1 Design of dosage forms

Peter York

CHAPTER CONTENTS of drug substances to form various medicines or

Principles of dosage form design . . . . . . 6 dosage forms.
The principal objective of dosage form design is to
Biopharmaceutical aspects of dosage
form design . . . . . . . . . . . . . . . . . 8 achieve a predictable therapeutic response to a drug
Routes of drug administration . . . . . . . . . 9
included in a formulation which can be manufactured
on a large scale with reproducible product quality. To
Drug factors in dosage form design. . . . 11
ensure product quality, numerous features are required:
Particle size and surface area . . . . . . . . . 12
chemical and physical stability, with suitable preserva-
Solubility . . . . . . . . . . . . . . . . . . . . 12
tion against microbial contamination if appropriate,
Dissolution . . . . . . . . . . . . . . . . . . . 13
uniformity of the dose of the drug, acceptability to
Partition coefficient and pKa . . . . . . . . . . 14
users, including both prescriber and patient, and suitable
Crystal properties: polymorphism. . . . . . . . 14
packaging and labelling. Ideally, dosage forms should
Stability . . . . . . . . . . . . . . . . . . . . . 15
also be independent of patient-to-patient variation,
Organoleptic properties. . . . . . . . . . . . . 15
although in practice this feature remains difficult to
Other drug properties . . . . . . . . . . . . . 16
achieve. However, recent developments are beginning
Therapeutic considerations in dosage to accommodate this requirement. These include drug
form design . . . . . . . . . . . . . . . . 16
delivery systems that rely on the specific metabolic
Summary . . . . . . . . . . . . . . . . . . 17 activity of individual patients and implants that respond,
Bibliography . . . . . . . . . . . . . . . . 17 for example, to externally applied sound or magnetic
fields to trigger a drug delivery function.
Consideration should be given to differences in
Principles of dosage the bioavailability of drugs (the rate and extent to
form design which they are absorbed) and their biological fate in
patients between apparently similar formulations and
Drugs are rarely administered as pure chemical possible causative reasons. In recent years, increasing
substances alone and are almost always given as attention has therefore been directed towards elimina-
formulated preparations or medicines. These can tion of variation in bioavailability characteristics,
range from relatively simple solutions to complex particularly for medicinal products containing an
drug delivery systems through the use of appropri- equivalent dose of a drug substance, as it is recognized
ate additives or excipients in the formulations. The that formulation factors can influence their therapeutic
excipients provide varied and specialized pharma- performance. To optimize the bioavailability of drug
ceutical functions. It is the formulation additives substances, it is often necessary to carefully select
that, amongst other things, solubilize, suspend, the most appropriate chemical form of the drug. For
thicken, preserve, emulsify, modify dissolution, example, such selection should address solubility
increase the compactability and improve the flavour requirements, drug particle size and drug physical

6
 Design of dosage forms CHAPTER 1

Table 1.1 Dosage forms available for different

chemical forms and formulation additives, a range of
administration routes effective anti-inflammatory preparations are available,
including tablets, gastro-resistant coated tablets,
Administration Dosage forms injections, eye drops and enemas. The extremely
route low aqueous solubility of the base prednisolone and
Oral Solutions, syrups, suspensions, emulsions, its acetate salt makes these forms useful in tablet and
gels, powders, granules, capsules, tablets slowly absorbed intramuscular suspension injection
Rectal Suppositories, ointments, creams, forms, whilst the soluble sodium phosphate salt enables
powders, solutions preparation of a soluble tablet form and solutions for
eye and ear drops, enemas and intravenous injections.
Topical Ointments, creams, pastes, lotions, gels,
The analgesic paracetamol is also available in a range
solutions, topical aerosols, foams,
transdermal patches
of dosage forms and strengths to meet the specific
needs of the user, including tablets, dispersible tablets,
Parenteral Injections (solution, suspension, emulsion paediatric soluble tablets, paediatric oral solution,
forms), implants, irrigation and dialysis
sugar-free oral solution, oral suspension, double-
solutions
strength oral suspension and suppositories.
Respiratory Aerosols (solution, suspension, emulsion, In addition, whilst many new drugs based on low
powder forms), inhalations, sprays, gases molecular weight organic compounds continue to be
Nasal Solutions, inhalations discovered and transformed into medicinal products,
Eye Solutions, ointments, creams the development of drugs from biotechnology is
increasing and the importance of these therapeutic
Ear Solutions, suspensions, ointments, creams agents is growing. Such active compounds are mac-
romolecular and of relatively high molecular weight,
form and should consider appropriate additives and and include materials such as peptides, proteins and
manufacturing aids coupled with selection of the most viral components. These drug substances present
appropriate administration route(s) and dosage different and complex challenges in their formulation
form(s). Additionally, suitable manufacturing pro- and processing into medicines because of their alterna-
cesses, labelling and packaging are required. tive biological, chemical and structural properties.
There are numerous dosage forms into which a Nevertheless, the underlying principles of dosage
drug substance can be incorporated for the convenient form design remain applicable.
and efficacious treatment of a disease. Dosage forms At present, these therapeutic agents are principally
can be designed for administration by a variety of formulated into parenteral and respiratory dosage
delivery routes to maximize therapeutic response. forms, although other routes of administration are
Preparations can be taken orally or injected, as well being considered and researched. Delivery of these
as being applied to the skin or inhaled; Table 1.1 lists biotechnologically based drug substances via these
the range of dosage forms which can be used to routes of administration imposes additional con-
deliver drugs by the various administration routes. straints on the selection of appropriate formulation
However, it is necessary to relate the drug substance excipients.
to the clinical indication being treated before the Another growing area of clinically important
correct combination of drug and dosage form can be medicines is that of polymer therapeutics. These agents
made, as each disease or illness often requires a include designed macromolecular drugs, polymer–drug
specific type of drug therapy. In addition, factors and polymer–protein conjugates as nanomedicines,
governing the choice of administration route and the generally in injection form. These agents can also provide
specific requirements of that route which affect drug drug-targeting features (e.g. treating specific cancers)
absorption need to be taken into account when dosage as well as modified pharmacokinetic profiles (e.g.
forms are being designed. changed drug metabolism and elimination kinetics).
Many drugs are formulated into several dosage It is therefore apparent that before a drug substance
forms of various strengths, each having selected can be successfully formulated into a dosage form,
pharmaceutical characteristics which are suitable for a many factors must be considered. These can be
specific application. One such drug is the glucocorticoid broadly grouped into three categories:
prednisolone used in the suppression of inflammatory 1. biopharmaceutical considerations, including
and allergic disorders. Through the use of different factors affecting the absorption of the drug

7
 CHAPTER 1

substance from different administration as drug distribution, metabolism and excretion. In

routes; general, a drug substance must be in solution before
2. drug factors, such as the physical and chemical it can be absorbed via absorbing membranes and
properties of the drug substance; and epithelia of the skin, gastrointestinal tract and lungs
3. therapeutic considerations, including into body fluids. Drugs are absorbed in two general
consideration of the clinical indication to be ways: by passive diffusion and by carrier-mediated
treated and patient factors. transport mechanisms. In passive diffusion, which is
thought to control the absorption of many drugs, the
High-quality and efficacious medicines will be for-
process is driven by the concentration gradient existing
mulated and prepared only when all these factors
across the cellular barrier, with drug molecules passing
are considered and related to each other. This is the
from regions of high concentration to regions of low
underlying principle of dosage form design.
concentration. Lipid solubility and the degree of
ionization of the drug at the absorbing site influence
Biopharmaceutical aspects the rate of diffusion. Recent research into carrier-
mediated transport mechanisms has provided much
of dosage form design information and knowledge, providing guidance in
some cases for the design of new drug molecules.
Biopharmaceutics can be regarded as the study of Several specialized transport mechanisms are postu-
the relationship between the physical, chemical and lated, including active and facilitated transport. Once
biological sciences applied to drugs, dosage forms absorbed, the drug can exert a therapeutic effect
and drug action. Clearly, understanding the principles either locally or at a site of action remote from the
of this subject is important in dosage form design, site of administration. In the latter case the drug has
particularly with regard to drug absorption, as well to be transported in body fluids (Fig. 1.1).

Gastrointestinal Skin
tract

Oral Buccal Topical

Vascular

Mouth
system

preparations Subcutaneous injection

Direct
Intramuscular injection
Vascular system

or
Stomach
hepato- Circulatory
enteric system Respiratory
Small (drug or tract
intestine metabolites)
Vascular

Aerosols
system

Large Gases
intestine
Intravenous injection
Rectal Rectal
Rectum
preparations Drug or
metabolite
in tissues,
extracellular
Drug in fluids and
faeces Kidneys lymphatics

Drug or metabolites Drug or metabolites in

in urine saliva, exhaled air, etc.

Excretion

Elimination

Fig. 1.1 • Pathways a drug may take following the administration of a dosage form by different routes.

8
 Design of dosage forms CHAPTER 1

When the dosage form is designed to deliver drugs since they will be dealt with in greater detail later
via the buccal, respiratory, rectal, intramuscular or in this book.
subcutaneous routes, the drug passes directly into
the circulating blood from absorbing tissues, whilst
the intravenous route provides the most direct route
Oral route
of all. When a drug is delivered by the oral route, The oral route is the most frequently used route for
onset of drug action will be delayed because of drug administration. Oral dosage forms are intended
the required transit time in the gastrointestinal usually for systemic effects resulting from drug
tract before absorption, the absorption process and absorption through the various epithelia and mucosa
factors associated with hepatoenteric blood circula- of the gastrointestinal tract. A few drugs, however,
tion. The physical form of the oral dosage form will are intended to dissolve in the mouth for rapid
also influence the absorption rate and onset of action, absorption or for local effect in the gastrointestinal
with solutions acting faster than suspensions, which tract because of poor absorption by this route or low
in turn generally act faster than capsules and tablets. aqueous solubility. Compared with other routes, the
Dosage forms can thus be listed in order of the time oral route is the simplest, most convenient and safest
of onset of the therapeutic effect (Table 1.2). means of drug administration. However, disadvantages
However, all drugs irrespective of their delivery route include the relatively slow onset of action and pos-
remain foreign to the human body, and distribution, sibilities of irregular absorption and destruction of
metabolic and elimination processes commence certain drugs by the enzymes and secretions of the
immediately following drug absorption until the gastrointestinal tract. For example, insulin-containing
drug is eliminated from the body via the urine, preparations are inactivated by the action of stomach
faeces, saliva, skin or lungs in unchanged or metabo- fluids.
lized form. Whilst drug absorption from the gastrointestinal
tract follows the general principles described later
in this book, several specific features should be
Routes of drug administration emphasized. Changes in drug solubility can result
from reactions with other materials present in the
The absorption pattern of drugs differs considerably
gastrointestinal tract; for example, interference with
between individual drug substances, as well as between
absorption of tetracyclines through the formation of
the different administration routes. Dosage forms
insoluble complexes with calcium, which can be
are designed to provide the drug in a suitable form
available from foodstuffs or formulation additives.
for absorption from each selected route of administra-
Gastric emptying time is an important factor for
tion. The following discussion considers briefly the
effective drug absorption from the intestine. Slow
routes of drug administration and, whilst dosage forms
gastric emptying can be detrimental to drugs inacti-
are mentioned, this is intended only as an introduction
vated by the gastric juices and can delay absorption
of drugs more effectively absorbed from the intestine.
In addition, since environmental pH can influence
Table 1.2 Variation in time of onset of action for the ionization and lipid solubility of drugs, the pH
different dosage forms change occurring along the gastrointestinal tract, from
Time of onset Dosage forms a pH as low as 1 in the stomach to approximately 7
of action or 8 in the large intestine, is important for both the
degree and the site of drug absorption. Since mem-
Seconds Intravenous injections
branes are more permeable to un-ionized forms than
Minutes Intramuscular and subcutaneous to ionized forms and since most drugs are weak acids
injections, buccal tablets, aerosols, gases or bases, it can be shown that weak acids, being
Minutes to Short-term depot injections, solutions, largely un-ionized, are well absorbed from the
hours suspensions, powders, granules, stomach. In the small intestine (pH from approxi-
capsules, tablets, modified-release tablets mately 4 to 6.5), with its extremely large absorbing
Several hours Gastro-resistant coated formulations surface, both weak acids and weak bases are well
Days to weeks Depot injections, implants
absorbed.
The most popular oral dosage forms are tablets,
Varied Topical preparations capsules, suspensions, solutions and emulsions. Tablets

