SECOND EDITION
`
`cl: SCIENCE Ys
`
`DOSAGE FORM DESIGN
`
`Edited by
`M. E. Aulton
`
`{)CHURCHILL
`4 LIVINGSTONE
`
`MYLAN - EXHIBIT 1029
`
`MYLAN - EXHIBIT 1029
`
`

`

`Contents
`
`
`
`Whatis ‘Pharmaceutics’? xiii
`
`1. The design of dosage forms
`Peter York
`
`1
`
`PART ONE
`Scientific principles of dosage form
`design 13
`
`2. Dissolution and solubility 15
`Michael Aulton
`
`3. Properties of solutions 33
`Michael Aulton
`
`4. Rheology 41
`Chris Marriott
`
`5. Surface and interfacial phenomena 59
`John Fell
`
`6. Disperse systems 70
`David Attwood
`
`7. Kinetics and productstability 101
`Fohn Pugh
`
`181
`13. Mixing
`Andrew Twitchell
`
`14. Powder flow 197
`John Staniforth
`
`PART THREE
`Biopharmaceuticalprinciples of drug
`delivery 211
`
`15. Introduction to biopharmaceutics 213
`Marianne Ashford
`
`16. The gastrointestinal tract — physiology and
`drug absorption 217
`Marianne Ashford
`
`17. Bioavailability — physicochemical and
`dosage form factors 234
`Marianne Ashford
`
`18. Assessment of biopharmaceutical
`properties 253
`Marianne Ashford
`
`8. Pharmaceutical preformulation 113
`Fames Wells
`
`19. Dosage regimens 275
`Stuart Proudfoot, (updated by Fohn Collett)
`
`PART TWO
`Particle science and powder
`technology 139
`9. Solid-state properties
`Graham Buckton
`
`141
`
`10. Particle-size analysis
`Fohn Stantforth
`
`152
`
`11. Particle-size reduction 166
`John Stantforth
`
`12. Particle-size separation 174
`Fohn Stantforth
`
`20. Modified-release peroral dosage form 289
`John Collett, Chris Moreton
`
`PART FOUR
`Dosage form design and
`manufacture 307
`
`21. Solutions 309
`Michael Billany
`
`22, Clarification 323
`Andrew Twitchell
`
`23. Suspensions and emulsions 334
`Michael Billany
`
`

`

`1T
`
`he design of dosage forms
`
`Peter York
`
`CHAPTER CONTENTS
`
`Principles of dosage form design 1
`
`Biopharmaceutical aspects of dosage form
`design 2
`Routes of drug administration 4
`Oral route 4
`Rectal route 5
`Parenteral route 5
`Topical route 5
`Respiratory route 6
`
`Drug factors in dosage form design 6
`Particle size and surface area 6
`Solubility 7
`Dissolution 7
`Partition coefficient and pKa 8
`Crystal properties; polymorphism 8
`Stability 9
`Organoleptic properties 10
`Other drug properties 10
`
`Therapeutic considerations in dosage form
`design 11
`
`Summary 11
`
`Bibliography 11
`
`PRINCIPLES OF DOSAGE FORM
`DESIGN
`
`Drugs are rarely administered as pure chemical sub-
`stances alone and are almost always given as formu-
`lated preparations or medicines. These can vary from
`relatively simple solutions to complex drug delivery
`systems through the use of appropriate additives or
`excipients in the formulations. The excipients
`provide varied and specialized pharmaceutical func-
`tions. It is the formulation additives that, among
`other things, solubilize, suspend, thicken, preserve,
`emulsify, modify dissolution, improve the compress-
`ibility and flavour drug substances to form various
`preparations 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 of large-
`scale manufacture with reproducible product
`quality. To ensure product quality, numerous fea-
`tures are required: chemical and physical stability,
`suitable preservation against microbial contamina-
`tion 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
`is difficult to achieve. However, recent developments
`that rely on the specific metabolic activity of individ-
`ual patients, or implants that respond, for example,
`to externally applied sound or magnetic fields to
`trigger a drug delivery function, are beginning to
`accommodate this requirement.
`Consideration should be given to differences in
`bioavailability between apparently similar formula-
`tions, and the possible causes for this. In recent years
`increasing attention has therefore been directed
`towards eliminating variation in bioavailability char-
`acteristics, particularly for chemically equivalent
`products, as it is now recognized that formulation
`
`1
`
`

