`

`CHURCHILL LIVINGSTONE
`l\n imprint of Harcourt Publishers Limited
`
`«) Harcourt Publishers Limited 2002 ,
`
`L)) is a registered trademark of Harcourt Publishers Limited
`
`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 either the prior permission of
`the publishers (Harcourt Publishers Limited, Harcourt Place,
`32 Jamestown Road, London NW! 7BY), or a licence
`permitting restricted copying in the United Kingdom issued
`by the Copyright Licensing Agency, 90 Tottenham Court
`Road, London WI!' OLP.
`
`First published 1988
`Second Edition 2002
`
`Standard edition ISBN 0 443 05517 3
`
`International Student Edition ISBN 0 443 05550 5
`
`Ilritish Library Cataloguing in Publication Data
`A catalogue record for this book is available from the British
`Library
`
`Library of Congress Cataloging in Publication Data
`A catalog record for this book is available from the Library of
`Congress
`
`Note
`Medical knowledge is constantly changing. As new
`information becomes available, changes in treatment,
`procedures, equipment and the use of drugs become
`necessary. The editor, contributors and the publishers have
`taken care to ensure that the information given in this text is
`accurate and up to date. However, readers are strongly
`advised to confirm that the information, especially with
`regard to drug usage, complies with the latest legislation and
`standards of practice.
`
`Printed in Spain
`
`The
`publisher's
`policy 1s to use
`paper manufactured
`from sustainable forests
`
`I
`
`This material \"¥as,cop:ied
`atth,e N LM and mav b'2
`
`

`

`CONTENTS
`
`24. Powders and granules 360
`Malcolm Summers
`
`25. Granulation 364
`lvlalcolnz Summers, Michael Aulto11
`
`26. Drying 379
`Michael Aulro11
`
`27. Tablets and compaction 397
`Goran Alderbom
`
`28. Coating of tablets and
`multiparticulates 441
`John Hogan
`
`29. Hard gelatin capsules 449
`Brian Jones
`
`30. Soft gelatin capsules 461
`Keith Hutchison, Josephine Ferdinando
`
`31. Pulmonary drug delivery 473
`Kevin Taylor
`
`32. Nasal drug delivery 489
`Peter Taylor
`
`33. Transdermal drug delivery 499
`Bria11 Barry
`
`34. Rectal and vaginal drug delivery 534
`Josef Tuld?er
`
`35. Delivery of pharmaceutical proteins 544
`Dael/I Cronmzelin, Ewoud van W'inden
`Albert Mcldd11g
`36. Packs and packaging 554
`Dixie Dean
`37. Pharmaceutical plant design 571
`Michael Aulum, Andrew Tzvi"lcl1e/l
`
`38. Heat transfer and the properties and use
`of steam 586
`Andrew Twitchell
`
`PART FIVE
`Pharmaceutical microbiology 597
`39. Fundamentals of microbiology 599
`Geoff Hanlon
`40. Pharmaceutical applications of
`microbiological techniques 623
`Norman Hodges
`41. The action of physical and chemical agents
`on microorganisms 643
`Geoff Hanlcm, Norman Hodges
`42. Microbiological contamination and
`preservation of pharmaceutical
`products 658
`Malcolm Parlwr, Norman Hodges
`
`Index 669
`
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`

