CHURCHILL LIWNGSTONE
`
`Medical Division of Longman 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
`21 Licence permitting restricted copying in the United
`Kingdom issued by the Copyright Licensing Agency Ltd,
`90 Tottenham Court Road, London, WIP 9HE.
`
`First published 1988
`Reprinted 1989
`Reprinted 1990
`Reprinted 1991
`Reprinted 1992
`
`ISBN El—LiLi3-E|3l:'-13-6
`
`British Library Cataloguing in Publication Data
`Pharmaceutics: the science of dosage form
`design.
`1. Pharmaceutics
`I. Aulton, Michael E.
`615‘.19
`RS403
`
`2. Drugs
`
`Library of Congress Cataloging in Publication Data
`Pharmaceutics: the science of dosage form design.
`Replaces: Cooper and Gurin’s tutorial pharmacy.
`6th ed. 1972.
`Includes bibliographies and index.
`1. Drugs —— Design of delivery systems.
`—— Dosage forms. 3. Biopharmaceutics.
`4. Pharmaceutical technology.
`5. Chemistry,
`Pharmaceutical.
`6. Microbiology, Pharmaceutical.
`I. Aulton, Michael E.
`2. Chemistry,
`[DNLM: 1. Biopharrnaceutics.
`Pharmaceutical.
`3. Dosage Forms.
`4. Technology,
`Pharmaceutical.
`5. Microbiology, Pharmaceutical.
`Q-V 785 P5366]
`RS420.P48
`1987
`
`615.5’8
`
`86-25888
`
`Printed in Hong Kong
`CPP/O5
`
`The
`publisher's
`policy is to use
`paper manufactured
`from sustainable forests
`
`Astrazeneca Ex. 2082 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 A
`ix
`xi
`xiii
`
`15
`17
`38
`
`50
`62
`81
`119
`
`129
`131
`135
`
`174
`191
`
`213
`215
`
`223
`254
`269
`282
`
`. 300
`3041
`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
`
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`

`
`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 pK,,
`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 compressibility I
`and flavour drug substances to form various prep-
`arations or dosage forms.
`The principal objective of dosage form design
`is to achieve a predictable therapeutic response to
`a drug included in a formulation which is capable
`‘lyf
`large scale manufacture with reproducible
`product quality. To ensure product quality,
`numerous features are required —- chemical and I
`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 developments
`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-
`ation in bioavailability characteristics, particularly
`for chemically equivalent products since it
`is
`
`1
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`

`
`2
`
`THE DESIGN OF DOSAGE FORMS
`
`recognized that formulation factors can influence
`their therapeutic performance. To optimize the
`bioavailability of drug 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 form, 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-
`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-
`peutic response. Preparations can be taken orally
`or injected, as well as being applied to the skin or
`inhaled, and Table 1.] lists the range of dosage
`forms which can be used to deliver drugs by the.
`various administration routes. However,
`it
`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. In addition factors governing choice
`of administration route and the specific require-
`
`Table 1.1 Range of dosage forms available for different
`administration routes
`
`Administration
`Dosage forms
`route
`
`
`Oral
`
`Rectal
`
`Topical
`
`Parenteral
`
`Lungs
`
`Solutions, syrups, elixirs, suspensions,
`emulsions, gels, powders, granules,
`capsules, tablets
`
`Suppositories, ointments, creams,
`powders, solutions
`
`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
`
`Nasal
`
`Solutions, inhalations
`
`Solutions, ointments
`Eye
`Ear Solutions, suspensions, ointments
`
`
`
`A
`
`ments of that route which affect drug absorption
`need to be taken into 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 tablet,
`injections, eye drops and enema.
`The extremely low aqueous solubility 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, enema and
`intravenous injection to be prepared. The antibac-
`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-
`furol, and strong sterile solution, 40% propylene
`glycol.
`that before a drug
`therefore apparent
`It
`is
`substance can be successfully formulated into a
`dosage form many factors must be considered.
`These can be broadly grouped into three
`categories:
`
`including
`1 biopharmaceutical considerations,
`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-
`ation of the disease to be treated and patient
`factors.
`
`Appropriate and efficacious dosage forms will
`be prepared only when all
`these factors are
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`

`
`.