`

`THE DESIGN OF DOSAGE FORMS
`
`factors can influence their therapeutic performance.
`To optimize the bioavailability of drug substances it
`is often necessary to carefully select the most appro-
`priate chemical form of the drug. For example, such
`selection should address solubility requirements,
`drug particle size and physical form, and consider
`appropriate additives and manufacturing aids
`coupled to selecting the most appropriate adminis-
`tration route (s) and dosage form(s). Suitable manu-
`facturing processes and packaging are also required.
`There are numerous dosage forms into which a
`drug substance can be incorporated for the conve-
`nient and efficacious treatment of a disease. Dosage
`forms can be designed for administration by alterna-
`tive delivery routes
`to maximize
`therapeutic
`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
`that can be used to deliver drugs by the various
`administration routes. However, it is necessary to
`relate the drug substance to the clinical indication
`being treated before the correct combination of drug
`and dosage form can be made, as each disease or
`illness often requires a specific type of drug therapy.
`In addition, factors governing the choice of adminis-
`tration route and the specific requirements of that
`route which affect drug absorption need to be taken
`into account when designing dosage forms.
`Many drugs are formulated into several dosage
`forms of varying strengths, each having selected phar-
`
`Tabte1.1 Dosage forms available for different
`administration mutes
`
`Administration route Dosage forms
`
`Solutions, syrups, 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
`Solutions, inhalations
`
`Solutions, ointments, creams
`
`Solutions, suspensions, ointments
`creams
`
`Oral
`
`Rectal
`
`Topical
`
`Parenteral
`
`Respiratory
`
`Nasal
`
`Eye
`Ear
`
`2
`
`maceutical characteristics suitable for a specific appli-
`cation. One such drug is the glucocorticoid pred-
`nisolone, used in the suppression of inflammatory and
`allergic disorders. Through the use of different chem-
`ical forms and formulation additives a range of effec-
`tive anti-inflammatory preparations are available,
`including tablet, enteric-coated tablet, injections, eye
`drops and enema. The extremely low aqueous solubil-
`ity of the base prednisolone and acetate salt makes
`these forms useful in tablet and slowly absorbed intra-
`muscular suspension injection forms, whereas the
`soluble sodium phosphate salt enables a soluble tablet
`form, and solutions for eye and ear drops, enema and
`intravenous injection to be prepared. The analgesic
`paracetamol is also available in a range of dosage
`forms and strengths to meet specific needs of the user,
`including tablets, dispersible tablets, paediatric
`soluble tablets, paediatric oral solution, sugar-free oral
`solution, oral suspension, double-strength oral sus-
`pension and suppositories.
`It is therefore apparent that before a drug sub-
`stance can be successfully formulated into a dosage
`form many factors must be considered. These can be
`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;
`3. Therapeutic considerations, including
`consideration of the clinical indication to be
`treated and patient factors.
`High-quality and efficacious medicines will be for-
`mulated and prepared only when all these factors are
`considered and related to each other. This is the
`underlying principle of dosage form design.
`
`BIOPHARMACEUTICAL ASPECTS OF
`DOSAGE FORM DESIGN
`
`Biopharmaceutics can be regarded as the study of the
`relationship between the physical, chemical and bio-
`logical sciences applied to drugs, dosage forms and
`drug action. Clearly, understanding the principles of
`this subject is important in dosage form design, par-
`ticularly 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 the absorbing mem-
`branes and epithelia of the skin, gastrointestinal tract
`and lungs into body fluids. Drugs are absorbed 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 that
`exists across the cellular barrier, with drug molecules
`passing from regions of high to those of low concen-
`tration. Lipid solubility and the degree of ionization of
`the drug at the absorbing site influence the rate of dif-
`fusion. Several specialized transport mechanisms are
`postulated, including active and facilitated transport.
`Once absorbed, the drug can exert a therapeutic effect
`either locally or at a site of action remote from that of
`administration. In the latter case the drug has to be
`transported in body fluids (Fig. 1.1).
`When the drug is administered from dosage forms
`designed to deliver via the buccal, respiratory, rectal,
`intramuscular or subcutaneous routes, it passes
`directly into the blood-stream from absorbing tissues,
`but the intravenous route is the most direct of all.
`When delivered by the oral route the onset of drug
`action will be delayed because of the required transit
`time in the gastrointestinal tract, the absorption
`process and hepatoenteric blood circulation features.
`
`THE DESIGN OF DOSAGE FORMS
`
`The physical form of the oral dosage form will also
`influence absorption rate and 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 time of onset of
`therapeutic effect (Table 1.2). However, all drugs, irre-
`
`Table 1 .2 Variation in time of onset of action for
`different dosage forms
`
`Time of onset of action
`
`Dosage forms
`
`Seconds
`
`Minutes
`
`Minutes to hours
`
`Several hours
`
`Days
`
`Varies
`
`i.v. injections
`
`i.m. and s.c. injections,
`buccal tablets, aerosols, gases
`
`Short-term depot injections,
`solutions, suspensions,
`powders, granules, capsules,
`tablets, modified-release
`tablets
`Enteric-coated formulations
`
`Depot injections, implants
`Topical preparations
`
`Fig. 1.1 Pathways a drug may take following the administration of a dosage form by different route.
`
`3
`
`

