COARSE DISPERSE SYSTEMS

PHARMACEUTICAL SUSPENSION

PHARMACEUTICS
Introduction
• dispersed system, or dispersion - a two-phase system in which
one phase is distributed as particles or droplets in the second, or
continuous, phase.
• In these systems, the dispersed phase frequently is referred to as
the discontinuous or internal phase,
• and the continuous phase is called the external phase or
dispersion medium
• In coarse dispersions, particle size exceeds 0.5 μm
• Knowledge of coarse dispersions is essential for the preparation
of both pharmaceutical suspensions (solid–liquid dispersions)
and emulsions (liquid–liquid dispersions)
 SUSPENSIONS
• A pharmaceutical suspension- a coarse dispersion containing
finely divided insoluble material suspended in a liquid
medium
• coarse dispersion in which insoluble particles, generally
greater than 0.5 μm in diameter, are dispersed in a liquid
medium, usually aqueous
Suspensions

• Suspension dosage forms are given by the oral route,

injected intramuscularly or subcutaneously, instilled
intranasally, inhaled into the lungs, applied to the skin as
topical preparations, or used for ophthalmic or otic purposes
in the eye or ear, respectively
Suspensions
This class of dosage form offer several advantages.
• Suspensions offer an alternative oral dosage form for
patients who cannot swallow a tablet or capsule such as
pediatric and geriatric patients.
Oral antibiotics, analgesic and antipyretic drugs are
commonly administered as suspensions to these groups of
patients.
• drugs that with unpleasant taste may preferably be
formulated as a suspension to reduce interaction of drug
with taste receptors in the mouth
Suspensions

• Suspensions are often used to deliver poorly water-soluble

drugs which cannot be formulated as aqueous solutions

The large surface area of dispersed drug ensures a high

availability for dissolution and hence absorption

• Suspensions are similarly used in veterinary practice

Desired qualities of an acceptable Suspension
• The dispersed/suspended particles should be of such a size that
they do not settle rapidly in the container
• However, in the event that sedimentation does occur, the sediment
must not form a hard mass/cake,
Rather, it should be capable of redispersion into a uniform mixture
when shaken, with a minimum of effort on the part of the patient
• The suspension must not be too viscous to pour freely from the
bottle or to flow through a syringe needle
• The product should have a pleasant taste, and be resistant to
microbial attack
Desired qualities of an acceptable Suspension
• In the case of an external lotion, the product must be fluid
enough to spread easily over the affected area,
and yet must not be so mobile that it runs off the surface to
which it is applied;
• The lotion must dry quickly and provide an elastic protective
film that will not rub off easily;
and it must have an acceptable color and odor
Desired qualities of an acceptable Suspension
• Thus, the three major concerns associated with suspensions
are:
1. ensuring adequate dispersion of the particles in the vehicle.
2. minimizing settling of the dispersed particles.
3. preventing caking of these particles when a sediment forms.
• Understanding factors that influence these processes and the
ways in which settling and caking can be minimized is key in
successful preparation of a desired Pharmaceutical
suspension
Physical Stability of Pharmaceutical
Suspension
• Physical stability of a pharmaceutical suspension-the
condition in which the particles do not aggregate and in
which they remain uniformly distributed throughout the
dispersion.
• As this ideal situation is seldom, if the particles do settle they
should be easily resuspended by a moderate amount of
agitation.
• the relatively large particles of a pharmaceutical suspension
makes them liable to sedimentation owing to gravitational
forces
Flocculation and Deflocculation
• Zeta potential (ζ) is a measurable indication of the potential
existing at the surface of a particle.
• When zeta potential is relatively high (25 mV or more), the
repulsive forces between two particles exceed the attractive
London forces.
• Accordingly, the particles are dispersed and are said to be
deflocculated.
• Even when brought close together by random motion or
agitation, deflocculated particles resist collision due to their
high surface potential.
Flocculation and Deflocculation
• Addition of a preferentially adsorbed ion whose charge is
opposite in sign to that on the particle leads to a progressive
lowering of zeta potential (ζ).
• At some concentration of the added ion, the electrical forces
of repulsion are lowered sufficiently and the forces of
attraction predominate.
• Under these conditions the particles may approach each
other more closely and form loose aggregates, termed flocs.
• Such a system is said to be flocculated
Flocculation and Deflocculation
• Thus, the adsorption of anions onto positively charged,
deflocculated particles in suspension will lead to flocculation
• The addition of more anions eventually can generate a net
negative charge on the particles.
• When this has achieved the required magnitude,
deflocculation may occur again.
• The only difference from the starting system is that the net
charge on the particles in their deflocculated state is negative
rather than positive
Flocculation and Deflocculation
• The primary minimum. This is a region of high attraction between
particles.
Particles that interact at distances corresponding to the primary
minimum will irreversibly coagulate and the formulation so produced
will be physically unstable.
• The primary maximum. This region is responsible for the repulsion
between particles, the magnitude of which is controlled by the zeta
potential.
Flocculation and Deflocculation

