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`CELGENE 2067
`CELGENE 2067
`APOTEX v. CELGENE
`APOTEX v. CELGENE
`IPR2023-00512
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`

`

`'C)Phar111aceutics: The Science of Dosage Fonn Design
`
`

`

`Pharn
`Dosag
`
`EDITED BY
`Michael
`
`Reader in Pharmac)
`
`t:> qt>
`h][:J[:J
`hlr:Jw
`t==7
`ClIURCH!
`EDINBURG
`
`r
`
`

`

`• ~harmaceutics: The Science of
`Dosage Form Design
`
`EDITED BY
`Michael E. Aulton BPharm PhD MPS
`
`Reader in Pharmacy, Leicester Polytechnic, Leicester, UK
`
`,I-
`
`r
`
`[> [:J· [>
`[:J [:J [:J
`[:J [:J [:J
`C J
`CHURCHILL LIVINGSTONE
`EDINBURGH LONDON MELBOURNE AND NEW Yo'RK 1988
`
`

`

`Contents
`
`Preface
`Contributors
`Acknowledgeme
`About this boo~
`1 The design 1
`PART ONE Pl
`principles of pl
`2 Rheology ar
`3 Solutions ar
`4 Surface and
`5 fpiubility a
`6 Disperse sy
`7 Kinetics an
`PART TWO:
`8 IntroductiQ
`9 Factors inf
`10 Assessmen1
`11 Dosage reg
`PART THRE
`12 Packs for I
`13 Preformuh
`14 Solutions
`15 Suspensio1
`16 Emulsions
`17 Powd~rs a
`18 Tablets
`19 Capsules
`20 Therapeu1
`21 Parenteral
`22 Topical p
`23 Suppositc
`
`J
`
`i
`
`CHURCHILL LIVINGSTONE
`Medical Division of Longman Group UK Limited
`Distributed in the United States of America by
`Churchill Livingstone Inc., 1560 Broadway, New
`York, N.Y. 10036, and by 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 EHl 3AF).
`
`First published 1988
`Reprinted 1989
`0-443-03643-8
`ISBN
`British Library Cataloguing in Publication Data
`Pharmaceutics: the science of dosage form
`·design.
`1. Pharmaceutics
`I. • Aulton, Michael E.
`RS403
`615'.19
`Library of Congress Cataloging in Publication Data
`P_harmaceutics: the science of dosage form design.
`Replaces: Cooper and Gunn's tutorial pharmacy.
`6th ed. 1972.
`Includes bibliographies and index.
`1. Drugs - Design of delivery systems. 2. Drugs
`- Dosage forms. 3. Biopharmaceutics.
`4. Pharmaceutical technology. 5. Chemistry,
`Pharmaceutical. 6. Microbiology, Pharmaceutical.
`I. Aulton, Michael E.
`[DNLM: 1. Biopharmaceutics. 2. Chemistry,
`Pharmaceutical. 3. Dosage Forms. 4. Technology,
`Pharmaceutical. 5. Microbiology, Pharmaceutical.
`QV 785 P5366J
`86-25888
`615.5'8
`RS420.P48 1987
`
`Produced by Longman Group (FE) Ltd
`Printed in Hong Kong
`
`

`

`Contents
`
`&✓
`lg-5
`t>531.p~
`} q it
`
`.J·
`
`Preface
`Contributors
`Acknowledgements
`About this book
`1 The design of dosage forms
`
`PART ONE Physicochemical
`principles of pharmaceut.ics
`2 Rheology and the flow of fluids
`3 Solutions and their properties
`4 Surface and interfacial phenomena
`~olubility and dissolution rate
`15 Disperse systems
`7 Kinetics and stability testing
`
`PART TWO Biopharmaceutics
`8 Introductiqn to biopharmaceutics
`9 Factors influencing bioavailability
`10 Assessment of bioavailability
`11 Dosage regimens
`
`PART THREE Drug delivery systems
`12 Packs for pharmaceutical products
`J3 Preformulation
`14 Solutions
`15 Suspensions
`16 Emul&ions
`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 0org!lnisms
`26 Principles of sterilization
`27 Microbiological contamination and
`preservation of pharmaceutical
`preparations·
`28 Pharmaceutical applitatioris of
`microbiological te:cliniques
`
`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
`
`vu
`lX
`xi
`Xlll
`
`1
`
`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
`
`