`

`THE DESIGN OF DOSAGE FORMS
`
`spective of their delivery route, remain foreign sub-
`stances to the human body, and distribution, metabolic
`and elimination processes commence immediately fol-
`lowing absorption until the drug is eliminated from the
`body via the urine, faeces, saliva, skin or lungs in either
`unchanged or metabolized form.
`
`Routes of drug administration
`The absorption pattern of drugs varies considerably
`between individual substances as well as between the
`different administration routes. Dosage forms are
`designed to provide the drug in a suitable form for
`absorption from each selected route of administra-
`tion. The following discussion considers briefly the
`routes of drug administration, and although dosage
`forms are mentioned this is intended only as an
`introduction, as they will be dealt with in greater
`detail in other parts of this book.
`
`Oral route
`The oral route is the one most frequently used for
`drug administration. Oral dosage forms are usually
`intended for systemic effects resulting from drug
`absorption through the various epithelia and 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, either
`because of the poor absorption by this route or
`because of their low aqueous solubility. Compared
`with other routes, the oral route is the simplest, most
`convenient and safest means of drug administration.
`Disadvantages, however, include the relatively slow
`onset of action, the possibilities of irregular absorp-
`tion and the 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.
`Several specific features relating to drug absorption
`from the gastrointestinal tract can be emphasized in
`the context of routes of administration. Changes in
`drug solubility can result from reactions with other
`materials present in the gastrointestinal tract, as for
`example the interference of absorption of tetracyclines
`through the formation of insoluble complexes with
`calcium, which can be available from foodstuffs or for-
`mulation additives. Gastric emptying time is an
`important factor for effective drug absorption from
`the intestine. Slow gastric emptying can be detrimen-
`tal to drugs inactivated by the gastric juices, or slow
`down the absorption of drugs that are more effectively
`absorbed from the intestine. In addition, because
`environmental pH can influence the ionization and
`
`4
`
`lipid solubility of drugs, the pH change that occurs
`along the gastrointestinal tract, from about 1 in the
`stomach to approximately 7 or 8 in the large intestine,
`is important to both degree and site of drug absorp-
`tion. As membranes are more permeable to unionized
`rather than ionized forms, and as 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,
`capsules, suspensions, solutions and emulsions.
`Tablets are prepared by compression and contain
`drugs and formulation additives, which are included
`for specific functions, such as disintegrants which
`promote tablet break-up into granules and powder
`particles in the gastrointestinal tract, thereby facili-
`tating drug dissolution and absorption. Tablets are
`often coated, either to provide a protection against
`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). Increasing use is being made of
`modified-release tablet products, such as fast-dis-
`solving systems and controlled, delayed or sustained-
`release
`formulations.
`The
`benefits
`of
`controlled-release tablet formulations, achieved for
`example by the use of polymeric-based tablet cores
`or coating membranes, include reduced frequency of
`drug-related side-effects and the maintenance of
`steady drug-plasma
`levels for extended periods.
`These factors are important when medications are
`delivered for chronic conditions, or where constant
`levels are required to achieve optimal efficacy, as in
`treating angina and hypertension.
`Capsules are solid dosage forms containing drug
`and usually appropriate filler(s), enclosed in a hard
`or soft gelatin shell. As with tablets, uniformity of
`dose can be readily achieved and various sizes,
`shapes and colours of shell are commercially avail-
`able. The gelatin shell readily ruptures and dissolves
`following oral administration, and in most cases the
`drug is released from a capsule faster than from a
`tablet. Recently, renewed interest has been shown in
`filling semisolid and microemulsion formulations
`into hard gelatin capsules to provide rapidly dispers-
