Pharmaceutical suspensions

Introduction
What is suspension dosage form?

 Suspensions are a class of disperse systems in which

finely divided drug particles are distributed uniformly
throughout a vehicle in which the drug exhibits a
minimum degree of solubility.
 The finely divided solids (disperse phase) are also
called internal phase or discontinuous phase
 The vehicle (dispersion medium) is also called
continuous phase or external phase .

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 Introduction.....cont’d

 The particles of the dispersed phase vary widely in

size, from large visible particles(coarse dispersion)
to colloidal dimensions.
 Most pharmaceutical suspensions consist of an
aqueous dispersion medium, although organic or
oily liquids are also used in some instances.
 When the particles constituting the internal phase
of the suspension are therapeutically active, the
suspension is known as pharmaceutical suspension

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 Introduction.....cont’d
 Based on the intended route of drug delivery,
pharmaceutical suspensions can be broadly classified
as:
 Parenteral suspensions (e.g., antidiarrheal susps
(I.M.); anticancer susps (I.V.)
Topical suspensions ( e.g.,lotions)
Oral suspensions (e.g., oral antacid susps, oral
antibacterial susps)

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 Introduction.....cont’d
What are the pharmaceutical applications of
suspensions?
 For people who have difficulty of swallowing solid
dosage forms ( e.g., pediatrics and geriatrics).
If a drug is insoluble or poorly soluble in
conventional, safe vehicles (e.g., water, syrup,
hydroalcoholic mixtures, water and glycerin
blends) to provide the desired dose in 5 to 15 mL
volumes.

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 Introduction.....cont’d
 Drugs that have unpleasant taste in their soluble
form can be made into insoluble derivatives, and
formulated as a suspension.
For example, chloramphenicol (soluble) has bitter
taste but chloramphenicol palmitate (slightly
soluble) is not bitter.
 Suspension form of a drug can be used to increase
stability of a drug
 e.g.,Oxytetracycline hydrochloride tablet (soluble
in aqueous solution) hydrolyzes rapidly.
 Oxytetracycline calcium (insoluble) is stable in
suspension.
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 Introduction.....cont’d
 Drugs which degrade in aqueous solution may be
suspended in a non-aqueous liquids.
for example, tetracycline hydrochloride is
suspended in a fractionated coconut oil for
ophthalmic use.
 Suspensions are also used to prolong the release of
drug (e.g., Suspensions in the form of intramuscular or
subcutaneous injections).

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 Introduction.....cont’d
The disadvantages of pharmaceutical suspensions:

 Pharmaceutical suspensions are thermodynamically

unstable.
 The formulation of aesthetic suspension is difficult.
 Suspension formulations may be bulky and therefore
difficult for a patient to carry.
 Pharmaceutical suspensions require to be shaked
before use.
 Accuracy of dose is likely to be less than with
equivalent solution dosage form.
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The desirable properties of pharmaceutical
suspensions
 The product must remain sufficiently homogenous
dispersion for at least the period between shaking the
container and taking the required amount.
 If any sediment formed, it must be easily
resuspended by moderate agitation of the container.
 The suspension should easily flow from the container
and be transferred to the site of application.
 Suspended particles should be small and uniformly
sized in order to give a smooth, elegant product, free
from a gritty texture.
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 Formulation of suspensions
 There is a direct similarity between the types of
excipients used for the formulation of suspensions
and solutions for oral administration.
 The difference between these two categories is
excipients included to physically stabilize suspensions.
 The physical stability of suspension formulation
depends on whether the particles are to be
flocculated or to remain deflocculated.

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 Formulation of suspensions.....(cont’d)

 In general a pharmaceutical suspension should

be:
 Smooth,
uniformly distributed,
easily flowing (pouring or spreading)
dispersion of particles possible with
minimum agitation.

