EXHIBIT 1006 
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1006
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01797
`
`Insys Exhibit 2016
`CFAD v. Insys
`IPR2015-01800
`
`Page 1 of 84
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`Dissertation for the Degree of Doctor of Philosophy (Faculty of Pharmacy) in Pharmaceutics
`presented at Uppsala University in 2003
`
`ABSTRACT
`
`Bredenberg, S., 2003. New Concepts in Administration of Drugs in Tablet Form: Formulation
`and Evaluation of a Sublingual Tablet for Rapid Absorption, and Presentation of an
`Individualised Dose Administration System. Acta Universitatis Upsaliensis. Comprehensive
`Summaries of Uppsala Dissertations from the Faculty of Pharmacy 287. 83 pp. Uppsala.
`ISBN 91-554-5600-6.
`
`This thesis presents two new concepts in oral drug administration and the results of evaluation
`of some relevant formulation factors.
`Investigation into improving the homogeneity of mixtures for tableting indicated that it
`may be possible to obtain interactive dry mixtures of micronised drugs containing drug
`proportions as low as 0.015% w/w. By studying the relationship between disintegration time
`and tensile strength, it was found that the microstructure surrounding the disintegrant particles
`may influence the disintegration process. Therefore, avoidance of excipients which are highly
`deformable or very soluble in water will result in more rapid disintegration. Further, it is
`possible to increase the bioadhesive properties of a non-bioadhesive carrier material by
`forming interactive mixtures containing a fine particulate bioadhesive material.
`The new sublingual tablet concept presented is based on interactive mixtures consisting of
`a water-soluble carrier covered with fine drug particles and a bioadhesive component. With
`this approach, it is possible to obtain rapid dissolution in combination with bioadhesive
`retention of the drug in the oral cavity. Clinical data indicate that this allows rapid sublingual
`absorption while simultaneously avoiding intestinal absorption.
`An individualised dose administration system is also presented. This system is based on
`the use of standardised units (microtablets), each containing a sub-therapeutic amount of the
`active ingredient. The required dose is fine-tuned by electronically counting out a specific
`number of these units using an automatic dose dispenser. A patient handling study supported
`the suggestion that the dosage of some medications can be more easily and safely
`individualised for each patient with this method than by using traditional methods of mixing
`different standard tablet strengths or dividing tablets.
`
`Susanne Bredenberg, Department of Pharmacy, Uppsala Biomedical Centre, Box 580,
`SE-751 23 Uppsala, Sweden
`
`© Susanne Bredenberg 2003
`ISSN 0282-7484
`ISBN 91-554-5600-6
`Printed in Sweden by Uppsala University, Tryck & Medier, Uppsala 2003
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`Till Lars & Ella
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`Contents
`
`Papers discussed
`
`Pharmaceutical tablets
`Pros and cons compared to other dosage forms
`The tablet as a divided dosage form
`Stability
`Drug release
`Manufacturing
`Compliance
`Tableting excipients
`Some factors affecting mechanical strength of tablets
`Volume reduction mechanisms for pharmaceutical powders
`during compression
`Bonding mechanisms
`Particle size
`Solid state structure
`Compression speed
`Some factors affecting drug release
`Wetting
`Water penetration
`Disintegration
`Dissolution
`Optimised tablet systems for instant drug release
`Ordered mixtures for low drug content
`Solid dispersions for medium/high drug content
`Modified release tablets
`
`Using the tablet form for a rapid onset of action
`Oromucosal drug delivery
`The design of a sublingual tablet with rapid oromucosal absorption
`for administration of a potent drug
`Dry mixing of low proportions of drugs
`Disintegration of tablets
`Bioadhesion of tablets, powders and interactive mixtures
`
`Individual dosage
`Current options for obtaining a more individualised dosage regimen
`Tablets
`Other dosage forms
`
`Aims of the thesis
`
`8
`
` 9
` 9
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` 11
` 12
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` 15
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`18
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`24
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`Materials and methods
`Drug substances
`Model compounds (paper II)
`Carrier materials in interactive mixtures
`Excipients
`Binders and fillers
`Disintegrants
`Materials tested for their bioadhesive properties in paper III
`Other excipients
`Storage conditions for materials
