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`,.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1006-0001
`
`

`

`RS
`2,.00
`. Pttz_f
`ZOO(
`
`Pharmaceutical
`Preformulation and
`Formulation
`· A Practical Guide from Candidate Drug
`Selection to Commercial Dosage Form
`
`Steptoe & Johnson LLP
`
`MAY 2 7 2022
`
`DC Library
`
`Edited by Mark Gibson
`
`r.?\ Taylor & Francis
`~ Taylor & Francis Group
`Boca Raton London New York Singapore
`
`A CRC title, part of the Taylor & Francis imprint, a member of the
`Taylor & Francis Group, the academic division of T&F lnforma pie.
`
`-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1006-0002
`
`

`

`Library of Congress Cataloging-in-Publication Data
`
`Catalog record is available from the Library of Congress
`
`This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with
`permission, and sources are indicated. A wide vaiiety of references are listed. Reasonable efforts have been made to publish
`reliable data and information, but the authors and the publisher cannot assume responsibility for the validity of all materials
`or for the consequences .of their use.
`
`Neither this book nor any pa1t may be reproduced or transmitted in any form or by any means, electronic or mechanical,
`including photocopying, microfilming, and recording, or by any information storage or retrieval system, without prior
`permission in writing from the publisher.
`
`The consent of CRC Press does not extend to copying for general distribution, for promotion, for creating new works, or
`for resale. Specific permission must be obtained in writing from CRC Press for such copying.
`
`Direct all inquiries to CRC Press, 2000 N.W. Corporate Blvd., Boca Raton, Florida 3343L
`
`Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for
`identification and explanation, without intent to infringe.
`
`Visit the CRC Press Web site at www.crcpress.com
`
`© 200 l CR C Press
`
`No claim to original U.S. Government works
`International Standard Book Number l-57491-120-1
`5 6 7 8 9 0
`Printed in the United States of America
`Ptinted on acid-free paper
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1006-0003
`
`

`

`CONTENTS
`
`Preface
`
`Contributors
`
`1.
`
`Introduction and Perspective
`
`Mark Gibson
`
`Drug Development Drivers, Challenges, Risks and Rewards
`Current Trends in the Pharmaceutical Industry
`Lessons Learnt and the Way Forward
`Scope of the Book
`References
`
`PART I: Aiding Candidate Drug Selection
`
`2.
`
`Aiding Candidate Drug Selection:
`Introduction and Objectives
`
`Mark Gibson
`
`Stages of the Drug Discovery and Development Process
`Summary
`References
`
`3.
`
`Preformulation Predictions from Small Amounts of Compound
`as an Aid to Candidate Drug Selection
`Gerry Steele
`
`Initial Physicochemical Characterization
`Initial Solubility
`Initial Stability Investigations
`Crystallinity
`Crystal Morphology
`Hygroscopicity
`Salt Selection
`Methods for Evaluating Physicochemical Properties
`Concluding Remarks
`Acknowledgements
`References
`
`vii
`
`ix
`
`1
`
`2
`6
`8
`10
`11
`
`15
`
`15
`20
`20
`
`21
`
`22
`28
`34
`41
`46
`48
`49
`58
`87
`88
`88
`
`iii
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1006-0004
`
`

`

`iv
`
`4.
`
`Pharmaceutical Preformulation and Formulation
`
`Biopharmaceutical Support in Candidate Drug Selection
`Anna-Lena Unge/1 and Berti/ Abrahamsson
`
`Drug Dissolution and Solubility
`Luminal Interactions
`Absorption/Uptake over the GI Membranes
`Models for Studying the Absorption Potential of Drugs
`Permeability Coefficients versus Fa
`In Vivo Techniques for Studies in Man
`Vehicles for Absorption Studies
`Functional Use of Absorption Models
`References
`
`PART II: Early Drug Development
`
`5.
`
`Early Drug Development: Product Design
`Mark Gibson
`
`The Importance of Product Design
`Product Design Considerations
`Concluding Remarks
`References
`
`6.
`
`Preformulation as an Aid to Product Design in Early Drug Development
`Gerry Steele
`
`Solid Dosage Forms
`Solution Formulations
`Freeze-Dried Formulations
`Suspensions
`Topical/Transdermal Formulations
`Inhalation Dosage Forms
`Compatibility
`References
`
`7.
`
`Biopharmaceutical Support in Formulation Development
`Berti/ Abrahamsson and Anna-Lena Unge/1
`
`In Vitro Dissolution
`Bioavailability Studies
`In Vitro/In Vivo Correlations
`Animal Models
`Imaging Studies
`References
`
`97
`
`100
`111
`117
`118
`134
`135
`139
`141
`143
`
`157
`
`157
`158
`173
`173
`
`175
`
`175
`196
`210
`214
`215
`217
`223
`228
`
`239
`
`241
`257
`269
`276
`279
`289
`
`PART 111: From Product Design to Commercial Dosage Form
`
`8.
`
`Product Optimisation
`
`Mark Gibson
`
`Product Optimisation Purpose and Scope
`Excipient and Pack Optimisation Considerations
`
`295
`
`295
`296
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1006-0005
`
`