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 Formulation of suspensions.....(cont’d)
Particle size control

 Small particle size is desirable:

 to reduce the rate of sedimentation
 to have smooth textured products
 Particles with diameter > 5 µm have gritty texture
 to reduce irritation if instilled into eyes
 to avoid blockage of capillary vessels
 to avoid blockage of hypodermic needles
 Particles over 25 µm diameter can block hypodermic
needles.
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 Formulation of suspensions...

 The three major concerns associated with

formulation of pharmaceutical suspensions are:

• Ensuring adequate dispersion of the particles in

the vehicle.
• Minimizing settling of the dispersed particles.
• Preventing caking of these particles when a
sediment forms.

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 Formulation of suspensions...
 There are two ways of formulating physically stable
suspensions:
1. The use of a structured vehicle to maintain deflocculated
particles in suspension,
 structured vehicles are pseudoplastic and plastic in nature;
 act by entrapping the particles so that, ideally no
settling occurs.
2. Production of flocculated particles (flocs), which may settle
rapidly, but are easily resuspended with a minimum of
agitation.
 Optimum physical stability is obtained when the suspension is
formulated with flocculated particles in a structured vehicle.
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Alternative approaches to the formulation of suspensions 15
 Formulation of suspensions.....(cont’d)

The use of wetting agents

 Some powders may not be wetted easily by water
due to either the surface is hydrophobic or due to
entraped air.
 formation of large porous clamps within
the liquid or
 clamps of powder remain on the surface of
the liquid or attached to container.

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 The use of wetting agents…

 Insoluble therapeutic agents should be sufficiently

wetted to be homogeneously distributed in the
formulation.
 This enables correct dose removal by the patient
when required.
 Poorly wetted drugs become aggregated and do not
disperse sufficiently.

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 Types of wetting agents
 Surface-active agents (surfactants)
 Hydrophilic polymers
 Natural polymers (eg, acacia, tragacanth, xanthan
gum, sodium alginate)
Cellulose derivatives (methylcellulose, sodium
carboxymethylcellulose)
 Clays ( eg, bentonite, veegum)
 Solvents ( ethyl alcohol, glycerol, propylene glycol)

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 Surface-active agents (surfactants)

 For a powder to be wetted by the dispersion medium,

there should be a decrease in the interfacial tension.

 Surfactants not only reduce the interfacial tension

between liquid and vapor (γ L/v) but also adsorb on
the surface of the powder thereby reducing (γS/V).
 Reduction of the contact angle which finally gives
improved dispersibility

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Surface-active agents (surfactants)……cont’d

 Surfactants are the mostly widely used wetting

agents.
 Surfactants possessing HLB value between 7 and 9
are suitable as wetting agents.
 Adsorption of hydrocarbon chain on the hydrophobic
particles surface and polar groups project into the
aqueous medium which leads to fall in interfacial
tension between solid and liquid finally wetting of
powder and enhanced dispersion occurs.

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 Hydrophilic polymers
 These materials include NATURAL POLYMERS (e.g.,
acacia, tragacanth, sodium alginate, xanthan gum),
and CELLULOSE DERIVATIVES and CLAYS (e.g.,
bentonite).
 They can also be used as suspending agents
(thickening agents).
 They form a protective film by coating the solid
hydrophobic particles with a multimolecular layer
and as the result provide hydrophilic character to the
solid and result in wetting.

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 Solvents
 Includes solvents such as ethyl alcohol, isopropyl
alcohol, glycerin, and propylene glycol.
 They are miscible with water.
 Penetrate the loose agglomerates of powder and
displace the air from the pores of the individual
particles and thereby result in wetting.

