`Preformulation and
`Formulation
`A Practical Guide from Candidate Drug
`Selection to Commercial Dosage Form
`
`! "-•..
`
`Edited by Mark Gibson
`
`Q
`Taylor & Francis
`~ Taylor&. Francis Group
`
`Boca Raton London New Yori< Singapore
`
`A CRC title, part of the Taylor & Francis imprint, a member of the
`Taylor & Francis Group, the academic division of T&F lnforma pte.
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`Par Pharm., Inc.
`Exhibit 1042
`Page 001
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`11
`
`Oral Solid Dosage Forms
`
`Peter Davies
`Roche Discovery
`Welwyn, United Kingdom
`
`In the last IS to 20 years, there has been a huge resource in both academia and industry de(cid:173)
`voted to the development of drug delivery systems that target drugs more effectively to their
`therapeutic site. Much of this work has been successful and is reported within this text. In spite
`of this, oral solid dosage forms such as tablets and hard gelatin capsules, which have been in
`existence since the nineteenth century, remain the most frequently used dosage forms. This is
`not simply a reflection of the continued use of established products on the market, tablets and
`capsules still account for about half of all new medicines licensed (Table 11.1 ).
`There are several reasons for the continued popularity of the oral solid dosage form. The
`oral route of delivery is perhaps the least invasive method of delivering drugs, it is a route that
`the patient understands and accepts. Patients are able to administer the medicine to them(cid:173)
`selves. For the manufacturer, solid oral dosage forms offer many advantages: they utilise cheap
`technology, are generally the most stable forms of drugs, are compact and their appearance
`can be modified to create brand identification.
`Tablets and capsules are also very versatile. There are many different types of tablets
`which can be designed to fulfil specific therapeutic needs (Table 11.2). It is beyond the scope
`of this chapter to cover all these dosage forms, instead it will review the common principles,
`with more specific detail being given for those most commonly used.
`For drugs that demonstrate good oral bioavailability and do not have adverse effects on
`the gastro-intestinal (GI) tract, there may be very little justification for attempting to design a
`specific drug delivery system. It is likely, therefore, that tablets and capsules will continue to
`remain one of the most used methods of delivering drugs to the patient in the future.
`This chapter reviews the science behind the development of solid dosage forms, particu(cid:173)
`larly tablets and hard gelatin capsules. Solid dosage forms are one of the most widely
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`Table 11.1
`Number of FDA drug approvals for tablet and capsules from 1995 to 1999.
`
`No. of Tablets
`Approved
`
`No. of Capsules
`Approved
`
`No. of Other
`Dosage Forms
`Approved
`
`Proportion of
`Tablets and
`Capsules (%)
`
`1995
`
`1996
`
`1997
`
`1998
`1999
`
`14
`
`69
`70
`
`48
`20
`
`0
`17
`
`15
`
`9
`
`10
`
`Source: Centrewatch.com, Clinical trials listing.
`
`14
`101
`
`96
`
`66
`
`30
`
`50
`46
`
`47
`
`46
`
`50
`
`Table 11.2
`Types of solid dosage forms.
`
`Formulation Type
`
`Immediate release
`
`Delayed release
`
`Description
`------------------------
`The dosage form is designed to release the drug substance immediately after
`ingestion.
`
`The drug substance is not released until a physical event has occurred, e.g., time
`elapsed, change in pH of intestinal fluids, change in gut flora.
`
`Chewable tablets
`
`Strong, hard tablets to give good mouth feel.
`
`Lozenges
`
`Strong, slowly dissolving tablets for local delivery to mouth or throat. Often
`prepared by a ca ndy moulding process.
`
`Buccal tablets
`
`Tablets designed to be placed in buccal cavity of mouth for rapid action.
`
`Effervescent tablets
`
`Taken in water. the tablet forms an effervescent. often pleasant-tasting drink.
`
`Dispersible tablets
`
`Tablets taken in water. the tablet forms a suspension for ease of swallowing.
`
`Soluble tablets
`
`Tablets taken in water, the tablet forms a solution for ease of swallowing.
`
`Hard gelatin capsules
`
`Two-piece capsule shells which can be filled with powders. pellets, semi-solids
`or liquids.
`
`Soft gelatin capsules
`
`One-piece capsules containing a liquid or semi-solid fill.
`
`Pastilles
`
`Intended to dissolve in mouth slowly for the treatment of local infections. Usually
`composed of a base containing gelatin and glycerin.