`Primary characterisation of materials
`Density
`External surface area
`Particle size
`Amorphous content
`Preparation of mixtures
`Determination of mixture homogeneity
`Theoretical models for prediction of mixture homogeneity
`Calculation of relative and absolute numbers of drug particles
`Preparation of granules for microtablets
`Compaction of tablets
`Characterisation of compaction behaviour
`Deformation properties
`Fragmentation tendency
`Characterisation of tablets
`Porosity
`Tensile strength
`Friability
`Disintegration
`Assay of drug content
`Drug dissolution
`Bioadhesion measurements
`Materials and characterisation of the mucosa
`Adhesion test
`Clinical studies
`Pharmacokinetic evaluation of the sublingual tablet (Papers IV and V)
`Handling study for the administration device (Paper VI)
`
`25
` 25
` 25
` 25
` 25
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` 26
` 26
` 27
` 27
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` 28
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` 32
` 32
` 33
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` 34
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` 35
`
` 36
`
`Evaluation of factors affecting the formulation of interactive mixtures
`containing a low proportion of drug
`38
` 38
`Effect of particle and sample size
`Comparison of theoretical predictions of a random distribution and an interactive
`distribution
` 40
`Particle number ratios
` 42
`
`6
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`Absolute particle numbers by weight
`
`Evaluation of formulation factors required for rapidly disintegrating
`Tablets
`Characteristics of the test materials
`The effect of addition of binders with different properties on tablet strength
`and disintegration time
`Addition of a superdisintegrant and the influence of binder properties on
`its efficacy
`
`Evaluation of methods and formulation factors related to bioadhesive
`properties using tablets, powders and interactive mixtures
`Tablets and powders
`Interactive mixtures
`The effect of bioadhesive component proportions
`The effect of carrier solubility
`The effect of size of the bioadhesive component particles
`The fracture path and the limiting maximum bioadhesive strength
`
`A new sublingual tablet concept for rapid oromucosal absorption
`Breakthrough pain and the use of fentanyl
`The new sublingual tablet concept
`Primary characteristics of the fentanyl tablets in vitro
`Pharmacokinetic study
`Clinical usefulness of the sublingual tablet
`
`A new approach for individualised dosage
`Parkinson’s disease and the use of levodopa
`The new concept
`The principle
`The counting device
`Properties of the microtablets
`Clinical usefulness of the automatic dose dispenser
`
`Summary and conclusions
`
`Acknowledgements
`
`References
`
` 43
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` 44
` 44
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` 47
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` 49
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` 50
` 50
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` 52
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`Papers discussed
`
`This thesis is based on the following papers which will be referred to by the corresponding
`Roman numerals in the text.
`
`I.
`
`Sundell-Bredenberg, S., Nyström, C., 2001. The possibility of achieving an
`interactive mixture with high dose homogeneity containing an extremely low
`proportion of a micronised drug. Eur. J. Pharm. Sci., 12, 285-295.
`
`II. Mattsson, S., Bredenberg, S., Nyström, C., 2001. Formulation of high tensile strength
`rapidly disintegrating tablets - Evaluation of the effect of some binder properties.
`S.T.P. Pharma Sci., 11, 211-220.
`
`III. Bredenberg, S., Nyström, C., 2003. In vitro evaluation of bioadhesion in particulate
`systems and possible improvement using interactive mixtures. J. Pharm. Pharmacol.,
`55, 169-177.
`
`IV. Bredenberg, S., Duberg, M., Lennernäs, B., Lennernäs, H., Pettersson, A.,
`Westerberg, M., Nyström, C. In vitro and pharmacokinetic evaluation of a new
`sublingual tablet system for rapid oromucosal absorption using fentanyl citrate as the
`active substance. Submitted.
`
`V.
`
`Lennernäs, B., Hedner, T., Holmberg, M., Bredenberg, S., Nyström, C., Lennernäs,
`H. Clinical pharmacokinetics and safety of fentanyl following sublingual
`administration of a rapidly dissolving tablet in cancer patients: a new approach for
`treatment of incident pain. In manuscript.
`
`VI. Bredenberg, S., Nyholm, D., Aquilonius, S.M., Nyström, C. An automatic dose
`dispenser for microtablets - A new concept for individual dosage of drugs in tablet
`form. Submitted.
`
`Reprints were made with permission from the journals.