`

`Sources of Information
`Expert Systems
`Experimental Design
`Stability Testing
`Developing Specifications
`Process Design, Process Optimisation and Scale-Up
`Validation and Launch
`Acknowledgements
`References
`
`9.
`
`Parenteral Dosage Forms
`
`Joanne Broadhead
`
`Guiding Principles for Simple Parenteral Solutions
`Choice of Excipients
`Sterility Considerations
`Strategies for Formulating Poorly Soluble Drugs
`Strategies for Formulating Unstable Molecules
`Strategies for the Formulation of Macromolecules
`Liposomal Delivery Systems
`Sustained-Release Parenteral Formulations
`In Vitro and In Vivo Testing Methods
`Packaging of Parenteral Products
`Manufacturing of Parenteral Products
`Administration of Parenteral Products
`Parenteral Products and the Regulatory Environment
`References
`
`10.
`
`Inhalation Dosage Forms
`
`Paul Wright
`
`Lung Deposition
`Particle Sizing
`Dry Powder Inhalers
`Metered Dose Inhalers
`Nebulisers
`Standards
`Future
`References
`Bibliography
`
`11. Oral Solid Dosage Forms
`
`Peter Davies
`
`Powder Technology
`Powder Flow
`Mixing
`Compaction
`Solid Dosage Forms
`Tablets
`Hard Gelatin Capsules
`
`Contents
`
`V
`
`304
`305
`309
`313
`316
`319
`323
`327
`327
`
`331
`
`332
`334
`336
`336
`340
`342
`343
`343
`346
`347
`348
`350
`351
`353
`
`355
`
`356
`357
`361
`364
`372
`374
`375
`376
`378
`
`379
`
`381
`382
`388
`390
`403
`403
`441
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1006-0006
`
`

`

`vi
`
`Pharmaceutical Preformulation and Formulation
`
`Soft Gelatin Capsules
`Summary
`References
`
`12. Ophthalmic Dosage Forms
`
`Mark Gibson
`
`Ocular Topical Drug Delivery Issues and Challenges
`Drug Candidate Selection
`Product Design Considerations
`Product Optimisation Considerations
`Processing Considerations
`Concluding Remarks
`References
`
`13. Aqueous Nasal Dosage Forms
`
`Nigel Day
`
`Nasal Anatomy and Physiology
`Formulation Selection Considerations
`Device Selection Considerations
`Regulatory Aspects
`Special Considerations for Peptide Nasal Delivery
`References
`Additional Reading
`
`14. Topical and Transdermal Delivery
`Kenneth A. Walters and Keith R. Brain
`
`The Skin and Percutaneous Absorption
`Drug Candidate Selection and Preformulation
`Formulation
`Concluding Remarks
`Bibliography
`References
`
`Index
`
`453
`455
`456
`
`459
`
`460
`464
`465
`473
`482
`486
`488
`
`491
`
`494
`496
`499
`506
`508
`511
`513
`
`515
`
`516
`534
`543
`567
`567
`569
`
`581
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1006-0007
`
`

`

`11
`
`Oral Solid Dosage Forms
`
`Peter Davies
`Roche Discovery
`Welwyn, United Kingdom
`
`In the last 15 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
`
`379
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1006-0008
`
`

`

`,
`
`t
`
`380
`
`Pharmaceutical Preformulation and Formulation
`
`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
`
`Source: Centrewatch.com, Clinical trials listing.
`
`0
`
`17
`
`15
`
`9
`
`10
`
`14
`
`101
`
`96
`
`66
`
`30
`
`50
`
`46
`
`47
`
`46
`
`50
`
`Formulation Type
`
`Immediate release
`
`Delayed release
`
`Table 11.2
`Types of solid dosage forms.
`
`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 candy 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.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1006-0009
`
`

`

`Oral Solid Dosage Forms
`
`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 intraparticulate 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.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1006-0010
`
`

`

`382
`
`Pharmaceutical Preformulation and Formulation
`
`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.
`
`1. 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.
`
`.
`porosity = 1-
`
`( bulk density)
`.
`true density
`
`Relative density is the ratio of the measured bulk density divided by the true density.
`
`.
`.
`relative density =
`
`bulk density
`true density
`
`POWDER FLOW
`
`(1)
`
`(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. 1985): forces due to electrostatic charging, van der Waals forces and forces
`due to moisture.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1006-0011
`
`

`

`Oral Solid Dosage Forms
`
`383
`
`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[ 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 50 µm 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 65-80 percent, it will form liquid
`bridges between particles. The attractive force due to the adsorbed layer may be about
`50 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 11.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.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1006-0012
`
`