• The secondary minimum. The secondary minimum is a region where

attractive forces predominate; however, the magnitude of the attraction
is less than that at the primary minimum.
• Particles located at the secondary minimum are termed floccules, this
process being termed flocculation.
• This interaction increases the physical stability of the suspension by
preventing the close approach to the primary minimum.
• Furthermore, the interaction between the particles may be temporarily
broken by shaking, thereby enabling the removal of an accurate dose.
• The process by which particles are engineered to reside in the secondary
minimum is referred to as controlled flocculation.
Deflocculated suspension
• Electrical repulsive forces between the particles allow them
to slip past one another to form a close-packed arrangement
at the bottom of the container,
• with the small particles filling the voids between the larger
ones
• Those particles lowermost in the sediment are gradually
pressed together by the weight of the ones above.
• The repulsive barrier is thus overcome, allowing the particles
to pack closely together.
Deflocculated suspension

• Physical bonding, leading to 'cake' or 'clay' formation, may

then occur owing to the formation of bridges between the
particles resulting from crystal growth and hydration effects,
forces greater than agitation usually being required to
disperse the sediment.
Deflocculated suspension
• In a deflocculated system containing a distribution of particle
sizes, the larger particles naturally settle faster than the
smaller particles.
• The very small particles remain suspended for a considerable
length of time, with the result that no distinct boundary is
formed between the supernatant and the sediment.
• Even when a sediment becomes discernible, the supernatant
remains cloudy.
Flocculated Suspensions
• Although sedimentation of flocculated suspensions is fairly
rapid,
a loosely packed, high-volume sediment is obtained in
which the flocs retain their structure and the particles are
easily resuspended
• The flocs tend to fall together, so a distinct boundary
between the sediment and the supernatant is readily
observed;
• the supernatant is clear, showing that the very fine particles
have been incorporated into the flocs
Controlled Flocculation
• The rate of flocculation depends on the number of particles
present
• The greater the number of particles the more collisions there
will be and the more flocculation is likely to occur
• it may be necessary, as with highly charged particles, to
induce a satisfactory flocculation state.
• This can be achieved by the addition of electrolytes or ionic
surface-active agents that reduce the zeta potential
• The production of a flocculated suspension in this manner is
termed controlled flocculation.
Flocculated Suspensions

• Controlled flocculation is therefore a desirable state for a

pharmaceutical suspension

• Controlled flocculation also referred to as ‘secondary

minimum flocculation’
 Relative Properties of Flocculated and Deflocculated
Particles in Suspension
Flocculated Deflocculated
Particles form loose aggregates Particles exist in suspension as separate entities
Rate of sedimentation is high, as particles settle as a Rate of sedimentation is slow, as each particle settles
floc, which is a collection of particles separately and particle size is minimal.

A sediment is formed rapidly A sediment is formed slowly

The sediment is packed loosely and possesses a
scaffold-like structure.
Particles do not bond tightly to each other and a hard,
dense cake does not form. The sediment is easy to
redisperse, so as to reform the original suspension
The sediment eventually becomes very closely packed,
due to weight of upper layers of sedimenting material.
Repulsive forces between particles are overcome and a
hard cake is formed that is difficult, if not impossible, to
redisperse

