liquid in the pores caused by capillary pressure and osmotic pressure (Newitt and Coleman, 1952; Scherer, 1990; Hasatani et al., 1993). Since the pellets contained no water-soluble components, it is reasonable to assume that capillary pressure was the driving force behind the contraction of the pellets studied here. It has been suggested (Scherer, 1990) that the maximum capillary pressure in a pore is related to the contact angle between the liquid and the solid and the liquid/vapour interfacial energy (or surface tension). The change in granulation liquid from water to the water/ethanol mixture will alter the interfacial energies of the system (Wells and