`

`Preface·
`
`The first edition
`6th edition of C
`macy published •
`there has been a
`in the title of th
`authors and a co
`all is not new a
`with Leicester
`Sidney Carter re,
`Leicester School
`book to me. He
`from 9fie of its fc
`was formerly He
`macy but sadly c
`-There are a g1
`of authors in thi:
`in the field . on v
`as important, ea
`imparting that ir
`macy students.
`
`f
`it
`
`

`

`Preface
`
`The first edition of Pharmaceutics has replaced the
`6th edition of Cooper and Gunn's Tutorial Phar(cid:173)
`macy published by Pitman in 1972. Since then,
`there has been a change in editorship, a change
`in the title of the book, a change in some of the
`authors and a completely redesigned content. But
`all is not new and disjointed, the editorial link
`with Leicester School of Pharmacy continues.
`Sidney Carter recently retired as Peputy Head of
`Leicester School of Pharmacy and passed on the
`book to me. He in turn had inherited the book
`from one of its founders, the late Colin Gunn who
`}vas formerly Head of Leicester School of Phar(cid:173)
`macy but sadly died on 25 February 1983.
`There are a greater number and a wider range
`of authors in this edition, each an accepted expert
`in the field on which they have written and, just
`as important, each has experience and ability in
`imparting that information to undergraduate phar(cid:173)
`macy students.
`
`,
`
`Dr ME Aulton
`School of Pharmacy
`Leicester Polytechnic
`
`The philosophy of the subject matter which the
`book covers has changed beca:use pharmaceutics
`has changed. Since the last edition of Tutorial
`Pharmacy there have been very marked changes
`in the con~ept . :gi.d content of pharmaceutics.
`Those changes ar~ reflected in this edition. The
`era of biopharma~ii;:,s was in its infancy at the
`time of the previous edition. Since then we have
`becom~. ip.creas1ngly concerned with not merely
`produc;,i~g ·~iegant and '.ac2tirate dosage forms but
`also; ensµring rl).a.k~he op~·mum amount of drug
`reaches ·the' req1iif-ed>pfac;,e in the body and stays
`there f6r.. the' optimµn\ amount of time. Now we
`are conc,:rped • much .more with designing dosage
`forms and1with all aspects of drug delivery. This
`book reflects that concern.
`
`•
`
`,•'l''"'
`
`

`

`Contributors
`
`Dr N A Armstrong
`Senior Lecturer in Pharmaceutics, Welsh School
`of Pharmacy, University of Wales Institute of
`Science and Technology, Cardiff, Wales.
`Dr ME Aulton
`Reader in Pharmacy, School of Pharmacy,
`Leicester Polytechnic, Leicester, England.
`Professor B W Barry
`Professor of Pharmaceutical Technology,
`Postgraduate School of Studies in Pharmacy,
`University of Bradford, Bradford, England.
`.
`T
`MR Billany
`Senior Lecturer· in Pharmaceutics, School of
`Pharmacy, Leicester Polytechnic, Leicester,
`England.
`DA Dean
`Science and Technology Laboratories,
`Pharmaceutical Division, Fisons plc,
`Loughborough, England.
`Dr C J de Blaey
`Secretary for Scientific Affairs, Royal Dutch
`Association for Advancement in Pharmacy
`(K.N.M.P.), 's-Gravenhage (The Hague),
`Netherlands. Formerly Professor of Subfaculty
`of Pharmacy, University of Utrecht, Utrecht,
`Netherlands.
`Dr J T Fell
`Lecturer in Pharmacy, Department of Pharmacy,
`University of Manchester, Manchester, England.
`Dr J L Ford
`Lecturer in Dosage Form Design and
`Microbiology, School of Pharmacy, Liverpool
`Polytechnic, Liverpool, England.
`
`Dr I Gonda
`Lecturer in Industrial Pharmacy, Department of
`Pharmacy, University of Sidney, Sidney,
`Australia and Honorary Member of Staff,
`Department of Pharmacy, University of Aston in
`Birmingham, Birmingham, England.
`Dr G W Hanlon
`Senior Lecturer in Microbiology, Department of
`Pharmacy, Brighton Polytechnic, Brighton,
`England.
`Dr NA Hodges
`Senior Lecturer in Microbiology, Department of
`Pharmacy, Brighton Polytechnic, Brighton,
`England.
`Dr J E Hogan
`Director of Scientific Affairs, Colorcon Ltd,
`Orpington, England.
`BE Jones
`Technical Services, Elanco. Division, Eli Lilly
`and Company Ltd, Basingstoke, England.
`Dr J B Kayes
`At time of writing, visiting Professor, School of
`Pharmaceutical Sciences, Universiti Sains
`Malaysia, Pulau Pinang, Malaysia. Formerly
`Senior Lecturer in Physical Pharmacy,
`Department 'of Pharmacy, University of Aston in
`Birmingham, Birmingham, England.
`Professor C Marriott
`Reader in Pharmacy, Department of Pharmacy,
`Brighton Polytechnic, Brighton, England.
`Dr F S S Morton
`Pharmaceutical Services Manager, R P Scherer
`Ltd, Swindon, England.
`
`