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 Incorporation of structured vehicles
 Structured vehicles are aqueous solutions of
hydrocolloids (hydrophilic polymers).
 Used to minimize sedimentation
 They entrap deflocculated particles and as a result
minimize settling of particles.
 Some are negatively charged in aqueous solutions.
 For example, methylcellulose,
carbooxymethylcellulose, bentonite, carbomer

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 The use of flocculating agents

Electrolytes
 Are the most widely used flocculating agents.
 Act by reducing the electrical forces of repulsion
between particles and thereby reduce zeta
potential and as result aid formation of loose flocs.
 The ability of an electrolyte to flocculate particles
depends on the valency of the ion.
 valency of ions   Flocculating power
Calcium ions are more powerful than sodium or
potassium ions.
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 The use of flocculating agents……(cont’d)

 Trivalent ions are more powerful flocculating ions than

divalent ions.
 Trivalent ions are less commonly used because of their
toxicity.
 The most widely used electrolytes include the sodium
salts of acetates, phosphates and citrates.
 If anionic hydrophilic polymers are included in the
formulation they may be precipitated by the
presence of trivalent ions.

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The use of flocculating agents……(cont’d)
 Excessive addition of electrolyte may lead to
deflocculated system due to charge reversal that
occurs on each particle.

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 The use of flocculating agents……(cont’d)
Surfactants

 Both ionic and nonionic surfactants can be used.

 Ionic surfactants neutralize the charge on particles
and thereby reduce zeta potential and then
flocculation occurs.
 Nonionic surfactants have long chemical structure
which adsorb onto more than one particle which
results in formation of loose flocculated structure.

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 Polymeric flocculating agents
 Many pharmaceutically useful polymers contain polar
functional groups that are separated by a
hydrocarbon backbone.
 Polymers act as bridges on the surfaces of different
particles and cause flocculation.
 Ionizable polymers also reduce zeta potential.
 The flocculating action of polymers is highly
concentration dependant.

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 Flocculation in structured vehicles
Disadvantages of controlled flocculation:
 The suspension can appear unsightly if the
sedimentation volume (F) is not close or equal to 1.
 Hence, in practice, a suspending agent is
frequently added to retard sedimentation of the
flocs.
 Materials such as carbooxymethylcellulose,
methylcellulose, veegum, tragacanth and bentonite
have been employed alone or in combination.

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Flocculation in structured vehicles…(cont’d)
 Care must be taken when using anionic polymers
as structured vehicles when electrolytes are used
as flocculating agents.
There will be an incompatibility with a
positively charged flocculating agent or ion as it
is used to flocculate a negatively charged
particle.
 In the presence of such a material, the negatively
charged suspending agent may coagulate and lose
its suspendability.
 GELATIN (a +vely charged protein, at low pH ) can
be used to reverse the charge on the negatively
charged particle to positive. 30
Flocculation in structured vehicles…(cont’d)

 Flocculation in this case will be accomplished with a

negatively charged electrolyte (e.g., citrate or
phosphate ions) and will be compatible with the
negatively charged suspending polymers.

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 Flocculation/deflocculation of
suspensions
 The forces at the surface of particles affect the degree
of flocculation in suspension.
 Forces of attraction are of the London-van der Waals
type.
 The repulsive forces arise from the interaction of the
electric double layers surrounding each particle.

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 Flocculation/deflocculation of
suspensions..................(cont’d)
 If the attractive force predominates repulsive force,
there is formation of flocs which rapidly settle at the
bottom of containers,
 The supernatant separates from floccules and the
suspension appears unattractive.

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 Flocculation/deflocculation of
suspensions................(cont’d)
 On the other hand, if the repulsive force predominates
attractive force there exists deflocculated particles.
 Deflocculated particles settle slowly. However, they
form hard cake at the bottom of container.
 Disadvantages of deflocculation is formation of a
hard cake upon storage

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 Interfacial properties of suspended
particles
 The process of dispersions creates a tremendous
increase in interfacial area between the dispersed
particles and the dispersion medium.

 When considering the interfacial properties of

dispersed particles, two factors must be taken into
account, regardless of whether the dispersed phase is
solid or liquid.

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 Interfacial properties of suspended
particles…….(cont’d)

 The first relates to an increase in the free energy of

the surface as the particle size is reduced and the
specific surface increased.

 The second deals with the presence of electrical

charge on the surface of dispersed particles.