9
 CHAPTER 1

are prepared by compaction and contain drugs and than solid dosage forms or suspensions since drug
formulation additives which are included for specific dissolution is not required.
functions, such as disintegrants, which promote tablet
break-up into granules and powder particles in the
gastrointestinal tract, facilitating drug dissolution and Rectal route
absorption. Tablets are often coated, either to provide Drugs given rectally in solution, suppository or emul-
a protective barrier to environmental factors for drug sion form are generally administered for local rather
stability purposes or to mask unpleasant drug taste, than systemic effects. Suppositories are solid forms
as well as to protect drugs from the acid conditions intended for introduction into body cavities (usually
of the stomach (gastro-resistant coating). Increasing rectal but also vaginal and urethral), where they melt,
use is being made of modified-release tablet products releasing the drug. The choice of suppository base
such as fast-dissolving systems and controlled-release, or drug carrier can greatly influence the degree and
delayed-release or sustained-release formulations. The rate of drug release. This route of drug administration
benefits of controlled-release tablet formulations, is also indicated for drugs inactivated by the
achieved, for example, by the use of polymeric-based gastrointestinal fluids when given orally or when the
tablet cores or coating membranes, include reduced oral route is precluded, for example when a patient
frequency of drug-related side effects and maintenance is vomiting or unconscious. Drugs administered
of steady levels of drug in the plasma for extended rectally enter the systemic circulation without passing
periods, which are important when medications are through the liver, an advantage for drugs significantly
delivered for chronic conditions or where constant inactivated by the liver following oral route absorption.
levels are required to achieve optimal efficacy, as in Disadvantageously, the rectal route is inconvenient
treatment of angina and hypertension. and drug absorption is often irregular and difficult
Capsules are solid dosage forms containing the to predict.
drug and, usually, appropriate filler(s), enclosed in a
hard or soft shell composed primarily of gelatin or
other suitable polymeric material. As with tablets, Parenteral routes
uniformity of dose can be readily achieved, and A drug administered parenterally is one injected via
various sizes, shapes and colours of the shell are a hollow needle into the body at various sites and to
commercially available. The capsule shell readily various depths. The three main parenteral routes are
ruptures and dissolves following oral administration, subcutaneous, intramuscular and intravenous. Other
and in most cases drugs are released from capsules routes, such as intracardiac and intrathecal, are used
faster than from tablets. Recently, increased interest less frequently. The parenteral route is preferred when
has been shown in the filling of hard capsules with rapid absorption is essential, as in emergency situations
semisolid and microemulsion formulations to provide or when patients are unconscious or unable to accept
rapidly dispersing dosage forms for poorly soluble oral medication, and in cases when drugs are
drugs. destroyed, inactivated or poorly absorbed following
Suspensions, which contain finely divided drugs oral administration. In general, the blood levels
suspended in a suitable vehicle, are a useful means attained are more predictable than those achieved
of administering large amounts of drugs that would by oral dosage forms.
be inconvenient if they were taken in tablet or capsule Injectable preparations are usually sterile solutions
form. They are also useful for patients who experience or suspensions of drugs in water or other suitable
difficulty in swallowing tablets and capsules and physiologically acceptable vehicles. As referred to
for paediatric use. Whilst dissolution of drugs is previously, drugs in solution are rapidly absorbed,
required before absorption, the fine solid particles and thus suspension injections act more slowly than
in a suspension have a large surface area to present solution injections. In addition, since body
to the gastrointestinal fluids, and this facilitates drug fluids are aqueous, by use of drugs suspended in oily
dissolution, thus aiding absorption and thereby the vehicles, a preparation exhibiting slower absorption
onset of drug action. Not all oral suspensions, however, characteristics can be formulated to give a depot
are formulated for systemic effects, and several are preparation, providing a reservoir of the drug, which
designed for local effects in the gastrointestinal tract. is released slowly into the systemic circulation. Such
On the other hand, solutions, including formulations preparations are administered by intramuscular
such as syrups and linctuses, are absorbed more rapidly injection deep into skeletal muscles (e.g. several

10
 Design of dosage forms CHAPTER 1

penicillin-containing injections). Alternatively, depot determining the character of drug release from the
preparations can be achieved by subcutaneous implants formulation. Ointments are hydrophobic, oleaginous-
or pellets, which are compacted or moulded discs based dosage forms, whereas creams are semisolid
of drug placed in loose subcutaneous tissue under emulsions. Pastes contain more solids than ointments
the outer layers of the skin. Such systems include and thus are stiffer. For topical application in liquid
solid microspheres and biodegradable polymeric form other than solution, lotions, suspensions of solids
microspheres (e.g. lactide and glycolic acid homopoly- in aqueous solution or emulsions are used.
mers and copolymers) containing proteins or peptides Application of drugs to other topical surfaces such
(e.g. human growth hormone and leuprolide). More as the eye, ear and nose is common, and ointments,
generally, subcutaneous injections are aqueous solutions creams, suspensions and solutions are used. Oph-
or suspensions which allow the drug to be placed in thalmic preparations are required, amongst other
the immediate vicinity of blood capillaries. The drug features, to be sterile. Nasal dosage forms include
then diffuses into the capillaries. Inclusion of vaso- solutions or suspensions delivered by drops or fine
constrictors or vasodilators in subcutaneous injections aerosol from a spray. Ear formulations, in general,
will clearly influence blood flow through the capillaries, are viscous to prolong contact with affected areas.
thereby modifying the capacity for absorption. This
principle is often used in the administration of local Respiratory route
anaesthetics with the vasoconstrictor adrenaline, which
delays drug absorption. Conversely, increased drug The lungs provide an excellent surface for absorption
absorption can result when vasodilators are included. when the drug is delivered in gaseous, aerosol mist
Intravenous administration involves injection of sterile or ultrafine solid particle form. For drug particles
aqueous solutions directly into a vein at an appropriate presented to the lungs as an aerosol, particle size
rate. The volumes delivered can range from a few largely determines the extent to which they penetrate
millilitres, as in emergency treatment or for hypnotics, the alveolar region, the zone of rapid absorption.
to litre quantities, as in replacement fluid treatment Drug particles that have diameters in the region of
or parenteral nutrition. 1 μm to 5 μm reach the deep lung. Particles smaller
Given the generally negative patient acceptance than 1 μm are largely exhaled, and particles larger
of this important route of drug delivery, primarily than 5 μm are deposited on larger bronchial airways.
associated with pain and inconvenience, recent This delivery route is particularly useful for the direct
developments to help with self-injection by patients treatment of asthma, with use of both powder aerosols
have focused on ‘needle-free’ injection systems and (e.g. salmeterol xinafoate) and pressurized metered-
devices which propel the drug in aqueous solution dose inhalers containing the drug in liquefied inert
or powder form at high velocity directly through the propellant (e.g. salbutamol sulfate inhaler). Impor-
external layers of the skin. tantly, this delivery route is being increasingly rec-
ognized as a useful means of administering the
therapeutic agents emerging from biotechnology
Topical route requiring systemic distribution and targeted delivery,
Drugs are applied topically (i.e. to the skin) mainly such as peptides and proteins.
for local action. Whilst this route can also be
used for systemic drug delivery, percutaneous absorp-
tion is often poor and erratic, although several
Drug factors in dosage
transdermal patches delivering drugs for systemic form design
distribution (e.g. fentanyl patches for severe pain
management and nicotine patches for cessation of Each type of dosage form requires careful study
smoking) are available. The drugs applied to the skin of the physical and chemical properties of drug
for local effect include antiseptics, antifungals and substances to achieve a stable, efficacious product.
anti-inflammatory agents, as well as skin emollients These properties, such as dissolution, crystal size and
for protective effects. polymorphic form, solid-state stability and drug–
Pharmaceutical topical formulations – ointments, additive interaction, can have profound effects on
creams and pastes – are composed of the drug in a the physiological availability and physical and chemical
suitable semisolid base which is either hydrophobic stability of the drug. Through combination of
or hydrophilic. The bases play an important role in such information and knowledge with that from

11
 CHAPTER 1

pharmacological and biochemical studies, the most of powders. Drug dissolution rate, drug absorption
suitable drug form and additives can be selected for rate, drug content uniformity in dosage forms and
the formulation of chosen dosage forms. stability are all dependent to various degrees on
Whilst comprehensive property evaluation will not particle size, particle size distribution and particle
be required for all types of formulations, those interaction with solid surfaces. In many cases, for
properties which are recognized as important in dosage both drugs and additives, particle size reduction is
form design and processing are listed in Table 1.3. required to achieve the desired physicochemical
The stresses to which the formulation might be characteristics.
exposed during processing and manipulation into It is now generally recognized that poorly water-
dosage forms, as well as the procedures involved are soluble drugs showing a dissolution-rate-limiting step
also listed in Table 1.3. Variations in physicochemical in the absorption process will be more readily bioavail-
properties, occurring, for example, between batches able when administered in a finely subdivided form
of the same material or resulting from alternative with a larger surface than as a coarse material. Examples
treatment procedures, can modify the formulation include griseofulvin, tolbutamide, indometacin and
requirements, as well as processing and dosage form nifedipine. The fine material, often of micrometre
performance. For instance, the fine milling of poorly or nanometre size, with large specific surface area,
water-soluble drug substances can modify their dissolves at a faster rate, which can lead to increased
wetting and dissolution characteristics, important drug absorption by passive diffusion. With many of
properties during granulation and product performance the new drugs being introduced exhibiting extremely
respectively. Careful evaluation of these properties low aqueous solubility, alternative formulation
and understanding of the effects of these stresses on strategies to enhance drug dissolution are being used,
these parameters are therefore important in dosage such as coprecipitates of drug and adjuvant particles,
form design and processing, as well as for product complexation with hydrophilic polymers or oligosac-
performance. charides, or the formation of co-crystals with
hydrophilic templating compounds.
The rate of drug dissolution can be adversely
Particle size and surface area affected, however, by unsuitable choice of formulation
additives, even though solids of appropriate particle
Particle size reduction results in an increase in the
size are used. Tableting lubricant powders, for
specific surface area (i.e. surface area per unit weight)
example, can impart hydrophobicity to a formulation
and inhibit drug dissolution. Fine powders can also
increase air adsorption or static charge, leading to
Table 1.3 Properties of drug substances important in wetting or agglomeration problems. Micronizing drug
dosage form design and potential stresses occurring powders can lead to changes in crystallinity and
during processes, with a range of manufacturing particle surface energy which cause reduced chemical
procedures stability. Drug particle size also influences content
Properties Processing Manufacturing uniformity in solid dosage forms, particularly for
stresses procedures low-dose formulations. It is important in such cases
Particle size, Pressure Precipitation to have as many particles as possible per dose to
surface area Mechanical Filtration minimize potency variation between dosage units.
Particle surface Radiation Emulsification Other dosage forms are also affected by particle size,
chemistry Exposure to Milling including suspensions (for controlling flow properties
Solubility liquids Mixing and particle interactions), inhalation aerosols (for
Dissolution Exposure to gases Drying optimal penetration of drug particles to absorbing
Partition and liquid vapours Granulation mucosa) and topical formulations (for freedom from
coefficient Temperature Compaction grittiness).
Ionization constant Autoclaving
Crystal properties, Crystallization
polymorphism Handling Solubility
Stability Storage
Organoleptic Transport All drugs, regardless of their administration route,
Molecular weight must exhibit at least limited aqueous solubility for