`
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`Exhibit 1042
`Page 004
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`381
`
`researched areas of pharmaceutics and, given the space allowed, this chapter can only cover
`the science at a very basic level. It is an area that is served by a number of excellent texts, and
`these will be referenced at the appropriate points.
`
`POWDER TECHNOLOGY
`
`Virtually all solid dosage forms are manufactured from powders, and an understanding of the
`unique properties of powder systems is necessary for their rational formulation and manu(cid:173)
`facture. Powders consist of solid particles surrounded by spaces filled with fluid (typically air)
`and uniquely possess some properties of solids, liquids and gases. Powders are not solids, even
`though they can resist some deformation, and they are not liquids, although they can be made
`to flow. Still further, they are not gases, even though they can be compressed. Powder tech(cid:173)
`nology is concerned with solid/fluid interactions, interparticle contact and cohesion between
`particles. These are strongly influenced by particle size and shape and by adsorption of the
`fluid or other contaminants onto the surface of the particles.
`While tablets and capsules, the two most common solid dosage forms, have their own
`unique requirements, there are similarities between them. They both require the flow of the
`correct weight of material into a specific volume, the behaviour of the material under pressure
`is important; and the wetting of the powder is critical for both granulation and subsequent
`disintegration and dissolution of the dosage form.
`While it is not possible to deal with all aspects of powder technology in a textbook cov(cid:173)
`ering such a diverse range of formulations, some basic principles of powder flow, mixing and
`compaction and compression properties will be described. For those interested in a more in(cid:173)
`depth treatment of the topic, there are a number of excellent texts available (Rhodes 1990; Ny(cid:173)
`strom 1995 ).
`
`Particle Size and Shape
`
`A knowledge of the particle shape and size distribution is essential to the understanding of the
`behaviour of powders, as it will contribute to knowledge of the secondary properties of a pow(cid:173)
`der, such as flow and deformation, which influence the processability. This topic is dealt with
`in detail in Chapter 6.
`
`Density
`
`When a powder is poured into a container, the volume that it occupies depends on a number
`of factors, such as particle size, particle shape and surface properties. In normal circumstances,
`it will consist of solid particles and interparticulate air spaces (voids or pores). The particles
`themselves may also contain enclosed or intra particulate pores. If the powder bed is subjected
`to vibration or pressure, the particles will move relative to one another to improve their pack(cid:173)
`ing arrangement. Ultimately, a condition is reached where further densification is not possible
`without particle deformation.
`The density of a powder is, therefore, dependent on the handling conditions to which it
`has been subjected, and there are several definitions that can be applied either to the powder
`as a whole or to individual particles.
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`Particle Densities
`
`British Standard 2955 ( 1958) defines three terms that apply to the particles themselves. Parti(cid:173)
`cle density is the mass of the particle divided by its volume. The different terms arise from the
`way in which the volume is defined.
`
`l. True particle density is when the volume measured excludes both open and closed
`pores and is a fundamental property of a material.
`
`2. Apparent particle density is when the volume measured includes intraparticulate
`pores.
`
`3. Effective particle density is the volume "seen" by a fluid moving past the particles. It
`is of importance in processes such as sedimentation or fluidisation but is rarely used
`in solid dosage forms.
`
`Powder Densities
`
`The density of a powder sample is usually referred to as the bulk density, and the volume in(cid:173)
`cludes both the particulate volume and the pore volume. The bulk density will vary depend(cid:173)
`ing on the packing of the powder, and several values can be quoted
`
`Minimum bulk density is when the volume of the powder is at a maximum, caused
`by aeration, just prior to complete breakup of the bulk.
`
`Poured bulk density is when the volume is measured after pouring powder into a
`cylinder, creating a relatively loose structure.
`
`Tapped bulk density is, in theory, the maximum bulk density that can be achieved
`without deformation of the particles. In practise, it is generally unrealistic to attain
`this theoretical tapped bulk density, and a lower value obtained after tapping the
`sample in a standard manner is used.
`
`The porosity of a powder is defined as the proportion of a powder bed or compact that
`is occupied by pores and is a measure of the packing efficiency of a powder.
`
`.
`porostty = 1-
`
`(bulk density)
`.
`true denstty
`
`Relative density is the ratio of the measured bulk density divided by the true density.