`

`27
`Tablets and compaction
`
`Goran Alderborn
`
`CHAPTER CONTENTS
`
`Introduction 398
`
`Quality attributes of tablets 398
`Tablet manufacturing 399
`Stages in tablet formation 399
`Die filling 399
`Tablet formation 399
`Tablet ejection 399
`Tablet presses 399
`Single-punch press (eccentric press) 399
`Rotary press 400
`Computerized hydraulic press 400
`Instrumentation of tablet presses 400
`Technical problems during tabletting 402
`Tablet production via granulation 403
`Rationale for granulating powders prior to
`tabletting 403
`Granulation by convective mixing 403
`Alternative granulation procedures 404
`Tablet production by direct compaction 404
`Tablet excipients 404
`Filler (or diluent) 404
`Disintegrant 406
`Binder 407
`Glidant 408
`Lubricant 408
`Antiadherent 41 O
`Sorbent 410
`Flavour 410
`Colourant 410
`Tablet types 410
`Classification of tablets 41 O
`Disintegrating tablets 411
`Chewable tablets 412
`Effervescent tablets 412
`Lozenges 413
`Sublingual and buccal tablets 413
`Extended-release tablets 413
`Classification of extended-release tablets 413
`Diffusion-controlled release systems 414
`Reservoir systems 414
`Matrix systems 415
`Dissolution-controlled release systems 415
`
`Erosion-controlled release systems 416
`Osmosis-controlled release systems 417
`Tablet testing 417
`Uniformity of content of active ingredient 417
`Disintegration 418
`Dissolution 419
`Stirred-vessel methods 419
`Continuous-flow methods 419
`Mechanical strength 420
`Attrition-resistance methods 422
`Fracture-resistance methods 422
`Fundamental aspects of the compression of
`powders 423
`Mechanisms of compression of particles 423
`Evaluation of compression behaviour 424
`Procedures 424
`Inspection of tablets 425
`Pore structure and specific surface area of
`tablets 425
`Force-displacement profiles 426
`Tablet volume-applied pressure profiles 427
`Heckel equation 427
`Strain-rate sensitivity 428
`Kawakita equation 428
`Evaluation of die-wall friction during
`compression 428
`Fundamental aspects of the compaction of
`powders 430
`Bonding in tablets 430
`The compactability of powders and the strength of
`tablets 431
`Post-compaction tablet strength changes 433
`Relationships between material properties and
`tablet strength 435
`Factors of importance for powder
`compactability 435
`The compaction of solid particles 435
`The compaction of granules 437
`The compaction of binary mixtures 438
`References 439
`Bibliography 439
`
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`397
`
`

`

`DOSAGE FORM DESIGN AND MANUFACTURE
`
`INTRODUCTION
`
`The oral route is the most common way of adminis(cid:173)
`tering drugs, and among the oral dosage forms tablets
`of various different types arc the most common.
`Although a variety of tablets exist, with few exceptions
`(primarily sugar lozenges) tablets arc formed by the
`compression of a powder held within a confined space.
`The idea of forming a solid dosage form by powder
`compression is not new. In 1843 the first patent for a
`hand-operated device used to form a tablet was
`granted. The use of tablets as dosage form became of
`interest to the growing pharmaceutical industry, but
`within pharmacies the pill (a dosage form for oral
`administration formed by hand into spherical particles
`about 4-6 mm in diameter) remained the most
`popular solid dosage form for a long time.
`A tablet consists of one or more drugs (active ingre(cid:173)
`dients) as well as a series of other substances used in
`the formulation of a complete preparation. In the
`European Pharmacopoeia (3rd edition, 1997) tablets
`are defined as 'solid preparations each containing a
`single dose of one or more active ingredients and
`obtained by compressing uniform volumes of particles.
`They arc intended for oral administration. Some arc
`swallowed whole, some after being chewed, some are
`dissolved or dispersed in water before being adminis(cid:173)
`tered and some are retained in the mouth, where the
`active ingredient is 'libcrated'.Thus, a variety of tablets
`exists and the type of cxcipicnts and also the way in
`which they are incorporated in the tablet vary between
`the different types. There arc also other dosage forms
`that can be prepared in a similar way, such as suppos(cid:173)
`itories, but which arc administered by other routes.
`Tablets arc used mainly for systemic drug delivery
`but also for local drug action. For systemic use the
`drug must be released from the tablet, i.e. normally
`dissolved in the fluids of the mouth, stomach or
`intestine, and thereafter be absorbed into the sys(cid:173)
`temic circulation, by which it reaches its site of
`action. Alternatively, tablets can be formulated for
`local delivery of drugs in the mouth or gastrointesti(cid:173)
`nal tract, or can be used to increase temporarily the
`pH of the stomach.
`Tablets arc popular for several reasons:
`
`The oral route represents a convenient and safe
`way of drug administration.
`Compared to liquid dosage forms tablets have
`general advantagcs_in terms of the chemical and
`physical stability of the dosage form.
`• The preparation procedure enables accurate
`dosing of the drug.
`
`• Tablets arc convenient to handle and can be
`prepared in a versatile way with respect to their
`use and to the delivery of the drug.
`• Finally, tablets can be mass produced, with robust
`and quality-controlled production procedures
`giving an elegant preparation of consistent quality
`and, in relative terms, low price.
`
`The main disadvantage of tablets as a dosage form
`concerns the bioavailability of poorly water-soluble
`or poorly absorbable drugs. In addition, some drugs
`may cause local irritant effects or otherwise cause
`harm to the gastrointestinal mucosa.
`
`QUALITY ATTRIBUTES OF TABLETS
`
`Like all other dosage forms, tablets should fulfil
`a number of specifications regarding their chemical,
`physical and biological properties. Quality issues relat(cid:173)
`ing to the final product are worth considering early in
`the development process (and thus early in this
`chapter) as they give an indication of the goal to be
`achieved during the development and manufacture of
`tablets.
`Tests and specifications for some of these proper(cid:173)
`ties arc given in pharmacopoeias. The most impor(cid:173)
`tant of these are dose content and dose uniformity,
`the release of the drug in terms of tablet disintegra(cid:173)
`tion and drug dissolution, and the microbial quality
`of the preparation. In addition, the authorities and
`manufacturers define a set of other specifications.
`One such important property is the resistance of the
`tablet towards attrition and fracture.
`The quality attributes a tablet must fulfil can be
`summarized as follows:
`
`1. The tablet should include the correct dose of the
`drug.
`2. The appearance of the tablet should be elegant
`and its weight, size and appearance should be
`consistent.
`3. The drug should be released from the tablet in a
`controlled and reproducible way.
`4. The tablet should be biocompatible, i.e. not
`include excipicnts, contaminants and
`microorganisms that could cause harm to
`patients.
`5. The tablet should be of sufficient mechanical
`strength to withstand fracture and erosion
`during handling.
`6. The tablet should be chemically, physically and
`microbiologically stable during the lifetime of
`the product.
`
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`