12
 Design of dosage forms CHAPTER 1

therapeutic efficacy. Thus, relatively insoluble com- The dissolution of a drug is described in a simplified
pounds can exhibit erratic or incomplete absorption, manner by the Noyes–Whitney equation:
and it might be appropriate to use a more soluble salt or
other chemical derivatives. Alternatively, micronizing, dm
= kA(Cs − C )
complexation or solid dispersion techniques might be dt
used. Solubility, and especially the degree of saturation (1.1)
in the vehicle, can also be important in the absorption
of drugs already in solution in liquid dosage forms, where dm/dt is the dissolution rate, k is the dissolution
since precipitation in the gastrointestinal tract can rate constant, A is the surface area of dissolving solid,
occur, modifying bioavailability. Cs is the drug’s solubility and C is the concentration
The solubilities of acidic or basic compounds are of the drug in the dissolution medium at time t. The
pH dependent and can be altered by their forming equation reveals that the dissolution rate can be raised
salts, with different salts exhibiting different equi- by increase of the surface area (reducing particle size)
librium solubilities. However, the solubility of a salt of the drug, by increase of the solubility of the drug in
of a strong acid is less affected by changes in pH the diffusion layer and by increase of k, which in this
than the solubility of a salt of a weak acid. In the equation incorporates the drug diffusion coefficient
latter case, when the pH is lower, the salt hydrolyses and the diffusion layer thickness. During the early
to an extent dependent on the pH and pKa, resulting phases of dissolution, Cs > C, and if the surface area,
in decreased solubility. Reduced solubility can also A, and experimental conditions are kept constant,
occur for slightly soluble salts of drugs through the then k can be determined for compacts containing
common-ion effect. If one of the ions involved is drug alone. The constant k is termed the intrinsic
added as a different, more soluble salt, the solubility dissolution rate constant and is a characteristic of
product can be exceeded and a portion of the drug each solid drug compound in a given solvent under
precipitates. fixed hydrodynamic conditions.
Drugs with values of k less than 0.1 mg cm−2
usually exhibit dissolution-rate-limited absorption.
Dissolution This value is a helpful guide figure indicating the
level below which drug dissolution becomes the
As mentioned already, for a drug to be absorbed it
rate-limiting step in absorption. Particulate dissolution
must first be dissolved in the fluid at the site of
can also be examined where an effort is made to
absorption. For example, an orally administered drug
control A, and formulation effects can be studied.
in tablet form is not absorbed until drug particles
Dissolution rate data, when combined with solubil-
are dissolved or solubilized by the fluids at some
ity, partition coefficient and pKa data, provide an
point along the gastrointestinal tract, depending on
insight into the potential in vivo absorption charac-
the pH–solubility profile of the drug substance.
teristics of a drug. However, in vitro tests have sig-
Dissolution describes the process by which the drug
nificance only when they are related to in vivo results.
particles dissolve.
Once such a relationship has been established, in
During dissolution, the drug molecules in the
vitro dissolution tests can be used as a predictor of
surface layer dissolve, leading to a saturated solution
in vivo behaviour. The importance of dissolution
around the particles to form the diffusion layer.
testing, for quality control purposes, has been widely
Dissolved drug molecules then pass throughout the
recognized by official compendia, as well as drug
dissolving fluid to contact absorbing mucosa and are
regulatory authorities, with the inclusion of dissolution
absorbed. Replenishment of diffusing drug molecules
specifications using standardized testing procedures
in the diffusion layer is achieved by further drug
for a range of preparations.
dissolution, and the absorption process continues. If
The Biopharmaceutics Classification System (BCS),
dissolution is fast or the drug remains in solution
established in 1995, is a guide for predicting the
form, the rate of absorption is primarily dependent
intestinal absorption of drugs for orally administered
on the ability of the drug to traverse the absorbing
medicines on the basis of the solubility, dissolu-
membrane. If, however, drug dissolution is slow
tion ability, and permeation ability of drugs. This
because of its physicochemical properties or formula-
system has proved extremely useful in aiding the
tion factors, then dissolution may be the rate-limiting
design of oral medicines and has recently been
step in absorption and impacts drug bioavailability.
extended with the Biopharmaceutics Drug Disposition

13
 CHAPTER 1

Classification System (BDDCS) to incorporate dosage forms. However, for those substances com-
drug absorption and transport, and the effects of posed of or containing powders or compacted powders
metabolism. in the finished product, the crystal properties and
solid-state form of the drug must be carefully con-
sidered. It is well recognized that drug substances
Partition coefficient and pKa can be amorphous (i.e. without regular molecular
lattice arrangements), crystalline, anhydrous, in various
As pointed out earlier, for relatively insoluble com- degrees of hydration or solvated with other entrapped
pounds the dissolution rate is often the rate- solvent molecules, as well as differing in crystal
determining step in the overall absorption process. hardness, shape and size. In addition, many drug
Alternatively, for soluble compounds the rate of substances can exist in more than one form with
permeation across biological membranes is the rate- different molecular packing arrangements in the
determining step. Whilst the dissolution rate can be crystal lattice. This property is termed polymorphism,
changed by modification of the physicochemical and different polymorphs may be prepared by
properties of the drug and/or alteration of the for- manipulation of the conditions of particle formation
mulation composition, the permeation rate is depend- during crystallization, such as solvent, temperature
ent on the size, relative aqueous and lipid solubilities and rate of cooling. It is known that only one form
and ionic charge of drug molecules, factors which of a pure drug substance is stable at a given tem-
can be altered through molecular modifications. The perature and pressure, with the other forms, termed
absorbing membrane acts as a lipophilic barrier to metastable, converting at different rates to the stable
the passage of drugs, which is related to the lipophilic crystalline form. The different polymorphs differ in
nature of the drug molecule. The partition coefficient, their physical properties such as dissolution ability
for example between oil and water, is a measure of and solid-state stability, as well as processing behaviour
lipophilic character. in terms of powder flow and compaction during
Most low molecular weight drugs are weak acids tableting in some cases.
or bases and, depending on the pH, exist in an ionized These different crystalline forms can be of con-
or un-ionized form. Membranes of absorbing mucosa siderable importance in relation to the ease or dif-
are more permeable to un-ionized forms of drugs ficulty of formulation and as regards stability and
than to ionized species because of the greater lipid biological activity. As might be expected, higher
solubility of the un-ionized forms and the highly dissolution rates are obtained for metastable poly-
charged nature of the cell membrane, which results morphic forms; for example, the alternative poly-
in the binding or repelling of the ionized drug, thereby morphic forms of rifaximin exhibit different in vitro
decreasing penetration. dissolution rates and bioavailability. In some cases,
The dominating factors that therefore influence amorphous forms are more active than crystalline
the absorption of weak acids and bases are the pH forms.
at the site of absorption and the lipid solubility The polypeptide hormone insulin, widely used in
of the un-ionized species. These factors, together with the regulation of carbohydrate, fat and protein
the Henderson–Hasselbalch equations for calculating metabolism, also demonstrates how differing degrees
the proportions of ionized and un-ionized species at of activity can result from the use of different crystal-
a particular pH, constitute the pH-partition theory line forms of the same agent. In the presence of
for drug absorption. However, these factors do not acetate buffer, zinc combines with insulin to form
describe completely the process of absorption as an extremely insoluble complex of the proteinaceous
certain compounds with low partition coefficients hormone. This complex is an amorphous precipitate
and/or which are highly ionized over the entire or crystalline product depending on the environmental
physiological pH range show good bioavailability, and pH. The amorphous form, containing particles of
therefore other factors are clearly involved. no uniform shape and smaller than 2 μm, is
absorbed following intramuscular or subcutaneous
injection and has a short duration of action, whilst
Crystal properties: polymorphism the crystalline product, consisting of rhombohedral
crystals of size 10 μm to 40 μm, is more slowly
Practically all drug substances are handled in powder absorbed and has a longer duration of action. Insulin
form at some stage during their manufacture into preparations which are intermediate in duration of

14
 Design of dosage forms CHAPTER 1

action are prepared by use of physical mixtures of Whilst the mechanisms of solid-state degradation are
these two products. complex and often difficult to analyse, a full under-
Polymorphic transitions can also occur during standing is not a prerequisite in the design of a suitable
milling, granulating, drying and compacting opera- formulation containing solids. For example, in cases
tions (e.g. transitions during milling for digoxin and where drug substances are sensitive to hydrolysis,
spironolactone). Granulation can result in solvate steps such as minimization of exposure to moisture
formation, and during drying, a solvent or water during preparation, low moisture content specifications
molecule(s) may be lost to form an anhydrous for the final product and moisture-resistant packaging
material. Consequently, the formulator must be can be used. For oxygen-sensitive drugs, antioxidants
aware of these potential transformations which can can be included in the formulation and, as with
result in undesirable modified product performance, light-sensitive materials, suitable packaging can reduce
even though routine chemical analyses may not or eliminate the problem. For drugs administered in
reveal any changes. Reversion from metastable liquid form, the stability in solution, as well as the
forms, if used, to the stable form may also occur effects of pH over the physiological range of pH 1–8,
during the lifetime of the product. In suspen- should be understood. Buffers may be required to
sions, this may be accompanied by changes in the control the pH of the preparation to increase stability;
consistency of the preparation, which affects its where liquid dosage forms are sensitive to microbial
shelf life and stability. Such changes can often be attack, preservatives are required.
prevented by additives, such as hydrocolloids and In these formulations, and indeed in all dosage
surface-active agents. forms incorporating additives, it is also important to
ensure that the components, which may include
additional drug substances as in multivitamin prepara-
Stability tions, do not produce chemical interactions them-
selves. Interactions between the drug(s) and added
The chemical aspects of formulation generally centre excipients such as antioxidants, preservatives, suspend-
on the chemical stability of the drug and its compat- ing agents, colourants, tablet lubricants and packaging
ibility with the other formulation ingredients. In materials do occur and must be checked for during
addition, the packaging of the dosage form is an the design of formulations. In recent years, data
important factor contributing to product stability and from thermal analysis techniques, particularly micro-
must be an integral part of stability testing pro- calorimetry and differential scanning calorimetry
grammes. It has been mentioned previously that one (DSC), when critically examined, have been found
of the principles of dosage form design is to ensure useful in rapid screening for possible drug–additive
that the chemical integrity of drug substances is and drug–drug interactions. For example, DSC has
maintained during the usable life of the product. At revealed that the widely used tableting lubricant
the same time, chemical changes involving additives magnesium stearate interacts with aspirin and should
and any physical modifications to the product must be avoided in formulations containing this drug.
be carefully monitored to optimize formulation
stability.
In general, drug substances decompose as a result Organoleptic properties
of the effects of heat, oxygen, light and moisture.
For example, esters such as aspirin and procaine are Modern medicines require that pharmaceutical dosage
susceptible to solvolytic breakdown, whilst oxidative forms are acceptable to the patient. Unfortunately,
decomposition occurs for substances such as ascorbic many drug substances in use today are unpalatable
acid. Drugs can be classified according to their sensitiv- and unattractive in their natural state, and dosage
ity to breakdown: forms containing such drugs, particularly oral prepara-
tions, may require the addition of approved flavours
1. stable in all conditions (e.g. kaolin)
and/or colours.
2. stable if handled correctly (e.g. aspirin)
The use of flavours applies primarily to liquid
3. only moderately stable even with special dosage forms intended for oral administration.
handling (e.g. vitamins) and Available as concentrated extracts, solutions, adsorbed
4. very unstable (e.g. certain antibiotics in solution onto powders or microencapsulated, flavours are
form). usually composed of mixtures of natural and synthetic

15
 CHAPTER 1

materials. The taste buds of the tongue respond manufactured and, in most cases, on a large scale.
quickly to bitter, sweet, salt or acid elements of a In addition to those properties previously discussed
flavour. Unpleasant taste can be overcome by use of such as particle size and crystal form, other charac-
water-insoluble derivatives of drugs which have little teristics such as hygroscopicity, flowability and
or no taste. An example is the use of amitriptyline compactability are particularly important when solid
pamoate, although other factors, such as bioavailability, dosage forms are being prepared where the drugs
must remain unchanged. If an insoluble derivative is constitute a large percentage of the formulation.
unavailable or cannot be used, a flavour or perfume Hygroscopic drugs can require low moisture manu-
can be used. However, unpleasant drugs in capsules facturing environments and need to avoid water during
or prepared as coated particles or tablets may be preparation. Poorly flowing formulations may require
easily swallowed, avoiding the taste buds. the addition of flow agents (e.g. fumed silica). Studies
Selection of flavour depends on several factors of the compactability of drug substances are frequently
but particularly on the taste of the drug substance. undertaken with use of instrumented tablet machines
Certain flavours are more effective at masking various in formulation laboratories to examine the tableting
taste elements; for example, citrus flavours are fre- potential of the material so as to foresee any potential
quently used to combat sour or acid-tasting drugs. problems during compaction, such as lamination or
The solubility and stability of the flavour in the vehicle sticking, which may require modification of the
are also important. In addition, the age of the intended formulation or processing conditions.
patient should also be considered, since children, for
example, prefer sweet tastes, as well as the psychologi-
cal links between colours and flavours (e.g. yellow is Therapeutic considerations
associated with lemon flavour). Sweetening agents
may also be required to mask bitter tastes. Sucrose in dosage form design
continues to be used, but alternatives, such as sodium
saccharin, which is 200–700 times sweeter depending The nature of the clinical indication, disease or illness
on the concentration, are available. Sorbitol is rec- for which the drug is intended is an important factor
ommended for diabetic preparations. when one is selecting the range of dosage forms to
Colours are used to standardize or improve an be prepared. Factors such as the need for systemic
existing drug colour, to mask a colour change or or local therapy, duration of action required, and
complement a flavour. Whilst colours are obtained whether the drug will be used in emergency situations
from natural sources (e.g. carotenoids) or are syn- need to be considered. In the vast majority of cases,
thesized (e.g. amaranth), most of the colours used a single drug substance is prepared in a number of
are synthetically produced. Dyes may be water soluble dosage forms to satisfy both the particular preferences
(e.g. amaranth) or oil soluble (e.g. Sudan IV) or of the patient or physician and the specific needs of
insoluble in water and oil (e.g. aluminium lakes). a certain clinical situation. For example, many
Lakes, which are generally calcium or aluminium asthmatic patients use inhalation aerosols, from which
complexes of water-soluble dyes, are particularly the drug is rapidly available to the constricted airways
useful in tablets and tablet coatings because of their following deep inhalation for rapid emergency relief,
greater stability to light than corresponding dyes, and oral products for chronic therapy.
which also differ in their stability to pH and reducing Patients requiring urgent relief from angina pectoris,
agents. However, in recent years, the inclusion of a coronary circulatory problem, place tablets of
colours in formulations has become extremely glyceryl trinitrate under their tongue (sublingual
complex because of the banning of many traditionally administration). This results in rapid drug absorption
used colours in many countries. directly into the blood capillaries under the tongue.
Thus, whilst systemic effects are generally obtained
following oral and parenteral drug administration,
Other drug properties other routes can be used as the drug and situation
demand. Local effects are generally restricted to
At the same time as ensuring that dosage forms dosage forms applied directly, such as those applied
are chemically and physically stable and are thera- to the skin, ear, eye, throat and lungs. Some drugs
peutically efficacious, one should also establish that may be well absorbed by one route but not by another
the selected formulation can be efficiently and must therefore be considered individually.

