SUSPENSIONS

Dr. Ayman Y. Waddad

Definition
Dispersion of finely divided insoluble
solid particles (disperse phase) in a fluid
(dispersion medium).
 Physical Properties Of
Well-Formulated
1. Suspensions
Remains homogenous for at least the period
between shaking the container and removing
the dose.
2. Re-suspension of drug particles occurs easily
with mild shaking.
3. During shelf life no hard cake is formed and is
not difficult to redisperse.
4. Maintains its stability and elegance during its
shelf-life.
5. Parenteral suspensions - 2 additional
characteristics:
o Free from microbial contamination and must
maintain its sterility during its storage and use.
o Easily drawn from syringe through gauge needle
(syringeability) and is readily injected from syringe
into the patient (injectability).
 Pharmaceutical Applications
Of Suspensions
Considered when:
 There is difficulty in swallowing solids by patients.
 Drug has poor solubility in aqueous medium, e.g.
hydrocortisone and neomycin.
 If drug is degraded in aqueous medium, can
synthesize an insoluble derivative and then
suspend in a suitable vehicle to form a
suspension.
 If contact time between soluble drug and
dispersion medium need to be decreased - can
supply as powder to be re-constituted before use.
Ø : 7 days at room
Stability temperature
: 14todays
 There is a need maskrefrigerated
taste - taste amplified if in
solution than if in an insoluble form (suspension).
E.g. Paediatric paracetamol: paediatric
paracetamol elixir BP – as a suspension is more
palatable and therefore more suitable for children.
 Topical application: Fluid preps e.g. Calamine
Lotion BP designed to leave a light deposit of
active agent on the skin after evaporation of the
dispersion medium.
 Parenteral application: in order to control the rate
of adsorption of the drug, by varying the size of
the dispersed particles of the active agent, the
duration of activity can be controlled.
 Vaccines (build up antibodies in the body) : For
induction of immunity, as suspension. Consists of
dispersions of killed microorganisms e.g Cholera
Vaccine. Thus a prolonged antigenic stimulus is
provided resulting in high antibody titre.
 X-Ray contrast media e.g. Barium sulphate – for
examination of alimentary tract-oral or rectal
administration.
 Aerosols also available as suspensions of active
agent in a mixture of propellant.
 Formulation Of
Suspensions
Overview
1. Particle Size Control Ø Viscosity Modifiers
2. Wetting Agents  Polysaccharides
 Water soluble cellulose
3. Flocculation or
 Hydrated silicates
Deflocculation
 Carboxymethylene (carbopol)
?
 Colloidal silicone dioxide
 Deflocculated
suspension 6. Other Formulation
 Flocculated Additives
suspension
4. Degree of
Flocculation
5. Rheology of
 1. Particle Size
 Control
Drug to be suspended must be finely subdivided prior
to formulation as rate of sedimentation of suspended
particle can be decreased by reduction in size.
 Large particles > 5µm diameter have gritty texture –
irritation if injected or instilled into eyes can occur.
 Ease of administration of parenteral suspension
depends on particle size and shape. > 25µm
diameter
– can block the needle.
 Even if small particle size during manufacturing –
crystal growth may occur on storage particularly
if temperature fluctuation occurs.
Reason: solubility of drug increase with increase
temperature but on cooling - drug crystallizes out, e.g.
paracetamol.
 2. Wetting Agents
 Some insoluble solids maybe easily wetted by
water and will disperse readily throughout
aqueous phase with minimum agitation.
 Most however exhibit varying degrees of
hydrophobicity. Clumping occurs.
 To ensure adequate wetting – interfacial
tension between solid and liquid must be
decreased so that adsorbed air is displaced
from solid surfaces by the liquid.
Examples of wetting agents:
Surfactants: surfactants with HLB value of 7-9 will be
suitable. The hydrophobic carbon chains would be
adsorbed by the hydrophobic particle surfaces while
the polar groups would project into the aqueous
medium becoming hydrated. Wetting occurs due to a
fall in interfacial tension between solid and liquid e.g.
polysorbates (Tweens), Sorbitan esters (Spans).
Hydrophilic colloids: will behave as protective
colloids by coating the solid hydrophobic particles
with a multimolecular layer. This imparts a
hydrophilic character to the solid and thus promotes
wetting. E.g. acacia, bentonite.
Solvents: solvent will penetrate the loose agglomerates
of powder displacing the air from the pores of the
individual particles thus enabling wetting to occur by the
dispersion medium e.g. glycerol.
 3. Flocculation or
Deflocculation?
Deflocculated suspension
 Particles exist in suspension as discrete entities.
 Rate of sedimentation is slow, since it depends on
the size of each unit.
 Sediment is formed slowly. Slow rate of settling
prevents the entrapment of liquid within the
sediment which thus becomes compacted.
 Sediment eventually becomes closely packed due
to weight of upper layers of sedimenting material.
Repulsive forces between particles are overcome
and a hard cake is formed which is difficult to
redisperse (caking).
 The suspension has a pleasing appearance since
the suspended material remains suspended for a
relatively long time.
 The supernatant also remains cloudy even when
settling is apparent.
 Have the advantage of a slow sedimentation rate
thus enabling a uniform dose to be taken from the
container, but when settling does occur- difficult
to redisperse.
Flocculated suspension
 Particles form loose aggregates.
 Rate of sedimentation is high, since particles
settle as flocs which is a collection of fine
particles.
 Sediment is formed rapidly.
 Sediment is loosely packed and possesses a
scaffold-like structure. Particles do not bond
tightly to each other and a hard, dense cake
does not form. Sediment is easy to redisperse
so as to form the original suspensions.
 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 the sediment is made
large.
 Forms loose sediments which are easily
redispersable but the sedimentation rate is fast
and there is a danger of an inaccurate dose being
administered and the product will look inelegant.
 A deflocculated suspension with sufficient high
viscosity to prevent sedimentation would be
an ideal situation.
http://www.uobabylon.edu.iq/eprints/public