`
`- «w‘.:7‘.%::
`
`considered and related to each other. This is the
`
`underlying 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,
`
`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-
`anisms are postulated including active and facili-
`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
`
`Topical
`
`S.c injection
`
`|.m. injection
`
`Gases
`
`I. v. injection
`
`Circulatory
`system
`(drug or
`metabolites)
`
`Gastro-
`intestinal tract
`
`
`
`Oral
`» preparations
`
`
`
`
`
`Rectal
`preparations
`
`metabolite
`in tissues
`and extra
`cellular
`fluids
`
`
`
`
`
`
`
`Drug in
`faeces
`
`
`
` Drug in saliva,
`exhaled air, etc.
`
`
`
`
`
`
`
`Fig. 1.1 Schematic diagram illustrating pathways a drug may take following adrninistration of a dosage form by different
`routes
`
`Astrazeneca Ex. 2082 p. 6
`
`
`
`Vascular
`
`
`
`
`
` Vascularsystem
`
` Vascular
`
`
`
`

`
`4
`
`THE DESIGN OF DOSAGE FORMS
`
`forms designed to deliver drugs via the buccal,
`rectal, intramuscular or subcutaneous routes, the
`drug passes directly into the circulation blood
`from absorbing tissues, whilst
`the intravenous
`route provides the most direct route of all. When
`delivered by the oral route onset of drug action
`will be delayed because of required transit time in
`the gastrointestinal
`tract,
`the absorption process
`and hepatoenteric blood circulation features. The
`physical form of the oral dosage form will also
`influence onset of action with solutions acting
`faster than suspensions which in turn generally act
`faster than capsules and tablets. Dosage forms can
`thus be listed in order of speed of onset of thera-
`peutic effect (see Table 1.2). However, all drugs
`irrespective of their delivery route remain foreign
`substances to the human body and distribution,
`metabolic and elimination processes commence
`immediately following drug absorption until the
`drug has been eliminated from the body via the
`urine, faeces, saliva, skin or lungs in unchanged
`or metabolized form.
`
`Table 1.2 Variation in time of onset of action for different
`dosage forms
`
`Time of onset of
`Dosage form
`action
`
`
`Seconds
`
`Minutes
`
`Minutes to hours
`
`I.v. injections
`
`I.m. and s.c. injections, buccal tablets,
`aerosols, gases
`
`Short term depot injections, solutions,
`suspensions, powders, granules,
`capsules, tablets, sustained release
`tablets
`
`Several hours
`
`Enteric coated formulations
`
`Depot injections, implants
`Days
`' Varies
`Topical preparations
`
`Routes of drug administration
`
`The absorption pattern of drugs varies consider-
`ably between one another as well as between each
`potential administration route. Dosage forms are
`designed to provide the drug in a suitable form for
`absorption from each selected route of adminis-
`tration. The following discussion considers briefly
`the routes of drug administration and whilst
`dosage forms are mentioned, this is intended only
`as an introduction since they will be dealt with in
`greater detail in the chapters of Part 3.
`
`Oral route
`
`The oral route is the most frequently used route
`for drug administration. Oral dosage forms are
`usually intended for systemic effects resulting
`from drug absorption through the various mucosa
`of
`the gastrointestinal
`tract. A few drugs,
`however, are intended to dissolve in the mouth for
`
`rapid absorption, or for local effect in the tract
`due to poor absorption by this route or
`low
`aqueous solubility. Compared with other routes,
`the oral route is the simplest, "most convenient and
`safest means of drug administration. Disadvan-
`tages, however,
`include relatively slow onset of
`action, possibilities of irregular absorption and
`destruction of certain drugs by the enzymes and
`secretions
`of
`the
`gastrointestinal
`tract. For
`example,
`insulin-containing preparations
`are
`inactivated by the action of stomach fluids.
`Whilst drug absorption from the gastrointestinal
`tract
`follows the general principles outlined in
`Chapter 9,
`several specific features should be
`emphasized. Changes in drug solubility can result
`from reactions with other materials present in the
`gastrointestinal
`tract, as for example the inter-
`ference of absorption of tetracyclines through the
`formation of insoluble complexes with calcium
`which can be available from foodstuffs or formu-
`
`lation additives. Gastric emptying time is an
`important
`factor
`for effective drug absorption
`from the intestine. Slow gastric emptying can be
`detrimental
`to drugs inactivated by the gastric
`juices, or slow down absorption of drugs more
`effectively absorbed from the intestine.