16
 Design of dosage forms CHAPTER 1

The age of the patient also plays a role in defining absorption and bioavailability, and the increasing
the types of dosage forms made available. Infants application of diagnostic agents will play a key role
generally prefer liquid dosage forms, usually solutions in this area.
and mixtures, given orally. In addition, with liquid Other areas of innovation in formulation science
preparations, the amount of drug administered can responding to drug regulatory agency requirements
be readily adjusted by dilution to give the required in applications for marketing authorization of medi-
dose for the particular patient, taking the patient’s cines are emerging, such as the concept of ‘compu-
weight, age and condition into account. Children can tational pharmaceutics’. This topic incorporates
have difficulty in swallowing solid dosage forms, and (1) the use of in silico procedures to predict drug
for this reason many oral preparations are prepared substance properties and (2) decision making and
as pleasantly flavoured syrups or mixtures. Adults optimization tools, such as experimental design,
generally prefer solid dosage forms, primarily because artificial intelligence and neural computing. All these
of their convenience. However, alternative liquid can facilitate faster and rational design of formulations
preparations are usually available for those unable to and manufacturing processes.
take tablets and capsules.
Interest has grown in the design of drug-containing
formulations which deliver drugs to specific ‘targets’ Summary
in the body (e.g. the use of liposomes and nanopar-
ticles), as well as providing drugs over longer periods This chapter has demonstrated that the formulation
at controlled rates. Alternative technologies for of drugs into dosage forms requires the interpretation
preparing particles with the required properties – and application of a wide range of information
crystal engineering – provide new opportunities. and knowledge from several study areas. Whilst the
Supercritical fluid processing using carbon dioxide physical and chemical properties of drugs and additives
as a solvent or antisolvent is one such method, allowing need to be understood, the factors influencing drug
fine-tuning of crystal properties and particle design absorption and the requirements of the disease to
and fabrication. Undoubtedly, these new technologies be treated also have to be taken into account when
and others, as well as sophisticated formulations, will potential delivery routes are being identified. The
be required to deal with the advent of gene therapy formulation and associated preparation of dosage
and the need to deliver such labile macromolecules forms demand the highest standards, with careful
to specific targets and cells in the body. Interest is examination, analysis and evaluation of wide-ranging
also likely to be directed to individual patient require- information by pharmaceutical scientists to achieve
ments such as age, weight and physiological and the objective of creating high-quality, safe and effica-
metabolic factors, features which can influence drug cious dosage forms.

Bibliography
Blagden, N., de Matas, M., Gavan, P.T., Drugs, second ed. SSCI, West Formulation and Clinical Use, sixth
et al., 2007. Crystal engineering of Lafayette. ed. Pharmaceutical Press, London.
active pharmaceutical ingredients to Colbourn, E., Rowe, R.C., 2005. Neural Shekunov, B.Yu, York, P., 2000.
improve solubility and dissolution computing and formulation Crystallisation processes in
rate. Adv. Drug Deliv. Rev. 59, optimization. In: Swarbrick, J., pharmaceutical technology and drug
617–630. Boylan, J. (Eds.), Encyclopedia of delivery design. J. Cryst. Growth
Brayfield, A. (Ed.), 2014. Martindale: Pharmaceutical Technology, third ed. 211, 122–136.
The Complete Drug Reference, Marcel Dekker, New York. Wu, C.Y., Benet, L.Z., 2005. Predicting
thirty-eighth ed. Pharmaceutical Duncan, R., 2011. Polymer therapeutics drug disposition via application of
Press, London. as nanomedicines: new perspectives. BCS: transport/absorption/
British Pharmacopoeia Commission, Curr. Opin. Biotechnol. 22, elimination interplay and
2017. British Pharmacopoeia. 492–501. development of a biopharmaceutics
Stationery Office, London. Florence, A.T., Attwood, D., 2016. drug disposition classification
Byrn, S.R., Pfeiffer, R.R., Stowell, J.G., Physicochemical Principles of system. Pharm. Res. 22, 11–23.
1999. Solid State Chemistry of Pharmacy: In Manufacture,

17
2 Part 1: Scientific principles of dosage form design
Dissolution and solubility

Michael E. Aulton

CHAPTER CONTENTS this is not always the case. The differences are
explained in this chapter.
Introduction . . . . . . . . . . . . . . . . 18
• The process of dissolution involves a molecule,
Definition of terms . . . . . . . . . . . . . 19 ion or atom of a solid entering a liquid phase in
Solution, solubility and dissolution . . . . . . . 19 which the solid is immersed.
Process of dissolution . . . . . . . . . . . 19 • The rate of dissolution is controlled either by the
Dissolution mechanisms . . . . . . . . . . . . 19 speed of removal of the molecule, ion or atom
from the solid surface or by the rate of diffusion
Energy/work changes during dissolution . . . . 20
of that moiety through a boundary layer that
Dissolution rates of solids in liquids. . . . 21 surrounds the solid.
Factors affecting the rate of dissolution • Various factors influence the rate of diffusion of
of diffusion-controlled systems . . . . . . . . . 22 a solute through a boundary layer. Some of
Intrinsic dissolution rate. . . . . . . . . . . . . 25 these may be manipulated by the formulator.
Measurement of dissolution rates of drugs • It is important for the formulator to be aware of
from dosage forms . . . . . . . . . . . . . . . 25 the parameters which affect the solubility of a
Solubility . . . . . . . . . . . . . . . . . . 26 solid in a liquid phase.
Methods of expressing solubility and • The dissolution rate and solubility of solids in
concentration . . . . . . . . . . . . . . . . . . 26 liquids, gases in liquids and liquids in liquids are
each important in pharmaceutical science, and
Expressions of concentration . . . . . . . . . . 26
these are discussed.
Solubility of solids in liquids. . . . . . . . . . . 28
Solubility of gases in liquids . . . . . . . . . . 32
Solubility of liquids in liquids . . . . . . . . . . 33
Blending . . . . . . . . . . . . . . . . . . . . 34
Introduction
Distribution of solutes between
immiscible liquids . . . . . . . . . . . . . . . . 34 Solutions are encountered frequently in pharmaceuti-
Solubility of solids in solids . . . . . . . . . . . 35 cal development, either as a dosage form in their
Summary . . . . . . . . . . . . . . . . . . 36 own right or as a clinical trials material. Additionally,
almost all drugs function in solution in the body.
Reference . . . . . . . . . . . . . . . . . 36
This chapter discusses the principles underlying
Bibliography . . . . . . . . . . . . . . . . 36 the formation of solutions from a solute and a solvent
and the factors that affect the rate and extent of the
KEY POINTS
dissolution process. This process will be discussed
particularly in the context of a solid dissolving in a
• Dissolution rate and solubility are two separate liquid as this is the situation most likely to be
properties. While a solid with a fast dissolution encountered in the formation of a drug solution, either
rate often has a high solubility (and vice versa), during manufacturing or during drug delivery.

18
 Dissolution and solubility CHAPTER 2

Dissolution of gases in liquids, solids in semisolids, Since the above definitions are general ones, they
liquids in semisolids and liquids in liquids is also may be applied to all types of solution involving any
encountered pharmaceutically. of the three states of matter (gas, liquid, solid) dis-
Further properties of solutions are discussed in solved in any of the three states of matter, i.e. solid
Chapters 3 and 24. Because of the number of in liquid, liquid in solid, liquid in liquid, solid in
principles and properties that need to be considered, vapour, etc. However, when the two components
the contents of each of these chapters should only forming a solution are either both gases or both liquids,
be regarded as introductions to the various topics. then it is more usual to talk in terms of miscibility
The student is encouraged, therefore, to refer to the rather than solubility. Other than the name, all
bibliography at the end of each chapter to augment principles are the same.
the present contents. The textbook written by Flor- One point to emphasize at this stage is that the
ence & Attwood (2016) is recommended particularly. rate of solution (dissolution rate) and amount which
The authors use a large number of pharmaceutical can be dissolved (solubility) are not the same and
examples to aid the understanding of physicochemical are not necessarily related. In practice, high drug
principles. solubility is usually associated with a high dissolution
rate, but there are exceptions; an example is the
Definition of terms commonly used film-coating material hydroxypropyl
methylcellulose (HPMC) which is very water soluble
yet takes many hours to hydrate and dissolve.
This chapter will begin by clarifying and defining
some of the key terms relevant to solutions.
Process of dissolution
Solution, solubility and dissolution
Dissolution mechanisms
A solution may be defined as a mixture of two or
more components that form a single phase which is
The majority of drugs are crystalline solids. Liquid,
homogeneous down to the molecular level. The
semisolid and amorphous solid drugs do exist but
component that determines the phase of the solution
these are in the minority. For now, we will restrict
is termed the solvent; it usually (but not necessarily)
our discussion to dissolution of crystalline solids in
constitutes the largest proportion of the system. The
liquid solvents. In addition, to simplify the discussion,
other components are termed solutes, and these are
it will be assumed that the drug is molecular in nature.
dispersed as molecules or ions throughout the solvent,
The same discussion applies to ionic drugs. Similarly,
i.e. they are said to be dissolved in the solvent.
to avoid undue complication in the explanations that
The transfer of molecules or ions from a solid
follow, it can be assumed that most solid crystalline
state into solution is known as dissolution. Funda-
materials, whether drugs or excipients, will dissolve
mentally, this process is controlled by the relative
in a similar manner.
affinity between the molecules of the solid substance
The dissolution of a solid in a liquid may be
and those of the solvent.
regarded as being composed of two consecutive stages.
The extent to which the dissolution proceeds under
a given set of experimental conditions is referred to 1. First is an interfacial reaction that results in the
as the solubility of the solute in the solvent. The liberation of solute molecules from the solid
solubility of a substance is the amount of it that has phase to the liquid phase. This involves a phase
passed into solution when equilibrium is established change so that molecules of the solid become
between the solute in solution and the excess (undis- molecules of the solute in the solvent in which
solved) substance. the crystal is dissolving.
The solution that is obtained under these conditions 2. After this, the solute molecules must migrate
is said to be saturated. A solution with a concentration through the boundary layer surrounding the
less than that at equilibrium is said to be subsaturated. crystal to the bulk of solution.
Solutions with a concentration greater than that at These stages, and the associated solution concentration
equilibrium can be obtained in certain conditions; changes, are illustrated in Fig. 2.1.
these are known as supersaturated solutions (see These two stages of dissolution are now discussed
Chapter 8 for further information). in turn.

19
 PART ONE Scientific principles of dosage form design

Crystal Solvent

CS

Concentration Fig. 2.3 • The theory of cavity creation in the

of solute mechanism of dissolution.
C

The process of dissolution may be considered,

therefore, to involve the relocation of solute molecules
Boundary from an environment where they are surrounded by
layers other identical molecules, with which they undergo
intermolecular attraction, into a cavity in a liquid
Fig. 2.1 • Boundary layer and concentration change
surrounding a dissolving particle.
where they are surrounded by nonidentical molecules,
with which they may interact to different degrees.

Diffusion through the boundary layer

This step involves transport of the drug molecules
away from the solid–liquid interface into the bulk
of the liquid phase under the influence of diffusion
or convection. Boundary layers are static or slow-
moving layers of liquid that surround all solid surfaces
that are surrounded by liquid (discussed further later
in this chapter and in Chapter 6). Mass transfer occurs
more slowly (usually by diffusion; see Chapter 3)
Fig. 2.2 • Replacement of crystal molecules with through these static or slow-moving layers. These
solvent molecules during dissolution. layers inhibit the movement of solute molecules from
the surface of the solid to the bulk of the solution.
The solution adjacent to the solid will be saturated
Interfacial reaction (because it is in direct contact with undissolved solid).
During diffusion, the solution in the boundary layer
Leaving the surface. Dissolution involves the changes from being saturated (CS) at the crystal
replacement of crystal molecules by solvent molecules.
surface to having a concentration equal to that of
This is illustrated in Fig. 2.2.
the bulk of the solution (C) at its outermost limit,
The process of the removal of drug molecules
as shown in Fig. 2.1.
from a solid, and their replacement by solvent
molecules, is determined by the relative affinity of
the various molecules involved. The solvent/solute Energy/work changes
forces of attraction must overcome the cohesive forces during dissolution
of attraction between the molecules of the solid.
Moving into the liquid. On leaving the solid surface, For the process of dissolution to occur spontaneously
the drug molecule must become incorporated in the at a constant pressure, the accompanying change in
liquid phase, i.e. within the solvent. Liquids are free enthalpy (i.e. the change in Gibbs free energy,
thought to contain a small amount of so-called free ΔG) must be negative. The free energy (G) is a
volume. This can be considered to be in the form of measure of the energy available to the system to
‘holes’ that, at a given instant, are not occupied by perform work. Its value decreases during a spontane-
the solvent molecules themselves. Individual solute ously occurring process until an equilibrium position
molecules are thought to occupy these holes, as shown is reached when no more energy can be made available,
in Fig. 2.3. i.e. ΔG = 0 at equilibrium.