The suspension is somewhat unsightly, due to rapid
sedimentation and the presence of an obvious, clear
supernatant region.
This can be minimized if the volume of sediment is
made large. Ideally, volume of sediment should
encompass the volume of the suspension
The suspension has a pleasing appearance, as the
suspended
material remains suspended for a relatively long time.
The supernate also remains cloudy, even when settling
is apparent.
Settling and control - Sedimentation Rate
• The rate at which particles in a suspension sediment is related to
their size and density and the viscosity of the suspension
medium
• The velocity of sedimentation of a uniform collection of spherical
particles is governed by Stokes’ law, expressed as
V = 2r2 (ρ1 – ρ2)g / 9Ƞ
• where v is the terminal velocity in cm/sec, r is the radius of the
particles in cm, ρ1 and ρ2 are the densities (g/cm 3) of the
dispersed phase and the dispersion medium, respectively, g is
the acceleration due to gravity (980.7 cm/sec 2), and η is the
Newtonian viscosity of the dispersion medium in poises (g/cm
sec).
Sedimentation Rate
• Stokes’ law holds only if the downward motion of the
particles is not sufficiently rapid to cause turbulence.
• Micelles and small phospholipid vesicles do not settle unless
they are subjected to centrifugation.
• Thus, sedimentation velocity will be reduced by decreasing
the particle size, provided that the particles are kept in a
deflocculated state.
• The rate of sedimentation will be an inverse function of the
viscosity of the dispersion medium.
Sedimentation Rate

• However, too high a viscosity is undesirable because it then

becomes difficult to redisperse material that has settled.
• It also may be inconvenient to remove a viscous suspension
from its container.
• When the size of particles undergoing sedimentation is
reduced to approximately 2 μm, random Brownian
movement is observed and the rate of sedimentation departs
markedly from the theoretical predictions of Stokes’ law
Quantitative Expressions of Sedimentation
and Flocculation
• It is necessary to assess a formulation in terms of the amount
of flocculation in the suspension and compare this with that
found in other formulations.

• The two parameters commonly used for this purpose are;

Sedimentation volume

Degree of flocculation
Sedimentation volume, F
• The ratio of the equilibrium volume of the sediment, Vu, to the
total volume of the suspension, Vo.
Thus, F = Vu /Vo
• F normally ranges from nearly 0 to 1
• As the volume of suspension that appears occupied by the
sediment increases, the value of F increases.
• In the system where F = 0.75, for example, 75% of the total
volume in the container is apparently occupied by the loose,
porous flocs forming the sediment
Sedimentation volume, F
• When F = 1, no sediment is apparent even though the system
is flocculated.
This is the ideal suspension for, under these conditions, no
sedimentation will occur.
Caking also will be absent.
Furthermore, the suspension is esthetically pleasing, there
being no visible, clear supernatant
Degree of Flocculation, β
• A better parameter for comparing flocculated systems
• β, relates the sedimentation volume of the flocculated
suspension, F, to the sedimentation volume of the
suspension when deflocculated, F∞
• β = F/F∞
• The degree of flocculation is, therefore, an expression of the
increased sediment volume resulting from flocculation.
Degree of Flocculation, β
• If, for example, β has a value of 5.0 this means that the
volume of sediment in the flocculated system is five times
that in the deflocculated state.
If a second flocculated formulation results in a value for β of
say 6.5, this latter suspension obviously is preferred, if the
aim is to produce as flocculated a product as possible.
• As the degree of flocculation in the system decreases, β
approaches unity, the theoretical minimum value
PHYSICAL STABILITY OF
PHARMACEUTICAL SUSPENSION
• This depends on the formulation strategies of the suspension

• Formulation of a suspension possessing optimal physical

stability depends on whether the particles in suspension are
to be flocculated or to remain deflocculated.
Formulation of physically stable Pharmaceutical
Suspension – Approaches commonly used

• One approach involves use of a structured vehicle to keep

deflocculated particles in suspension;