`
`relative density =
`
`bulk density
`true density
`
`POWDER FLOW
`
`(I)
`
`(2)
`
`Good flow properties are a prerequisite for the successful manufacture of both tablets and
`powder-filled hard gelatin capsules. It is a property of all powders to resist the differential
`movement between particles when subjected to external stresses. This resistance is due to the
`cohesive forces between particles. Three principal types of interparticle force have been iden(cid:173)
`tified (Hamby et al. I 985 ): forces due to electrostatic charging, van der Waals forces and forces
`due to moisture.
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`Exhibit 1042
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`Electrostatic forces are dependent on the nature of the particles, in particular, on their
`conductivity. For non-conducting particles, high cohesive stresses in the range of 104 to
`107 Nlm 2 have been reported.
`Van der Waals forces are the most important forces for most pharmaceutical powders.
`The forces of attraction between two spherical particles is given by:
`
`F=Ad(~)
`12x 2
`
`(3 )
`
`where A is the Hamaker constant (L = 10-19 J), xis the distance of separation of the particles
`and d is the particle diameter. The forces are inversely proportional to the square of the dis(cid:173)
`tance between the two particles, and hence diminish rapidly as particle size and separation in(cid:173)
`creases. Powders with particles below SO ~m will generally exhibit irregular or no flow due to
`van der Waals forces. Particle shape is also important; for example, the force between a sphere
`and plane surface is about twice that between two equal sized spheres.
`At low relative humidities, moisture produces a layer of adsorbed vapour on the surface
`of particles. Above a critical humidity, typically in the range 6S-80 percent, it will form liquid
`bridges between particles. The attractive force due to the adsorbed layer may be about
`SO times the van der Waals force for smooth surfaces, but surface roughness will reduce the ef(cid:173)
`fect. Where a liquid bridge forms, it will give rise to an attractive force between the particles
`due to surface tension or capillary forces.
`The role of the formulator is to ensure that the flow properties of the powder are suffi(cid:173)
`cient to enable its use on modern pharmaceutical equipment. Two types of flow present the
`formulator with particular challenges: flow from powder hoppers and flow through orifices.
`
`Powder Flow in Hoppers
`
`Tablet machines and capsule filling machines store the powder to be processed in a hopper
`above the machine. It is important that the powder flows from the hopper to the filling sta(cid:173)
`tion of the machine at an appropriate rate and without segregation occurring. There are two
`types of flow that can occur from a powder hopper: core flow and mass flow (Figure 11.1).
`The flow pattern of a core flow is shown in Figure ll.la. When a small amount of pow(cid:173)
`der is allowed to leave the hopper, there is a defined region in which downward movement
`takes place and the top surface begins to fall in the centre. As more material leaves the hopper,
`the area which moves downward begins to widen, and the upper surface becomes conical. In
`the areas of the hopper outside the falling region, near the walls, the material has not moved.
`Even when the hopper has almost emptied, there will be regions where the powder is undis(cid:173)
`turbed. A core flow hopper is characterised by the existence of dead spaces during discharge.
`A mass flow hopper is one in which all the material is in motion during discharge, in partic(cid:173)
`ular the areas adjacent to the hopper wall (Figure 11.1 b). As a small amount of powder is dis(cid:173)
`charged, the whole bulk of the powder will move downwards.
`Core flow hoppers have two significant disadvantages. First, flow from the hopper can
`stop for no apparent reason. The stoppage may be due to the formation of an arch between
`the walls of the hopper that is strong enough to support the weight of powder above it.
`Alternatively, it may be the result of piping or rat holing, in which the material directly above
`the outlet falls out, leaving an empty cylinder. The second disadvantage is that the flow
`pattern is likely to encourage segregation, and there may be a considerable loss of mixing
`quality.
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`Pharmaceutical Preformulation and Formulation
`
`Compressibility indices are a measure of the tendency for arch formation and the ease
`with which the arches will fail and, as such, is a useful measure of flow. A limitation of the bulk
`density indices is that they only measure the degree of consolidation; they do not describe how
`rapidly consolidation occurs.
`
`Angle of Repose
`
`If powder is poured from a funnel onto a horizontal surface, it will form a cone. The angle
`between the sides of the cone and the horizontal is referred to as the angle of repose. The
`angle is a measure of the cohesiveness of the powder, as it represents the point at which the
`interparticle attraction exceeds the gravitational pull on a particle. A free-flowing powder will
`form a cone with shallow sides, and hence a low angle of repose, while a cohesive powder will
`form a cone with steeper sides.