`

`384
`
`Pharmaceutical Preformulation and Formulation
`
`Figure 11.1 Powder flow patterns in hoppers.
`
`- -
`
`- -
`- - - - -
`
`a. Core flow
`
`'- /
`'---
`/
`''----
`/
`'-- __../
`
`b. Mass flow
`
`Whether core flow or mass flow is achieved is dependent on the design of the hopper
`(geometry and wall material) and the flow properties of the powder. For most pharmaceutical
`applications, the hopper design for a particular machine will be fixed; thus, it is incumbent on
`the formulator to ensure that mass flow is achieved by modification of the powder properties.
`
`Powder Flow into Orifices
`
`Flow into orifices is important when filling dies in tablet machines and in certain types of cap(cid:173)
`sule filling machines. For a given material, the flow into or through an orifice is dependent on
`the particle size, and typically, a plot of flow rate versus particle size will display the trend
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1006-0013
`
`

`

`Oral Solid Dosage Forms
`
`385
`
`shown in Figure 11.2. At the lower end of the particle size range, cohesive forces will result in
`poor flow. As the particle size increases, the flow rate increases until a maximum is achieved,
`at an orifice diameter/particle diameter ratio of 20-30. As the particle size continues to in(cid:173)
`crease, the rate decreases due to mechanical blocking or obstruction of the orifice. Flow will
`stop completely when the orifice/particle ratio falls below 6.
`
`Measuring Powder Flow Properties
`
`There are several different methods available for determining the flow properties of powders,
`and there are many literature examples demonstrating correlations between a test method and
`the manufacturing properties of a formulation. Listed below are some of the more commonly
`used tests, together with references, detailing their use in pharmaceutical applications.
`
`Shear Cell Methods
`
`Developed to aid silo and hopper design, shear cells provide an assessment of powder flow
`properties as a function of consolidation load and time. There are a number of types of shear
`cells available, the most common type being the Jenike shear cell (Figure 11.3 ).
`The shear cell is filled in a standard manner to produce a powder bed with a constant bulk
`density. A vertical (normal) force is applied to the powder bed and a horizontal force applied
`to the moveable ring. As the powder bed moves due to the horizontal shear stress, it will
`change volume, either expanding or contracting depending on the magnitude of the vertical
`force. A series of tests are performed to determine the vertical load under which the bed re(cid:173)
`mains at constant volume when sheared, referred to as the critical state. Once the critical state
`has been determined, a series of identical specimens are prepared, and each is sheared under
`a different vertical load, with all loads being less than the critical state.
`
`Figure 11.2 Effect of particle size on the rate of powder flow through an orifice.
`
`Powder Flow
`
`Particle Size
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1006-0014
`
`

`

`386
`
`Pharmaceutical Preformulation and Formulation
`
`Figure 11.3 Jenike shear cell.
`
`Normal force
`
`•
`
`Shear Ii.
`force "
`
`Moveable ring
`
`The test results are used to produce a graph referred to as a Jenike yield locus in which the
`shear stress required to initiate movement is plotted against the normal stress (Figure 11.4)
`The line gives the stress conditions needed to produce flow for the powder when compacted
`to a fixed bulk density. If the material is cohesive, the yield locus does not produce a straight
`line, and it does not pass through the origin. The intercept OT is the tensile strength of the
`consolidated specimen, and OC is the cohesion of the specimen, that is, the shear stress
`needed to initiate movement of the material when it is not subjected to normal force. The ap(cid:173)
`plication of the yield loci to pharmaceuticals is well documented in the literature (Kocova and
`Pilpel 1972, 1973; Williams and Birks, 1967).
`The limitations of the Jenike shear cell are that it is not very useful for measuring bulk
`solids with large shear deformations, e.g., plastic powders. The level of consolidation stresses
`required are inappropriate for pharmaceutical materials, and the quantity of material required
`is often beyond that available in the early stages of development. Alternative shear cells that
`have been used include annular shear cells (Nyquist and Brodin 1982; Irono and Pilpel 1982)
`and ring shear testers (Schulze 1996).
`
`Changes in Bulk Density
`
`The increase in bulk density of a powder is related to the cohesivity of a powder. Ratios of the
`poured to tapped bulk densities are expressed in two ways to give indices of flowability.
`
`Hausner Ratio =
`
`tapped bulk density
`poured bulk density
`
`(4)
`
`100 x ( tapped bulk density- poured bulk density)
`Compressibility (Carr Index) = ---~-----~~---------'- (5)
`poured bulk density
`
`The Hausner Ratio varies from about 1.2 for a free-flowing powder to 1.6 for cohesive pow(cid:173)
`ders. The Carr Index classifications are listed in Table 11.3.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1006-0015
`
`

`

`Oral Solid Dosage Forms
`
`387
`
`Figure 11.4 Jenike yield locus.
`
`Shear Stress
`
`T
`
`0
`
`Normal Stress
`
`Table 11.3
`Carr indices.
`
`Carr Index ( 0/o)
`
`5-12
`
`12-16
`
`18-21
`
`23-35
`
`33-38
`
`>40
`
`Flow
`
`Free flowing
`
`Good
`
`Fair
`
`Poor
`
`Very poor
`
`Extremely poor
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1006-0016
`
`

`

`388
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`
`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).
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1006-0017
`
`

`

`Oral Solid Dosage Forms
`
`389
`
`Figure 11.5 Perfect mix.
`
`Figure 11.6 Random mix.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1006-0018
`
`

`

`390
`
`Pharmaceutical Preformulation and Formulation
`
`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
`mo