`ing 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 that 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. Whereas dissolution of drugs is required prior to
`absorption following administration, fine particles
`with a large surface area are presented to dissolving
`fluids, which facilitate dissolution in the gastroin-
`testinal tract, absorption, and hence the onset of
`drug action. Not all oral suspensions are formulated
`for systemic effects however, and several, for
`example kaolin and morphine mixture, are designed
`for local effects in the gastrointestinal tract. On the
`other hand, solutions, including formulations such
`as syrups and linctuses, are absorbed more rapidly
`than solid dosage forms or suspensions, as drug dis-
`solution is not required.
`
`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 sup-
`pository base or drug carrier can greatly influence
`the degree and rate of drug release. This route of
`administration is indicated for drugs that are inacti-
`vated by the gastrointestinal fluids when given orally,
`or when the oral route is precluded, as for example
`when a patient is vomiting or unconscious. Drugs
`administered rectally also enter the systemic circula-
`tion without passing through the liver, an advantage
`for drugs that are significantly inactivated by the liver
`following oral absorption. However, the rectal route
`is inconvenient and drug absorption is often irregu-
`lar 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 intra-
`venous (i.v.). Other routes, such as intracardiac and
`intrathecal, are used less frequently. The parenteral
`route is preferred when rapid absorption is essential,
`as in emergency 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.
`Absorption after parenteral drug delivery is rapid
`and, in general, blood levels attained are more pre-
`dictable 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 previously
`
`THE DESIGN OF DOSAGE FORMS
`
`mentioned, drugs in solution are rapidly absorbed and
`so injection suspensions are slower acting than solu-
`tions. In addition, because body fluids are aqueous, by
`using drugs suspended in oily vehicles a preparation
`exhibiting slower absorption characteristics can be
`formulated to provide a depot preparation, providing
`a reservoir of drug which is slowly released into the
`systemic circulation. Such preparations are adminis-
`tered by intramuscular injection deep into skeletal
`muscles (e.g. several penicillin-containing injections).
`Alternatively, depot preparations can be achieved by
`subcutaneous implants or pellets, which are com-
`pressed or moulded discs of drug placed in loose sub-
`cutaneous tissue under the outer layers of the skin.
`Such systems include solid microspheres, polymeric
`biodegradable polymeric microspheres (e.g. polylac-
`tide co-glycollic acid homo- and copolymers) con-
`taining proteins or pep tides (e.g. human growth
`hormone and leuprolide). More generally, subcuta-
`neous injections are aqueous solutions or suspensions
`that allow the drug to be placed in the immediate
`vicinity of blood capillaries. The drug then diffuses
`into the capillaries. The 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 anaesthet-
`ics with the vasoconstrictor adrenaline, which delays
`drug absorption. Conversely, improved drug absorp-
`tion can result when vasodilators are included.
`Intravenous administration involves the 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 hyp-
`notics, up to litre quantities, as in replacement fluid
`treatment or nutrient feeding.
`Given the generally negative patient acceptance of
`this important route of drug delivery, primarily asso-
`ciated with pain and inconvenience, recent develop-
`ments have focused on
`'needle-free'
`injection
`systems which propel drugs in aqueous solution or
`powder form at high velocity directly through the
`external layers of the skin.
`
`Topical route
`Drugs are applied topically, that is to the skin,
`mainly for local action. Although this route can also
`be used for systemic drug delivery, percutaneous
`absorption is often poor and erratic, although several
`transdermal patches delivering drug for systemic dis-
`tribution are available (e.g. glyceryl trinitrate patches
`for the prophylaxis and treatment of angina). Drugs
`applied to the skin for local effect include antiseptics,
`
`5
`
`

