Mouthwashes and gargles
Mouthwashes/gargles are designed for the treatment of infection
and inflammation of the oral cavity. Formulations designed for
this purpose employ water as the vehicle, although a co-solvent,
e.g. alcohol, may be employed to solubilise the active agent. The
use of alcohol as a co-solvent may act to enhance the
antimicrobial properties of the therapeutic agent. Other
formulation components are frequently required to enhance the
palatability and acceptability of the preparation. These include
preservatives, colours, flavouring agents and non-cariogenic
Enemas are pharmaceutical solutions that are administered
rectally and are employed to ensure clearance of the bowel,
usually by softening the faeces or by increasing the amount of
water in the large bowel (osmotic laxatives). Enemas may be
aqueous or oil-based solutions and, in some formulations, the
vehicle is the agent that promotes bowel evacuation, e.g. arachis
oil retention enema. Aqueous formulations usually contain salts
(e.g. phosphates) to alter the osmolality within the rectum,
thereby increasing the movement of fluid to the rectal contents.
Viscosity-enhancing agents, e.g. glycerol, may be included to aid
retention of the formulation within the rectum and to reduce the
incidence of seepage.
Pharmaceutical suspensions are
commonly referred to as dispersions in
which the therapeutic agent is
dispersed in the external phase (the
vehicle). According to this definition
the solubility of the therapeutic agent
in the vehicle is low. The diameter of
the disperse phase may range from
circa 0.5 to 100 lm. Systems in which
the particle size diameter falls below
the above range are termed colloidal.
In pharmaceutical dispersions
(suspensions) the internal (drug) phase
will separate upon storage; however,
the main aim of the formulation
scientist is to control the process of
separation and, in so doing, optimise
the stability of the formulation. A
pharmaceutical suspension would be
considered stable if, after agitation
(shaking), the drug particles are
Advantages and disadvantages of pharmaceutical
■ Pharmaceutical suspensions are a useful drug delivery
system for therapeutic agents that have a low solubility.
Although low-solubility therapeutic agents may be
solubilised and therefore administered as a solution, the
volume of the solvent required to perform this may be large.
In addition, formulations in which the drug has been
solubilised using a co-solvent may exhibit precipitation
issues upon storage.
■ Pharmaceutical suspensions may be formulated to mask the
taste of therapeutic agents.
■ Pharmaceutical suspensions may be employed to administer
drugs to patients who have difficulty swallowing solid-dosage
■ Pharmaceutical suspensions may be formulated to provide
controlled drug delivery, e.g. as intramuscular injections
(see Chapter 5).
■ Pharmaceutical suspensions are fundamentally unstable and
therefore require formulation skill to ensure that the physical
stability of the formulation is retained over the period of the
■ The formulation of aesthetic suspension formulations is
■ Suspension formulations may be bulky and therefore difficult
for a patient to carry.
The physical stability of pharmaceutical
As detailed above, pharmaceutical suspensions are fundamentally
unstable, leading to sedimentation, particle–particle interactions
and, ultimately, caking (compaction). To gain an understanding of
the physical stability of suspensions it is necessary to consider
briefly two phenomena: the electrical properties of dispersed
particles and the effect of distance of separation between
particles on their subsequent interaction. It must be stressed that
this is only a brief outline and the reader should consult the
companion textbook in this series by David Attwood and
Alexander T Florence (FASTtrack: Physical Pharmacy: London:
Pharmaceutical Press; 2008) for a more comprehensive
description of this topic.
Electrical properties of dispersed particles
Following dispersion within an aqueous medium, particles may
acquire a charge due to either the ionisation of functional groups
on the drug molecule and/or adsorption of ions to the surface of
the particle. These are addressed independently below.
Ionisation of functional groups
Insoluble drug particles may possess groups at the surface that
will ionise as a function of pH, e.g. COOH, NH2. In this situation
the degree of ionisation is dependent on the pKa of the molecule
and the pH of the surrounding solution.