`
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`Pharmaceutical tablets
`
`Pros and cons compared to other dosage forms
`
`Because oral administration of drugs is simple, convenient and safe, it is the most
`frequently used route. Over 80% of the drugs formulated to produce systemic effects in the
`United States are produced as oral dosage forms (Rudnic and Kottke, 1996). In the past, it
`was even thought in some cultures (e.g. China) that the drug effect could only be achieved
`via the oral route and therefore other dosage forms, such as ointments, were considered
`ineffective. The oral tablet has a relatively short history, however, and was introduced as
`late as 1843 by the Englishman Brockedon, who invented the first hand-operated device for
`compressed pills. Nonetheless, for a long time the tableting machine was not available at
`pharmacies, and pills, divided powders and capsules, which were made by hand, were more
`common. With the development of the modern pharmaceutical industry and effective
`production methods, mass production of tablets became possible and their popularity
`increased worldwide. The European Pharmacopoeia (2002) defines tablets as “solid
`preparations each containing a single dose of one or more active substances and usually
`obtained by compressing uniform volumes of particles. Tablets are intended for oral
`administration. Some are swallowed whole, some after being chewed, some are dissolved
`or dispersed in water before being administered and some are retained in the mouth where
`the active substance is liberated.” Despite the long and continuing history of the
`development of new technologies for administration of drugs, the tablet form remains the
`most commonly used dosage form. However, advantages and disadvantages associated with
`this well-established form could be discussed, in order to form the basis for the
`development of new improved systems for tablet administration.
`
`The tablet as a divided dosage form
`The dispensation of drug preparations into single doses, such as divided powders, capsules
`or tablets, is convenient for the patient. In contrast to drugs dispensed in bulk for self-
`administration, such as oral liquids and ointments, the divided dosage form provides a well-
`defined drug dose that is convenient and safe. The change from early hand-made divided
`powders to the standardised volume-based filling of a die during automatic tableting
`procedures has resulted in improved homogeneity of drug between dosage units. This is
`especially important for preparations containing a small amount of a potent drug. However,
`the use of standardised tablet strengths does compromise the individualisation of doses,
`since this can only be achieved by dividing the tablets or by combining tablets of different
`strengths.
`
`Stability
`One of the main contributors to degradation of an active drug substance in a pharmaceutical
`formulation is the presence of moisture. Tablets, which are essentially dry dosage forms
`containing only minute amounts of water, commonly have a much longer shelf life than
`other formulations, such as oral and parenteral liquids. Nonetheless, it cannot be taken for
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`granted that all tablets will have a long shelf life. The choice of excipients, for example, is
`an important factor in this respect. Some excipients are hygroscopic, and even minute
`amounts of moisture can decrease the stability of the drug. This is especially important for
`effervescent tablets; the packaging material plays an important role in the protection of this
`tablet form from moisture.
`
`Drug release
`Before an active substance administered in tablet form can be absorbed into the systemic
`blood circulation, it has to be broken down to its component molecules. Obviously, the
`drug will not be released from conventional tablets as fast as from, for example, an
`injection formulation, which would normally contain the active substance already in
`molecular form. However, it is now possible to design a range of different release patterns
`by changing tablet excipients and/or the manufacturing process. The site of absorption is
`also a factor in this respect; using the oral mucosa as the administration site can improve
`the speed of both tablet disintegration and drug release and subsequently increase the
`absorption rate compared with conventional tablets.
`
`Manufacturing
`The manufacture of conventional tablets is a cost-effective process. Modern tableting
`machines are able to cater for large-scale production; a rotary press can output over 10 000
`tablets per minute (Alderborn, 2002). This speed of production gives the tablet form its
`superior edge over other solid dosage forms such as capsules. Additionally, the direct
`compression process involves only a few steps: one or more dry mixing steps followed by
`compression of the powder. However, direct compression of a powder mass requires certain
`properties, such as a low tendency for segregation, good flowability and high
`compactability. If direct compression is not possible, the formation of aggregates or
`granules from the drug excipients can improve the tableting properties. Granulation
`requires a few more steps than direct compression, but it is still a relatively simple process
`compared with processes like the production of injectable dosage forms.
`
`Compliance
`The tablet form is convenient to handle and easy and safe for the patient to take. Since
`tablets are a well known dosage form for most patients, there will be fewer requirements for
`explanatory information and compliance is assumed to be better. However, there are also
`compliance disadvantages; some people, especially the elderly and children, find it difficult
`to swallow tablets. Further, most people require water to facilitate swallowing tablets.
