Suspension

Pharmaceutical
Suspensions
Introduction
o Suspensions are heterogeneous systems containing
two phases
o The internal (dispersed) phase
is made up of particulate matter, which is
practically insoluble in the external phase

Introduction…
o The external phase (continuous phase or dispersion

medium)
generally a liquid (liquid suspensions) or
semisolid (gels)
Most pharmaceutical suspensions consist of an
aqueous dispersion medium
organic or oily liquids (some times)
Introduction…
o Depending on the routes of administration

pharmaceutical suspensions can be classified as
oral suspensions
externally applied lotions
injectable preparations
o Suspensions are also available as aerosols
which can be applied topically on the skin or

 internally by pulmonary route
Introduction…
o Oral and parenteral suspensions, may be prepared
as dry powders for reconstitution with water prior to
dispensing
o Topical suspensions can be
liquid preparations
semisolid
o Parenteral preparations can be formulated in an oily

vehicle to sustain drug release
Criteria for good suspension
o Suspended particle should not settle rapidly

o The particle which settle should not form cake
 should redisperse uniformly in the continuous
phase, upon moderate shaking
o Should not be too viscous to pour
o In case of parenteral preparation
 the suspension should follow out of the syringe
Criteria for good suspension…
 Suspended particles should be small and uniform in size
 Topical suspensions should be easy to apply, not run
off and not dry off too quickly
 It must have an acceptable color and odor
 The suspended particle should not degrade too quickly or
undergo change in polymorphic form
 Suspension should exhibit psuedolasticity along
with thixotropy
Advantage and disadvantage
Advantages of suspension dosage forms
o Efficient for delivering hydrophobic drugs
o Avoidance of the use of cosolvents
o Masking of unpleasant taste of certain ingredients
E.g. Chloramphenicol suspension and Erythromycin Estolate susp.
o Offer resistance to degradation of drugs due to hydrolysis, oxidation
E.g. Antibiotic suspension

Advantage and disadvantage…
 Easy swallowing
 Efficient for IM depot therapy
 Compared to solution dosage forms, relatively higher
concentration of drugs can be incorporated into
suspension products
 Compared to solid dosage forms provide high
dissolution and absorption
Advantage and disadvantage…
Disadvantages of suspension dosage forms
o The possibility of dose variation
o Requirement of large storage area
o Lack of elegance
Interfacial Properties
o The solid phase remains as finely divided particles in
the dispersion medium
 Therefore, a large amount of interface is involved
in the formulation
 This affects the stability of suspension
preparations
o The two most important interfacial properties include
surface free energy and surface potential
Interfacial Properties…
Surface Free Energy

o The relation between the surface free energy and the
surface area can be expressed by
where
 ∆G is the increase in surface free energy
 ∆A is the increase in surface area, and
γ is the interfacial tension between the solid particles
and the dispersion medium
o The smaller the ∆G is, the more thermodynamically stable
is the suspension
A system with very fine particles is thermodynamically
unstable
 The particles tends to flocculate (desirable)
 i.e. to form light, fluffy aggregates that are held
together by weak Vander waals forces
 the particles may also adhere by stronger forces to
form what are termed coagulation (caking-undesirable)
o Surface free energy can be reduced by
1. reducing interfacial tension

 When a wetting agent is added to the suspension
formulation, it is adsorbed at the interface
 result in a reduction of the interfacial tension,
making the system more stable
2. decreasing the interfacial area

 flocculation or loose aggregation
Surface Potential
o exists when dispersed solid particles in a suspension
possess charge in relation to their surrounding liquid
medium
o Solid particles may become charged through d/f
ways
 Selective adsorption of a particular ionic species
 Ionization of SAA which are already adsorbed at the

solid–liquid interface
 Ionization of functional group of the particles
 Peptide and protein molecules contain ionizable
groups, such as –COOH and –NH2
 The sign and magnitude of the ionization mostly
depend on the pH of the surrounding vehicle
o The part of the solvent immediately surrounding the particles
will almost entirely comprise of the counter-ions.
 This part of the solvent, along with these counter-ions is
tightly bound to the particle surface and is known as the
Stern layer
 When particles move through the dispersion medium, the
Stern layer moves along with them and thus the shear
plane is the one peripheral to the Stern layer
o Electric neutrality occurs where the mobile diffuse layer
ends
o Beyond the diffuse layer, the concentrations of co- and
counter-ions are equal
o The thickness of the double layer depends upon the type and
concentration of ions in solution
o The suspension, as a whole, is electrically neutral despite the
presence of unequal distribution of charges in the double
layer
 The aggregation of solid particles in suspension