`

`7. The tablet should be formulated into a product
`acceptable by the patient.
`8. The tablet should be packed in a safe manner.
`
`The process of tab letting can be divided into three
`stages (sometimes known as the co1npactio11 cycle)
`(Pig. 27.1).
`
`TABLETS AND COMPACTION
`
`TABLET MANUFACTURING
`
`Stages in tablet formation
`
`Tablets arc prepared by forcing particles into close
`proximity to each other by powder compression, which
`enables the particles to cohere into a porous, solid
`specimen of defined geometry. The compression takes
`place in a die by the action of two punches, the lower
`and the upper, by which the compressive force is
`applied. Powder compression is defined as the reduc(cid:173)
`tion in volume of a powder owing to the application of
`a force. Because of the increased proximity of particle
`surfaces accomplished during compression, bonds are
`formed between particles which provides coherency to
`the powder, i.e. a compact is formed. Compaction is
`defined as the formation of a porous specimen of
`defined geometry by powder compression.
`
`@_____-Die,'""'" ,iew
`
`:
`I
`I
`I
`
`'
`
`I
`I
`I
`I
`
`'
`
`I
`I
`I
`I
`
`'
`
`:
`I
`I
`I
`
`' ---- Die, section
`
`}
`
`------------ Lower punch
`
`Position 1
`Upper punch 1s raised;
`lower punch has dropped
`
`Foot of hopper shoe
`
`Granules
`
`Position 2
`Hopper shoe has moved
`forward over die and
`granules fall into die
`
`}
`
`Position 3
`Hopper shoe has moved
`back. Upper punch has
`come down compressing
`granules into tablet
`
`}
`
`Position 4
`Upper punch has moved
`upwards. Lower punch
`has moved upwards to
`eject tablet. The cycle
`is now repeated
`
`}
`
`qp
`qp
`
`Fig. 27.1 The sequence of events involved in the formation of
`tablets.
`
`Die filling
`
`This is normally accomplished by gravitational flow
`of the powder from a hopper via the die table into
`the die (although presses based on centrifugal die
`filling are also used). The die is closed at its lower
`end by the lower punch.
`
`Tablet formation
`
`The upper punch descends and enters the die and
`the powder is compressed until a tablet is formed.
`During the compression phase, the lower punch can
`be stationary or can move upwards in the die. After
`maximum applied force is reached, the upper punch
`leaves the powder, i.e. the decompression phase.
`
`Tablet ejection
`
`During this phase the lower punch rises until its tip
`reaches the level of the top of the die. The tablet is
`subsequently removed from the die and die table by
`a pushing device.
`
`Tablet presses
`There are two types of press in common use during
`tablet production: the single-punch press and the
`rotary press. In addition, in research and develop(cid:173)
`ment work hydraulic presses arc used as advanced
`equipment for the evaluation of the tabletting prop(cid:173)
`erties of powders and the prediction of scale-up on
`the properties of the formed tablets (scale-up refers
`to the change to a larger apparatus for performing a
`certain operation on a larger scale).
`
`Single-punch press (eccentric press)
`
`A single-punch press possesses one die and one pair
`of punches (Pig. 27.2). The powder is held in a
`hopper which is connected to a hopper shoe located
`at the die table. The hopper shoe moves to and fro
`over the die, by either a rotational or a translational
`movement. When the hopper shoe is located over the
`die, the powder is fed into the die by gravity. The
`amount of powder filled into the die is controlled by
`the position of the lower punch. When the hopper
`shoe is located beside the die, the upper punch
`descends and the powder is compressed. The lower
`punch is stationary during compression and the
`pressure is thus applied by the upper punch and
`
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`
`