`However, several new types of tablets, intended for rapid disintegration and drug release in
`the oral cavity, have been developed over the last decade. This approach may be useful for
`increasing patient compliance, since disintegration of the tablet in the mouth facilitates
`swallowing, and concomitant intake of water can sometimes be omitted.
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`Tableting excipients
`
`In a tablet formulation, a range of excipient materials is normally required along with the
`active ingredient in order to give the tablet the desired properties. For example, the
`reproducibility and dose homogeneity of the tablets are dependent on the properties of the
`powder mass. The tablet should also be sufficiently strong to withstand handling, but
`should disintegrate after intake to facilitate drug release. The choice of excipients will
`affect all these properties.
`
`Filler: Fillers are used to make tablets of sufficient size for easy handling by the patient and
`to facilitate production. Tablets containing a very potent active substance would be very
`small without additional excipients. A good filler will have good compactability and flow
`properties, acceptable taste, will be non-hygroscopic and preferably chemically inert. It
`may also be advantageous to have a filler that fragments easily, since this counteracts the
`negative effects of lubricant additions to the formula (de Boer et al., 1978).
`
`Binder: A material with a high bonding ability can be used as a binder to increase the
`mechanical strength of the tablet. A binder is usually a ductile material prone to undergo
`plastic (irreversible) deformation. Typically, binders are polymeric materials, often with
`disordered solid state structures. Of special importance is the deformability of the
`peripheral parts (asperities and protrusions) of the binder particles (Nyström et al., 1993).
`Thereby, this group of materials has the capacity of reducing interparticulate distances
`within the tablet, improving bond formation. If the entire bulk of the binder particles
`undergo extensive plastic deformation during compression, the interparticular voids will, at
`least partly, be filled and the tablet porosity will decrease. This increases the contact area
`between the particles, which promotes the creation of interparticular bonds and
`subsequently increases the tablet strength (Olsson et al., 1998; Mattson and Nyström,
`2000). However, the effect of the binder depends on both its own properties and those of
`the other compounds within the tablet. A binder is often added to the granulation liquid
`during wet granulation to improve the cohesiveness and compactability of the powder
`particles, which assists formation of agglomerates or granules. It is commonly accepted that
`binders added in dissolved form, during a granulation process, is more effective than used
`in dry powder form during direct compression.
`
`Disintegrating agent: A disintegrant is normally added to facilitate the rupture of bonds and
`subsequent disintegration of the tablets. This increases the surface area of the drug exposed
`to the gastrointestinal fluid; incomplete disintegration can result in incomplete absorption
`or a delay in the onset of action of the drug. There are several types of disintegrants, acting
`with different mechanisms: (a) promotion of the uptake of aqueous liquids by capillary
`forces, (b) swelling in contact with water, (c) release of gases when in contact with water
`and (d) destruction of the binder by enzymatic action (Rudnic and Kottke, 1995). Starch is
`a traditional disintegrant; the concentration of starch in a conventional tablet formulation is
`normally up to 10% w/w. The starch particles swell moderately in contact with water, and
`the tablet disrupts. So-called superdisintegrants are now commonly used; since these act
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`primarily by extensive swelling, they are effective in only small quantities (Shangraw et al.,
`1980; Bolhuis et al., 1982; Pesonen et al., 1989). Cross-linked sodium carboxymethyl
`cellulose (e.g. Ac-Di-Sol®), which is effective in concentrations of 2-4%, is a commonly
`used superdisintegrant. Larger particles of disintegrants have been found to swell to a
`greater extent and with a faster rate than finer particles, resulting in more effective
`disintegration (Rudnic et al., 1982).
`
`Glidant, antiadherent and lubricant: Glidants are added to increase the flowability of the
`powder mass, reduce interparticular friction and improve powder flow in the hopper shoe
`and die of the tableting machine. An antiadherent can be added to decrease sticking of the
`powder to the faces of the punches and the die walls during compaction, and a lubricant is
`added to decrease friction between powder and die, facilitating ejection of the tablet from
`the die. However, addition of lubricants (here used as a collective term, also including
`glidants and antiadherents) can have negative effects on tablet strength, since the lubricant
`often reduces the creation of interparticular bonds (e.g. de Boer et al., 1978). Further,
`lubricants can also slow the drug dissolution process by introducing hydrophobic films
`around drug and excipient particles (e.g. Westerberg and Nyström, 1991). These negative
`effects are especially pronounced when long mixing times are required (Bolhuis et al.,
`1975). Therefore, the amount of lubricants should be kept relatively low and the mixing
`procedure kept short, to avoid a homogenous distribution of lubricant throughout the
`powder mass. An alternative approach could then be to admix granulated qualities of
`lubricant (Johansson, 1984).