`In
`addition, since environmental pH can influence
`the ionization and lipid solubility of drugs, the pH
`change occurring along the gastrointestinal tract,
`from a pH of about 1 in the stomach to approxi-
`mately 7 or 8 in the large intestine, is important
`to both degree and site of drug absorption. Since
`membranes are more permeable to unionized
`rather than ionized forms and since most drugs are
`weak acids or bases, it can be shown that weak
`acids being largely unionized are well absorbed
`from the stomach.
`In the small
`intestine (pH
`about 6.5) with its extremely large absorbing
`surface both weak acids and weak bases are well
`absorbed.
`
`The most popular oral dosage forms are tablets,
`
`Astrazeneca Ex. 2082 p. 7
`
`

`
`capsules, suspensions,‘ solutions and emulsions.
`Tablets are prepared by compression and contain
`drugs and formulation additives which are
`included for specific functions, such as disinte-
`grants which promote tablet break-up into gran-
`ules and powder particles in the gastrointestinal
`tract facilitating drug dissolution and absorption.
`Tablets are often coated, either
`to provide a
`protective coat
`from environmental
`factors for
`drug stability purposes or
`to mask unpleasant
`drug taste, as well as to protect drugs from the
`acid conditions of the stomach (enteric coating).
`Specialized tablet formulations are also available
`to provide controlled drug release
`systems
`through,
`for example,
`the use of
`tablet core
`matrices or polymeric coating membranes.
`Capsules are solid dosage forms containing drug
`and usually appropriate filler(s), enclosed in a hard
`or soft shell composed of gelatin. As with tablets,
`uniformity of dose can be readily achieved and
`various sizes, shapes, and colours of shell ‘are
`commercially available. The gelatin shell readily
`ruptures and dissolves following oral adminis-
`tration and in most cases drugs are released from
`capsules
`faster
`than from tablets. Recently,
`renewed interest has been shown in filling semi-
`solid formulations into hard gelatin capsules to
`provide rapidly dispersing dosage forms for poorly
`soluble drugs.
`Suspensions, which contain finely divided drugs
`suspended in a suitable vehicle, are a useful means
`of administering large amounts of drugs which
`would be inconvenient if taken in tablet or capsule
`form. They are also useful
`for patients who
`experience difficulty in swallowing tablets and
`capsules and for paediatric use. Whilst dissolution
`of drug is required prior to absorption following
`administration of a dose of drug, fine particles
`with ' a
`large
`surface
`area
`are presented to
`dissolving fluids which facilitates drug dissolution
`and thereby the onset of drug action. Not all oral
`‘suspensions, however, are formulated for systemic
`effects and several, for example Kaolin and Mor-
`phine Mixture B.P.C., are designed for
`local
`effects
`in the gastrointestinal
`tract. Solutions,
`including formulations such as elixirs, syrups and
`linctuses, on the other hand are absorbed more
`rapidly than solid dosage forms or suspensions
`since drug dissolution is not required.
`
`THE DESIGN OF DOSAGE FORMS
`
`5
`
`Rectal route
`
`Drugs given rectally in solution, suppository or
`emulsion form, are generally administered for
`local rather than systemic effects. Suppositories
`are solid forms intended for introduction into
`
`body cavities (usually rectal, but also vaginal and
`urethral) where they melt, releasing the drug, and
`the choice of suppository base or drug carrier can
`greatly influence the degree and rate of drug
`release. This route of drug administration is indi-
`cated for drugs inactivated when given orally by
`the gastrointestinal fluids, when the oral route is
`precluded, as
`for example when a patient
`is
`vomiting or unconscious. Drugs administered
`rectally also enter the systemic circulation without
`.passing through the liver, an advantage for drugs
`significantly inactivated by the liver following oral
`route absorption. Disadvantageously the rectal
`route is inconvenient and drug absorption is often
`irregular and difficult to predict.
