Pharmaceutics
`“ll! Sfliflllflll III “053% [fll‘lll llflSiflll
`
`
`
`_
`
`AstraZeneca Exhibit 2098 p. 1
`InnoPharma Licensing LLC V. AstraZeneca AB IPR2017-00905
`
`

`

`CHURCHILL LIVINGSTONE
`
`Medical Division of Longrnan Group UK Limited
`Distributed in the United States of America by
`Churchill Livingstone Inc., 650 Avenue of the Americas,
`New York, 10011, and associated companies, branches
`and representatives throughout the world.
`
`© Michael Aulton 1988
`
`All rights reserved. No part of this publication may
`be reproduced, stored in a retrieval system, or
`transmitted in any form or by any means, electronic,
`mechanical, photocopying, recording, or otherwise,
`without the prior permission of the publishers
`(Churchill Livingstone, Robert Stevenson House, 1-3
`Baxter’s Place, Leith Walk, Edinburgh EH1 3AF), or
`a Licence permitting restricted copying in the United
`Kingdom issued by the Copyright LiCensing Agency Ltd,
`90 Tottenham Court Road, London, W1? 9HE.
`
`First published 1988
`Reprinted 1989
`Reprinted 1990
`Reprinted 1991
`Reprinted 1992
`
`ISBN D-LlLlB-UBELlB-fi
`
`British Library Cataloguing in Publication Data
`Pharmaceutics: the science of dosage form
`design.
`1. Pharmaceutics
`I. Aulton, Michael E.
`615’.19
`RS403
`
`Library of Congress Cataloging in Publication Data
`Pharmaceutics: the science of dosage form design.
`Replaces: Cooper and Gunn’s tutorial pharmacy.
`6th ed. 1972.
`
`2. Drugs
`
`Includes bibliographies and index.
`1. Drugs — Design of delivery systems.
`— Dosage forms. 3. Biopharmaceutics.
`4. Pharmaceutical technology.
`5. Chemistry,
`Pharmaceutical.
`6. Microbiology, Pharmaceutical.
`1. Aulton, Michael E.
`2. Chemistry,
`[DNLM2 1. Biopharmaceutics.
`Pharmaceutical.
`3. Dosage Forms.
`4. Technology,
`Pharmaceutical.
`5. Microbiology, Pharmaceutical.
`QV 785 P5366]
`RS420.P48
`1987
`
`615.5’8
`
`86—25888
`
`Printed in Hong Kong
`CPP/OS
`
`The
`publisher’s
`policy is to use
`paper manufactured
`from sustainable forests
`
`AstraZeneca Exhibit 2098 p. 2
`
`

`

`Contents
`
`
`
`Preface
`
`Contributors
`
`Acknowledgements
`About this book
`
`1 The design of dosage forms
`
`PART ONE Physicochemical
`principles of pharmaceutics
`2 Rheology and the flow of fluids
`3 Solutions and their properties
`4 Surface and interfacial phenomena
`5 Solubility and dissolution rate
`6 Disperse systems
`7 Kinetics and stability testing
`
`PART TWO Biopharmaceutics
`8 Introduction to biopharmaceutics
`9 Factors influencing bioavailability
`10 Assessment of bioavailabilit
`
`11 Dosage regimens
`
`"
`
`PART THREE Drug delivery systems
`12 Packs for pharmaceutical products
`13 Preformulation
`
`14 Solutions
`
`15 Suspensions
`16 Emulsions
`
`17 Powders and granules
`18 Tablets
`
`19 Capsules
`20 Therapeutic aerosols
`21 Parenteral products
`22 Topical preparations
`23 Suppositories and pessaries
`
`PART FOUR Pharmaceutical
`
`microbiology
`24 Fundamentals of microbiology
`25 The action of physical and chemical
`agents on micro—organisms
`26 Principles of sterilization
`27 Microbiological Contamination and
`preservation of pharmaceutical
`preparations
`28 Pharmaceutical applications of
`microbiological techniques
`
`PART FIVE Pharmaceutical
`
`technology
`29 Materials of fabrication and corrosion
`
`30 Heat transfer and the properties of
`steam
`
`31 Filtration
`
`32 Mixing
`33 Particle size analysis
`34 Particle size reduction
`
`35 Particle size separation
`36 Powder flow
`
`37 Granulation
`
`38 Drying
`39 Tableting
`40 Tablet coating
`41 Encapsulation
`42 Design and operation of clean rooms
`43 Sterilization practice
`'
`44 Packaging technology
`
`Index
`
`Vii V
`ix
`
`xi
`
`xiii
`
`15
`
`17
`
`38
`
`50
`
`62
`
`81
`
`119
`
`129
`
`131
`
`135
`
`174
`
`191
`
`213
`215
`
`223
`
`254
`
`269
`
`282
`
`. 300
`
`304-
`
`322
`
`341
`
`359 ’
`
`381
`
`412
`
`423
`
`425
`
`452
`
`472
`
`479
`
`491
`
`509
`
`511
`
`525
`
`538
`
`550
`
`564
`
`581
`
`591
`
`600
`
`616
`
`629
`
`647
`
`669
`
`678
`
`686
`
`700
`
`712
`
`725
`
`AstraZeneca Exhibit 2098 p. 3
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`