20
 Dissolution and solubility CHAPTER 2

In most cases heat is absorbed when dissolution rate constant (s−1). The energy difference between
occurs, and the process is usually defined as an the two concentration states provides the driving
endothermic one and the solution often cools. In some force for the diffusion.
systems, where there is marked affinity between In the present context, ΔC is the difference in
solute and solvent, the process is an exothermic one the concentration of the solution at the solid surface
and heat may be evolved. (C1) and the bulk of the solution (C2). Thus ΔC =
C1 − C2. If C2 is less than saturation, the molecules
Dissolution rates of solids will move from the solid to the bulk of solution (as
during dissolution). If the concentration of the bulk
in liquids (C2) is greater than saturation, the solution is referred
to as being supersaturated and movement of solid
Like any reaction that involves consecutive stages, molecules will be in the direction of bulk solution
the overall rate of dissolution will be dependent on to the surface (as occurs during crystallization).
which of the steps previously described is the slowest
(the rate-determining or rate-limiting step). In dis- Noyes–Whitney equation
solution, the interfacial step (as described earlier) is
An equation known as the Noyes–Whitney equation
almost always virtually instantaneous, and so the rate
was developed to define the dissolution from a single
of dissolution will most frequently be determined
spherical particle. This equation has found great
by the rate of the slower step of diffusion of dissolved
usefulness in the estimation or prediction of the
solute through the static boundary layer of liquid
dissolution rate of pharmaceutical particles. The rate
that exists at a solid–liquid interface.
of mass transfer of solute molecules or ions through
a static diffusion layer (dm/dt) is directly proportional
Interface-controlled dissolution rate
to the area available for molecular or ionic migration
On the rare occasions when the release of the (A) and the concentration difference (ΔC) across
molecule from the solid into solution is slow and the the boundary layer and is inversely proportional to
transport across the boundary layer to the bulk solu- the thickness of the boundary layer (h). This relation-
tion is faster, dissolution is said to be interfacially ship is shown in Eq. 2.3:
controlled.
dm k1 A∆C
=
Diffusion-controlled dissolution rate dt h
If the rate of diffusion of the solute molecules through (2.3)
the boundary layer is the slowest step, dissolution is The constant k1 is known as the diffusion coefficient.
said to be diffusion controlled. The movement of It is commonly given the symbol D and has the units
solute molecules through the boundary layer will of m2 s−1).
obey Fick’s first law of diffusion. This law states that An alternative form of the Noyes-Whitney equation
the rate of change in the concentration of a dissolved can be used when, at equilibrium, the solution in
material with time is directly proportional to the contact with the solid (C1) will be saturated. In this
concentration difference between the two sides of case, the symbol CS is used. It is also common practice
the diffusion layer, i.e. to use the symbol C in place of C2 (the bulk con-
centration). This gives Eq. 2.4:
dC
∝ ∆C dm k1 A(CS − C )
dt =
dt h
(2.1)
(2.4)
or
If the volume of the solvent is large, or solute is
dC removed from the bulk of the dissolution medium
= k∆C by some process at a faster rate than it passes into
dt
solution, then C remains close to zero and the term
(2.2)
(CS – C) in Eq. 2.4 may be approximated to CS. In
where C is the concentration of solute in solution at practice, if the volume of the dissolution medium is
any position and at time t, and the constant k is the so large that C is not allowed to exceed 10% of the

21
 PART ONE Scientific principles of dosage form design

Table 2.1 Factors affecting in vitro dissolution rates of solids in liquids

Term in the Noyes–Whitney equation (Eq. 2.4) Affected by
A: surface area of undissolved solid Size of solid particles (A increases with particle size reduction)
(rate of dissolution increases proportionally with Dispersibility of powdered solid in dissolution medium
increasing A) Porosity of solid particles
CS: saturated solubility of solid in dissolution medium Temperature
(Rate of dissolution increases proportionally with Nature of dissolution medium
increasing difference between CS and C. Thus high CS Molecular structure of solute
speeds up dissolution rate) Crystalline form of solid
Presence of other compounds
C: concentration of solute in solution at time t Volume of dissolution medium (increased volume decreases C)
(Rate of dissolution increases proportionally with Any process that removes dissolved solute from the dissolution
increasing difference between CS and C. Thus low C medium (hence decreasing C)
speeds up dissolution rate)
k: dissolution rate constant Diffusion coefficient D of solute in the dissolution medium
Viscosity of medium
h: thickness of boundary layer Degree of agitation of dissolution medium (increased agitation
(Rate of dissolution decreases proportionally with decreases boundary layer thickness)
increasing boundary layer thickness)

value of CS, then the same approximation may be can be predicted by examination of the Noyes–
made. In either of these circumstances dissolution Whitney equation (Eq. 2.3 or Eq. 2.4). Most of the
is said to occur under ‘sink’ conditions and Eq. 2.4 effects of these factors are included in the summary
may be simplified to given in Table 2.1.
Clearly, increases in those factors in the numerator
dm k1 ACS
= on the right-hand side of the Noyes–Whitney equation
dt h
will increase the rate of diffusion (and therefore the
(2.5) overall rate of dissolution), and increases in factors
Sink conditions may arise in vivo when a drug is in the denominator of the equation will result in a
absorbed into the body from its solution in the decreased rate of dissolution. The opposite situation
gastrointestinal fluids at a faster rate than it dissolves obviously applies regarding a reduction in these
in those fluids from a solid dosage form, such as a parameters. Each of these is discussed in the following
tablet. The phrase is illustrative of the solute molecules sections.
‘disappearing down a sink’!
If solute is allowed to accumulate in the dissolution
Surface area of undissolved solid (A)
medium to such an extent that the aforementioned
approximation is no longer valid, i.e. when C > Size of solid particles. The Noyes–Whitney equa-
(CS/10), then ‘nonsink’ conditions are said to be in tion (Eq. 2.4) shows that there is a directly propor-
operation. When C builds up to such an extent that tional increase in dissolution rate with increasing area
it equals CS, i.e. the dissolution medium is saturated of solid available for dissolution. The surface area of
with solute, it is clear from Eq. 2.4 that the overall a fixed mass of isodiametric particles is inversely
rate of dissolution will be zero. proportional to the particle size, i.e. as the particle
size is reduced, the area of solid surface available to
Factors affecting the rate the liquid phase increases. The effect can be visualized
in Fig. 2.4, and the consequences are described in
of dissolution of diffusion- Box 2.1.
controlled systems A further illustration of this property is shown in
Table 2.2, with the increase in surface area as the
The various factors that affect the in vitro rate of particle size is decreased quantified mathematically.
diffusion-controlled dissolution of solids in liquids In each row of Table 2.2 the mass and volume of

22
 Dissolution and solubility CHAPTER 2

a b c

Fig. 2.4 • Visualization of increase in available surface area as the particle size of a fixed mass of powder is reduced.

Box 2.1

Worked example In Fig. 2.4b, 9 × 6 = 54 molecules can be

accommodated on the surface of each cube. For all
Consider the model size reduction shown in Fig. 2.4.
eight cubes this gives 432 molecules that will be in
The total surface area is equal to the surface area of
contact with the dissolution medium and available for
each particle (approximated here as a cube) multiplied
dissolution.
by the number of cubes in total. Considering the
In Fig. 2.4c, 4 × 6 = 24 molecules can be
surface area in terms of the number of molecules
accommodated on the surface of each cube. For all
available for dissolution (represented by light green
27 cubes this gives 648 molecules that will be in
spheres) that can fit around the surface, it can be
contact with the dissolution medium and available for
seen that:
dissolution.
In Fig. 2.4a, 36 × 6 = 216 molecules can be
Note that the total mass of the solid remains
accommodated on the surface of the single starting
unchanged during the size reduction.
cube. These will be in contact with the dissolution
medium and available for dissolution.

Table 2.2 Calculation of the surface area generated during size reduction of a single cube
Dimensions of Number of cubic Area of one face Total surface area Total surface area
one face of each particles (with same of each particle of one particle of all particles
cubic particle total mass) (i.e. all six faces)
100 μm × 100 μm 1 10 000 μm2 60 000 μm2 60 000 μm2
10 μm × 10 μm 1000 100 μm 2
600 μm 2
600 000 μm2
(10 × 10 × 10)
1 μm × 1 μm 1 000 000 1 μm2 6 μm2 6 000 000 μm2
(100 × 100 × 100)

solid material remain the same; however, the increase There is much practical evidence to show that, in
in surface area is dramatic as the size of the particles general, milling or other means of particle size reduc-
is reduced. In order to simplify the explanation, the tion will increase the rate of dissolution of sparingly
particles are assumed to be cubes and remain as cubes soluble drugs.
during size reduction. Dispersibility of powdered solid in dissolution
It can be seen that reducing the size of the same medium. If solid particles form cohered masses in
mass of powder from one 100 μm cube to 1000 the dissolution medium, then the surface area available
10 μm cubes will increase the surface area by a factor for dissolution is reduced. This effect may be over-
of 10. Further size reduction to 1 000 000 1 μm come by the addition of a wetting agent to improve
cubes will result in a further tenfold increase in area. the dispersion of the solid into primary powder
Thus there is an overall increase by a factor of 100. particles.

23
 PART ONE Scientific principles of dosage form design

Presence of other compounds. The common-ion

effect, complex formation and the presence of solu-
bilizing agents can affect the rate of dissolution.

Concentration of solute in solution

at time t (C)
Volume of dissolution medium. If the volume of
the dissolution medium is large (whether in vitro or
dr in vivo), then C may be negligible with respect to
CS and thus ‘sink’ conditions will operate. If the
volume is small, C can rapidly increase during dis-
Fig. 2.5 • The reduction in surface area and volume
solution and approach CS. The volume of the dissolu-
during the dissolution of a spherical particle.
tion can be controlled easily in vitro but must be
taken into account in vivo as the volume of the
Porosity of solid particles. Pores in some materials, stomach contents can vary greatly. The common
particularly granulated ones, may be large enough to
instruction ‘To be taken with a glass of water’ takes
allow access of the dissolution medium into these
this into account. In addition, the volume of the fluid
pores, dissolution to occur within the pores and then
at other drug delivery sites, e.g. in the rectum and
outward diffusion of dissolved solute molecules.
vagina, is small (see Chapter 41) and so this considera-
Changing area during dissolution. An added tion can be important in drug delivery from sup-
complication in practice is that the particle size will positories and pessaries.
change during the dissolution process, because large
Any process that removes dissolved solute from
particles will become smaller and will eventually
the dissolution medium. Adsorption onto an
disappear. This effect is shown in Fig. 2.5.
insoluble adsorbent, partitioning into a second liquid
Compacted masses of solid may also disintegrate
that is immiscible with the dissolution medium, and
into smaller particles, thus increasing the surface area
removal of solute by dialysis or by continuous replace-
available for dissolution as the disintegration process
ment of solution by fresh dissolution medium can
progresses. (This effect is shown in Fig. 30.7 and
all result in a decrease in C and thus an increased
explained further in the associated discussion).
rate of dissolution. This can also occur in vivo in the
case of a drug with a high gastrointestinal tract perme-
Solubility of solid in dissolution ability, i.e. a high rate of absorption.
medium (CS) In the case of a drug that has very low aqueous
solubility and poor absorption, the concentration of
Temperature. Dissolution may be an exothermic the drug in solution in the gastrointestinal tract (C)
or an endothermic process. Temperature changes will may rise until it is equal to CS. At that point (CS
influence the energy balance and thus the energy − C) will be zero, and hence from the Noyes–Whitney
available to promote dissolution. These relationships equation (Eq. 2.4) the rate of dissolution will be
are discussed later in this chapter in the section headed zero, i.e. dissolution will cease. This scenario is
‘Factors affecting the solubility of solids in liquids’. sometimes called solubility-limited dissolution.
Nature of dissolution medium. Factors such as
solubility parameters, pH and the presence of
cosolvents will affect the rate of dissolution. Dissolution rate constant (k)
Molecular structure of solute. The use of salts of Thickness of the boundary layer. This is affected
either weakly acidic or weakly basic drugs, or esteri- in vitro by the degree of agitation, which in turn
fication of neutral compounds, can influence solubility depends on the speed of stirring or shaking, the shape,
and the dissolution rate. size and position of the stirrer, the volume of the
Crystalline form of solid. The presence of poly- dissolution medium, the shape and size of the con-
morphs, hydrates, solvates or the amorphous form of tainer, and the viscosity of dissolution medium. Note
the drug can have an influence on the dissolution rate the inverse relationship in the Noyes–Whitney
and solubility (see later in this chapter and Chapter 8). equation (Eq. 2.4) between rate of dissolution (dm/

24
 Dissolution and solubility CHAPTER 2

dt) and the thickness of the boundary layer (h).