`

`X CONTRIBUTORS
`
`Professor M S Parker
`Head of Department, Department of Pharmacy,
`Brighton Polytechnic, Brighton, England.
`
`Dr S G Proudfoot
`Senior Lecturer in Pharmaceutics, School of
`Pharmacy, Leicester Polytechnic, Leicester,
`England.
`Dr J H Richards
`Principal :Lecturer in Pharmaceutics, School of
`Pharmacy, Leicester Polytechnic, Leicester,
`England.
`
`Dr M H Rubinstein
`Reader, School of Pharmacy, Liverpool
`Polytechnic, Liverpool, England.
`
`Dr H Seager
`Research and Development Director (Europe),
`R P Scherer Ltd., Swindon, England.
`.
`Dr CJ Soper
`Lecturer in Pharmaceutics, -School of Pharmacy
`and Pharmacology, University of Bath, Bath,
`England.
`
`.
`
`Dr J N Staniforth
`Lecturer in Pharmaceutics, School of Pharmacy
`and Pharmacology, University of Bath, Bath,
`England.
`Dr M P Summers
`Lecturer in Pharmaceutics, School of Pharmacy,
`University of London, London, England.
`D N Travers
`Principal Lecturer in Pharmaceutical
`Technology, School of Pharmacy, Leicester
`Polytechnic, Leicester, England.
`Dr J J Tukker
`Subfaculty of Pharmacy, University of Utrecht,
`Utrecht, Netherlands.
`Dr JI Wells
`Pharmaceutical Research and Development, •
`Pfizer Central Research, Sandwich, Kent, .
`England.
`Dr P York
`Senior Lecturer in Pharmaceutics, Postgraduate
`Scho_ol of Studies in Pharmacy, University of
`J'
`Bradford, Bradford; England.
`
`Ii
`!I
`II
`H r
`
`Acknowh
`
`The Editor wis
`. thank the follm
`preparation of t:
`Mr Sidney 1
`predecessor, C(
`macy' for passin
`the first editi<
`invaluable expc
`throughout the
`greatly apprecia
`The authors
`put ,flho · their
`numerous otht
`The many ur
`assisted the aut
`
`