`

`M H Rubinstein
`18
`
`
`Tablets
`
`
`
`TABLETS AS A DOSAGE FORM
`Advantages of compressed tablets
`Types of tablet
`Essential properties of tablets
`
`TABLET FORMULATION
`Influence of tableting method on formulation
`Powder fluidizy
`Powder compressibility
`The need for granulation prior to compression
`Tableting methods
`Direct compression
`Dry granulation
`Wet granulation
`Tablet excipients
`Diluents
`Adsorbents
`Moistening agents
`Binding agents (adhesives)
`Glidants
`Lubricants
`Disintegrating agents
`Specific formulation requirements of other
`compressed dosage forms
`Lozenges
`Effervescent tablets
`Chewable tablets
`Sublingual and buccal tablets
`Implants.
`Multilayer tablets
`Sustained—release tablets
`Sustained-release tablets
`Advantages and disadvantages as a dosage form
`Types of sustained—release tablets
`‘
`Formulation of sustained-release tablets
`Methods ofachieving sustained release
`Diffusion-controlled release
`
`_
`
`304
`
`Dissolution-controlled release
`Release controlled by ion exchange
`Release controlled by osmotic pressure
`
`FORMULATION FACTORS AFFECTING THE
`RELEASE OF A DRUG FROM TABLETS
`The effecnye furface area 0f the drug
`Effect of binding agents
`Effect of disintegrants
`EffeCt 0f hfbl‘lcams
`Effect of diluents
`EffeCt 0f gramme Size
`
`TABLETS AS A DOSAGE FORM
`
`In December 1843 a patent was granted to the
`Englishman, William Brockedon, for a machine
`to compress powders to form compacts. This very
`simple device consisted essentially of a hole (or
`die) bored through a piece of metal within which
`the powder was compressed between two cylin-
`drical punches; one was inserted into the base of
`the die and at a fixed depth, the other was inserted
`at the top ‘of the die and struck with a hammer.
`The invention was first used to produce compacts
`of potassium bicarbonate and caught the imagin-
`ation of a number of pharmaceutical companies.
`Later, Wellcome in Britain was the first company
`to use the term tablet to describe this compressed
`dosage form. The British Pharmacopoeia defines
`tablets as being circular in shape with either flat
`or convex faces and prepared by compressing
`the medicament or mixture of medicaments,
`usually with added substances. Tablets are now
`the most popular dosage form, accounting for
`
`AstraZeneca Exhibit 2098 p. 4
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`some 70% of all ethical pharmaceutical prep-
`arations produced.
`Indeed the importance of
`tablets as a form of drug administration can be
`seen from the fact that the British Pharmacopoeia
`(BP) in 1932 included only one tablet monograph
`(glyceryl trinitrate), which rapidly increased to 82
`in the 1953 BP. By 1963 the BP had 183 tablet
`preparations, and in 1973 this figure had risen to
`310 and to 384 in the 1980 edition.
`
`Advantages of compressed tablets
`
`The compressed tablet has a number of advan-
`tages as a dosage form. It enables an accurate
`dosage of medicament to be administered simply.
`It is easy to transport in bulk and carry by the
`patient. The tablet is a uniform final product as
`regards weight and appearance, and is usually
`more stable than liquid preparations. The release
`rate of the drug from a tablet can be tailored to
`meet pharmacological requirements. Finally,
`the
`major advantage of the compressed tablet as a
`dosage form is that tablets can be mass produced
`simply and quickly and the resultant manufac-
`turing cost
`is therefore very much lower when
`compared with other dosage forms.
`
`Types of tablet
`
`Several categories of tablet can be distinguished
`dependent on the mode of use. The commonest
`type are those intended to be swallowed whole. A
`less common type of tablet is that formulated to