`
`Parenteral route
`
`A drug administered parenterally is one injected
`via a hollow needle into the body at various sites
`and to varying depths. The three main parenteral
`routes
`are
`subcutaneous
`(s.c.),
`intramuscular
`(i.m.) and intravenous
`(i.v.),
`although other
`routes are less frequently used such as intracardiac
`and intrathecal. The parenteral route is preferred
`when rapid absorption is essential, as in emerg-
`ency situations or when patients, are unconscious
`or unable to accept oral medication, and in cases
`when drugs are destroyed or inactivated or poorly
`absorbed following oral administration. Absorp-
`tion after parenteral drug delivery is rapid and, in
`general, blood levels attained are morepredictable
`than those achieved by oral dosage forms.
`Injectable preparations
`are usually sterile
`solutions or suspensions of drugs in water or other
`suitable physiologically acceptable vehicles. As
`referred to previously, drugs must be in solution
`to be absorbed and thus injection suspensions are
`slower acting than solution injections. In addition,
`since body fluids are aqueous, by using suspended
`drugs in oily vehicles a preparation exhibiting
`slower absorption characteristics can be formu-
`lated to provide a depot preparation providing a
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`
`

`
`6
`
`THE DESIGN OF DOSAGE FORMS
`
`reservoir of drug which is slowly released into the
`systemic circulation. Such preparations are admin-
`istered by intramuscular injection deep into skel-
`etal muscles
`(e.g.
`several penicillin-containing
`injections). Alternatively, depot preparations can
`be achieved by subcutaneous implants or pellets,
`which are compressed or moulded discs of drug
`placed in loose subcutaneous tissue under the
`outer
`layers of
`the
`skin. More generally,
`subcutaneous injections are aqueous solutions or
`suspensions which allow the drug to be placed in
`the immediate vicinity of blood capillaries. The
`drug then diffuses into the capillary. Inclusion of
`vasoconstrictors or vasodilators in subcutaneous
`
`injections will clearly influence blood flow through
`the capillaries, thereby modifying the capacity for
`absorption. This principle is often used in the
`administration of local anaesthetics with the vaso-
`
`constrictor adrenaline which delays drug absorp-
`tion. Conversely improved drug absorption can
`result when vasodilators are included. Intravenous
`
`administration involves injection of sterile aqueous
`solutions directly into a vein at an appropriate
`rate. Volumes delivered can range from a few
`millilitres,
`as
`in emergency treatment or
`for
`hypnotics, up to litre quantities as in replacement
`fluid treatment or nutrient feeding.
`
`Topical route
`
`Drugs are applied topically, that is to the skin,
`mainly for local action. Whilst this route can also
`be used for systemic drug delivery, percutaneous
`absorption is generally poor and erratic. Drug
`absorption is via the sweat glands, hair follicles,
`sebaceous glands and through the
`stratum
`corneum and drugs applied to the skin for local
`effect
`include antiseptics,
`antifungals,
`anti-
`inflammatory agents, as well as skin emollients for
`protective effects.
`formulations — oint-
`topical
`Pharmaceutical
`ments, creams and pastes — are composed of drug
`' in a suitable semisolid base which is either hydro-
`phobic or hydrophilic in character. The bases play
`an important role in determining the drug release
`character from the formulation. Ointments are
`
`forms
`hydrophobic, oleaginous-based dosage
`whereas creams are semisolid emulsions. Pastes
`contain more solids than ointments and thus are
`
`stiffer in consistency. For topical application in '
`liquid form other than solution, lotions, suspen-
`sions of solids in aqueous solution or emulsions,
`are used.
`
`Application of drugs to other topical surfaces
`such as the eye, ear and nose is common and oint-
`ments,
`suspensions and solutions are utilized.
`Ophthalmic preparations are required amongst
`other features to be sterile. Nasal dosage forms
`include solutions or
`suspensions delivered by
`drops or fine aerosol from a spray. Ear formu-
`lations in general are viscous to prolong Contact
`with affected areas.
