Polymorphs of the same drug have different X-ray diffraction
patterns, may have different melting points and solubilities and
also usually exist in different habits.
Certain classes of drug are particularly susceptible to
polymorphism; for example, about 65% of the commercial
sulfonamides and 70% of the barbiturates used medicinally are
known to exist in several polymorphic forms.
The particular polymorph formed by a drug depends on the
conditions of crystallisation; for example, the solvent used, the rate
of crystallisation and the temperature.
Under a given set of conditions the polymorphic form with the
lowest free energy will be the most stable, and other polymorphs
will tend to transform into it.
Polymorphism has the following pharmaceutical implications
When some compounds crystallise they may entrap solvent in the
crystal. Crystals that contain solvent of crystallisation are called
crystal solvates, or crystal hydrates when water is the solvent of
crystallisation. Crystals that contain no water of crystallisation are
There are two main types of crystal solvate:
1. Polymorphic solvates are very stable and are diffi cult to
desolvate because the solvent plays a key role in holding the
crystal together. When these crystals lose their solvent they
collapse and recrystallise in a new crystal form.
2. Pseudopolymorphic solvates lose their solvent more readily
and desolvation does not destroy the crystal lattice. In these
solvates the solvent is not part of the crystal bonding and
merely occupies voids in the crystal.
The particular solvate formed by a drug depends on the conditions
of crystallisation, particularly the solvent used.
The solvated forms of a drug have different physicochemical
properties to the anhydrous form:
The melting point of the anhydrous crystal is usually higher
than that of the hydrate.
Anhydrous crystals usually have higher aqueous solubilities
The rates of dissolution of various solvated forms of a drug
differ but are generally higher than that of the anhydrous form.
There may be measurable differences in bioavailabilities of the
solvates of a particular drug; for example, the monoethanol
solvate of prednisolone tertiary butyl acetate has an absorption
rate in vivo which is nearly fi ve times greater than that of the
anhydrous form of this drug.
Wetting of solid surfaces and
The wetting of a solid when a liquid spreads over
its surface is referred to as spreading wetting.
The forces acting on a drop on the solid
surface (Figure 1.4a) are represented by
γS/A = γS/L + γL/A cos θ
where γS/A is the surface tension of the
solid, γS/L is the solid–liquid interfacial tension, γL/A is the
surface tension of the liquid and θ is the contact angle.
The tendency for wetting is expressed by the spreading
coeffi cient, S, as:
S = γL/A (cos θ – 1)
For complete spreading of the liquid over the solid surface, S
should have a zero or positive value.
If the contact angle is larger than 0°, the term (cos θ – 1) will be
negative, as will the value of S.
The condition for complete, spontaneous wetting is thus a zero
value for the contact angle.
The wetting of a powder when it is initially immersed in a liquid
is referred to as immersional wetting (once it has submerged, the
process of spreading wetting becomes important).
The rate of dissolution of solids is described by the Noyes–Whitney
= ( – ) d
d cs c D A
where dw/dt is the rate of increase of the amount of material in
solution dissolving from a solid; cs
is the saturation solubility
of the drug in solution in the diffusion layer and c is the
concentration of drug in the bulk solution, A is the area of the
solvate particles exposed to the solvent, δ is the thickness of the
diffusion layer and D is the diffusion coeffi cient of the dissolved
solute. This equation predicts:
a decrease of dissolution rate because of a decrease of D when
the viscosity of the medium is increased
an increase of dissolution rate if the particle size is reduced by
micronisation because of an increase in A
an increase of dissolution rate by agitation in the gut or in a
fl ask because of a decrease in δ
an increase of dissolution rate when the concentration of drug
is decreased by intake of fl uid, and by removal of drug by
partition or absorption
a change of dissolution rate when cs
is changed by alteration of
pH (if the drug is a weak electrolyte).
A solid solution comprises a solid solute molecularly dispersed in
a solid solvent and is designed to improve the biopharmaceutical
properties of drugs that are poorly soluble or diffi cult to wet.
Solid dispersions are eutectic mixtures comprising drug in
microcrystalline form and a substance that is readily soluble in
water (a carrier).
Drugs containing ester, amide, lactam,
imide or carbamate groups are susceptible
Hydrolysis can be catalysed by hydrogen
ions (specifi c acid catalysis) or hydroxyl
ions (specifi c base catalysis).
Solutions can be stabilised by formulating
at the pH of maximum stability or, in
some cases, by altering the dielectric
constant by the addition of non-aqueous
Oxidation involves the removal of an
electropositive atom, radical or electron,
or the addition of an electronegative atom
Oxidative degradation can occur by auto-
oxidation, in which reaction is uncatalysed
and proceeds quite slowly under the
infl uence of molecular oxygen, or may
involve chain processes consisting of three
In this chapter we will:
identify those classes of drugs that are particularly susceptible to chemical breakdown
and examine some of the precautions that can be taken to minimise the loss of activity
look at how reactions can be classifi ed into various orders, and how we can calculate the
rate constant for a reaction under a given set of environmental conditions
look at some of the factors that infl uence drug stability
examine methods for accelerating drug breakdown using elevated temperatures
and see how to estimate drug stability at the required storage conditions from these
Drugs may break down in
solution and also in the solid
state (for example, in tablet or
It is often possible to predict
which drugs are likely to
decompose by looking for
specifi c chemical groups in their
The most common causes of
decomposition are hydrolysis
and oxidation, but loss of
therapeutic activity can also
result from isomerisation,
and polymerisation of drugs.
It is possible to minimise
breakdown by optimising the
formulation and storing under
carefully controlled conditions.
Isomerisation is the process of conversion of a drug into
its optical or geometric isomers, which are often of lower
Examples of drugs that undergo isomerisation include
adrenaline (epinephrine: racemisation in acidic solution),
tetracyclines (epimerisation in acid solution), cephalosporins
(base-catalysed isomerisation) and vitamin A (cis–trans