`

`:hool of Pharmacy
`of Bath, Bath,
`
`:hool of Pharmacy,
`o, England.
`
`:eutical
`1cy, Leicester
`,d.
`
`ersity of Utrecht,
`
`Develop'merit,
`vich, Kent,
`
`tics, Postgraduate
`·, University of
`
`Acknowledgements
`
`The Editor wishes to take this opportunity to
`. thank the following who have assisted with the
`preparation of this text:
`
`Mr Sidney Carter, who edited this book's
`predecessor, Cooper and Gunn's Tutorial Phar(cid:173)
`macy, for passing on to me the opportunity to edit
`the first edition of this new
`textbook. His
`invaluable experience and guidance aided me
`throughout the preparation of this edition and are
`greatly appreciated.
`The authors for the work and time that they
`/put into their texts, often under pressure from
`numerous other commitments, and from me.
`The many unnamed
`typists and artists who
`assisted the authors.
`
`My wife Christine, for typing and other sec(cid:173)
`ret~rial assistance, and help in many other ways
`which enabled me to spend time on this book. •
`My BBC micro.
`Katharine Watts and Alison Walsh of Churchill
`Livingstone, and Howard Bailey of Pitman for
`their special expertise and assistance in i~tro(cid:173)
`ducing me to the world of publishing.
`The many academic and industrial pharmacists
`who helped during the design of the contents of
`this edition to ensure that it corresponds as closely
`as possible with modern practice and with the
`•
`syllabuses of most schools of pharmacy.
`Those publishing companies who have given
`their permission to reproduce material here.
`
`

`

`About this book
`
`One of the earliest impressions that many new
`pharmacy students have of their chosen subject is
`the large number of long and sometimes unusual
`sounding names that are used to describe the
`various. subject areas within pharmacy. The aim
`• of this section is to explain to the reader what is
`meant by the term 'pharmaceutics', how the term
`• has been interpreted for the purpose of this book
`and how pharmaceutics fits
`into the overall
`scheme of pharmacy. It will also lead the reader
`through the organization of this book and explain
`the necessity of an understanding of the material
`,rt1Jntained in its chapters.
`The word pharmaceutics if; used in pharmacy
`to encompass many subject areas which are all
`associated with the steps to which a drug is
`subjected towards the end of its development -
`i.e. after its discovery or synthesis, isolation and
`purification, and testing for advantageous phar(cid:173)
`macological effects and absence from serious
`toxicological properties. Pharmaceutics is arguably
`the most diverse of all the subject areas in ,phar(cid:173)
`macy and traditionally encompasses the design
`and formulation of medicines (physical pharma(cid:173)
`ceutics, dosage form design), the manufacture of
`these medicines on both a smaU ( compounding)
`and large (pharmaceutical technology) scale, the
`cultivation, avoidance and elimination of micro(cid:173)
`organisms (microbiology) and the distribution of
`medicines · to patients ( dispensing and pharmacy
`practice).
`As the subtitle of this edition indicates, this
`book concentrates on that part of· pharmaceutics
`which is concerned with the conversion of a drng
`chemical into a medicine -
`the design of dosage
`forms. Medicines are drug delivery systems; they
`are means of getting drugs into the body in a safe,
`
`efficient, reproducible and convenient manner.
`The first chapter in the book describes, in a
`general way, the considerations that must be made
`so that this conversion of drug to medicine can
`take place. It emphasizes the fact that medicines
`are rarely drugs alone but require additives to
`make them into dosage forms and this in turn
`introduces
`the concept of formulation. The
`chapter explains
`that
`there are
`three major
`considerations in the design of dosage forms:
`1 the physicochemical properties of the drug
`itself,
`2 biopharmaceutical considerations, such as how
`the route of administration of a dosage form
`affects the rate and extent of drug absorption
`into the body,
`3 therapeutic considerations of the disease state to
`be treated, which in turn decide the most suit(cid:173)
`able type of dosage form, possible routes of
`administration and the most suitable duration
`of action and dose frequency for the drug in
`question.
`
`As a consequence of the first of these points,
`Part 1 of this book describes some of the more
`important physicochemical properties that one
`needs to know .about in order to study and under(cid:173)
`stand the design and preparation of dosage forms.
`The chapters ,have been designed to give the
`reader an insight into those physicochernical prin(cid:173)
`ciples which are important to the formulation
`scientist. They are not intended as a substitute for
`a thorough understanding of physical chemistry
`and specific more detailed texts are recommended
`throughout. For many reasons, which are
`discussed in the book, the vast majority of dosage
`forms. are orally administere<i in the form of solid
`
`