ation_3_31242_6264.pdf
 4. Degree of
 Flocculation
NB for suspension to have correct degree of
flocculation. Underflocculation = undesirable
properties and overflocculation may be
irreversible. Product will be inelegant and the
viscosity high, resulting in difficult redispersion.
 Controlled flocculation achieved by
combination of particle size control, use of
electrolytes to control zeta potential and
addition of polymers to enable cross linking to
occur between particles.
Examples of Flocculating Agents:
 Electrolytes: will alter the zeta potential of dispersed
particles and if lowered sufficiently then flocculation
may occur. (sodium salts of acetates, phosphates and
citrates)
 Surfactants: ionic surfactant agents may also cause
flocculation or deflocculation depending on the charge
of the particles. Non ionic surfactants – because of
linear configuration adsorb on to more than one
particle thus forming a loose flocculated system.
 Polymeric flocculating agents: linear branched chain
molecules form a gel like network within the system
and become adsorbed onto the particle surfaces thus
holding them in a flocculated state. If excessive
blending-inhibits cross linking- can lead to
deflocculated system (starch, alginates, cellulose
derivatives, tragacanth etc.)
 5. Rheology of
 Suspension
Ideal pharmaceutical suspension must have a
high apparent viscosity at low shear rates,
therefore, particles settle very slowly on
storage or remains permanently suspended.
 At high shear rates, e.g. shaking, suspension
apparent viscosity should decrease, product
can be easily poured from container.
 If for external use, spread easily but not so fluid
that it runs off.
 Viscosity Modifiers
1. Polysaccharides
A. Acacia gum (gum arabic)
Used as a thickening agent – but not good
Value as suspending agent – due to action as
a protective colloid.
Acacia mucilage – becomes acidic on storage due
to enzyme activity – also has oxidase enzyme
which causes deterioration of active substances
which are susceptible to oxidation. But enzyme can
be inactivated by heat.
Sticky material – therefore not used in preps.
For external use
B. Tragacanth
Forms viscous aqueous solutions
Thixotropic and pseudoplastic properties -
therefore better thickening agent than acacia.
Used for internal and external preps
Stable over pH 4-7.5
Viscosity affected by heat.
Several grades are available.
C. Alginates
Made up of monomers: mannuronic acid, guluronic
acid
Not to be heated above 60°C. Depolymerization –
loss in viscosity.
Max viscosity at pH 5 - 9.
Low pH – precipitation of alginic acid.
Sodium alginate – most widely used.
 D.
Starch
 Used in combination with tragacanth.

2. Water soluble cellulose

A. Methylcellulose
Semi-synthetic polysaccharide
Several grades available.
More stable in cold water, often dispersed in
warm water, cooled, forms clear or opalescent
viscous solution.
Nonionic – therefore stable at pH 3-11
compatible
B. Hyroxyethylcellulose
Advantage – soluble in both hot and cold water and will not
gel on heating.
Similar properties to methylcellulose.