systems can be termed either as “flocculation” or
“coagulation”
 flocculation occurs at the secondary energy
minimum
 coagulation occurs at the primary energy minimum
of the potential energy curve of two interacting
particles
Sedimentation in suspensions
 sedimentation velocity of the particles of a

suspension is given by Stoke’s law
Sedimentation in suspensions…
where
v (cm/sec) is the velocity of sedimentation
d (cm) and r (cm) are the diameter and radius of the
particle, respectively;
 ρ1 and ρ2 (g/cm3) are the densities of the dispersed phase
and dispersion medium, respectively;
g is the acceleration due to gravity; and
η (poise) is the viscosity of the dispersion medium
o Viscosity of the medium can be increased in order to

reduce settling
 Common viscosity-increasing agents are
 cellulose derivatives (e.g., methylcellulose, NaCMC
and hydroxypropyl methylcellulose)
 natural gums (e.g., acacia and tragacanth)
o The difference in density b/n the dispersed phase
and dispersion medium can affect the rate of
settling
o Since the density of the dispersed phase cannot be
changed, it would be necessary to increase the
density of the medium
 by using some density modifiers e.g., sorbitol and
mannitol
Limitation of stock’s law
 Stokes’ equation was derived for an ideal situation in which
uniform, perfectly spherical particles in a very dilute
suspension (NMT 2% solids) settle without
 producing turbulence
 colliding with other particles of the dispersed phase, and
 chemical or physical attraction or affinity for the dispersion
medium
 Stokes’ equation does not apply precisely to the usual

pharmaceutical suspension in which
 the dispersed particle is irregularly shaped and of
various particle diameters,
 the fall of the particles does result in both
turbulence and collision, and
 the particles may have some affinity for the
suspension medium
o Dielectric constant is ignored in Stokes’ equation
 The electrical potential between two charges is
inversely proportional to the dielectric constant of
the medium.
 Therefore, Zeta potential is dependent on the
dielectric constant of the medium.
o Brownian movement is another factor that can
influence the accuracy of the results obtained in
Stokes’ equation
Flocculated/deflocculated suspensions
o A deflocculated system has a zeta potential higher

than the critical value and the repulsive forces
supersede the attractive forces
 Particles remains suspended for a long period of
time
 Only a small portion of the solid is found in the
sediment due to the force of gravitation
Flocculated/deflocculated suspensions …
o During sedimentation
 the smaller particles fill the void between the larger
ones; and
 the particles lowest in the sediment are gradually
pressed together by the weight of the particles
above
 These increase the closeness of the particles;
and, thus, they are attracted by a large amount of
van der Waals force
o Upon the addition of a small amount of electrolyte
 the zeta potential of the system reduces
 Once it is below the critical value, the attractive
forces supersede the repulsive forces, resulting in
flocculation
o Flocs get settled faster than the deflocculated
particles
o they will not form hard cake like deflocculated

suspensions and will resuspended with minute
agitation
o a clear supernatant liquid is found at the top of the
flocculated suspensions
o deflocculated suspensions remain cloudy due
to the very fine dispersed solids
 The deflocculated system shows
 almost no change in appearance after a
few minutes of manufacture (a)
 After several hours, the whole dispersion
is still cloudy; however, a small and
compact sediment appears (b)
 After prolonged storage, a clear
supernatant in contact with compact
sediment is obtained (c)
 In case of a flocculated system
 Within a few minutes of manufacture,
a clear supernatant with a distinct
boundary from the sediment is evident
(d)
 After several hours, a larger volume of
clear supernatant occurs (e).
 After prolonged standing, the volume
of the sediment shows little change (f)
 Table: comparative properties of flocculated and deflocculated
suspensions
Sedimentation parameters
o The extent of flocculation of a system can be
assessed by sedimentation parameters
o Two important sedimentation parameters are
sedimentation volume and degree of flocculation