Adsorption of ions on to the surface of the particle
Following immersion in an aqueous solution containing
electrolytes, ions may be adsorbed on to the surface of the
particle. Furthermore, in the absence of added electrolytes,
preferential adsorption of hydroxyl ions on to the surface of the
particle will occur. Hydronium ions, by contrast, are more
hydrated than hydroxyl ions and are therefore more likely to
remain within the bulk medium. Following adsorption of ions on
to the surface, a phenomenon referred to as the electrical double
layer is established (Figure 2.1), the main features of which are as
■ Ions, e.g. cations, are adsorbed on to the surface of the
particle, leaving the anions and remaining cations in solution.
This generates a potential on the surface of the particle,
termed the Nearnst potential. The ions responsible for this
potential are termed potential-determining ions. Anions are
then electrostatically attracted to the (positive) surface of the
particle. The presence of these anions will repel the
subsequent approach of further anions. This is referred to as
Principles and formulation of suspensions 27
the first section of the double layer and is therefore composed
of adsorbed ions on the surface, counterions and bound
hydrated solvent molecules.
■ The boundary between the first and second layers of the
electrical double layer is referred to as the Stern plane. The
Stern plane is characterised by:
– the adsorbed ions on the surface of the particle
– the adsorbed counterions at the surface of the particle
– the Stern plane falls through the centre of the counterion
– normally the charge at the surface of the particle is greater
than that at the Stern plane.
■ The second layer contains predominantly hydrated
counterions that are loosely attracted to the surface of the
particle, the features of which include:
– The boundary of this second layer will possess a potential,
referred to as the zeta potential. The magnitude of this is
generally less than that at the Stern plane.
– If the particle is rotated, this second layer forms the shear
plane, i.e. the effective surface.
■ At a certain distance from the surface of the particle,
electrical neutrality is restored.
28 Pharmaceutics – Dosage Form and Design
Fi st laye : The Stern Plane
Second laye : Shea Plane
Elect ical neu ality attained
Distance Electrical potential
Potential at the surface: Nearnst potential (Wn
Stern potential (Ws)
Zeta potential (n
Potential at the Stern Plane:
Potential at the Shea Plane:
Figure 2.1 Diagrammatic representation of the electrical double layer.
■ A number of related alternative scenarios to that described
above are possible:
– Scenario 1. Electrical neutrality may be achieved at the
boundary of the second plane of the electrical double layer,
i.e. the magnitude of the zeta potential is zero. In this the
counterions are sufficiently present in this layer to neutralise
the net positive charge on the surface of the particle.
– Scenario 2. If the number of counterions in the electrical
double layer exceeds the adsorbed ions, the zeta potential will
exhibit an opposite charge to that of the Nearnst potential. For
example, if the Nearnst potential is positive, the zeta potential
may be positive.
– Scenario 3. In certain circumstances molecules may interact
with the charged particle surface via non-electrostatic
mechanisms. For example, surface-active agents interact with
surfaces via hydrophobic interactions. If the surface-active
agents are charged, this will alter the Stern and zeta
potentials. In this the magnitude of the Stern potential may be
increased (i.e. exceeds the Nearnst potential) or may be totally
reversed. There is a reduction in this charge at the shear plane
(i.e. the zeta potential). Similarly, non-ionic surfactants may
adsorb to the surface of the particle (again via hydrophobic
interactions), thereby affecting both the Stern and zeta
The presence of electrolytes directly affects the above situations.
As the concentration of electrolyte is increased there is a
compression of the electrical double layer. The magnitude of the
Stern potential is unaltered whereas the zeta potential decreases
in magnitude. As the reader will discover, this approach may be
used to stabilise pharmaceutical suspensions.
The relationship between distance of separation
and the interaction between particles
The interaction between suspended particles in a liquid medium
is related to the distance of separation between the particles. In
principle, three states of interaction are possible:
1. No interaction, in which the particles are maintained
sufficiently distant from one another. In the absence of
sedimentation this is the thermodynamically stable state.
2. Coagulation (agglomeration), in which the particles form an
intimate contact with each other. This results in the
production of a pharmaceutically unacceptable formulation
due to the inability to redisperse the particles upon shaking.
3. Loose aggregation (termed floccules), in which there is a loose
reversible interaction between the particles, enabling the
particles to be redispersed upon shaking.