C. Sodium carboxymethylcellulose
Viscosity depends on the degree of polymerization.
Anionic – therefore incomparable with polyvalent cations.
Soluble in hot and cold water, stable pH5.
Heat sterilization – decreases its viscosity.
Preferred conc. for use is 1%

D. Microcrystalline cellulose
Readily disperses in water – but not soluble
Forms a thixotropic gel
Widely used suspending agent with between 8 and 11%
sodium carboxymethylcellulose added to aid its dispersion
and to act as a protective colloid.
3. Hydrated silicates
Bentonite, magnesium aluminium silicate, hectorite.
Readily hydrated – absorb up to 12 times the weight
of water.
Gels are thixotropic – therefore suspending agent.

4. Carboxymethylene (carbopol)
Used in conc. Up to 5% for external application
Some grades used internally
When dispersed in water forms acidic low
viscosity solutions, which when adjusted to pH 6-
11 become highly viscous.

5. Colloidal silicone dioxide (Aerosil®)

When dispersed in water – forms aggregate with
3D networks.
Also used for thickening non-aqueous suspension.
 6. Other Formulation
 Additives
Buffers to maintain chemical stability, control
tonicity or to ensure physiological compatibility.
 Density modifiers – so that disperse and
continuous phases have same densities –
sedimentation will not occur.
 Flavours, colorants, perfumes.
 Humectants – glycerol and propylene glycol – to
prevent the product from drying out after
application to skin.
 Preservatives.
 Sweetening agents.
Manufacture of
Suspensions
 Suitable size reduction equipment required for
ensuring that powder to be suspended is
suitably subdivided to ensure minimum
sedimentation rate and adequate
bioavailability.
 Small scale: powdered drug mixed with
suspending agent and vehicle using mortar
and pestle. Can include wetting agent at this
stage to aid dispersion. Other ingredients
should be dissolved in another portion of
vehicle, mixed with concentrated suspension
and made up to volume.

 Large scale: concentrated dispersion of

suspending agent made first. Material added
slowly to vehicle while mixing. Suitable mixers:
impeller type of blenders or turbine mixers.
 1. Physical
 Stability
Assessed by measurement of the rate of
sedimentation, the final volume or the height of
sediment and the ease of redispersion.
 First two parameters – assessed by measuring
total initial volume or height of suspension
(Vo) and the volume or height of the sediment
(V)
 By plotting the value of V/Vo against time for a
series of trial formulations, the slope of the line
can show the slowest rate of sedimentation.
 When the same ratio is constant - indicates
that sedimentation has ceased.
 Alternatively the flocculation value can be
used (Ratio of final volume of height of
sediment and the value or height of the fully
sedimented cake of the same system
which has been deflocculated).
 Ease of redispersion can be assessed by
simple agitation of the product in its container
 2. Centrifugation
 Centrifugation would also be a suitable method for
increasing the rate of sedimentation of a
suspension, but this is accelerated testing - it is
not possible to predict the behavior displayed
under normal circumstances.
 Centrifugation may destroy the structure of the
flocculated system, which may remain intact under
normal storage conditions. Sediment formed
would become tightly packed and difficult to
redisperse whether or not initial suspension is
flocculated or deflocculated.
 This method may however provide useful
information of relative stabilities of a series of
trial preparations.
 3. Rheological

Assessment
Apparent viscosity measurements are used to
assess physical stability, but the high shear rates
may destroy the structure of the suspension.
 Very low shear rates can give an indication of the
change in the structure of the system after various
storage times.
 Maybe possible to combine the results from the
sedimentation techniques with those from
rheological assessments.
 Measurements of residual apparent viscosity after
breaking down the structure of the suspension can
be used as a routine quality control procedure
after manufacture.
 4. Temperature Cycling
 By exaggeration of temperature fluctuations that any
product is subjected to under normal conditions – it is
possible to compare physical stabilities of a series of
suspensions.
 Cycling done-this is storage for several hours at a
temperature greater than 40°C followed by
freezing.
 Useful for assessment of crystal growth.
 Measurement of the particle size can indicate crystal
growth changes → size measured microscopically,
laser diffraction, coulter counter.
 Important to ensure that suspension is deflocculated
to ensure that individual particle is measured rather
than each floccule.