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 Surface free energy
 When solid and liquid materials are reduced in size,
they tend to agglomerate or stick together.
 This clumping is an attempt to reduce the excess free
energy of the system.
 The increase in surface free energy (∆G) is related to
the increase in surface area

 The smaller ∆G is, the more thermodynamically stable

is the suspension of particles.

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 Electrical properties of suspended particles
 Suspensions contain uncharged particles suspended in
uncharged medium.
 But suspended particles acquire charge by two ways:

1. Adsorption of a particular ionic species

 It can be from an ion added to the solution (e.g.,
electrolytes added as flocculating agent) or
hydroxyl ion from dissociated water (vehicle)

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 Electrical properties of suspended
particles………..(cont’d)
2. Ionization of groups (such as COOH and NH2) that may
be situated at the surface of particles.
The degree of ionization is a function of pKa of
the molecule and the pH of the surrounding
solution.

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 Electric double layer

Electric double layer: It is a layer of ions that appears

on the surface of particles due to adsorbed ions.

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41
 Electric double layer………..(cont’d)
 Electric double layer has two layers. The stern layer
and diffuse layer.
 Stern layer is a tightly bound layer which contains
solvent and the counter-ions.
o Contains more co-ions than counter-ions, hence
determines the potential at the shear plane
 Diffuse layer
o A layer surrounding the stern layer
o contains more counter-ions than co-ions
o The ions in this layer are relatively mobile
o Electric neutrality occurs where the mobile diffuse
layer ends 42
 Electric double layer………..(cont’d)
 Potential-determining ions (co-ions)
 The ions which are selectively adsorbed on the
surface of particle
 Provides its charge to the particle on which it is
adsorbed
 Counter-ions (gegenions)
Are ions attracted by co-ions on to the surface of
the particle.
They have charge opposite to that of the
potential-determining ions.

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44
 Electric double layer………..(cont’d)
 Beyond the diffuse layer the concentration of co- and
counter-ions are equal (i.e.,electric neutrality)
 Despite the presence of unequal distribution of charges
in the double layer, the suspension is electrically
neutral.
 Electric potential between the actual or true surface of
the particle and the electro neutral region is referred to
as the surface or electrothermodynamic or Nernst
potential (E)
 Nernst potential is determined by potential
determining ions .
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 Electric double layer………..(cont’d)
 The potential difference between the shear plane and
the electroneutral region is known as the
electrokinetic or zeta (ζ ) potential.
 Zeta potential governs the degree of repulsion
between adjacent, similarly charged solid dispersed
particles.
 If Zeta potential is below a certain value, van der Waals
force of attraction overcome the forces of repulsion
and the particles attach together to form floccules.
 This phenomenon is known as flocculation

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 Sedimentation in suspensions
 The rate at which particles in a suspension sediment is
related to size and density of suspended particles and
density and viscosity of the dispersion medium.
 Stoke’s law
 Velocity of sedimentation (sedimentation rate) of a
uniform collection of spherical particles is governed
by Stoke’s law.

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 Sedimentation in
suspensions..............(cont’d)

or

v is the terminal velocity(sedimentation rate) in

cm/sec; d is the diameter of the particle in cm; ρs is
the density (g/cm3) of the dispersed phase; ρo is the
densities (g/cm3) of dispersion medium; g is
acceleration due to gravity (980.7 cm/sec2 ); ηo is
viscosity of the dispersion medium in poises
(g/cm.sec).
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 Limitations of Stoke’s law
 The lower limit of particles obeying Stoke’s equation
is about 0.5 µm.
 This is because Brownian movement becomes
significant and tends to offset sedimentation.
 To settle particles with diameter less than 0.5 µm,
stronger force must be applied.
 This is accomplished by the use of the ultracentrifuge,
which can produce a force 1 million times that of
gravity.

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 Limitations of Stoke’s law…….(cont’d)
 In centrifuge, the acceleration of gravity is replaced by
where ω is angular velocity and x is the distance
of the particle from the center of the rotation.