`

`DOSAGE FORM DESIGN AND MANUFACTURE
`
`_______ Hopper shoe
`
`_____ Upper punch
`
`______ Ejection regulating screw
`
`_ - Capacity regulating screw
`
`Fig. 27.2 A single-punch tablet press.
`
`controlled by the upper punch displacement. After
`ejection the tablet is pushed away by the hopper shoe
`as it moves back to the die for the next tablet.
`The output of tablets from a single-punch press is
`about 200 tablets per minute. A single-punch press
`thus has its primary use in the production of small
`batches of tablets, such as during formulation devel(cid:173)
`opment, and during small-scale production, such as
`production for clinical trials.
`
`Rotary press
`The rotary press (also referred to as a multistation
`press) was developed to i~cre~se the. out?ut of
`tablets. The primary use of this machine 1s thus
`during scale-up in the latter part of t_he formulation
`work, and during large-scale production. Outputs of
`over IO 000 tablets per minute can be achieved by
`rotary presses.
`.
`.
`A rotary press operates with a number of dies and
`sets of punches, which can vary considerably from
`three for small rotary presses up to 60 or more for
`large presses. The dies arc mounted in a circle in the
`die table and both the die table and the punches
`rotate together during operation of the machine, so
`that one die is always associated with one pair of
`
`1 Die filling
`2 Powder volume control
`3 Powder compaction
`4 Tablet ejection
`
`Stationary
`hopper
`
`=-------------(cid:141) 0
`4
`Rotating
`die table
`
`®
`
`Fig. 27.3 Schematic illustration of the events involved in the
`formation of tablets with a rotary press.
`
`punches (Figs. 27.3 and 27.4). The vertical move(cid:173)
`ment of the punches is controlled by tracks that pass
`over cams and rolls used to control the volume of
`powder fed into the die and the pressure applied
`during compression.
`The powder is held in a hopper whose lower
`opening is located just above the die table. The
`powder flows by gravity on to the die table and is fed
`into the die by a feed frame. The reproducibility of
`the die feeding can be improved by a rotating device,
`referred to as a force-feeding device. During powder
`compression both punches operate by vertical move(cid:173)
`ment. After tablet ejection, the tablet is knocked
`away as the die passes the feed frame.
`
`Computerized hydraulic press
`
`For computerized hydraulic presses the movement
`of the punches can be controlled and varied consid(cid:173)
`erably. Thus,
`tablets can be prepared under
`controlled conditions with respect to the loading
`pattern and loading rate. Possible applications are
`the investigation of the sensitivity of a drug to such
`variations, or to mimic the loading pattern of
`production presses to predict scale-up problems.
`Because of this latter application, this type of press is
`also referred to as a 'simulator'.
`
`Instrumentation of tablet presses
`
`Significant research on the process of tablet prepara(cid:173)
`tion was initiated in the 1940s and 1950s, i.e. about
`I 00 years after the introduction of tablets as a dosage
`form. An important step in the development of such
`fundamental research was the introduction of instru(cid:173)
`mented tablet machines. By this instrumentation, the
`forces involved in the compaction process, i.e. the
`press forces from the upper and lower punches and
`
`400
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`