`
`Flavour, sweetener and colourant: Flavour and sweeteners are primarily used to improve
`or mask the taste of the drug, with subsequent substantial improvement in patient
`compliance. Colouring tablets also has aesthetic value, and can improve tablet
`identification, especially when patients are taking a number of different tablets.
`
`Some factors affecting mechanical strength of tablets
`
`When the powder is compressed into a coherent compact, the particles bond together. How
`strong the tablet is going to be is dependent on the properties of the component materials
`and particles, but the tablet instrument settings can also affect the tensile strength. Tablet
`strength is important for withstanding handling during coating processes, transport and
`normal patient use. However, the strength of tablets should not be increased at the expense
`of rapid disintegration and drug release.
`
`Volume reduction mechanisms for pharmaceutical powders during compression
`During compression of powders, the force applied increases as a function of reduced
`distance between the punches while the powder bed decreases in volume. The volume
`reduction mechanism that dominates during compression is dependent on the properties of
`the component materials. In fact, there is usually more than one mechanism involved
`(Duberg and Nyström, 1985). Under initial low pressures in the die, the powder particles
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`rearrange to form a more closely packed structure, the voids between the particles are
`reduced in size, and the porosity of the tablet unit decreases. The degree of particle slippage
`and rearrangement is dependent on the particle size and surface roughness (York, 1978).
`Subsequently, after an initial elastic (reversible) deformation, the materials undergo plastic
`(irreversible) deformation and eventually, if the applied stress is high enough,
`fragmentation (Nyström et al., 1993). Pharmaceutical materials, which mainly consist of
`organic compounds with complex particle structures, sometimes undergo limited initial
`elastic/plastic deformation and then extensive particle fragmentation at low pressures,
`followed by a second deformation process, involving the newly formed smaller particles, at
`higher loads (Duberg and Nyström, 1982; 1986). This is especially pronounced for
`pharmaceutical materials composed of aggregates of primary particles or highly porous
`particles, which after the initial fragmentation undergo plastic or elastic deformation at
`higher compaction loads (Duberg and Nyström, 1986). After the maximum load has been
`reached, the compaction pressure is gradually released. If the material has undergone
`extensive elastic deformation, the tablet will expand, which can cause breakage of
`interparticulate bonds and possibly capping of the tablet.
`
`Bonding mechanisms
`The particles in pharmaceutical compacts or tablets are thought to be held together by three
`dominating bonding mechanisms: weak distance forces, interparticular solid bridges and
`mechanical interlocking (Führer, 1977).
`
`Distance forces
`Intermolecular forces or bonding forces acting over some distance between atoms,
`molecules or surfaces primarily comprise van der Waals forces, hydrogen bonds or
`electrostatic interactions. Van der Waals forces are attraction forces between ions,
`molecules or particles and can occur in vacuum, gas and liquid environments. They
`primarily act over distances of 1-100 nm with strengths dependent on the distance between
`the surfaces (Israelachvili, 1992). Since the hydrogen atom is small in size, electronegative
`atoms or molecules can approach closely, with the formation of relatively strong
`electrostatic attractions, so-called hydrogen-bonding interactions (Israelachvili, 1992).
`Electrostatic forces may arise during the handling process, e.g. during mixing and tableting,
`from triboelectric charging. These forces are considered not to make any significant
`contribution to the mechanical strength of pharmaceutical tablets since they are neutralised
`rather quickly over time (Nyström et al., 1993).
`
`Solid bridges
`During powder compression, it is possible that the particles come into such close contact,
`i.e. at an atomic level, that solid bridges are formed. These solid bridges are considered to
`be relatively strong, and they can contribute substantially to the mechanical strength of the
`tablets (Führer, 1977, Nyström et al., 1993). There are several possibilities for the mode of
`formation of these solid bridges, including melting (if high temperatures arise as a result of
`friction between particles at their contact points during compaction) diffusion of atoms
`between surfaces, and recrystallisation of soluble materials (Shotton and Rees, 1966;
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`Führer, 1977). The nature of the solid bridge is dependent on the chemical structure of the
`material (Adolfsson and Nyström, 1996). It is primarily materials with a simple crystal
`structure that form solid bridges, which necessarily excludes many pharmaceutical
`materials (Führer, 1977). Adsorption of moisture at particle surfaces may also contribute to
`the formation of solid bridges (Ahlneck and Alderborn, 1989).