Sedimentation parameters…
The sedimentation volume (F)

 is the ratio of the equilibrium volume of the sediment, Vu to
the total volume of the suspension, Vo
 The value of F normally ranges from 0 to 1
 Suspension with F = 1
 there is no sedimentation
 there is no visible clear supernatant
 Look elegant
 It is possible to have F > 1
 The particles in the suspension create such a loose
and fluffy flocs that comes out of the dispersion
medium
 Encompasses greater than the original volume of the
suspension
o The sedimentation volume gives only a qualitative idea
about the sedimentation of the suspension because it
lacks any meaningful reference point
Degree of flocculation
o relates the SV of the flocculated suspension, F, to
the SV of the suspension when it is deflocculated,
F∞
o The sedimentation volume of the deflocculated

suspension can be shown as
 where F∞ is the SV of the deflocculated system and V∞ is the
ultimate volume of the sediment
 These two equations for SV of flocculated and deflocculated can be
combined as follows:
E.g If β = 4 what does it indicate?
it implies flocculated suspension creates 4 times more sediment

than the deflocculated one
Formulation of suspension
o The approach used in the preparation of physically

stable suspension are three types
 The use of structured vehicle to maintain
deflocculated particles in the suspension
 The application of principle of flocculation to
produce flocs that are easily re-dispersed with a
minimum of agitation
 Combination of the above two approaches
Formulation of suspension…
Wetting of the particles

 Some insoluble solids may easily be wet by water
and disperse readily throughout the aqueous phase
with minimal agitation
 Many solid materials are too hydrophobic to be wet
and thus
 form large porous clumps within the liquid or
remain floated on the surface
o Poor wetting of hydrophobic powders materials

occurs due to high interfacial tension between the
powders and the dispersion medium
 the contact angle between the solid and liquid
phases remains very high
o The poor wetting may also result from a layer of air
or greasy materials or other impurities covering the
surface of the particles
 Wetting of solids can be determined by using Young’s
equation
where θ is the contact angle
γ is the interfacial tension between the different phases, solid

(S), vapor (V), and liquid (L)
o Surfactants with HLB value b/n 7 and 9 can function

as wetting agents
 lower interfacial tension to decrease the contact
angle, resulting in good wetting
 The hydrocarbon chain of the SAA is adsorbed
onto the hydrophobic surface of the particles and
the polar end remains with the liquid medium
 used at conc. up to 0.1% as wetting agents
 Commonly used surfactants as wetting agents for
oral use are polysorbates and sorbitan esters
 SDS (sodium dodecyl sulfate) is an example of a
surfactant that is used externally
 Parenteral preparation may contain polysorbates,
some of the poloxamers, and lecithin

o Hydrophilic polymers can be used as wetting agent
 Form a hydrophilic coating around the solid
particles and thus promote wetting
 Examples: acacia, tragacanth, xanthan gum and
cellulose derivatives, such as CMC

o Hygroscopic solvents can also improve wetting
 displace the air from the pores of the individual
particles
 Flow into the void space b/n the particles, coat the
particles and separate them and thus bringing
dispersion
 E.g. alcohol, glycerol, and propylene glycols
Structured vehicle
o act by entrapping the particles so that, ideally, no
settling occur
o Some degree of sedimentation will usually take place
 The “shear-thinning” properties of these vehicle does,
however facilitates the re-formation of a uniform
dispersion when shear is applied
 E.g gum arabics, sodium algenate, CMC
Controlled flocculation
o The main aim is to prevent formation of compact
sediment which is difficult to redisperse
o Controlled flocculation can be achieved by
a combination of control of particle size and the
use of flocculating agents
o The most common categories of flocculating agents
are electrolytes, surfactants and polymers
Electrolytes
o act by reducing the zeta potential
 The flocculating power increases with the valency of the
ions
o When anionic electrolytes are added to a positively charged
deflocculated suspension, zeta potential decreases slowly
 At a certain stage, upon persistent addition, it becomes
zero
 Beyond that limit, zeta potential becomes negative
 As zeta potential decreases, the F increases

sharply up to a point
F reaches its maximum value and remains
relatively constant within a certain range of zeta
potential
 When the potential becomes too negative, F
decreases again
 Similar behavior is observed with sulfamerazine
suspension (negatively charged) when aluminium
ions are added as electrolyte

Surfactants
o Both ionic and nonionic surfactants can be used as
flocculating agents
 Ionic surfactants cause flocculation reducing zeta
potential
 Because of long structure, nonionic surfactants are
adsorbed onto more than one particle, thereby,
forming a loose flocculated structure
Polymers
o Linear and branched chain polymer form a gel-like
network that adsorbs onto the surface of dispersed
particles, holding them in a flocculated state
o Hydrophilic polymers can also function as protective
colloids
 In this capacity, flocs are sterically prevented
from adhering to one another
o Some polymers, known as polyelectrolytes, can ionize
in aqueous medium E.g. NaCMC
 The extent of ionization depends on the pH and
the ionic strength of the dispersion medium
 These polymers are able to act both
electrostatically and sterically