`TABLETS AND COMPACTION
`
`Fig. 27.4 Diagram of punch tracks of a rotary tablet press. UR, upper roller; LR, lower roller; W, powder volume adjuster; F, feed frame
`with granules. U1 to US, upper punches in raised position; L 1, lower punch at top position, tablet ejected; L2 to L7, lower punches
`dropping to lowest position and filling die with granules to an overfill at L7; LB, lower punch raised to expel excess granules giving
`correct volume; U9 to U 12, upper punches lowering to enter die at U 12; L 13 and U 13, upper and lower punches pass between rollers
`and granules are compacted to a tablet; U 14 to U 16, upper punch rising to top position; L 14 to L 16, lower punch rising to eject tablet.
`
`the force transmitted to the die, and the displacement
`of the upper and lower punch during the compression
`and decompression phases, could be recorded.
`Instrumented presses arc used in research, in
`development and in the production of tablets. In
`research and development, instrumented machines
`arc used to provide fundamental information on the
`mechanical and compaction properties of powders
`that should be used in tablet formulations. \X!ith this
`application, the work is normally carried out by
`instrumented single-punch presses or with instru(cid:173)
`mented hydraulic presses (compaction simulators).
`The two main applications for an instrumented press
`in research and development arc:
`
`1. to prepare tablets under defined conditions, e.g.
`in terms of applied force during compaction.
`These tablets arc thereafter characterized by
`different procedures, such as imaging, surface
`area and tensile strength analysis;
`2. to describe and analyse the compression
`properties of materials by studying punch forces
`and punch displacements during the
`compression and decompression phases. A series
`of different procedures exists involving, for
`example, the assessment of deformation
`behaviour of particles during compression and
`friction properties during ejection. Some of these
`are described below.
`
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`
`

`

`DOSAGE FORM DESIGN AND MANUFACTURE
`
`In production, instrumented production machines,
`i.e. rotary presses, arc used to control the tablctting
`operation and to ensure that tablets of consistent
`quality arc produced. Normally, only force signals
`are used on production machines and the variation
`in force signal during compression is followed as it
`reflects variations in tablet weight.
`Force transducers commonly used in the instru(cid:173)
`mentation of tablet machines arc of two types. The
`most common type is called a strain gauge, which
`consists of wires through which an electric current is
`passed. The strain gauge is bonded to a punch or
`punch holder. During powder compression, a force
`is applied to the punches and they will temporarily
`deform. The magnitude of this deformation is
`dependent on the elastic modulus of the punches
`and the force applied. When the punch is deformed
`the wire of the strain gauge is also deformed, and the
`electrical resistance of the strain gauge will change.
`This change in electrical resistance can be recorded
`and calibrated in terms of a force signal. Another,
`less common, type of force transducer, employs
`piezoelectric crystals. These are devices which emit
`an electrical charge when loaded, the magnitude of
`which is proportional to the applied force.
`Displacement transducers measure the distance
`which the punches travel during the compression and
`decompression processes. The most common type of
`displacement transducer delivers an analogue signal.
`It consists of a rod and some inductive elements
`mounted in a tube. When the rod moves within the
`tube, a signal is obtained which directly reflects the
`position of the rod. The movable rod is connected to
`the punch so that they move in parallel, i.e. the signal
`from the displacement transducer reflects the posi(cid:173)
`tion of the punch. Digital displacement transducers
`arc also used in instrumented tablet machines. Such
`transducers arc based on differences in signal level
`depending on the position of an indicator. One
`advantage of a digital displacement transducer is that
`it is insensitive to electrical noise ..
`necessarily
`Displacement
`transducers
`arc
`mounted some distance from the punch tip. There is
`therefore a difference in the position given by the
`transducer and the real position of the punch tip
`owing to deformation of the punch along the dis(cid:173)
`tance between its tip and the connection point of the
`transducer. This deviation must be determined by a
`calibration procedure, e.g. by compressing the
`punch tips against each other, and a co_rrection for
`this error must be made before the displacement
`data can be used.
`The signals from the force and displacement
`transducers are normally amplified and sampled into
`
`a computer. After conversion into digital form, the
`signals are transformed into physically relevant
`units, i.e. N, Pa, µ,m etc., and organized as a function
`of time. To obtain reliable data the calibration of the
`signals, the resolution of the measuring systems and
`the reproducibility of the values must be carefully
`considered.
`
`Technical problems during tabletting
`A number of technical problems can arise during the
`tabletting procedure, among which the most impor(cid:173)
`tant arc:
`• high weight and dose variation of the tablets
`• low mechanical strength of the tablets
`• capping and lamination of the tablets
`• adhesion or sticking of powder material to punch
`tips
`• high friction during tablet ejection.
`
`Such problems arc related to the properties of the
`powder intended to be formed into tablets, and also
`to the design and conditions of the press. They
`should therefore be avoided by ensuring that the
`powder possesses adequate technical properties and
`also that a suitable, well conditioned tablet press is
`used, e.g. in terms of the use of forced-feed devices
`and polished and smooth dies and punches.
`Important technical properties of a powder which
`must be controlled to ensure the success of a tablet(cid:173)
`ting operation arc:
`
`• homogeneity and segregation tendency
`• flowability
`• compression properties and compactability
`• friction and adhesion properties.
`
`The technical properties of the powder are con(cid:173)
`trolled by the ingredients of the formulation (i.e. the
`drug and excipients) and by the way by which the
`ingredients are combined into a powder during
`precompaction processing. The precompaction pro(cid:173)
`cessing often consists of a series of unit operations in
`sequence. The starting point is normally the drug in
`a pure, most often crystalline form; the subsequent
`treatment of the drug particles is sometimes referred
`to as downstream processing. The unit operations
`used during this precompaction treatment are
`mainly particle size reduction, powder mixing, parti(cid:173)
`cle size enlargement and powder drying. For further
`details sec Chapters 11, 13, 25 and 26, respectively.
`Traditionally, the use of a particle size enlargement
`operation, normally referred to as granulation, is the
`dominant procedure in preparing a powder for
`tablctting. To save time and energy, precompaction
`
`402
`
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`