`

`nological problem
`ture of solid dosa~
`reader will quick
`in preparing solid
`powders and thm
`of particle size o1
`size reduction and
`those of other :
`associated with th
`capsule productio
`enough to achiev
`also be uniform.
`effectively enlarg1
`necessary partly
`and tableting pro
`are themselves a
`commonly invoh
`and so the drying
`
`xiv ABOUT THIS BOOK
`
`products such as tablets and capsules. This means
`that one of the most important stages in drug
`administration is the dissolution of solid particles
`to form a solution in the gastrointestinal tract.
`This necessitates that the formulation scientist
`has a knowledge of both liquid and solid materials
`and particularly the properties of drugs in solution
`and the factors influencing drug dissolution from
`solid particles. However, before these subjects can
`be examined, the reader must first understand the
`way in which fluids flow and know a little about
`some of the resulting problems (additionally,
`solutions and semisolids are dosage forms in their
`right). The.· properties of solutions are
`own
`discussed next. • The reader will see later in the
`book how drug release and absorption are strongly
`dependent on solution properties such as solute
`dissociation and diffusion. The properties of inter(cid:173)
`faces are described in the following chapter. These
`are important to an understanding of adsorption
`onto solid surfaces and • as a prelude to the
`dissolution of solid particles and the study of
`disperse systems such as colloids, suspensions and
`emulsions. Before finalizing on a possible dosage
`form there must be a clear understanding of the
`stability of the drug(s) and other additives in the
`formulation with respect to the reasons why and
`the rates at which they degrade and there must be
`an awareness of means of inhibiting decomposition
`and increasing the shelf life of a product.
`• Even with this fundamental knowledge it is not
`possible to begin to design a dosage form without
`having an understanding of how drugs are
`absorbed into the body, the various routes that
`can be used for this purpose and the fate of the
`drugs once they enter the body and reach their site
`of action. This book concentrates . on the prep(cid:173)
`aration, administration, release and absorption of
`drugs, but stops short at the cellular level and
`leaves to other texts the detail of how drugs enter
`individual cells, how they act, how they are
`metabolized and how they are eliminated. These
`cellular considerations are not within the remit of
`this book.
`The terms bioavailability and biopharmaceutics
`are defined and explained in Part 2 of the book.
`The factors influencing the bioavailability of a
`• drug and methods of assessing it are described.
`Finally in that section consideration is given to the
`
`manner in which the frequency of administration
`of a drug affects its level in the blood at any given
`time.
`In Part 3, the book then goes on to discuss the
`actual drug delivery systems which are available.
`It covers their formulation, the release of drugs
`from them, and their advantages and disadvan(cid:173)
`tages as a dosage form. This part starts with a
`consideration of the pack into which the medicine
`is put. This may seem odd since packaging is
`often the last stage in a manufacturing process but
`the pack and any possible interactions between it
`and the drug or medicine it contains are so vitally
`linked that it must not be considered as an after(cid:173)
`thought; these should be uppermost in the minds
`of the formulators as soon as they receive the drug
`powder on which to work. The steps that need to
`be considered before formulation itself can begin
`are discussed next. Results
`preformulation -
`-
`of tests carried out at this stage can give a much
`clearer indication of the possible dosage forms for
`a new drug candidate. Part 3 then considers
`existing dosage forms suitable for the adminis-
`• tration of drugs through almost every possible -
`body orifice and external surface, as well.WI' an
`to novel or future drug delivery
`intimation
`systems.
`Microbiology is a very wide ranging subject that
`is traditionally associated with pharmaceutics in
`schools of pharmacy. This book, in Part 4, has
`concentrated only on those aspects of micro(cid:173)
`biology that are directly relevant to the design,
`production and distribution of dosage forms. This
`mainly involves avoiding (asepsis) and eliminating
`(sterilization) their presence in medicines (contam(cid:173)
`the growth of any
`ination), and preventing
`microorganism which might enter the product
`during storage and use (preservation). Techniques
`intentions have been
`these
`that
`testing
`for
`achieved are also described.
`The actual production of medicines on a large
`scale is dealt with in the final part of the book,
`pharmaceutical technology. This begins with a
`consideration of the reaction vessels that are used
`during the manufacture of the drug chemical,
`other additives and the dosage form itself.
`There then follows an examination of those
`aspects of production mainly associated with
`liquids, i.e. heat transfer and filtration. The tech-
`
`r
`
`