Decreasing the thickness of the boundary layer (e.g.
by increased agitation) increases the rate of dissolu-
tion. It is beyond the control of the formulator to
manipulate boundary layer thickness in vivo.
Diffusion coefficient of solute in the dissolution
medium. The diffusion coefficient of the solute in
the dissolution medium is affected by the viscosity
of the dissolution medium, and the molecular char-
acteristics and size of diffusing molecules.
It should be borne in mind that pharmaceutical
scientists are often concerned with the rate of dis-
solution of a drug from a formulated product such Fig. 2.6 • Measurement of intrinsic dissolution rate.
as a tablet or a capsule, as well as with the dissolution
rates of pure solids. In practice, the rate of dissolution (Fig. 2.6). The holder and disc are immersed in the
can have zero-order, first-order, second-order or dissolution medium and either held in a fixed position
cube-root kinetics. These are discussed later in the in the static disc method or rotated at a given speed
book when they are relevant to particular dosage in the rotating disc method. Samples of dissolution
forms. Later chapters in this book can also be con- medium are removed after known times, filtered and
sulted for information on the influence of formulation assayed for the dissolved substance. Further informa-
factors on the rates of release of drugs into solution tion on this method can be found in Chapter 23.
from various dosage forms. This design of the test attempts to ensure that
the surface area, from which dissolution can occur,
Intrinsic dissolution rate remains constant. Under these conditions, the amount
of substance dissolved per unit time and unit surface
Since the rate of dissolution is dependent on so many area can be determined. This should be referred to
factors, it is advantageous to have a measure of the as the intrinsic dissolution rate (IDR) and should be
rate of dissolution that is independent of some of distinguished from the measurements obtained by
these – rate of agitation and area of solute available other methods. In nondisc methods (see Chapter
in particular. 35) the surface area of the drug that is available for
A useful parameter is the intrinsic dissolution rate dissolution changes considerably during the course
(IDR). The IDR is the rate of mass transfer per unit of the determination because the dosage form usually
area of dissolving surface and typically has the unit disintegrates into many smaller particles and the size
of mg mm−2 s−1). The IDR should be independent of these particles then decreases as dissolution
of the boundary layer thickness and the volume of proceeds and, generally, the area of dissolving surface
the solvent (i.e. it is assumed that sink conditions is unknown at any particular time.
have been achieved). The IDR is given by
IDR = k1CS Measurement of dissolution rates
(2.6)
of drugs from dosage forms
Thus the IDR measures the intrinsic properties of Many methods have been described in the literature,
the drug only as a function of the dissolution medium, particularly in relation to the determination of the
e.g. its pH, ionic strength, and presence of counte- rate of release of drugs into solution from tablet and
rions, and is independent of many other factors. capsule formulations, because such release may have
an important effect on the therapeutic efficacy of
Techniques for measuring the IDR these dosage forms (see Chapter 20). In vitro dissolu-
Rotating and static disc methods are used. In these tion tests for assessing the rates of dissolution of drugs
methods, the compound to be assessed for the rate from solid-unit dosage forms are discussed fully in
of dissolution is compacted into a nondisintegrating Chapter 35. Other chapters in Part Five of this book
disc. This is mounted in a holder so that only one should be referred to for information on the dissolution
face of the disc is exposed to the dissolution medium methods applied to other specific dosage forms.

25
 PART ONE Scientific principles of dosage form design

Solubility Equivalent percentages based on weight (w) and

volume (v) ratios (expressed as % v/w, % v/v and %
w/w) can also be used for solutions of liquids in
The solution produced when equilibrium is established
liquids and solutions of gases in liquids.
between undissolved and dissolved solute in a dis-
It should be realized that if concentration is
solution process is termed a saturated solution. The
expressed in terms of the weight of solute in a given
amount of substance that passes into solution in order
volume of solution, then changes in volume caused by
to establish this equilibrium at constant temperature
temperature fluctuations will alter the concentration.
and so produce a saturated solution is known as the
solubility of the substance. It is possible to obtain Parts
supersaturated solutions but these are unstable and
precipitation of the excess solute tends to occur Pharmacopoeias give information on the approximate
readily and spontaneously. solubility of official substances in terms of the number
of ‘parts’ of solute dissolved in a stated number of
Methods of expressing solubility ‘parts’ of solution. Use of this method to describe
the concentration of a solution of a solid in a liquid
and concentration suggests that a certain number of parts by weight
(g) of solid are contained in a given number of parts
Solubilities may be expressed by any of the variety by volume (mL) of solution. In the case of solutions
of concentration terms explained in the following of liquids in liquids, parts by volume of solute in
sections. In general, solubility is expressed in terms parts by volume of solution are intended, whereas
of the maximum mass or volume of solute that will with solutions of gases in liquids, parts by weight of
dissolve in a given mass or volume of solvent at a gas in parts by weight of solution are inferred. The
particular temperature and at equilibrium. use of ‘parts’ in scientific work, or indeed in practice,
is not recommended as there is the chance for some
Expressions of concentration degree of ambiguity.

Quantity per quantity Molarity

Concentrations are often expressed simply as the This is the number of moles of solute contained in
weight or volume of solute that is contained in a 1 dm3 (more commonly expressed in pharmaceutical
given weight or volume of the solution. Most solutions science as 1 L) of solution. Thus solutions of equal
encountered in pharmaceutical practice consist of molarity contain the same number of solute molecules
solids dissolved in liquids. Consequently, concentration in a given volume of solution. The unit of molarity
is expressed most commonly by the weight of solute (M) is mol L−1) (equivalent to 103 mol m−3 if con-
contained in a given volume of solution. Although verted to the strict SI unit).
the SI unit is kg m−3 the terms that are used in
practice are based on more convenient or appropriate Molality
weights and volumes. For example, in the case of a This is the number of moles of solute divided by the
solution with a concentration of 1 kg m−3 the strength mass of the solvent, i.e. its SI unit is mol kg−1.
may be denoted by any one of the following concentra- Although it is less likely to be encountered in phar-
tion terms, depending on the circumstances: maceutical science than the other terms, it does offer
1 g L−1, 0.1 g per 100 mL, 1 mg mL−1, 5 mg in a more precise description of concentration because
5 mL or 1 μg μL−1. it is unaffected by temperature.

Percentage Mole fraction

Pharmaceutical scientists have a preference for quoting This is often used in theoretical considerations, and is
concentrations in percentages. The concentration of defined as the number of moles of solute divided by
a solution of a solid in a liquid is given by the total number of moles of solute and solvent, i.e.
weight of solute n1
concentration (% w v ) = × 100 mole fraction of solute ( x1 ) =
volume of solution n1 + n2
(2.7) (2.8)

26
 Dissolution and solubility CHAPTER 2

Table 2.3 Descriptive solubility: United States Pharmacopeia and European Pharmacopoeia terms for describing
solubility
Descriptive term Approximate volume of solvent (mL) necessary to dissolve Solubility range
1 g of solute (at a temperature between 15 °C and 25 °C) (mg mL−1)
Very soluble <1 ≥1000
Freely soluble From 1 to 10 100–1000
Soluble From 10 to 30 33–100
Sparingly soluble From 30 to 100 10–33
Slightly soluble From 100 to 1000 1–10
Very slightly soluble From 1000 to 10 000 0.1–1
Practically insolublea
>10 000 ≤ 0.1
Some pharmacopoeias include the term ‘partially soluble’. This refers to a mixture of components, of which only some dissolve.
a
This term is absent from the European Pharmacopoeia.

where n1 and n2 are the numbers of moles of solute soluble’ and ‘sparingly soluble’. The interrelationship
and solvent respectively. between such terms and approximate solubility is
shown in Table 2.3.
Milliequivalents and normal solutions
The concentrations of solutes in body fluids and in Prediction of solubility
solutions used as replacements for these fluids are Probably the most sought after information about
usually expressed in terms of the number of millimoles solutions in formulation problems is ‘what is the best
(1 millimol = one-thousandth of a mol) in 1 L of solvent for a given solute?’. Theoretical prediction
solution. In the case of electrolytes, however, these of precise solubility is an involved and occasionally
concentrations may still be expressed in terms of unsuccessful operation but, from knowledge of the
milliequivalents per litre. A milliequivalent (mEq) structure and properties of the solute and solvent,
of an ion is, in fact, one-thousandth of the gram an educated guess is possible. This guess is best
equivalent of the ion, which is, in turn, the ionic expressed in qualitative terms, such as ‘very soluble’
weight expressed in grams divided by the valency of or ‘sparingly soluble’, as previously described. Often
the ion. Alternatively, (particularly in preformulation or early formulation)
ionic weight ( mg ) this approximation is all that the formulator requires.
1 mEq = A more precise value can be obtained later in the
valency
development process.
(2.9) Speculation on what is likely to be a good solvent
Knowledge of the concept of chemical equivalents is usually based on the ‘like dissolves like’ principle.
is also required in order to understand the use That is, a solute dissolves best in a solvent with similar
of ‘normality’ as a means of expressing the concentra- chemical properties. The concept traditionally follows
tion of solutions. A normal solution, i.e. one with a two rules:
concentration of 1 N, is one that contains the 1. Polar solutes will dissolve better in polar
equivalent weight of the solute, expressed in grams, solvents.
in 1 L of solution. It was expected that this term 2. Nonpolar solutes will dissolve better in nonpolar
would have disappeared following the introduction solvents.
of SI units but it is still encountered in some volu-
Chemical groups that confer polarity to their parent
metric assay procedures.
molecules are known as polar groups. In the context
of solubility, a polar molecule has a high dipole
Qualitative descriptions of solubility moment.
Pharmacopoeias also express approximate solubilities To rationalize these rules, you can consider the
that correspond to descriptive terms such as ‘freely forces of attraction between solute and solvent

27
 PART ONE Scientific principles of dosage form design

molecules. The following section explains the basic e.g. Hansen parameters and interaction param-
physicochemical properties of solutions that lead to eters. These have improved the quantitative
such observations. treatment of systems in which polar effects and
interactions occur.
Physicochemical prediction of solubility Solubility parameters, in conjunction with the
electrostatic properties of liquids, e.g. dielectric
Similar types of intermolecular force may contribute constant and dipole moment, have often been linked
to solute–solvent, solute–solute and solvent–solvent by empirical or semiempirical relationships either to
interactions. The attractive forces exerted between these parameters or to solvent properties. Studies
polar molecules are much stronger, however, than on solubility parameters are reported in the pharma-
those that exist between polar and nonpolar molecules ceutical literature. The use of dielectric constants as
or between nonpolar molecules themselves. Conse- indicators of solvent power has also received attention
quently, a polar solute will dissolve to a greater extent but deviations from the behaviour predicted by such
in a polar solvent (where the strength of the solute– methods may occur in practice.
solvent interaction will be comparable to that between Mixtures of liquids are often used as solvents. If
solute molecules) than in a nonpolar solvent (where the two liquids have similar chemical structures, e.g.
the solute–solvent interaction will be relatively weak). benzene and toluene, then neither tends to associate
In addition, the forces of attraction between the in the presence of the other and the solvent properties
molecules of a polar solvent will be too great to of a 50 : 50 mixture would be the mean of those of
facilitate the separation of these molecules by the each pure liquid. If the liquids have dissimilar
insertion of a nonpolar solute between them, because structures, e.g. water and propanol, then the molecules
the solute–solvent forces will again be relatively weak. of one liquid tend to associate with each other and
Thus solvents for nonpolar solutes tend to be restricted so form regions of high concentration within the
to nonpolar liquids. mixture. The solvent properties of this type of system
These considerations thus follow the very general are not so simply related to its composition as in the
‘like dissolves like’ principle. Such generalizations previous case.
should be treated with caution in practice, because
the intermolecular forces involved in the process
of dissolution are influenced by factors that are Solubility of solids in liquids
not obvious from a consideration of the overall
polarity of a molecule. For example, the possibil- Solutions of solids in liquids are the most common
ity of intermolecular hydrogen bond formation type of solution encountered in pharmaceutical practice.
between solute and solvent may be more significant A pharmaceutical scientist should therefore be aware
than polarity. of the general method of determining the solubility
Solubility parameters. Attempts have been made of a solid in a liquid and the various precautions that
to define a parameter that indicates the ability of should be taken during such determinations.
a liquid to act as a solvent. The most satisfactory
approach, introduced by Hildebrand and Scott in Determination of the solubility
1962, is based on the concept that the solvent power of a solid in a liquid
of a liquid is influenced by its intermolecular cohesive
forces and that the strength of these forces can The following points should be observed in all solubil-
be expressed in terms of a solubility parameter. ity determinations:
The initial parameters, which are concerned with • The solvent and solute must be as pure as
the behaviour of nonpolar, noninteracting liquids, are possible. The presence of small amounts of
referred to as Hildebrand solubility parameters. Whilst many impurities may either increase or decrease
these provide good quantitative predictions of the the measured solubility. This is a particular
behaviour of a small number of hydrocarbons, they problem with early preformulation samples,
provide only a broad qualitative description of the which are often impure, and here special care
behaviours of most liquids, because of the influence must be taken. This point is discussed further
of factors such as hydrogen bond formation and in Chapter 23.
ionization. The concept has been extended, however, • A saturated solution must be obtained before
by the introduction of partial solubility parameters, any solution is removed for analysis and then all