`

`TABLETS AND COMPACTION
`
`This is considered to be the most effective means in
`terms of production time and cost to prepare good(cid:173)
`quality granulations. The process is often referred to
`as wet granulation.
`The ingredients to be granulated in a convective
`mixer are first dry mixed. The objective is to achieve
`a good homogeneity. As the components are often
`cohesive powders, a convective mixer operating at
`high intensity is normally used (a high-shear mixer).
`The mixture often consists of the drug and a filler. A
`disintegrant may also be included (i.e. an intragran(cid:173)
`ular disintcgrant), but it is also common to add the
`disintegrant to the dry granulation (i.e. an extra(cid:173)
`granular disintcgrant). After wet mixing the wet
`mass is dried in a separate drier (a fluidized-bed
`dryer or a tray dryer). Because granulation in a con(cid:173)
`vective mixer is not a very well controlled operation,
`large granules (above 1 mm) arc often formed which
`must be broken down into smaller units. This is nor(cid:173)
`mally done by milling in a hammer mill or by press(cid:173)
`ing the granulation through a screen in an oscillating
`granulator. Granules ranging in size from about 100
`to 800 µ.,m arc thus obtained.
`The prepared granulation is finally dry-mixed with
`the other ingredients, for example in a double-cone
`mixer, before tabletting. Common cxcipicnts added
`in this final mixing operation arc disintegrants, lubri(cid:173)
`cants, glidants and colourants. Figure 27.5 summa(cid:173)
`rizes the sequence of unit operations used in the
`production of tablets with prccompaction treatment
`by granulation.
`
`Example of
`apparatus
`
`Unit
`operation
`
`Excipient
`
`High-shear mixer
`
`Mixing
`
`..
`
`Filler
`
`High-shear mixer
`
`Agglomeration ..
`
`/ Solution binder
`l liquid
`
`Fluidized-bed dryer
`
`Hammer mill
`
`Double cone mixture
`
`~ l Dry binder
`
`Disintegrant
`
`~
`I Mifing
`, .... ~ Lubdcant
`I Tabletting I
`
`t
`
`Ant1adherent
`Glidant
`
`.
`.
`processing witho t ,
`, .
`.
`u a paruclc size enlargement oper-
`ation is chosen if
`"bl
`.
`,
`poss1 e. fh1s procedure is called
`t bl
`a et Product·
`b
`d"
`d.
`ion Y
`zrect conzpression or
`zrect conipaction.
`'
`
`Tablet production via granulation
`
`Ration_ale for granulating powders prior to
`tablettmg
`
`Bccaus_e both granulation and tabletting involve the
`~or_mau_on of aggregates, tablet production by granu(cid:173)
`auon is based on the combination of two size
`enlargement processes in sequence. The main ratio-
`n~lcs for granulating the powder (drug and filler
`mixture) before tabletting are:
`
`• to_ increase the bulk density of the powder
`mixture and thus ensure that the required
`volume of powder can be filled into the die·
`• to improve the flowability of the powder in 'order
`to ensure that tablets with a low and acceptable
`tab_let weight variation can be prepared;
`• to improve mixing homogeneity and reduce
`segregation by mixing small particles which
`subsequently adhere to each other;
`• to improve the compactability of the powder by
`adding a solution binder, which is effectively
`distributed on the particle surfaces;
`• to ensure a homogcnous colour in a tablet by
`adding the colour so it is distributed effectively
`over the particle surfaces;
`• to affect the dissolution process for hydrophobic,
`poorly soluble particles by using a fine particulate
`drug which is thoroughly mixed with a
`hydrophilic filler and a hydrophilic binder.
`
`Before granulation the drug might be processed sepa(cid:173)
`rately in order to obtain a suitable quality in terms of
`solid-state and particulate properties, such as spray(cid:173)
`drying and milling. Normally, the drug exists in dry
`particulate form before granulation. However, it might
`be suspended or dissolved in a liquid and be added to
`the filler as a part of the agglomeration liquid.
`Different procedures may be used to prepare a
`granulation, among which the most important arc
`the use of convective mixers, fluidized-bed driers,
`spray driers and compaction machines
`(sec
`Chapter 25 for further detail).
`
`Granulation by convective mixing
`
`Rotary press
`
`Agitation of a powder by convection in the presence
`of a liquid followed by drying, is the main procedure
`for the preparation of a pharmaceutical granulation.
`
`Fig. 27.5 Overview of the sequence of unit operations used in
`the production of tablets with precompaction treatment by
`granulation.
`
`This material 1,"¥as,cop:ied
`atth,e N LM and may bi2
`
`403
`
`