`

`logical problems associated with the manufac(cid:173)
`µore of solid. dosage forms are then described. The
`tu ader will quickly realize that a major problem
`:e preparing solid dosage forms is the handling of
`10
`0wders and thus the . book explains the concept
`pf particle size of powders and its measurement,
`0
`jze reduction and size separation of powders from
`:hose of other sizes and the many problems
`associated with the flow of powders. In tablet and
`capsule production, for example, it is not simply
`enough to achieve fast flow, but that flow must
`also be uniform. We then see how powders are
`effectively enlarged in size (granulation). This is
`necessary partly to overcome some powder flow
`and tableting problems and also because granules
`are themselves a dosage form. Granulation most
`commonly involves the wetting of dry powders
`and so the drying of this wet material is ~escribed
`
`ABOUT THIS BOOK XV
`
`next. The book then moves on to tableting, tablet
`coating and encapsulation.
`Following this, techniques associated with the
`microbiological aspects of production are discussed.
`These are necessary in industry to eliminate
`microorganisms from the product both before or
`during manufacture. The technology of packaging
`and filling of products completes the book since
`this is the final production stage before warehousing,
`distribution and finally dispensing to the public.
`At this point the pharmaceutical technologist
`passes the product on to that other aspect of phar(cid:173)
`maceutics -
`the interface with the patient, i.e.
`dispensing and pharmacy practice. These aspects
`are dealt with in the companion volume Cooper
`and Gunn's Dispensing for Pharmaceutical Students
`later to become Pharmaceutical Practice.
`
`y of administration
`blood at any given
`
`:s on to discuss the
`rhich are available.
`1e release of drugs
`tges and disadvan-
`part starts with a
`..vhich the medicine
`since packaging is
`cturing process but
`ractions between it
`ntains are so vitally
`sidered as an after(cid:173)
`rmost in the minds
`1ey receive the drug
`! steps that need to
`.on itself can begin
`ISsed next. Results
`re can give a much
`le. dosage forms for
`3 then considers
`! for the adminis(cid:173)
`.ost every possibk
`ace, as well as a11_,
`tre drug,#delivery
`
`anging subject that
`pharmaceutics in
`::>k, in Part 4, has
`aspects of micro(cid:173)
`ant to the design;
`iosage forms. This
`is) and eliminating
`nedicines (contam(cid:173)
`: growth of any
`~nter the product
`ation). Techniques
`ttions have been
`
`:dicines on a large
`part of the book,
`1is begins with a
`ssels that are used
`te drug chemical,
`form itself.
`nination of those
`r associated with
`ltration. The tech-
`
`

`

`P York
`1
`----------------------------
`
`The design of dosage forms
`
`PRINCIPLES OF DOSAGE FORM DESIGN
`
`PRINCIPLES OF DOSAGE FORM DESIGN
`
`BIOPHARMACEUTICAL CONSIDERATIONS IN
`DOSAGE FORM DESIGN
`Routes of drug administration
`Oral route
`Rectal route
`Parenteral route
`Topical route
`Respiratory route
`
`DRUG FACTORS IN DOSAGE FORM DESIGN
`Organoleptic properties
`Particle size and surface area
`Solubility
`Dissolution
`Partition coefficient and pKa
`Crystal properties; polymorphism
`Stability
`Other drug properties
`
`THERAPEUTIC CONSIDERATIONS IN DOSAGE
`FORM DESIGN
`
`SUMMARY
`
`Drugs are rarely administered solely as pure
`chemical substances but are almost always given
`in formulated preparations. These can vary from
`relatively simple solutions
`to complex drug
`delivery systems, through the use of appropriate
`additives or excipients in the formulations to
`provide varied and specialized pharmaceutical
`functions. It is the formulation additives that,
`amongst other things, solubilize, suspend, thicken,
`preserve~ emulsify, improve the com pressi bili ty
`and flavour drug substances to form various prep(cid:173)
`arations or dosage forms.
`The principal objective of d0sage form design
`is to achieve a predictable therapeutic response to
`a drug included in a· formulation which is capable
`of large scale manufacture with reproducible
`product quality. To ensure product quality,
`numerous features are required -
`chemical and
`physical stability, with suitable preservation
`against microbial contamination if appropriate,
`uniformity of dose of drug, acceptability to users
`including both prescriber and patient, as well as
`suitable packaging and labelling. Ideally, dosage
`forms should also be independent of patient to
`patient variation although in practice this feature
`remains difficult to achieve. Future developme~ts
`in dosage form design may well attempt to.accom~
`modate to some extent this requirement.
`Reference is made in Part 2 of this book to
`differences in bioavailability between apparently·
`similar
`formulations and possible causative
`reasons. In recent years increasing attention has
`therefore been directed towards eliminating vari(cid:173)
`ation in bioavailability characteristics, particularly
`for chemically equivalent products since it 1s
`
`1
`
`