`allow dissolution or dispersion in water prior to
`administration. Many tablets are formulated to be
`effervescent and have become increasingly wider
`used in recent years because of their more rapid
`release of medicament and reduced chance of
`
`tablets are
`causing gastric irritation. Some
`designed to be chewed and used where buccal
`absorption is desired. Alternatively they may be
`intended to dissolve slowly in the mouth, e.g.
`lozenges or under the tongue (sublingual). There
`are now available many types of tablets which
`provide for the release of the drug to be delayed
`or allow a controlled, sustained rate of release.
`Many of these preparations are highly sophisti-
`cated and are referred to as
`‘complete drug
`delivery systems’. Tablets can also be coated so as
`
`TABLETS
`
`305
`
`to protect the drug against decomposition or to.
`disguise or minimize the unpleasant
`taste of
`certain medicaments (see Chapter 40 for further
`details). Coating also enhances the appearance of
`tablets and makes them more readily identifiable.
`
`In addition, coatings can be applied which are
`resistant
`to gastric
`juices but which readily
`dissolve in the small
`intestine. These ‘enteric’
`
`coatings can protect drugs against decomposition
`in the acid environment of the stomach. The
`
`traditionally involved the
`coating process has
`application of surface layers of sucrose so as to
`build up a thick sugar coat around the tablets.
`This process can take several days. For this reason
`the spray application of a film of material is now
`becoming more popular. This film coating tech-
`nique can be carried out
`in a coating pan or
`alternatively in specialized fluidized bed equipment.
`Compressed coating around a tablet core has also
`been developed. These compression machines can
`produce multilayer tablets with different
`ingre-
`dients in each layer, so that potentially incompat-
`ible ingredients can be formulated in the same
`tablet.
`'
`
`Essential properties of tablets
`
`The major advantage of tablets as a dosage form
`is that they provide an accurate dosage of medic-
`ament. Each tablet must
`contain a known
`
`amount of drug and this must be checked by
`content uniformity tests. Tablets must also be
`uniform in weight, appearance and diameter.
`Another prerequisite of tablets for oral use is that
`when they are swallowed whole they should
`readily disintegrate in the stomach. This property
`represents a great paradox in formulation, since
`tablets should be produced with sufficient strength
`to withstand the rigors of processing, coating and
`packing, yet be capable of rapid breakdown when
`administered in order to release the drug rapidly.
`This disintegration involves the bursting apart of
`the compact by aqueous fluids penetrating the fine
`residual pore structure of the tablet. These fluids
`come into contact with tablet components that
`either swell or release gases and so break apart the
`intact tablet. Perhaps the most significant property
`of tablets is that of dissolution rate. The active
`
`ingredient must be available pharmacologically
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`306 DRUG DELIVERY SYSTEMS
`
`and Since drugs cannot be absorbed into the blood
`Stream from the solid state, the active ingredient
`must first dissolve in the gastric or intestinal fluids
`before absorption can take place (see Chapter 9 for
`further discussion). Thus dissolution of the drug
`from tablets
`into aqueous
`fluids
`is
`a very
`important property of solid dosage forms (Chapter
`5). Tablets should also be stable to air and the
`temperature of the environment over a reasonable
`period of time and, in addition, light and moisture