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 Limitations of Stoke’s law…….(cont’d)
 Stoke’s law holds only if the downward motion of the
particles is not sufficiently rapid to cause turbulence.
 valid for dilute pharmaceutical suspensions
containing not more than 2.0% w/v of dispersed
phase.
In dilute suspensions, the particles do not interfere
with one another during sedimentation, and free
settling occurs.

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 Quantitative expression of
sedimentation and flocculation

Sedimentation volume ( )
Vu = final or ultimate volume of sediment
Vo = total volume of suspension

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 Quantitative expression of sedimentation
and flocculation……(cont’d)
 F=0.75 means 75% of the total volume of the
suspension is occupied by loose, porous flocs forming
the sediment.
 When F= 1(ideal suspension):
 no sediment is apparent
 the susp. is aesthetically pleasing( no visible
clear supernatant)
 Limitation of F: no reference for comparison

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Quantitative expression of sedimentation
and flocculation……(cont’d)
The degree of flocculation (β)
 A better parameter for comparing flocculated systems
 An expression of the increased sediment volume
resulting from flocculation

For example, 𝛃 = 5 implies vol. of sediment in the

flocculated system is five times greater than in the
deflocculated state. 54
 Preparation of suspensions
 Diffusible solids
 Some insoluble powders are light and easily
wettable; hence, they readily mix with water and, on
shaking, diffuse evenly through the liquid for long
enough to ensure even distribution in each dose.
Such substances are known as diffusible or
dispersible solids.
 Example, calcium carbonate, light kaolin, light
magnesium carbonate, magnesium trisilicate

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 Preparation of suspensions (cont’d)

 Indiffusible solids
 Indiffusible solids will not remain uniformly
distributed in a vehicle long enough to ensure
uniformity of dose.
 This problem can be corrected by increasing the
viscosity by adding thickening agent.
 This delays sedimentation by impeding fall of particles
under gravity and by obstructing particle collisions.
e.g. Calamine, ZnO, Sulphur pricipitated

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 Preparation of suspensions (cont’d)
 Poorly wettable solids
 Some substances, e.g sulphur and hydrocortisone, are
both insoluble in water and poorly wetted by it.
 When preparing simple aqueous dispersions it is difficult to
disperse clumps,
 To ensure satisfactory wetting, the interfacial energy
between the solid and liquid must be reduced.
 This may be achieved by adding a suitable wetting agent
which is adsorbed at the solid/liquid interface in such a
way that the affinity of the particles for the surrounding
medium is increased, while the interparticular forces are
decreased.

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 Solid
particles Hydrophilic can be
dispersed easily

Suspending
media

Difficult to disperse and

float on the surface due to
hydrophobic surface or
entrapped air

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 Preparation of suspensions (cont’d)

 General method of preparation

 Carefully tare the container,
 Finely powder any ingredient not already in fine
form.
 Mix the insoluble powders in a mortar,
 Adding first the ingredient of smallest bulk
and diluting it with the others in increasing
order of bulk,
 Add a portion of the vehicle to mix well and
produce a smooth paste.
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 Preparation of suspensions (cont’d)

 Examine the suspension critically,

 If it contains foreign particles, strain through muslin
into the tared bottle.
 Add any volatile & liquid ingredients into the bottle.
 Rinse the mortar and pestle with successive volumes
of vehicle until they are quite clean and transfer the
rinse to bottle.
 Make up to volume with vehicle and shake
thoroughly.
 Finally, label it
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 Label and storage of suspensions

Label
 The most important additional label for suspensions is
‘SHAKE WELL BEFORE USE’
Storage
 Store in refrigerator- ‘STORE IN COOL PLACE’
 1-4 week expiry date

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Rheology (flow property) of suspensions

The ideal suspendion should have a high viscosity at

negligible shear (i.e., during storage to prevent
sedimentation) but a low viscosity at high shearing
rate, that is, it should be free flowing during agitation,
pouring, and spreading.

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