`

`2 THE DESIGN OF DOSAGE FORMS
`
`recognized that formulation factors can influence
`their therapeutic performance. To optimize the
`bioavailability of <lrug substances
`it
`is often
`necessary to carefully select the most appropriate
`chemical derivative of the drug, for example to
`obtain a specific solubility requirement, as well as
`its particle size and physical frirm, to combine it
`with appropriate additives and manufacturing aids
`that will not significantly alter the properties of
`the drug, to select the most appropriate adminis(cid:173)
`tration route(s) and dosage form(s) and to consider
`aspects of manufacturing processes and suitable
`packaging.
`There are numerous dosage forms into which
`a drug substance can be incorporated for the
`convenient and efficacious treatment of a disease.
`Dosage forms can be designed for administration
`by all possible delivery routes to maximize thera(cid:173)
`peutic response. Preparations can be taken orally
`or injected, as well as being applied to the skin or
`inhaled, and Table 1. 1 lists the range of dosage
`forms which can be used to deliver drugs by the
`ir
`various ad.ministration
`routes. However,
`is
`necessary to relate the drug substance and the
`disease state before the correct combination of
`drug and dosage form can be made since each
`disease or illness will require a specific type of
`drug therapy. Jn addition factors governing choice
`of administration route and the specific require-
`
`Table 1.1 Range of dosage forms available for different
`administration rnntcs
`
`/\dminisrm1ion
`route
`
`Oral
`
`Rce1al
`
`Topical
`
`Parenteral
`
`Lungs
`
`Nasal
`Eye
`Ear
`
`Do.HH;e jol'rns
`
`Solutions, syrups, elixirs. suspensions,
`emulsions, gels, pm.vdcrs, granules,
`capsules, tablets
`S11pposiwrics, ointment,. creams,
`powders, '.,olmions
`Ointments, creams, pastes, lotions, gels,
`solutions, topical aerosols
`Injections (solution, suspension, emulsion
`forms), implants, irrigation and dialysis
`solutions
`Aerosols (solution, suspension, emulsion,
`powder forms), inhalations, sprays,
`gases
`Solutions, inhalations
`Solutions, ointments
`Solutions, sµspensions, ointments
`
`ments of that route which affect drug absorption
`need to be taken imo account when designing
`dosage forms.
`Versatile drugs are often formulated into several
`dosage forms of varying strengths, each having
`particular pharmaceutical characteristics which are
`suitable for a specific application. One such drug
`is the glucocorticoid prednisolone. Through the
`use of different chemical forms and formulation
`additives a range of effective anti-inflammatory
`preparations are available including tablet, enteric
`coated tahlet, injections, eye drops and enema.
`The extremely low aqueous soluhility of the base
`prednisolone and acetate salt makes these forms
`useful in tablet and slowly absorbed intramuscular
`suspension injection forms, whilst the soluble
`sodium phosphate salt enables a soluble tablet
`form, and solutions for eye drops, l:nerna and
`intravenous injection to be prepared. The antibac(cid:173)
`terial drug combination co-trimoxazole, consisting
`of a mixture of five parts of sulphamethoxazole
`and one part trimethoprim, is also available in a
`range of dosage forms and strengths to meet
`specific needs of the user,
`including tablets,
`dispersible tablets, double strength tablets, double
`strength dispersible tablets, paediatric mixture,
`intramuscular
`injection, and a strong sterile
`solution for the preparation of an intravenous
`infusion. Because of the low aqueous solubility of
`both drug substances, specialized solvents are
`used for the intramuscular injection: 52% glyco(cid:173)
`furol, and strong sterile solution, 40% propylene
`glycol.
`therefore apparent that before a drug
`It is
`substance can he successfully formulated into a
`dosage form many factors ,must be considered.
`These can he broadly grouped
`into
`three
`categories:
`
`1 biopharmaceutical considerations, including
`factors affecting the absorption of the drug
`substance from different administration routes,
`2 drug factors, such as the physical and chemical
`properties of the drug substance, and
`3 therapeutic considerations including consider(cid:173)
`ation of the disease to be treated and patient
`factors.
`
`Appropriate and efficacious dosage forms will
`be prepared only when all
`the_se factors are
`
`ll
`
`B
`r:
`
`B
`ti
`a,
`
`f(
`
`ti
`d
`d
`n
`s:
`b
`
`L
`
`