`Should not affect tablet properties. Finally tablets
`Should be reasonably robust and be capable of with-
`standing normal patient handling and' handling
`during transport. The formulation of a tablet is
`thus designed so that the final tablet has all these
`essential properties.
`
`TABLET FORMULATION
`
`Influence of tableting method on formulation
`
`The majority of tablets are not composed solely
`of the drug. Various materials are usually added
`that make the powder system more compressible.
`Indeed powders intended for compression into
`tablets must possess
`two essential properties:
`fluidity and compressibility.
`
`Powder fluidity
`
`Fluidity iS required so that the material can be
`transported through the hopper of a tableting
`machine. If adequate fluidity does not exist, this
`gives rise to ‘arching’,
`‘bridging’ or ‘rat-holing’
`(see Chapter 36). Fluidity is also essential so that
`adequate filling of the dies occurs in the tableting
`machine to produce tablets of a consistent weight.
`If the powder formulation does not flow satisfac-
`torily, variable die filling will result, which will
`produce tablets that vary in weight and Strength
`and therefore steps must be taken to ensure that
`fluidity is maintained. Powder
`flow can be
`improved mechanically by the use of vibrators.
`However,
`the use of these devices can cause
`powder segregation and stratification and much
`care needs to be exercised. A better method to
`
`enhance powder fluidity is to incorporate a glidant
`into the formulation (see later). Materials such as
`fumed Silicon dioxide are excellent flow promoters
`
`even in concentrations of
`
`less
`
`than 0.01%.
`
`Another way to improve powder flow is to make
`the particles as Spherical as possible, for example
`by spray drying or by the use of spheronization
`machines such as the marumarizor. The most
`
`popular method of increasing the flow properties
`of powders is by granulation. Most powdered
`materials can be granulated and the improvement
`in flow can be quite Startling. Icing sugar, for
`example, will not flow, but if it is granulated with
`water it flows more easily.
`
`Powder compressibility
`
`the property of forming a
`Compressibility is
`stable,
`intact compact mass when pressure is
`applied. Paracetamol
`is poorly compressible
`whereas lactose compresses well. The physics of
`powder compression and why some materials
`compact better than others is a subject on its own
`and is described in Chapter 39. Much research
`work is in progress to characterize compaction
`behaviour but suffice to say that little is known
`about why some materials compress better than
`others. It is known, however, that in nearly all
`cases, granulation improves compressibility.
`
`The need for granulation prior to compression
`
`Granulation is the process of particle size enlarge—
`ment of powdered ingredients (see Chapter 37 for
`details) and is carried out to confer fluidity and
`compressibility to powder systems. In addition the
`ideal properties of a granule include the following:
`
`1 When compacted a tablet granulation should
`confer physical strength and form to the tablets.
`The granulation should be capable of being.
`subjected to high compression pressures without
`defects forming.
`2 A good granulation should have a uniform
`distribution of
`all
`the
`ingredients
`in the
`formulation.
`
`3 The particle Size range of the granulation should
`be log normally distributed. There should be a
`small percentage of both fine
`and coarse
`particles.
`4 Granules should be as near spherical Shape as
`possible and robust enough to withstand hand-
`ling, without breaking down.
`
`AstraZeneca Exhibit 2098 p. 6
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`