`This method is simple in concept, but not particularly discerning. As a rough guide, an(cid:173)
`gles less than 30° are usually indicative of good flow, while powders with angles greater than
`40° are likely to be problematic.
`
`Avalanching Behaviour
`
`If a powder is rotated in a vertical disc, the cohesion between the particles and the adhesion
`of the powder to the surface of the disc will lead to the powder following the direction of ro(cid:173)
`tation until it reaches an unstable situation where an avalanche will occur. After the avalanche,
`the powder will again follow the disc prior to a further avalanche. Measurement of the time
`between avalanches and the variability in time is a measure of the flow properties of the
`powder.
`
`MIXING
`
`The mixing of powders is a key step in the manufacture of virtually all solid dosage forms. A
`perfect mixture of two particles is one in which any group of particles taken from any posi(cid:173)
`tion within a mix will contain the same proportions of each particle as the mixture as a whole
`(Figure 11.5). With powders, unlike liquids, this is virtually unattainable. All that is possible to
`achieve is a maximum degree of randomness, that is, a mixture in which the probability of
`finding a particle of a given component is the same at all positions in the mixture (Figure
`11.6).
`To determine the degree of mixing obtained in a pharmaceutical operation, it is necessary
`to sample the mixture and determine the variation within the mix statistically. In assessing the
`quality of a mixture, the method of sampling is more important than the statistical method
`used to describe it. Unless samples that accurately represent the system are taken, any statisti(cid:173)
`cal analysis is worthless. Furthermore, to provide meaningful information, the scale of
`scrutiny of the powder mix should be such that the weight of sample taken is similar to the
`weight that the powder mix contributes to the final dosage form .
`A large number of statistical analyses have been applied to the mixing of powders. These
`tend to be indices where the variance of the actual mix is compared to the theoretical random
`mix. The statistics are beyond the scope of this text and can be found in a number of standard
`texts on powder technology (Rhodes 1990).
`
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`Exhibit 1042
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`Pharmaceutical Preformulation and Formulation
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`Segregation
`
`If a powder consisting of two materials both having identical physical properties is mixed for
`sufficient time, random mixing will eventually be achieved. Unfortunately, most pharmaceu(cid:173)
`tical powders consist of mixtures of materials with differing properties. This leads to segrega(cid:173)
`tion , where particles of similar properties tend to collect together in part of the powder. When
`segregating powders are mixed, as the mixing time is extended, the powders appear to unmix
`and equilibrium is reached between the action of the mixer introducing randomness and the
`resistance of the particles due to segregation.
`While a number of factors can cause segregation, differences in particle size are far and
`away the most important in pharmaceutical powders. There are a number of mechanisms by
`which segregation of different sized particles can occur, and consideration should be given to
`these when designing pharmaceutical processes. Trajectory segregation occurs when a powder
`is projected horizontally in a fluid or gas; larger particles are able to travel greater horizontal
`distances than small particles before settling out. This could cause segregation at the end of
`conveyor belts or vacuum transfer lines. When a powder is discharged into a hopper or con(cid:173)
`tainer, air is displaced upward. The upward velocity of this air may be sufficient to equal or ex(cid:173)
`ceed the terminal velocity of some of the smaller particles, and these will remain suspended as
`a cloud after the large particles have settled out. This process is known as elutriation segrega(cid:173)
`tion. The most common cause of segregation is due to percolation of fine particles. If a pow(cid:173)
`der bed is handled in a manner that allows individual particles to move, a rearrangement in
`the packing of the particles will occur. As gaps between particles arise, particles from above
`will be able to drop into them. If the powder contains particles of different sizes there will be
`more opportunities for the smaller particles to drop, so there will be a tendency for these to
`move to the bottom of the powder, leading to segregation. This process can occur whenever
`movement of particles takes place, including vibration, shaking and pouring.
`
`Ordered Mixing
`
`As stated above, differences in particle size are the most common cause of segregation in phar(cid:173)
`maceutical powders. One exception to this is when one component of a powder mix has a very
`small particle size (less than 5 J.Lm) and the other is relatively large. In such circumstances, the
`fine powder may coat the surface of the larger particles, and the adhesive forces will prevent
`segregation. This is known as ordered mixing, and using this technique, it is possible to pro(cid:173)
`duce greater homogeneity than by random mixing.
`
`COMPACTION
`
`The manufacture of tablets, and to a lesser extent powder-filled hard gelatin capsules, involves
`the process of powder compaction, the purpose of which is to convert a loose incoherent mass
`of powder into a single solid object. Knowledge of the behaviour of powders under pressure,
`and the way in which bonds are formed between particles, is essential for the rational design
`of formulations.