`

`THE DESIGN OF DOSAGE FORMS
`
`antifungals, anti-inflammatory agents, as well as skin
`emollients for protective effects.
`Pharmaceutical topical formulations - ointments,
`creams and pastes - are composed of drug in a suit-
`able semisolid base which is either hydrophobic or
`hydrophilic in character. The bases play an impor-
`tant role in determining the character of drug release
`from the formulation. Ointments are hydrophobic,
`oleaginous-based dosage forms, 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 solu-
`tion, lotions - suspensions of solids in aqueous solu-
`tion - or emulsions are used. More recently, interest
`in transdermal electrotransport systems has grown.
`Here a low electrical potential maintained across the
`skin can improve drug transport.
`The application of drugs to other topical surfaces,
`such as the eye, ear and nose, is common and oint-
`ments, creams, suspensions and solutions are utilized.
`Ophthalmic preparations are required, among other
`features, to be sterile. Nasal dosage forms include
`solutions or suspensions delivered by drops or fine
`aerosol from a spray. Ear formulations in general are
`viscous to prolong contact with affected areas.
`
`Respiratory route
`The lungs provide an excellent surface for absorp-
`tion when the drug is delivered in gaseous, aerosol
`mist or ultrafine solid particle form. For drug pre-
`sented in an aerosol or solid form, particle size
`largely determines the extent to which they penetrate
`the alveolar region, the zone of rapid absorption.
`Particles in the region 0.5-1 Jim diameter reach the
`alveolar sacs. Particles outside this range are either
`exhaled 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. salbutamol sulphate
`aerosol). Importantly, this delivery route is being
`increasingly recognized as a means of administering
`the therapeutic agents emerging from biotechnology,
`such as peptides and proteins.
`
`DRUG FACTORS IN DOSAGE FORM
`DESIGN
`
`Each type of dosage form requires careful study of
`the physical and chemical properties of drug sub-
`
`6
`
`stances to achieve a stable, effective product. These
`properties, such as dissolution, crystal size and poly-
`morphic form, solid-state stability and drug - addi-
`tive interactions, can have profound effects on the
`physiological availability and physical and chemical
`stability of the drug. By combining such data with
`those from pharmacological and biochemical studies,
`the most suitable drug form and additives can be
`selected for the formulation of chosen dosage forms.
`Although comprehensive property evaluation will not
`be required for all types of formulations, those prop-
`erties that are recognized as important in dosage
`form design and processing are listed in Table 1.3,
`together with the stresses to which the formulation
`might be exposed during processing and manipula-
`tion 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 pro-
`cedures, can modify formulation requirements as
`well as processing and dosage form performance. For
`instance, the fine milling of poorly soluble drug sub-
`stances can modify their wetting and dissolution
`characteristics, properties that are important during
`granulation and product performance, respectively.
`Careful evaluation of these properties and under-
`standing of the effects of these stresses upon these
`parameters is therefore important in dosage form
`design and processing, as well as in product perfor-
`mance.
`
`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 additives particle size
`reduction is required to achieve the desired physio-
`chemical characteristics.
`It is now generally recognized that poorly aqueous-
`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,
`tolbutamide,
`indomethacin, spironolactone and nifedipine. The
`fine material, often in micrometre or submicrometre
`(nanometre) form with large specific surface, dis-
`solves at a faster rate, which can lead to improved
`drug absorption by passive diffusion. On the other
`hand, with formulated nitrofurantoin preparations an
`
`