`

`5 The granulation should be relatively dust free
`thus minimizing powder spread during tableting.
`
`Tableting methods
`
`The preparation of tablets can be divided into
`(a) dry methods
`and (b) wet methods. Dry
`methods include direct compression, slugging and
`roller compaction, and wet methods include wet
`granulation. The reader is referred to Chapter 39
`for details.
`
`Direct compression
`
`Dry methods and in particular direct compression
`are superior to those methods employing liquids,
`since dry processes do not require the equipment
`and handling expenses required in wetting and
`drying procedures and can avoid hydrolysis of
`water-sensitive drugs. Some drugs, for example
`aspirin, can be tableted without further treatment,
`but the vast majority of drugs require the addition
`of
`a direct
`compression vehicle
`to
`aid
`compression. Great interest in direct compression
`has been evident
`in recent years and this has
`resulted in a wide range of direct compression
`tablet
`formulations being introduced. A direct
`compression vehicle is an inert substance which
`can be compacted with no difficulty and which
`may do so even when fairly large quantities of
`drugs are mixed with it. Materials currently avail-
`able as direct compression diluents may be divided
`into three groups according to their disintegration
`properties and their flow characteristics:
`
`1 disintegration agents with poor flow, e. g. micro-
`crystalline cellulose, microfine cellulose and
`directly compressible starch,
`2 free-flowing materials which do not disintegrate,
`e.g. dibasic calcium phosphate,
`3 free-flowing powders which disintegrate by
`dissolution, e.g. spray—dried lactose, anhydrous
`lactose,
`spray-crystallized maltose, dextrose,
`sucrose, dextrose, mannitol and amylose.
`
`Tablets are produced by mixing the drug with
`the compression vehicle in a blender. The powder
`mix is then compressed directly on a tableting
`machine. The process of direct compression is
`described in Chapter 39.
`
`TABLETS
`
`307
`
`should be free
`Direct compression vehicles
`flowing, physiologically inert, tasteless, colourless,
`and have a good mouth feel. Vehicles should also
`improve the compressibility of poorly compress-
`ible drugs, be relatively inexpensive and be
`capable of being reworked with no loss of flow or
`compressibility. Finally, direct compression diluents
`should promote rapid disintegration, be white and
`able
`to produce tablets containing 'a high
`proportion of non-compressible material (known
`as capacity). In practice, no one single material
`fulfils all these criteria and it may be necessary to
`blend—two or more compressionaids together.
`The quantity of medicament which can be
`mixed with the carrier so that direct compression
`properties are retained is governed by the capacity
`of the carrier. The more compressible the active
`ingredient, the greater the proportion that can be
`carried successfully by the vehicle. When
`considering the capacity potential, it is normal to
`consider
`the active ingredient as being non-
`compressible. Generally, unless the drug itself is
`easily compressible,
`the amount of drug present
`is limited to a maximum of about 25% of the
`
`tablet weight. Another potential problem with
`direct compression is static electricity.
`The formulation and release of drugs from
`tablets prepared by direct compression has been
`extensively investigated. Fox et al. (1963) made a
`detailed study of the tableting properties of micro-
`crystalline cellulose. It was found that extremely
`hard tablets could be made with ease with no sign
`of lubrication difficulties. Flowability was very
`good and tablets exhibited excellent friability and
`rapid disintegration time. The dissolution of
`phenobarbitone and prednisone from directly
`compressed tablets and from tablets prepared by
`wet granulation was investigated by Kim (1970).
`It was found that,
`in general,
`tablets prepared
`from soluble direct compression vehicles containing
`a disintegrant showed faster dissolution times than
`those prepared by wet granulation. Bolhuis and
`Lerk (1973) evaluated eleven excipients and found
`that microcrystalline cellulose and extra fine
`lactose had the best overall properties.
`Microcrystalline cellulose (MCC) is perhaps the
`most widely used direct compression excipient. It
`exhibits the highest capacity and compressibility
`of all known direct compression vehicles (Mendell,
`
`AstraZeneca Exhibit 2098 p. 7
`
`