`A powder in a container subjected to a low compressive force will undergo particle re(cid:173)
`arrangement until it attains its tapped bulk density. Ultimately, a condition is reached where
`further densification is not possible without particle deformation. If, at this point, the powder
`
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`Exhibit 1042
`Page 014
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`Pharmaceutical Preformulation and Formulation
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`Measurement of Compaction Properties
`
`To characterise the compaction properties of a material or formulation, it must be possible to
`measure the relationship between the force applied to a powder bed and the volume of the
`powder bed. A typical instrumentation will consist of measurement of the forces on the upper
`and lower punches by means of strain gauges or load cells together with a measure of the
`punch movement, which is performed using displacement transducers, the most common
`type being linear variable-differential transducers (LVDTs). The positioning and installation
`of the load and displacement transducers are critical to obtain meaningful information. The
`topic of instrumentation is comprehensively covered by Ridgway Watt ( 1988). There are three
`approaches that have been used to generate compaction information, as discussed below.
`
`Conventional Testing Machines
`
`Testing machines are widely used in materials science and engineering laboratories for the
`measurement of physical properties of various materials. Many of the basic principles of com(cid:173)
`paction and the test methodologies currently employed in pharmaceutical formulation have
`been developed on testing machines by the metallurgy and ceramic industries. The drawback
`with testing machines is that the compression speeds that can be achieved are well below those
`enco·untered on tabletting machines, so while they are of value in fundamental studies, they are
`not necessarily useful for predicting the behaviour of a material or formulation in the fa ctory.
`
`Conventional Tablet Machines
`
`The first tablet machines to be instrumented were single punch eccentric presses. While these
`provide useful information, the compression profiles differ from those of rotary tablet ma(cid:173)
`chines used for commercial production. The profile of a single punch involves the powder bed
`being compressed between a moving upper punch and a stationary lower punch, while on a
`rotary machine, both punches move together simultaneously. Consequently, rotary machines
`have been instrumented, even though this is technically more challenging than single punch
`machines. The instrumented rotary press provides information that is directly relevant to pro(cid:173)
`duction conditions, although it should be borne in mind that profiles do vary between ma(cid:173)
`chines, and any results obtained may be peculiar to that machine. A major advantage of
`instrumented machines is that they provide information not only on the compaction proper(cid:173)
`ties but also on flow and lubrication. The disadvantage of using instrumented rotary machines
`is the quantity of material required to perform tests, making them unsuitable for pref()rmula(cid:173)
`tion activities, when material is in short supply.
`
`Compaction Simulators
`
`Compaction simulators are a development of testing machines. They consist of single punch
`machines in which the upper and lower punches are driven individually by hydraulic rams.
`The movement of the hydraulic rams is controlled by computer and can be programmed ei(cid:173)
`ther to simulate the movement of any tablet machine or to follow a simple profile similar to a
`testing mat:hine. The big advantage of the compaction simulator is that it can be used to pre(cid:173)
`pare a single compact using a profile that might be encountered on a production machine, so
`only small quantities of material are required.
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`Table 11.4
`Yield pressure for excipients.
`
`Excipient
`
`Yield Pressure (Mpa)
`
`A-8
`
`Defonnation Mechanism
`
`Microcrystalline cellulose
`
`Anhydrous lactose
`
`Calcium phosphate dihydrate
`
`Starch 1500
`
`54
`
`174
`
`396
`
`53
`
`0.15
`
`0.5
`
`0.95
`
`0.1
`
`Plastic/deforming
`
`Brittle/fragmenting
`
`The effect of compression speed on the yield pressure of a material has been suggested as
`a method of determining the time-dependent nature of materials compression properties
`(Roberts and Rowe 1985). Heckel plots are produced at two punch velocities, 0.03 and
`300 mm sec, and the yield pressures determined. The strain rate sensitivity (SRS) is calculated as:
`
`Pz-PI
`SRS= y
`y xlOO
`
`Pyl
`
`(7)
`
`where Pyl = the yield pressure at 0.03 m ms and P 2 = the yield pressure at 300 m ms. Mate(cid:173)
`rials that exhibit plastic deformation have larger SRS than values fragmenting materials.