• a second depends on controlled flocculation as a means of

preventing cake formation

A combination of the two these two methods, results in a

product with optimum stability
Formulation of Suspension - Dispersion of
Particles
• Surface-active agents commonly are used as wetting agents
• maximum efficiency is obtained when the HLB value lies
within the range of 7 to 9.
• A concentrated solution of the wetting agent in the vehicle
may be used to prepare a slurry of the powder;
this is diluted with the required amount of vehicle
Formulation of Suspension - Dispersion of
Particles
• Only the minimum amount of wetting agent should be used,
compatible with producing an adequate dispersion of the
particles.
• Excessive amounts may lead to foaming or impart an
undesirable taste or odor to the product.
• Invariably, as a result of wetting, the dispersed particles in
the vehicle are deflocculated
Formulation of Suspension - Structured Vehicles
• Structured vehicles are generally aqueous solutions of
polymeric materials, such as the hydrocolloids
• They are usually negatively charged in aqueous solution.
• Typical examples are methylcellulose,
carboxymethylcellulose, bentonite, and carbomer
• They function as viscosity-imparting suspending agents and,
as such, reduce the rate of sedimentation of dispersed
particles.
• Ideally, these form pseudo-plastic or plastic systems that
undergo shear-thinning. (Show thixotropic properties)
Formulation of Suspension - Structured Vehicles
• Non-Newtonian materials of this type are preferred over
Newtonian systems because,
• if the particles eventually settle to the bottom of the container,
their redispersion is facilitated by the vehicle thinning when
shaken.
• Thixotropy-the property of becoming less viscous when
subjected to an applied stress
• (Newtonian fluid is a fluid that follow Newton's law of viscosity -
constant viscosity independent of stress)
• (In non-Newtonian fluids, viscosity can change when under force
to either more liquid or more solid)
Formulation of Suspension - Structured
Vehicles
• When the shaking is discontinued, the vehicle regains its
original consistency and the redispersed particles are held
suspended.
• This process of redispersion, facilitated by a shear-thinning
vehicle, presupposes that the deflocculated particles have
not yet formed a cake.
• If sedimentation and packing have proceeded to the point
where considerable caking has occurred, redispersion is
virtually impossible.
Controlled Flocculation
• In this approach the deflocculated, wetted dispersion of
particles and flocculated by the addition of a flocculating
agent
• most commonly, flocculating agents are electrolytes,
polymers, or surfactants.
• The aim is to control flocculation by adding that amount of
flocculating agent that results in the maximum
sedimentation volume.
Controlled Flocculation - Flocculation using Electrolytes
• Electrolytes are probably the most widely used flocculating
agents
• They act by reducing the electrical forces of repulsion between
particles,
thereby allowing the particles to form the loose flocs so
characteristic of a flocculated suspension.
• The ability of particles to come together and form a floc depends
on their surface charge,
• Thus, zeta potential measurements on the suspension, as an
electrolyte is added, provide valuable information as to the
extent of flocculation in the system
Controlled Flocculation - Flocculation by Polymers
• Polymers also play an important role as flocculating agents in
pharmaceutical suspensions.
• Many of the hydrocolloids that produce structured vehicles can
also be used to flocculate drug particles.
• Flocculation by polymers is generally less well understood than
flocculation by inorganic electrolytes
• Their successful use as flocculants may require trial and error in
order to identify optimal selection of a polymer and an appropriate
concentration.
• Nonetheless, the production of stable and elegant suspensions
using polymers is common in pharmaceutical suspensions.
Controlled Flocculation - Flocculation by Polymers
• The effectiveness of a polymer as a stabilizing agent for
suspensions primarily depends on;
 the affinity of the polymer for the particle surface, charge and
size,
As well as orientation of the polymer molecule in the continuous
phase
• An ionic polymer has the potential to affect the zeta potential of
a particle in a manner similar to inorganic electrolytes.
• However, it is believed that polymers can also act as flocculating
agents due to the bridging of the polymer between the surfaces
of different particles
Controlled Flocculation - Flocculation by
Polymers
• At high concentrations of polymer, complete coverage of the
particle surface with polymer occurs

• Insufficient binding sites remain on the particles to permit

interparticle bridging.

• In this case, the degree of flocculation is low, but the close

association of individual particles is inhibited by a
phenomenon known as steric stabilization.
Controlled Flocculation - Flocculation by
Polymers
• steric stabilization- ability of adsorbed polymers to prevent
close approach and cohesion of dispersed particles due to
the fact that the mixing of polymers adsorbed at the particle
surfaces is energetically unfavorable.

• Suspensions formulated with relatively high concentrations

of polymer would be deflocculated and therefore tend to
have small sedimentation volumes
Small-scale preparation of suspensions
• May be undertaken readily by the practicing pharmacist with
the minimum of equipment.
• The initial dispersion of the particles is best carried out by
trituration in a mortar, the wetting agent being added in
small increments to the powder.
• Once the particles have been wetted adequately, the slurry
may be transferred to the final container and vehicle added.
• The next step depends on whether the deflocculated
particles are to be suspended in a structured vehicle,
flocculated, or flocculated and then suspended
Small-scale preparation of suspensions
• Pre-formulated vehicles are commercially available to
pharmacists to facilitate the extemporaneous preparation of
suspensions.
These products are essentially aqueous structured vehicles
that contain cellulosic suspending agents, surfactants,
buffering agents, and electrolytes.
Some products may contain sweetening agents.
• Pre-formulated suspending vehicles are available at acidic or
basic pH to match physical and chemical stability
requirements of different drugs
END