`

`
`
`308 DRUG DELIVERY SYSTEMS
`
`1972), however, its flow properties are relatively
`poor. MCC is chemically an inert material and is
`compatible with most drugs. Its high initial moist-
`ure content and its hygroscopicity may preclude
`its use with very moisture-sensitive drugs.
`However, there is some evidence that MCC may
`in fact stabilize drugs susceptible to hydrolysis, by
`perhaps acting as a moisture scavenging agent
`(Sixsmith, 1976). This has been demonstrated for
`ascorbic acid and aspirin. It has been reported that
`MCC has a specific stabilizing effect on nitro-
`glycerine tablets (Richman et al., 1965). It was
`later found byGoodhart et al. (1976), after a. very
`comprehensive Study,
`that nitroglycerine tablets
`formulated with MCC produced tablets with
`superior Stability and more uniform content than
`tablets prepared by the popularly used moulded
`technique.
`Another popular direct compression excipient
`is dibasic calcium phosphate, a comparatively cheap
`insoluble diluent with good flow properties. Khan
`and Rhodes (1972a, b) and Khan and Rooke
`(1976) have examined its compressional, disinte-
`gration and dissolution properties in the presence
`of various disintegrants. They have shown that a
`cationic ion exchange resin and sodium starch
`glycollate are effective disintegrants for dibasic
`calcium phosphate system even at
`low concen-
`tration. Dibasic calcium phosphate is Slightly
`alkaline, so must not be used where the active
`ingredient
`is sensitive to pH values of 7.3 or
`above. Shah and Arambulo (1974) have shown
`from accelerated stability tests that dibasic calcium
`phosphate (Emcompress) was probably unsuitable
`for ascorbic acid and thiamine hydrochloride,
`since deteriorating crushing strength and
`disintegration properties
`resulted as well
`as
`chemical degradation in the case of ascorbic acid.
`Calcium salts in general. have been shown to
`adversely effect
`the absorption properties of
`several drugs
`including tetracycline and they
`should not, therefore, be coformulated. Khan and
`Rhodes
`(1976) have
`shown that
`for directly
`compressing griseofulvin, dicalcium phosphate
`yielded tablets of better weight uniformity than
`MCC. Direct compression formulations of ampi-
`cillin have been successfully produced by Niazi et
`al.
`(1976) and shown to be better than Similar
`tablets produced by moist granulation.
`
`Dry granulation
`
`Granulation by compression or slugging is one of
`the dry methods which has been used for many
`years for moisture- or heat-sensitive ingredients.
`The blend of powders is forced into dies of a large
`heavy-duty tableting press and compacted. The
`compacted masses are called ‘slugs’. An alternative
`technique is to squeeze the powder blend into a
`solid cake between rollers. This is known as roller
`compaction. The slugs or roller compacts are then
`milled and screened in order to produce a granular
`form of
`tableting material ‘ which flows more
`uniformly than the original powder mix. These
`processes are described in more detail in Chapters
`37 and 39.
`Slugging has the advantage over direct compression
`in that once the slugs are formed, no segregation
`of drug and excipient can occur. In addition the
`method is useful for hydrolysable and thermola-
`bile drugs. Although used, slugging is a lengthy
`process and involves
`a
`relatively high capital
`investment since heavy-duty presses are expens—
`ive. Compared with other granulation processes,
`the throughput is slow.
`The effect of various tablet formulations and
`processing factors on the rate of dissolution of
`salicylic acid tablets prepared by slugging was
`investigated by Levy et al. (1963). It was found
`that the dissolution rate increased with decreasing
`granule Size and starch content of the granules.
`Increasing the
`slugging pressure of granules
`caused an increase in dissolution rate due to frac-
`
`turing of the harder granules into smaller particles
`with greater specific surface area. Langridge and
`Wells
`(1980)
`have"
`recently shown that pre-
`compression or slugging of a mixture of micro—
`crystalline
`cellulose
`and dicalcium phosphate
`dihydrate significantly reduced compressibility of
`both excipients. Although slugging is one of the
`oldest
`and most widely used processes
`for
`tableting,
`it has
`received very little scientific
`attention.
`
`Wet granulation
`
`Tableting by the wet granulation process is the
`most widely used method for pharmaceutical
`materials. The technique involves a number of
`
`AstraZeneca Exhibit 2098 p. 8
`
`