`
`Respiratory route
`
`The lungs provide an excellent surface for ab-
`sorption when the drug is delivered in gaseous
`or aerosol mist
`form. For drug particles pre-
`sented as
`an
`aerosol, droplet particle
`size
`largely determines
`the extent
`to which they
`penetrate the alveolar region,
`the zone of rapid
`absorption. Soluble drug particles that are in the
`range 0.5-] ,u.m diameter reach the alveolar sacs.
`Particles outside this range are either expired or
`deposited upon larger bronchial airways. This
`delivery route has been found particularly useful
`for the treatment of asthmatic problems, using
`both powder aerosols (e.g. sodium cromoglycate)
`and metered aerosols containing the drug in
`liquefied inert propellant
`(e.g.
`isoprenaline
`sulphate aerosol and salbutamol aerosol).
`'
`
`DRUG FACTORS IN DOSAGE FORM
`DESIGN
`
`Each type of dosage form requires careful study
`of the physical and chemical properties of drug
`substances to achieve a stable, efficacious product.
`These properties, such as dissolution, crystal size
`and polymorphic form, solid state stability and
`drug-additive interaction,
`can have profound
`effects on the physiological
`availability and
`physical and chemical stability of the drug. By
`combining such data with those from pharmaco-
`logical and biochemical studies, the most suitable
`drug form and additives can be selected for the
`formulation of chosen dosage
`forms. Whilst
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`THE DESIGN OF DOSAGE FORMS
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`7
`
`and dosage forms, particularly oral preparations,
`containing such drugs may require the addition of
`approved flavours, perfumes and/or colours.
`The use of
`flavours and perfumes applies
`primarily to liquid dosage forms intended for oral
`administration. Available as concentrated extracts,
`solutions, adsorbed onto powders or microencap-
`sulated,
`flavours
`and perfumes
`are usually
`composed of mixtures of natural and synthetic
`materials. The taste buds of the tongue respond
`quickly to bitter, sweet, salt or acid elements of
`a flavour. All other elements are recognized by
`smell, which can be altered more readily than taste
`using perfumes. Unpleasant taste can be overcome
`by using water-insoluble derivatives of drugs
`which have little or no taste. Examples are the use
`of chloramphenicol palmitate and arnitriptyline
`pamoate, although other factors, such as bioavail—
`ability, must remain unchanged. If an insoluble
`derivative is unavailable or cannot be used, a
`flavour or perfume
`can be used. However,
`unpleasant drugs in capsules or prepared as coated
`tablets may be easily swallowed avoiding the taste
`buds.
`
`flavour depends upon several
`Selection of
`factors but particularly on the taste of the drug
`substance. Certain flavours are more effective at
`masking various taste elements — for example
`citrus flavours are frequently used to combat sour
`or acid tasting drugs. Solubility and stability of
`the flavour in the vehicle are also important. In
`addition the age of the intended patient should
`also be considered, since children for example
`prefer sweet tastes, as well as the psychological
`links between colours and flavours (e.g. yellow
`colour is associated with lemon flavour). Sweet-
`ening agents may also be required to mask bitter
`tastes. Sucrose remains widely used but alterna-
`tives, such as sodium saccharin which is 200—700
`times sweeter depending on concentration, are
`available. Sorbitol
`is recommended for diabetic
`
`preparations.
`Colours are employed to standardize or improve
`an existing drug colour, to mask a colour change,
`or complement a flavour or perfume. Whilst
`colours are obtained both from natural sources
`(e.g. carotenoids) or synthesized (e.g. amaranthji,
`the majority used are synthetically produced?
`we _
`Dyes may be aqueous (e.g._ amaranth)_;f‘o
`
`
`
`
`comprehensive property evaluation will not be
`required for all types of formulations those prop-
`erties which are recognized as important in dosage
`'form design and processing are listed in Table 1.3.
`Also listed in Table 1.3 are the stresses to which
`the
`formulation might be
`exposed during
`processing or manipulation into dosage forms, as
`well as
`the procedures involved. Variations in
`physicochemical properties, occurring for example
`between batches of the same material or resulting
`from alternative treatment procedures can modify
`formulation requirements as well as processing
`and dosage form performance. For instance the
`fine milling of poorly soluble drug substances can
`modify their wetting and dissolution character-
`istics, important properties during granulation and
`product performance respectively. Careful evalu-
`ation of these properties and understanding of the
`effects of these stresses upon these parameters is
`therefore important
`in dosage form design and
`processing as well as product performance.