`

`THE DESIGN OF DOSAGE FORMS
`
`Table 1.3 Properties of drug substances important in dosage form design and potential stresses occurring during
`processes, with range of manufacturing procedures
`
`Properties
`
`Processing stresses
`
`Manufacturing procedures
`
`Particle size, surface area
`
`Solubility
`Dissolution
`Partition coefficient
`
`lonization constant
`
`Pressure
`
`Mechanical
`Radiation
`
`Exposure to liquids
`
`Exposure to gases and liquid vapours
`
`Crystal properties, polymorphism
`
`Temperature
`
`Stability
`
`Organoleptic
`
`(Other properties)
`
`Precipitation
`Filtration
`
`Emulsification
`
`Milling
`
`Mixing
`
`Granulation
`
`Drying
`Compression
`
`Autoclaving
`
`Crystallization
`Handling
`
`Storage
`Transport
`
`optimal particle size of 150 um reduces gastrointesti-
`nal distress while still permitting sufficient urinary
`excretion of this urinary antibacterial agent.
`Rates of drug dissolution can be adversely
`affected, however, by unsuitable choice of formula-
`tion additives, even though solids of appropriate par-
`ticle size are used. Tableting lubricant powders, for
`example, can impart hydrophobicity to a formula-
`tion and inhibit 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 sta-
`bility. Drug particle size also influences content uni-
`formity in solid dosage forms, particularly for
`low-dose formulations. 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 proper-
`ties and particle interactions), inhalation aerosols
`(for optimal penetration of drug particles to absorb-
`ing mucosa) and topical formulations (for freedom
`from grittiness).
`
`Solubility
`All drugs, by whatever route they are administered,
`must exhibit at least limited aqueous solubility for
`therapeutic efficiency. Thus relatively insoluble com-
`
`pounds can exhibit erratic or incomplete absorption,
`and it might be appropriate to use more soluble salt or
`other chemical derivatives. Alternatively, micronizing,
`complexation or solid dispersion techniques might be
`employed. Solubility, and especially degree of satura-
`tion in the vehicle, can also be important in the
`absorption of drugs already in solution in liquid
`dosage forms, as precipitation in the gastrointestinal
`tract can occur and bioavailability be modified.
`The solubilities of acidic or basic compounds are
`pH dependent and can be altered by forming salt
`forms with different salts exhibiting different equi-
`librium solubilities. However, the solubility of a salt
`of a strong acid is less affected by changes in pH
`than is the solubility of a salt of a weak acid. In the
`latter case, when pH is lower the salt hydrolyses to an
`extent dependent on pH and pKa, resulting in
`decreased solubility. Reduced solubility can also
`occur for slightly soluble salts of drugs through the
`common ion effect. If one of the ions involved is
`added as a different, more water-soluble salt, the sol-
`ubility product can be exceeded and a portion of the
`drug precipitates.
`
`Dissolution
`As mentioned above, for a drug to be absorbed it
`must first be dissolved in the fluid at the site of
`absorption. For example, an orally administered drug
`in tablet form is not absorbed until drug particles are
`
`7
`
`

`

`THE DESIGN OF DOSAGE FORMS
`
`dissolved or solubilized by the fluids at some point
`along the gastrointestinal tract, depending on the
`pH-solubility profile of
`the drug substance.
`Dissolution describes the process by which the drug
`particles dissolve.
`During dissolution, the drug molecules in the
`surface layer dissolve, leading to a saturated solution
`around the particles that forms the diffusion layer.
`Dissolved drug molecules then pass throughout the
`dissolving fluid to contact absorbing mucosa, and are
`absorbed. Replenishment of diffusing drug molecules
`in the diffusion layer is achieved by further drug dis-
`solution, and the absorption process continues. If dis-
`solution is fast, or the drug is delivered and remains
`in solution form, the rate of absorption is primarily
`dependent upon its ability to transverse the absorbing
`membrane. If, however, drug dissolution is slow
`owing to its physicochemical properties or formula-
`tion factors, then dissolution may be the rate-limiting
`step in absorption and influence drug bioavailability.
`The dissolution of a drug is described in a simplified
`manner by the Noyes-Whitney equation:
`
`dm/dt = M(CS-C)
`at
`where ^ is the dissolution rate, k is the dissolution
`rate constant, A is the surface area of dissolving solid,
`and Cs is the concentration of drug in the dissolution
`medium at time t. The equation reveals that dissolu-
`tion rate can be raised by increasing the surface area
`(reducing particle size) of the drug, by increasing the
`solubility of the drug in the diffusing layer and by
`increasing k, which incorporates the drug diffusion
`coefficient and diffusion layer thickness. During the
`early phases of dissolution Cs > C, and if the surface
`area A and experimental conditions are kept con-
`stant, then k can be determined for compacts con-
`taining drug alone. The constant k is now termed the
`intrinsic dissolution rate constant, and is a character-
`istic of each solid drug compound in a given solvent
`under fixed hydrodynamic conditions.
`Drugs with k values below 0.1 mg"1 cm~2 usually
`exhibit
`dissolution
`rate-limiting
`absorption.
`Paniculate dissolution can also be examined where
`an effort is made to control A, and formulation
`effects can be studied.
`Dissolution rate data, when combined with solu-
`bility, partition coefficient and pKa) provide an
`insight to the formulator into the potential in vivo
`absorption characteristics of a drug. However, in
`vitro tests only have significance when they are
`related to in vivo results. Once such a relationship
`has been established, in vitro dissolution tests can be
`used as a predictor of in vivo behaviour. The impor-
`
`8
`
`tance of dissolution testing has been widely recog-
`nized by official compendia, as well as drug registra-
`tion authorities, with the inclusion of dissolution
`specifications using standardized testing procedures
`for a range of preparations.
`
`Partition coefficient and pKa
`As pointed out above, for relatively insoluble c