`

`stages which are described in detail in Chapter 39.
`The wet granulation process has a number of
`advantages over the other granulation methods but
`it is not readily suitable for hydrolysable and/or
`thermolabile drugs such as antibiotics. During the
`development of
`a
`tablet
`formulation,
`all
`the
`physical variables which can affect the resultant
`granules have to be considered also so as
`to
`minimize the effect of process variation on the
`quality of the final product.
`In wet
`Influence of granulation media
`granulation, the binder is normally incorporated
`as a solution or mucilage. The choice of the liquid
`phase will depend upon the properties of the
`materials to be granulated. Water
`is the most
`widely used binder vehicle but non-aqueous
`granulation using isopropanol, ethanol or methanol
`may be preferred if the drug is readily hydrolysed.
`Changes in drug solubility resulting from a change
`in solvent have been shown by Wells and Walker
`(1983)
`to affect granule strength due to solute
`
`'
`migration.
`In wet granulation, granule growth is initiated
`by the formation of
`liquid bridges between
`primary particles (see Chapter 37). Soluble ex-
`cipients will dissolve in the binder solution to
`increase the liquid volume available for wet granu-
`lation, consequently granules of large mean size
`are formed. The soluble components recrystallize
`on drying to form a greater number of solid
`bridges. If one of the components absorbs water,
`this reduces the volume of binder liquid available
`to form wet granules and so smaller granules will
`result
`(Jaiyeoba and Spring, 1980). Thus the
`choice of binder vehicle can affect the character-
`
`istics of the dry granules.
`Influence of binder concentration and volume
`
`Techniques of binder addition to powders include
`the incorporation of
`a concentrated binder
`solution followed by additional fluid, which main-
`tains a standard binder content. Shubair and
`
`(1976) studied the rate of release of
`Dingwall
`erythrosine from lactose tablets without disinte-
`grant or lubricant. It was found that release rate
`was inversely related to starch binder content.
`Release rates decreased progressively from 2 to
`10% w/w mucilage, but an unexpected rapid
`release followed use of 20% w/w starch mucilage.
`Further research did not indicate that poor binder
`
`TABLETS
`
`309
`
`distribution gave a complete explanation, since
`addition of water to dilute the 20% w/w mucilage
`to 10% w/w did not reduce the dissolution rate.
`Therefore the method of incorporation of the
`binder may also have an effect on drug release.
`The effect of increasing the volume of binder fluid
`used to granulate blends of lactose and boric acid,
`has been investigated by Opakunle and Spring
`(1976).
`Increasing the volume of binder
`fluid
`produced stronger granules, thought to be due to
`the formation of more binder bonds and the pres-
`ence of more recrystallized bridges. Thus the
`amount of binder
`fluid must be very closely
`controlled in order
`to produce granules of a
`consistent hardness.
`
`Tablet excipients
`
`A tablet does not just contain the active ingredient
`but also includes other substances, known as
`excipients, which have specific functions. The
`various classes of excipients which are normally
`incorporated into tablet formulations are discussed
`here.
`
`Diluents
`
`Diluents or ‘bulking agents’ are ‘inert’ substances
`which are added to the active ingredient in suffi-
`cient quantity to make‘a reasonably sized tablet.
`This agent may not be necessary if the dose of the
`drug per tablet is high. Generally, a tablet should
`weigh at least 50 mg and therefore very low dose
`drugs will invariably require a diluent to bring the
`overall tablet weight to at least 50 mg. The prin-
`cipal substance employed as a diluent is lactose. It
`has a pleasant taste, rapidly dissolves in water,
`absorbs very little moisture and is fairly neutral
`in reaction.
`Its main disadvantage is that
`it
`is
`somewhat expensive and has poor flow character-
`istics. Lactose deforms easily under pressure and,
`as a result of this ductility, good tablets are
`normally produced. The spray-dried form I of
`lactose flows much more readily and is used as a
`direct compression vehicle. Dicalcium phosphate is
`another diluent that is used extensively as a tablet
`diluent. It is insoluble in water and makes good
`hard, white granules. It absorbs even less moisture
`than lactose and is therefore used with hygro-
`
`AstraZeneca Exhibit 2098 p. 9
`
`