`
`Elasticity
`
`While Heckel plots are able to distinguish between plastic and fragmenting mechanisms, they
`do not readily distinguish between plastic and elastic deformation. The data presented in
`Table 11.4 would suggest that microcrystalline cellulose and starch 1500 have very similar
`properties, yet the elastic nature of starch and its derivative products is well documented in
`the literature. Additional methods are, therefore, required to measure elasticity.
`Elasticity can be determined either by monitoring the elastic energy during the decom(cid:173)
`pression phase of a compact within the die or by comparing the dimensions of the ejected
`compact with the dimensions of the compact within the die at peak compaction pressure.
`The elastic energy is determined by plotting a force-displacement curve. If punch force is
`plotted against punch tip displacement or punch tip separation, a curve with a progressively
`increasing slope is obtained, reaching a maximum force at the point of minimum separation.
`As the punch begins to retract, the compact will expand due to elastic recovery and will re(cid:173)
`main in contact with the punch. This recovery is apparent from the force-displacement curve.
`If the material being compressed was truly elastic, the curve for the decompression phase
`would overlay the compression phase. For a truly plastic material the force would fall to zero
`immediately the punch began to retract. Pharmaceutical materials tend to show a combina(cid:173)
`tion of elastic and plastic deformation.
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`397
`
`material with a measured load and the size of the indentation produced measured. The hard(cid:173)
`ness of a material is the load divided by the area of the indentation, to give a measure of the
`contact pressure.
`There are two types of hardness test: static tests that involve the formation of a perma(cid:173)
`nent indentation on the surface of the test material and dynamic tests in which a pendulum
`is allowed to strike the test material from a known distance. Vickers and Brinell tests, two ex(cid:173)
`amples of static methods, are the most commonly used methods for determining the hard(cid:173)
`ness of pharmaceutical materials. In the Brinell test, a steel ball of diameter D is pressed on
`to the surface of the material, and a load F is applied for 30 sec and then removed. The di(cid:173)
`ameter d1 of the indentation produced is measured, and the Brinell Hardness Number
`(BHN) calculated by
`
`2F
`BHN = - - . , - - -= : - - - - , -
`rtD{ D[ -R -d})
`
`(9)
`
`The Vickers Hardness test uses a square-based diamond pyramid as the indenter. The Vickers
`Hardness, Hv, is calculated by
`
`2F sin 68°
`H =----
`d2
`v
`
`(I O)
`
`where d is the length of the diagonals of the square impression.
`Traditionally, it has been necessary to perfom indentation testing on compacts due to the
`size of the indenters. The surface of compacts are not homogeneous, and this introduced
`variability. Recently, nanoindentation testers have been developed which are capable of per(cid:173)
`forming indentation tests on single crystals. Such testers offer significant potential for
`characterising the mechanical properties of materials at an early stage of development.
`
`Pressure/Strength Relationships
`
`The strength of tablets has traditionally been determined in terms of the force required to
`fracture a specimen across its diameter, the diametral compression test. The fracture load ob(cid:173)
`tained is usually reported as a hardness value, an unfortunate use of a term that has a specific
`meaning in materials science, associated with indentation. The use of the fracture load does
`not allow for compacts of different shapes, diameters or thicknesses to be directly compared.
`For flat-faced circular tablets, a complete analytical solution exists for the stress state induced
`during the test (Barcellos and Carneiro 1953 ), allowing the tensile strength to be determined
`from the fracture load:
`
`2P
`(J =--
`1tDt
`X
`
`(11)
`
`where Pis the fracture load, D the tablet diameter and t the tablet thickness. The solution for
`tensile stresses can only be used for tablets that fail in tension, characterised by failure along
`the loaded diameter.
`The stresses developed in convex tablets tested undergoing the diametral compression
`test have been examined by Pitt eta!. ( 1989), who proposed the following equation for the cal(cid:173)
`culation of the tensile strength:
`
`Supplied by the British Library 06 Mar 2017 , 17:18 (GMT)
`
`Par Pharm., Inc.
`Exhibit 1042
`Page 021
`
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`
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`
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`
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`402
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`Pharmaceutical Preformulation and Formulation
`
`Figure 11.15 Elastic recovery of compact during ejection from die leading to capping
`(after Train 1956).
`
`Radial relaxation
`\~-~--if
`--------
`
`Shear plane
`
`Long it udinal relaxation
`
`to occur with materials having a llFI of 0.8 or more. The BFI will be dependent on the rela(cid:173)
`tive density of a material; at low densities, pores may act as stress concentrators in the same
`way as the central hole, so the measurements should be made at fixed, hig