`

`onsidered and related to each other. This is the
`~nderlying principle of dosage form design.
`
`BIOPHARMACEUTICAL CONSIDERATIONS
`IN DOSAGE FORM DESIGN
`
`Biopharmaceutics can be regarded as the study of
`the relationship between the physical, chemical
`and biological sciences applied to drugs, dosage
`forms and drug action. Clearly, understanding of
`the principles of this subject is
`important in
`dosage form design particularly with regard to
`drug absorption, as well as drug distribution,
`metabolism and excretion. In general, a drug
`substance must be in solution form before it can
`be absorbed via absorbing membranes of the skin,
`
`Gastro-
`intestinal tract
`
`Oral
`--+
`preparations
`
`Mouth_ f+
`
`Buccal
`
`Stomach ~
`...
`-E
`
`Q) -en
`
`>
`~ en
`Small -
`,__ L.
`.!!:!
`intestine
`=i
`(.)
`en
`I-.:. Ctl _>
`Large -
`intestine'
`- -- --
`Rectal ~
`Rectum-
`preparations
`
`-- -
`
`~
`
`ugin
`Dr
`fae ces
`
`"
`
`I
`
`Circulatory
`system
`(drug or
`metabolites)
`
`Direct
`or
`-
`Hepato-
`enteric
`
`Rectal .
`
`'
`
`I,
`
`Kidneys
`
`Drug in
`urine
`
`1
`
`Excretion
`
`I Elimination
`
`THE DESIGN OF DOSAGE FORMS
`
`3
`
`gastrointestinal tract and lungs into body fluids.
`Drugs. penetrate these membranes in two general
`ways -
`by passive diffusion and by specialized
`transport mechanisms. In passive diffusion, which
`is thought to control the absorption of most drugs,
`the process is driven by the concentration gradient
`existing across the membrane with drug molecules
`passing from regions of high to low concentration.
`The .lipid solubility and degree of ionization of the
`drug at the absorbing site influence the rate of
`diffusion. Several specialized
`transport mech(cid:173)
`anisms are postulated including active and facili(cid:173)
`tated transport. Once absorbed, the drug can exert
`a therapeutic effect yet the site of action is often
`remote from the site of administration and has to
`be transported in body fluids (see Fig. 1. 1).
`When the drug is administered from dosage
`
`Skin
`
`L.
`
`.!!:!E
`=i Q) - _,._
`u -
`en en.., -
`Ctl >
`> en
`
`-
`
`Topical
`~
`
`~ -
`
`S.c injection
`
`1.m. injection
`
`Lungs
`
`=> ~--
`
`_ ro E
`vl ~ ... -
`co en >
`
`-
`
`~
`
`Aerosols
`
`Gases
`I. v. injection
`
`Drug or
`- metabolite
`in tissues
`and extra
`cellular
`fluids
`
`'
`
`'
`
`,....
`
`Drug in saliva,
`exhaled air, etc.
`
`"
`
`I
`
`Fig. 1.1 Schematic diagram illustrating pathways a drug may take following administration of a dosage form by different
`routes
`
`1
`
`7
`:,
`
`.1
`
`7
`:,
`
`7
`:,
`
`1
`V
`
`s
`r
`
`t
`i
`
`7
`:,
`
`3.
`t
`