`
`Table 1.3 Physical and chemical properties of drug
`substances important in dosage form design and potential
`stresses with range of manufacturing procedures used in
`
`processing “
`
`Properties
`
`Processing stresses
`
`Organoleptic
`Particle size,
`Surface area
`
`Temperature
`Pressure
`Mechanical
`
`Manufacturing
`procedures
`
`Crystallization
`Precipitation
`Filtration
`
`Solublhty
`Dissolution
`Partition coefficient
`Ionization constant
`Crystal properties,
`polymorphism
`Stability
`.
`(Other properties)
`
`Radiation
`Emulsification
`Exposure to liquids Milling
`Exposure to gases
`Mixing
`and liquid vapours Drying
`Granulation
`.
`Compression
`A
`l
`'
`umc _avmg
`Handling
`
`Storage
`Transport
`
`Organoleptic properties
`
`Modern medicines require that pharmaceutical
`dosage forms are acceptable to the patient. Unfor-
`tunately many drug substances in use today are
`unpalatable and unattractive in their natural state
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`THE DESIGN OF DOSAGE FORMS
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`soluble (e.g. Sudan III) or insoluble in both (e.g.
`aluminium lakes). Lakes which are generally
`calcium or aluminium complexes of water-soluble
`dyes are particularly useful in tablets and tablet
`coatings because of greater stability to light than
`corresponding dyes, which also Vary in their
`stability to pH and reducing agents. However, in
`recent years,
`the inclusion of colours in formu-
`lations has become extremely complex because of
`the banning of many traditionally used colours in
`some countries and not others. (A useful summary
`on colours is given in Martindale, The Extra
`Pharmacopoeia).
`
`Particle size and surface area
`
`Particle size reduction results in an increase in the
`specific surface (i.e. surface area per unit weight)
`of powders. Drug dissolution rate, absorption
`rate, dosage form content uniformity and stability
`are all dependent to varying degrees on particle
`size, size distribution and interactions of solid
`surfaces. In many cases for both drugs and addi-
`tives particle size reduction is required to achieve
`the desired physicochemical characteristics.
`It
`is now generally recognized that poorly
`soluble drugs showing a dissolution rate-limiting
`step in the absorption process will be more readily
`bioavailable when administered in a
`finely
`subdivided form with larger surface than as a
`coarse material. Examples include griseofulvin,
`phenothiazine, diphenylhydantoin, chloramphen-
`icol,
`tolbutamide,
`indomethacin and spironolac-
`tone. The fine material often in micronized form
`with larger
`specific surface dissolves at
`faster
`rates which can lead to improved drug absorp-
`tion by passive diffusion. On the other hand,
`with formulated nitrofurantoin preparations an
`optimal particle size of 150 um reduced gastro-
`intestinal distress whilst still permitting sufficient
`urinary excretion of
`this urinary antibacterial
`agent.
`
`Rates of drug dissolution can be adversely
`affected, however, by unsuitable choice of formu-
`lation additives even though solids of appropriate
`particle
`size
`are used. Tableting lubricant
`powders, for example, can impart hydrophobicity
`to a formulation which inhibits drug dissolution.
`Fine powders can also increase air adsorption or
`
`static charge leading to wetting or agglomeration
`problems. Micronizing drug powders can lead to
`polymorphic and surface energy changes which
`cause reduced chemical stability. Drug particle
`size also influences content uniformity in solid
`dosage forms, particularly for low dose formu-
`lations. It is important in such cases to have as
`many particles as possible per dose to minimize
`potency variation between dosage units. Other
`dosage forms are also affected by particle size
`including suspensions (for controlling flow prop-
`erties and particle interactions), inhalation aerosols-
`(for optimal penetration of drug particles
`to
`absorbing mucosa) and topical formulations (for
`freedom from grittiness).
`
`Solubility
`
`All drugs, whatever route they are administered
`by, must exhibit at least limited aqueous solubility
`for therapeutic efficiency. Thus relatively insoluble
`compounds
`can exhibit erratic or
`incomplete
`absorption, and it might be appropriate to use
`more soluble salt or ester de