`

`310 DRUG DELIVERY SYSTEMS
`
`scopic drugs such as pethidine hydrochloride. The
`starches are used as diluents and as binding agents.
`They are available as finely divided powders and
`aid the disintegration process. Starches contain up
`to 14% moisture and can therefore lead to stability
`problems for a moisture—sensitive drug. Another
`very popular diluent
`is microcrystalline cellulose.
`This substance is supplied as a free-flowing ingre—
`dient and is normally used as a direct compression
`vehicle.
`It has disintegrating properties
`and
`requires less lubricant
`in the formulation than
`other diluents. Dextrose has been used as a bulking
`agent, but the granules produced are much softer
`and not very white. In addition, dextrose absorbs
`moisture. Sucrose is very hygroscopic and goes
`sticky on exposure to moisture. Its pleasant taste
`makes it especially useful in lozenges. Mannitol is
`another’sugar which, although expensive, is very
`quick dissolving and is therefore used for tablets
`that have to be dissolved, e.g. glyceryl trinitrate
`tablets. Since it has a negative heat of solution, it
`is used for chewable tablets because it imparts a
`pleasant taste and a cooling sensation when sucked
`or chewed. Table 18.1 summarizes the commonly
`used diluents.
`
`Table 18.1 Tablet diluents used in the wet granulation
`process
`
`
`
`Diluent Comments
`
`Dextrose
`
`Hygroscopic
`
`Dicalcium phosphate
`
`Inexpensive, insoluble in water
`
`a-Lactose BP
`
`Mannitol
`
`Microcrystalline
`cellulose
`
`Sodium chloride
`
`Inexpensive, relatively inert; the
`most frequently used diluent
`
`Freely soluble; used particularly for
`chewable tablets
`
`Excellent compression properties; has
`some disintegrating ability
`
`Freely soluble; used for solution
`tablets
`
`Sucrose
`Sweet taste but hygroscopic; may be
`diluted with lactose
`
`
`Courtesy of N. A. Armstrong.
`
`Adsorbents
`
`Adsorbents are substances included in a formu—
`
`lation that are capable of holding quantities of fluids
`in an apparently dry state. Oil-soluble drugs, fluid
`extracts or oils can be mixed with adsorbents and
`
`then granulated and compressed into tablets.
`Fumed silica, microcrystalline cellulose, magnesium
`carbonate, kaolin and bentonite are examples of
`adsorbents commonly employed.
`
`Moistening agents
`
`In wet granulation, a moistening agent is required
`which is usually water. If the formulated powder
`contains sucrose,
`for example,
`it may only be
`necessary to add water,
`since sucrose rapidly
`dissolves and acts as its own binding agent. In
`cases where water cannot be used because the
`drug is hydrolysed, then alcohol is often substi-
`tuted. Absolute alcohol
`is expensive and thus
`industrial methylated spirits is used. Care must be
`taken to remove all traces of the solvent during
`drying or the tablets will possess an alcoholic
`odour.
`Isopropyl alcohol
`is an alternative moist-
`ening agent. It is difficult, however, to remove the
`last traces from granules and it possesses an objec-
`tionable odour.
`
`Binding agents (adhesives)
`
`The substances that act as adhesives to bind
`
`powders together in the wet granulation process
`are known as binders. They also help to bind
`granules together during compression. If too little
`binding agent is included in a formulation, soft
`granules result. Conversely,
`too much binding
`agent produces large, hard granules.
`Binding agents can be added in two ways
`depending on the method of granulation:
`
`1 as a powder in the formulation as in ‘slugging’
`or in dry granulation methods,
`2 as a solution to the mixed powders as in wet
`
`granulation.
`
`There are not many examples of (1) since most
`substances require some moisture present to make
`them adhesive.
`
`Common binding agents include starch muci—
`lage and gelatin solution. Starch is a good and
`popular binder and needs to be present
`in an
`amount equal
`to 2%.
`It
`is
`incorporated as a
`mucilage-in water. When dry, the starch binder
`is insoluble in water, unlike gelatin which remains
`soluble in the dry state. Gelatin is often used as
`a binder
`in lozenges. Among the other most
`
`AstraZeneca Exhibit 2098 p. 10
`
`

`

`important binders is polyvinylpyrrolidone (PVP).
`This substance is soluble both in water and in
`
`alcohol and has been shown to release drugs faster
`than with other binders. Rubinstein and Rughani
`(1978), using four binders in a tablet formulation
`of frusemide, showed how the choice of binder
`affects dissolution rate. They observed £50 values
`between 3.65 minutes with PVP to 117 minutes
`
`with starch mucilage. Other less common binders
`include hydrolysed gelatin, derivatives of seaweed
`(such as alginic acid, sodium alginate and calcium
`alginate) and cellulose derivatives (in particular
`ethyl cellulose and hydroxypropylmethylcellulose).
`Common binders used in the wet granulation
`process are listed in Table 18.2.
`
`Table 18.2 Adhesives (binders) used in the wet granulation
`process
`
`Adhesive
`
`Comments
`
`Concentration
`171
`
`granulaling
`fluid (% w/v)
`
`Yields very hard granules
`
`Forms gel in cold,
`therefore warm
`
`solution used; strong
`, adhesive, often used in
`lozenge granules
`
`Strong adhesive;
`hygroscopic, so tablet
`may weaken in humid
`conditions
`
`So