`
`Mechanical interlocking
`This bonding mechanism involves the hooking or twisting together of the particles (Führer,
`1977). Particles with irregular shapes, e.g. needle forms, and/or with a rough surface texture
`can hook or twist together during compaction (Nyström et al., 1993). However, materials
`forming compacts predominantly by this bonding mechanism often require high
`compression forces and the resultant tablets have low tablet strength, high friability and
`long disintegration times (Führer, 1977).
`
`Particle size
`Generally, tablet strength increases with decreased initial particle size of the compacted
`material (Shotton and Ganderton, 1961; Alderborn and Nyström, 1982a; McKenna and
`McCafferty, 1982; Vromans et al., 1985a; Leuenberger et al., 1989). The effect of particle
`size is dependent on the volume reduction mechanism of the compressed material (e.g.
`Alderborn and Nyström, 1982a). For materials with a high fragmentation tendency, the
`effect of initial particle size is more limited. For these materials, the large particles
`fragment into smaller particles, creating larger surface areas and increasing the number of
`interparticulate contact points, which promotes the creation of interparticulate bonds. For
`materials which deform during compaction, the effect of particle size may be more
`pronounced. For these materials, the surface area partitioning in the bonding structure is not
`changed to a large extent during compaction and therefore the effect of initial particle size
`is more pronounced. The dominating bonding mechanism of the material may also be
`important. Alderborn and Nyström (1982a) found that the tensile strength of the tablet
`increased with increases in the particle size of sodium chloride. This material bonds
`predominantly by solid bridges (e.g. de Boer et al., 1978; Alderborn and Nyström, 1982a;
`Adolfsson et al., 1998) and since the contact points between the particles are fewer for
`larger particles, increasing the applied stress increases the probability of strong bridges.
`However, the effect of particle size on tablet strength is also dependent on the compression
`speed (Sheikh-Salem and Fell, 1982). Particle shape and surface texture can also influence
`powder compactability (e.g. Alderborn and Nyström, 1982b; Alderborn et al., 1988; Wong
`and Pilpel, 1990).
`
`Solid state structure
`The bonding properties of a material are dependent on differences in the physical and
`chemical properties, i.e. the solid state structure, of the material. Analyses of the
`relationships between crystalline (ordered) or disordered structures of substances and their
`mechanical properties can be found in the literature (e.g. York, 1983, for review).
`Generally, compacts containing amorphous materials result in stronger tablets. This has
`been explained by the higher degree of plastic deformation seen with these materials, which
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`results in an increased ability to form interparticulate bonds (e.g. Hüttenrauch, 1977).
`Lactose, a commonly used filler which is available in several crystalline forms and in an
`amorphous form, has been widely studied (e.g. Hüttenrauch, 1977; Vromans et al., 1985a,
`b; Sebathu and Alderborn, 1999). Tablets of the anhydrate form of lactose have higher
`tensile strengths than tablets of the monohydrate form (Vromans et al.,1985a; b), the
`amorphous form resulted in stronger tablets than the crystalline form (Sebathu and
`Alderborn, 1999) and the strength of tablets of alpha-lactose monohydrate increased with
`decreases in crystallinity (Hüttenrauch, 1977). However, Hancock et al. (2002) did not find
`any differences in tensile strength between crystalline and amorphous states of active
`pharmaceutical substances, although they did find that the amorphous form had a higher
`propensity for fracture when controlled flaws were introduced into the tablet before
`measurement of the radial tensile strength. Further, during compression of the powder and
`after mechanical activation (such as grinding), energy is transformed into the material
`(Hüttenrauch et al., 1985). This can cause disordering of the crystal lattice of the material,
`which could influence the tablet strength.
`
`Compression speed
`Generally, higher compression speeds result in tablets with lower tensile strength (Fell and
`Newton, 1971; Sheikh-Salem and Fell, 1982). The effect of compression speed on the tablet
`tensile strength is dependent on the volume reduction mechanism of the compressed
`material (Sheikh-Salem and Fell, 1982; Roberts and Rowe, 1985; Armstrong and Palfrey,
`1989; Olsson, 2000