28
 Dissolution and solubility CHAPTER 2

undissolved material must be removed prior to improve the solubility and bioavailability of drugs, is
analysis. given in Chapters 20 and 24.
• The method of separating a sample of saturated
solution from undissolved solute must be
Temperature and heat input
satisfactory. The dissolution process is usually an endothermic
• The method of analysing the solution must be one, i.e. heat is normally absorbed when dissolution
sufficiently accurate and reliable. occurs. In this type of system, supply of heat will lead
to an increase in the solubility of a solid. Conversely,
• Temperature must be adequately controlled.
in the case of the less commonly occurring systems
A saturated solution is obtained either by stirring that exhibit exothermic dissolution, which attempt
excess powdered solute with solvent for several hours to evolve heat, an increase in supplied heat will result
at the required temperature, until equilibrium in a decrease in solubility.
has been attained, or by warming the solvent with Plots of solubility versus temperature, referred to
an excess of the solute and allowing the mixture to as solubility curves, are often used to describe the
cool to the required temperature. It is essential that effect of temperature on a given system. Some
some undissolved solid should be present at the examples are shown in Fig. 2.7. Most of the curves
completion of the cooling stage to ensure that the are continuous. However, abrupt changes in slope
solution is saturated and not either subsaturated or may be observed with some systems if a change in
supersaturated. the nature of the dissolving solid occurs at a specific
A sample of the saturated solution is obtained for transition temperature. For example, sodium sulfate
analysis by separating out undissolved solid from the exists as the decahydrate Na2SO4⋅10H2O up to 32.5
solution. Filtration is usually used, but precautions °C and its dissolution in water is an endothermic
should be taken to ensure that: process. Its solubility therefore increases with a rise
• it is carried out at the temperature of the in temperature until 32.5 °C is reached. Above this
solubility determination in order to prevent any temperature the solid is converted into the anhydrous
change in the equilibrium between dissolved form (Na2SO4), and the dissolution of this compound
and undissolved solute; is exothermic. The solubility therefore exhibits a
• loss of any volatile component does not occur; change from a positive to a negative slope as the
and temperature exceeds the transition value, i.e. the
• adsorption of sample material onto surfaces solubility falls.
within the filter is minimized.
Membrane filters that can be used in conjunction 1.0
with conventional syringes fitted with suitable in-line
adapters have proved to be successful.
The amount of solute contained in the sample 0.8 KNO3
of saturated solution may be determined by a
Solubility (kg per kg of water)

variety of methods, e.g. gravimetric analysis, UV

spectrophotometry and chromatographic methods 0.6
(particularly high-performance liquid chromatog-
raphy [HPLC]). The selection of an appropriate Na2SO4
method is affected by the nature of the solute 0.4 NaCl
and the solvent and by the concentration of the
solution. (CH3COO)2Ca·2H2O
0.2
Factors affecting the solubility Na2SO4·10H2O
of solids in liquids
Knowledge of these factors, together with their 0
0 20 40 60 80 100
practical applications, as discussed in the following
sections, is an important aspect of a pharmaceutical Temperature (°C)
scientist’s expertise. Additional information, which Fig. 2.7 • Solubility curves for various substances in
shows how some of these factors may be used to water.

29
 PART ONE Scientific principles of dosage form design

Molecular structure of solute water. This is achieved by using cosolvents such as

It should be appreciated from the previous comments ethanol or propylene glycol, which are miscible with
in this chapter on the prediction of solubility that water and which act as better solvents for the solute
the nature of the solute and the solvent will be of in question.
paramount importance in determining the solubility For example, the aqueous solubility of metroni-
of a solid in a liquid. It should also be realized that dazole is about 100 mg in 10 mL. The solubility of
even a small change in the molecular structure of a this drug can be increased markedly by the incorpora-
compound can have a marked effect on its solubility tion of one or more water-miscible cosolvents so that
in a given liquid. For example, the introduction of a a solution containing 500 mg in 10 mL (and thus
hydrophilic hydroxyl group to a molecule can produce suitable for parenteral administration in the treatment
a large increase in water solubility. This is evidenced of anaerobic infections) can be obtained.
by the more than 100-fold greater aqueous solubility Crystal characteristics: polymorphism
of phenol compared with benzene.
and solvation
In addition, the conversion of a weak acid to its
sodium salt leads to a much greater degree of ionic When the conditions under which crystallization is
dissociation of the compound when it dissolves in allowed to occur are varied, some substances produce
water. The overall interaction between solute and crystals in which the constituent molecules are aligned
solvent is increased markedly and the solubility in different ways with respect to one another in the
consequently rises. An example of this effect is lattice structure. These different crystalline forms
provided by a comparison of the aqueous solubility of the same substance, which are known as polymorphs,
of salicylic acid and that of its sodium salt, which consequently possess different lattice energies, and
are 1 in 550 and 1 in 1 respectively. this difference is reflected by changes in other proper-
The reduction in aqueous solubility of a parent ties. For example, the polymorphic form with the
drug by its esterification may also be cited as an lowest free energy will be the most stable and possess
example of the effects of changes in the chemical the highest melting point. Other less stable (or
structure of the solute. Such a reduction in solubility metastable) forms will tend to transform into the
may be beneficial to provide a suitable method for: most stable one at rates that depend on the energy
differences between the metastable and stable forms.
• masking the taste of a parent drug, e.g. Many drugs exhibit polymorphism, e.g. steroid
chloramphenicol palmitate has been used in polymorphs are common. Polymorphs are explained
paediatric suspensions rather than the more more fully in Chapter 8 (which also includes an
soluble but very bitter tasting chloramphenicol explanation of why polymorphs may have different
base; solubilities) and Chapter 23. Examples of the impor-
• protecting the parent drug from excessive tance of polymorphism with respect to the bioavail-
degradation in the gastrointestinal tract, e.g. ability of drugs are given in Chapter 20.
erythromycin propionate is less soluble and The effect of polymorphism on solubility is par-
consequently less readily degraded than ticularly important from a pharmaceutical point of
erythromycin base; and view, because it provides a means of increasing the
• increasing the ease of absorption of drugs from solubility of a crystalline material, and hence its rate
the gastrointestinal tract, e.g. erythromycin of dissolution, by using a metastable polymorph.
propionate is also more readily absorbed than Although the more soluble polymorphs are meta-
erythromycin base. stable and will convert to the stable form, the rate
of such conversion is often slow enough for the
Nature of solvent: cosolvents metastable form to be regarded as being sufficiently
The importance of the nature of the solvent has stable from a pharmaceutical viewpoint. The degree
already been discussed in terms of the statement of conversion should obviously be monitored during
‘like dissolves like’ and in relation to solubility storage of the drug product to ensure that its efficacy
parameters. In addition, the point has been made is not altered significantly. There are products on the
that mixtures of solvents may be employed. Such market containing a more soluble, but less stable,
mixtures are often used in pharmaceutical practice polymorph of the drug, where the chosen polymorph
in order to obtain aqueous-based systems that contain is stable enough to survive the approved storage
solutes in excess of their individual solubility in pure conditions and declared shelf life.

30
 Dissolution and solubility CHAPTER 2

Conversion to the less soluble and most stable of un-ionized acid molecules in the solution increases.
polymorph may contribute to the growth of crystals Precipitation may occur, therefore, because the solu-
in suspension formulations. Examples of the impor- bility of the un-ionized species is usually less than
tance of polymorphism with respect to the occur- that of the ionized form. Conversely, in the case
rence of crystal growth in suspensions are given in of solutions of weakly basic drugs or their salts,
Chapter 26. precipitation is favoured by an increase in pH. Such
The absence of a crystalline structure that is usually precipitation is an example of one type of chemical
associated with an amorphous powder (discussed in incompatibility that may be encountered in the
Chapter 8) may also lead to an increase in the solubil- formulation of liquid medicines.
ity of a drug when compared with that of its crystalline This relationship between pH and solubility of
form. ionized solutes is extremely important with respect
In addition to the effect of polymorphism, the to the ionization of weakly acidic and basic drugs as
lattice structures of crystalline materials may be they pass through the gastrointestinal tract where
altered by the incorporation of molecules of the they can experience pH changes of between about
solvent from which crystallization occurred (discussed 1 and 8 pH units. This will affect the degree of
in Chapter 8). The resultant solids are called solvates ionization of the drug molecules, which in turn
and the phenomenon is referred to correctly as solva- influences their solubility and their ability to be
tion. It is sometimes incorrectly and confusingly absorbed. This aspect is discussed elsewhere in this
referred to as pseudopolymorphism. The alteration in book in some detail, and the reader is referred in
crystal structure that accompanies solvation will affect particular to Chapters 3 and 20.
the internal energetics of the solid such that the The relationship between pH, pKa and solubility
solubility of the solvated and unsolvated crystals will of weakly acidic or weakly basic drugs is given by a
differ. modification of the Henderson–Hasselbalch equations.
If water is the solvating molecule, i.e. a hydrate To avoid repetition here, the reader is referred to
is formed, then the interaction between the substance the relevant section of Chapter 3.
and water that occurs in the crystal phase reduces
the amount of energy liberated when the solid hydrate Common-ion effect
dissolves in water. Consequently, hydrated crystals The equilibrium in a saturated solution of a sparingly
tend to exhibit a lower aqueous solubility than their soluble salt in contact with an undissolved solid may
unhydrated forms. This decrease in solubility can be represented by
lead to precipitation of drugs from solutions.
A + + B− ⇔ AB
In contrast, the aqueous solubility of other, i.e. ( ions ) ( solid )
nonaqueous, solvates is often greater than that of
(2.10)
the unsolvated forms. Examples of the effects
of solvation and the attendant changes in solubilities From the law of mass action,
of drugs on their bioavailabilities are given in
[ A + ][B− ] = K[ AB]
Chapter 20.
(2.11)
Particle size of the solid
where the square brackets signify the concentrations
It has been postulated that the solubility of particles of the respective components. Thus the equilibrium
changes with the particle size. These changes arise constant K for this reversible reaction is given by
from the presence of an electric charge on the par- Eq. 2.12:
ticles. The effect of this charge becomes more
important as the particle size decreases, particularly [ A + ][B− ]
K=
when the particles have a very small radius (less than [ AB]
about 1 μm). Thus such solubility changes are rarely (2.12)
an issue in conventional dosage forms but could be
significant with nanotechnology products. Since the concentration of a solid may be regarded
as being constant, the equation may be written as
pH
If the pH of a solution of either a weakly acidic drug KS′ = [ A + ][B− ]
or a salt of such a drug is reduced, then the proportion (2.13)