`

`DOSAGE FORM DESIGN AND MANUFACTURE
`
`Alternative granulation procedures
`
`A series of alternative granulation procedures can be
`preferable in certain situations. Granulation in a
`fluidized-bed apparatus is less common than the use
`of convective mixers as it is considered to be more
`time-consuming. However, granulations of high
`quality in terms of homogeneity, flowability and
`compactability can be prepared by this operation.
`By spray drying a suspension of drug particles in a
`liquid, which can contain a dissolved binder, rela(cid:173)
`tively small spherical granules with uniform size can
`be prepared. The process is of limited use except for
`the preparation of fillers or dilucnts for direct com(cid:173)
`paction. The granulation can show a good com(cid:173)
`pactability and presents a possibility to granulate a
`drug suspension without a separate drying step for
`the drug substance.
`The formation of granules by compacting the
`powder into large compacts which arc subsequently
`comminuted into smaller granules (often referred to
`as dry granulation, or slugging) is a possible gran(cid:173)
`ulation procedure which, however, is not widely used
`in pharmaceutical production. The procedure can be
`employed as a means to avoid exposure of the powder
`to moisture and heat. In addition, for powders of very
`low bulk density compaction can be an effective
`means to increase markedly their bulk density.
`
`Example of
`apparatus
`
`Unit
`operation
`
`Excipient
`
`High shear mixer
`
`Mixing
`
`Rotary presss
`
`Tabletting
`
`Dry binder
`_ Disintegrant
`
`l Mixing
`l Lubricant
`
`Antiadherent
`Glidant
`
`Fig. 27.6 Overview of the sequence of unit operations used in
`the production of tablets by direct compaction.
`
`ing mainly of drug will be difficult to form into
`tablets if the drug itself has poor compactability.
`Finally, an even colouring of tablets can be difficult
`to achieve with a colourant in dry particulate form.
`Direct compaction has been used mainly for two
`types of drug, firstly, relatively soluble drugs which
`can be processed as coarse particles (to ensure good
`flowability) and, secondly, relatively potent drugs
`which are present in a few milligrams in each tablet
`and can be mixed with relatively coarse excipient
`particles (in this latter case the flow and compaction
`properties of the formulation are controlled mainly
`by the cxcipients).
`
`Tablet production by direct compaction
`An obvious way to reduce production time and
`hence cost is to minimize the number of operations
`involved in the pretreatment of the powder mixture
`before tabletting. Tablet production by direct com(cid:173)
`paction involves only two operations in sequence,
`powder mixing and tabletting (Fig. 27.6). The
`advantage with direct compaction is primarily a
`reduced production cost. However, in a direct com(cid:173)
`pactable formulation speciall? design_ed fillers and
`dry binders arc normally requ_1~cd, which usually are
`more expensive than the tradmonal ones. They may
`also require a larger number of quality tests before
`processing. As heat and water ar~ not involved,
`product stability can be improved. Finally, drug dis(cid:173)
`solution might be faster from a tablet prepared by
`direct compa