31
 PART ONE Scientific principles of dosage form design

where KS′ is a constant known as the solubility product because the alcohol lowers the dielectric constant of
of compound AB. the solvent and ionic dissociation of the electrolyte
If each molecule of the salt contains more than becomes more difficult.
one ion of each type, e.g. A +x B−y , then in the definition Effect of electrolytes on the solubility of none-
of the solubility product, the concentration of each lectrolytes. Nonelectrolytes do not dissociate into
ion is expressed to the appropriate power, i.e. ions in aqueous solution, and in dilute solution the
KS′ = [ A ] [B ]
+ x − y dissolved species therefore consists of single molecules.
Their solubility in water depends on the formation
(2.14) of weak intermolecular bonds (hydrogen bonds)
These equations for the solubility product are between their molecules and those of water. The
applicable only to solutions of sparingly soluble salts. presence of a very soluble electrolyte, the ions of
The presence of additional A+ in the dissolution which have a marked affinity for water, will reduce
medium, i.e. where A+ is a common ion, would push the solubility of a nonelectrolyte by competing for
the equilibrium shown in Eq. 2.10 towards the right the aqueous solvent and breaking the intermolecular
in order to restore the equilibrium. Solid AB will be bonds between the nonelectrolyte and water. This
precipitated and the solubility of this compound is effect is important in the precipitation of proteins.
therefore decreased. This is known as the common-ion Complex formation. The apparent solubility of a
effect. The addition of common B− ions would have solute in a particular liquid may be increased or
the same effect. An example is the reduced solubility decreased by the addition of a third substance which
of a hydrochloride salt of a drug in the stomach. forms an intermolecular complex with the solute.
The precipitating effect of the presence of ions The solubility of the complex will determine the
and other ingredients in the dissolution medium (as apparent change in the solubility of the original solute.
may be encountered in the gastrointestinal tract, for
Solubilizing agents. These agents are capable of
example) is often less apparent in practice than
forming large aggregates or micelles in solution when
expected from this discussion. The reasons for this
their concentrations exceed certain values. In aqueous
are explained in the following sections.
solution the centre of these aggregates resembles a
Effect of different electrolytes on the solubil- separate organic phase, and organic solutes may be
ity product. The solubility of a sparingly soluble taken up by the aggregates, thus producing an apparent
electrolyte may be increased by the addition of a increase in their solubility in water. This phenomenon
second electrolyte that does not possess ions common is known as solubilization. A similar phenomenon
to the first electrolyte, i.e. it is a different electrolyte. occurs in organic solvents containing dissolved solu-
Effective concentration of ions. The activity of bilizing agents because the centre of the aggregates
a particular ion is related to its effective concentration. in these systems constitutes a more polar region than
In general, this is lower than the actual concentration the bulk of the organic solvent. If polar solutes are
because some ions produced by dissociation of the taken up into these regions, their apparent solubility
electrolyte are strongly associated with other oppo- in the organic solvents is increased.
sitely charged ions and do not contribute so effectively
to the properties of the system as completely unal- Solubility of gases in liquids
located ions.
Effect of nonelectrolytes on the solubility of The amount of gas that will dissolve in a liquid is
electrolytes. The solubility of electrolytes depends determined by the nature of the two components
on the dissociation of dissolved molecules into ions. and by temperature and pressure.
This dissociation is affected by the dielectric constant Provided that no reaction occurs between the gas
of the solvent, which is a measure of the polar nature and the liquid, then the effect of pressure is indicated
of the solvent. Liquids with a high dielectric constant by Henry’s law, which states that at constant tem-
(e.g. water) are able to reduce the attractive forces perature the solubility of a gas in a liquid is directly
that operate between oppositely charged ions pro- proportional to the pressure of the gas above the
duced by dissociation of an electrolyte. liquid. The law may be expressed by Eq. 2.15:
If a water-soluble nonelectrolyte, such as alcohol,
w = kp
is added to an aqueous solution of a sparingly soluble
electrolyte, the solubility of the latter is decreased (2.15)

32
 Dissolution and solubility CHAPTER 2

where w is the mass of gas dissolved by unit volume number of degrees of freedom, i.e. the number of
of solvent at an equilibrium pressure p, and k is a variable conditions such as temperature, pressure and
proportionality constant. Although Henry’s law is composition, that must be stated in order to define
most applicable at high temperatures and low pres- completely the state of the system at equilibrium.
sures, when solubility is low, it provides a satisfactory The overall effect of temperature variation on the
description of the behaviour of most systems at normal degree of miscibility in these systems is usually
temperatures and reasonable pressures, unless the described by means of phase diagrams, which are
solubility is very high or a reaction occurs. Eq. 2.15 graphs of temperature versus composition at constant
also applies to the solubility of each gas in a solution pressure. For convenience of discussion of their phase
of several gases in the same liquid provided that p diagrams, the partially miscible systems may be
represents the partial pressure of a particular gas. divided into the following types.
The solubility of most gases in liquids decreases
as the temperature rises. This provides a means of Systems showing an increase in
removing dissolved gases. For example, water for miscibility with rise in temperature
injections free from either carbon dioxide or air may
be prepared by boiling water with minimum exposure A positive deviation from Raoult’s law arises from a
to air and preventing access of air during cooling. difference in the cohesive forces that exist between
The presence of electrolytes may also decrease the the molecules of each component in a liquid mixture.
solubility of a gas in water by a ‘salting-out’ process, This difference becomes more marked as the tem-
which is caused by the marked attraction exerted perature decreases, and the positive deviation may
between the electrolyte and water. then result in a decrease in miscibility sufficient to
cause the separation of the mixture into two phases.
Each phase consists of a saturated solution of one
Solubility of liquids in liquids component in the other liquid. Such mutually satu-
rated solutions are known as conjugate solutions.
The components of an ideal solution are miscible in
The equilibria that occur in mixtures of partially
all proportions. Such complete miscibility is also
miscible liquids may be followed either by shaking
observed in some real binary systems, e.g. ethanol
the two liquids together at constant temperature and
and water, under normal conditions. However, if one
analysing samples from each phase after equilibrium
of the components tends to self-associate because
has been attained, or by observing the temperature
the attractions between its own molecules are greater
at which known proportions of the two liquids,
than those between its molecules and those of the
contained in sealed glass ampoules, become miscible
other component, i.e. if a positive deviation from
(as indicated by the disappearance of turbidity).
Raoult’s law occurs, the miscibility of the components
may be reduced (Raoult’s law is discussed more fully
in Chapter 3). The extent of the reduction in miscibil-
Systems showing a decrease in
ity depends on the strength of the self-association miscibility with rise in temperature
and, therefore, on the degree of deviation from A few mixtures, which probably involve compound
Raoult’s law. Thus partial miscibility may be observed formation, exhibit a lower critical solution temperature
in some systems, whereas virtual immiscibility may (CST), e.g. triethylamine plus water and paraldehyde
be exhibited when the self-association is very strong plus water. The formation of a compound produces
and the positive deviation from Raoult’s law is large. a negative deviation from Raoult’s law, and miscibility
In those cases where partial miscibility occurs under therefore increases as the temperature falls.
normal conditions, the degree of miscibility is usually
dependent on the temperature. This dependency is Systems showing upper and lower
indicated by the phase rule, introduced by J. Willard
critical solution temperatures
Gibbs. This is expressed quantitatively by Eq. 2.16:
The decrease in miscibility with increase in tempera-
F =C−P+2 ture in systems having a lower CST is not indefinite.
(2.16) Above a certain temperature, positive deviations from
Raoult’s law become important and miscibility starts
where P and C are the numbers of phases and to increase again with further rise in temperature.
components in the system respectively, and F is the This behaviour is shown by the nicotine–water system.

33
 PART ONE Scientific principles of dosage form design

Table 2.4 The effects of additives on the critical solution temperature

Type of CST Solubility of additive in each component Effect on CST Effect on miscibility
Upper Approximately equally soluble in both Lowered Increased
components
Upper Readily soluble in one component but not in Raised Decreased
the other
Lower Approximately equally soluble in both Raised Increased
components
Lower Readily soluble in one component but not in Lowered Decreased
the other
CST, critical solution temperature.

In some mixtures where an upper and a lower CST distributed between the two liquids in such a way
are expected, these points are not, in fact, observed that the ratio of the activities of the substance in
since a phase change by one of the components occurs each liquid is a constant. This is known as the Nernst
before the relevant CST is reached. For example, distribution law and may be expressed by Eq. 2.17:
the ether–water system should exhibit a lower CST, aA
but water freezes before the temperature is reached. = constant
aB
Effects of added substances on critical (2.17)
solution temperatures where aA and aB are the activities of the solute in
CST is an invariant point at constant pressure, but solvent A and solvent B respectively. When the
this temperature is very sensitive to impurities or solutions are dilute or when the solute behaves ideally,
added substances. The effects of additives are sum- the activities may be replaced by concentrations (CA
marized in Table 2.4. and CB):
CA
=K
CB
Blending
(2.18)
The increase in miscibility of two liquids caused by the The constant K is known as the distribution coefficient,
addition of a third substance is referred to as blending. or partition coefficient. In the case of sparingly soluble
An example is the use of propylene glycol as a blending substances, K is approximately equal to the ratio of
agent to improve the miscibility of volatile oils and the solubility (SA and SB) of the solute in each liquid.
water. Full understanding of this interrelationship Thus
requires the use of a ternary-phase diagram. This SA
diagram is a triangular plot which indicates the effects =K
SB
of changes in the relative proportions of all three
components at constant temperature and pressure. The (2.19)
plot shows the areas (i.e. combinations of the three In most other systems, however, deviation from ideal
ingredients) that result in a single ‘blended’ phase. behaviour invalidates Eq. 2.19. For example, if the
solute exists as monomers in solvent A and as dimers
Distribution of solutes between in solvent B, the distribution coefficient is given by
Eq. 2.20, in which the square root of the concentration
immiscible liquids of the dimeric form is used:
C
Partition coefficients K= A
CB
When a substance which is soluble in both components
of a mixture of immiscible liquids is dissolved in (2.20)
such a mixture, when equilibrium is attained at If the dissociation into ions occurs in the aqueous
constant temperature, it is found that the solute is layer, B, of a mixture of immiscible liquids, then the

34
 Dissolution and solubility CHAPTER 2

degree of dissociation (α) should be taken into • the molecular size of the solute is similar to
account, as indicated by Eq. 2.21: that of the solvent so that a molecule of the
former can be substituted for one of the latter
CA
K= in its crystal lattice structure; or
CB (1 − α )
• the solute molecules are much smaller than the
(2.21) solvent molecules so that the former can be
The solvents in which the concentrations of the solute accommodated in the spaces of the solvent
are expressed should be indicated when partition lattice structure.
coefficients are quoted. For example, a partition These two types of solvent system are referred
coefficient of 2 for a solute distributed between oil to as substitutional solid solutions and interstitial solid
and water may also be expressed as a partition coef- solutions respectively, and are illustrated in Fig. 2.8.
ficient between water and oil of 0.5. This can be A typical pharmaceutical example of an interstitial
represented as Kwater
oil
= 2 and Koil
water
= 0.5. The abbrevia- solid solution would be when one of these solids is
o
tion Kw is often used for the former, and this notation a drug and the other is a polymeric material with
has become the most commonly used. large spaces between its intertwined molecules that
The determination of partition coefficients is can accommodate solute molecules.
important in preformulation, and so this is discussed Since the criteria for a solid solution are only
further in Chapter 23. satisfied in relatively few systems, it is more common
to observe partial miscibility of solids. Often (fol-
Solubility of solids in solids lowing coprecipitation is an example) the resulting
matrix may contain undissolved particles or groups
If two solids are either melted together and then of matrix particles. In this case, the resulting system
cooled or dissolved in a suitable liquid solvent that is known as a solid dispersion.
is then removed by evaporation, the solid that is When the carrier solid (the polymer) is dissolved
redeposited from the melt or the solution will either away, the molecules or small crystals of insoluble
be a one-phase solid solution or a two-phase solid drug may dissolve more rapidly than a conventional
dispersion. powder because the contact area between the drug
In a solid solution, as in other types of solution, and water is increased. The rate of dissolution and,
the molecules of one component (the solute) are consequently, the bioavailability of poorly soluble
dispersed molecularly throughout the other component drugs may be improved by the use of solid solutions
(the solvent). Complete miscibility of two solid or solid dispersions. Disperse systems are discussed
components is only achieved if: more fully in Chapters 6 and 26.

Substituted Interstitial
Lattice of carrier molecules
drug molecule drug molecule

Substitutional solid Interstitial solid

solution solution

Fig. 2.8 • Substitutional and interstitial solid solutions.

35
 PART ONE Scientific principles of dosage form design

concept of solubility in a pharmaceutical context

Summary has also been discussed. The chapter that follows
will describe the properties of the solution thus
This chapter has shown that the process of dis- produced.
solution is a change in phase of a molecule or ion.
Most often this is from solid to liquid. Simple Please check your eBook at https://studentconsult.
diffusional mechanisms and equations usually inkling.com/ for self-assessment questions. See inside
define the rate and extent of this process. The cover for registration details.

Reference
Florence, A.T., Attwood, D., 2016.
Physicochemical Principles of
Pharmacy: In Manufacture,
Formulation and Clinical Use, sixth
ed. Pharmaceutical Press, London.

Bibliography
Barton, A.F.M., 1991. Handbook of Noyes, A.A., Whitney, W.R., 1897. The United States Pharmacopeial
Solubility Parameters and Other rate of solution of solid substances Convention, 2016. United States
Cohesion Parameters. CRC Press, in their own solutions. J. Am. Pharmacopeia and National
Boca Raton. Chem. Soc. 19, 930. Formulary. United States
British Pharmacopoeia Commission, Rowe, R.C., Sheskey, P.J., Cook, Pharmacopeial Convention,
2017. British Pharmacopoeia. W.G., et al., 2016. Handbook Rockville.
Stationery Office, London. of Pharmaceutical Excipients, Wichmann, K., Klamt, A., 2010. Drug
European Pharmacopoeia Commission, eighth ed. Pharmaceutical Press, solubility and reaction
2017. European Pharmacopoeia, London. thermodynamics. In: am Ende, D.J.
ninth ed. Council of Europe, Troy, D.B. (Ed.), 2006. Remington: The (Ed.), Chemical Engineering in the
Strasbourg. Science and Practice of Pharmacy, Pharmaceutical Industry: R&D to
Florence, A.T., Siepmann, J. (Eds.), twenty first ed. Lippincott Williams Manufacture. John Wiley & Sons (in
2009. Modern Pharmaceutics, vol. 1 & Wilkins, Baltimore. conjunction with AIChE), Hoboken.
and 2, fiveth ed. Informa, New York.

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