Flocculation in structured vehicles
o the controlled flocculation approach is capable of fulfilling the desired
physical chemical requisites of pharmaceutical suspension
 But the product can not look attractive if F is not closer or equal to 1
 Consequently an ideal formulation would be one with controlled flocculation
in structured vehicle where vehicle retard sedimentation of the flocs
 Suspending agents are added to form structured vehicle
 e.g. CMC, Carbopol 934, Veegum, tragacanth and bentonite
 This may lead to incompatibilities, depending on

 the initial particle charge and
 the charge carried by the flocculating agent and
suspending agent
 If we flocculate a suspension of negatively charged
particles with a cationic electrolyte the subsequent
addition of a hydrocolloid (e.g. gums) may result in
an incompatible product
 it becomes necessary to use a protective colloid to
change the sign on the particle from -ve to +ve
 by the adsorption onto the particle surface of a
fatty acid amine or material such as gelatin
 We are then able use an anionic electrolyte to
produce flocs that are compatible with negatively
charged suspending agent
 Rheologic Considerations are important in

pharmaceutical suspensions since they affect
viscosity
 This in turn affects the sedimentation rate
and re-dispersion
 Rheological attributes also influence the flow
property of the suspensions when the containers are
shaken and the product is poured from
Rheologic Considerations…
 Externally applied suspension products should spread
easily, but they are not expected to be so fluid that
they run off the skin surface
 Parenteral products have to be fluid enough to pass
through needles when moderate pressure is
applied
 Rheology can affect the manufacturing process of
suspensions
 Highly viscous mixture produces excessive
frictional drag on the mixing vessel and other
machinery accessories, thereby resulting in wasted
energy
o Concentrated flocculated suspensions show high
viscosity when static, due to high interparticle
attraction
A minimum force is required to overcome that
attraction
 Once that force is applied, viscosity decreases
substantially
 These characters are typical to plastic flow
 Most suspensions exhibit pseudo plastic flow
 Both plastic and pseudo plastic systems can be
beneficial to formulate stable suspension products
because at high stress, such as shaking the bottle,
the products become thinner and make withdrawal
and application easier

 The principle of thixotropy can be applied to

pharmaceutical suspensions
It is applicable to both plastic and pseudo plastic
systems
When the bottle is shaken, the products become
thin and thus will remain thin for a sufficient period
of time even upon withdrawal of the force to allow
an accurate dose withdrawal
 Concentrated deflocculated suspensions appear to be more
structured and viscous with the increase in shearing stress

Preparation of suspension
On small scale
 Lavigating the insoluble material in the mortal to smooth
paste with a vehicle containing the dispersion stabilizer and
 Gradually adding the remainder of the liquid phase in which
any soluble ingredients is dissolved
 The slurry transferred to conical measure
 the mortal is rinsed with portion of the vehicle and this is
added to the conical measure
 The dispersion is finally brought to final volume
 This transferred from the conical measure to the bottle
Preparation of suspension…
On large scale
 is accomplished by use of ball, colloid mills, mixers
Colloid mills
o Is based on the principles of a high-velocity
o Cone-shaped rotor is centered with respect to a stators at
small adjustable clearance
 The suspension fed by gravity from a hopper
 sheared between the rotor and the stator and
 forced out below or drawn off , where it may be recycled
or drawn off
Preparation of suspension…
o The efficiency of mills is based on
 The clearance b/n the disks
 The peripheral velocity of the rotor
 Non-newtonian viscosity of the suspensions

Physical Stability of suspensions
o Raising the temperature leads to flocculation or
coagulation of sterically stabilized suspensions
o When the suspension is heated the energy of
repulsion b/n the particles reduced owning to
dehydration of the polyoxyethylene groups of the
surfactant
 The attractive energy increased and the particles
flocculate or coagulate
Physical Stability of suspensions…
 Particle growth is also a destabilizing process
resulting from
 temperature fluctuation or
 Ostwald ripening during storage
 Change the PSD and polymorphic form of a drug,
altering the dissolution rate and drug BA

 Particle growth is particularly important when the

solubility of the drug is strongly dependent on the
temperature
 Thus when temperature is raised, crystals of drug
may dissolve and form supersaturated solutions,
which favor crystal growth
 This can be prevented by the addition of polymers
or surfactants
 The stability of suspensions may also decrease
owning to the interaction with excipients dissolved in
dispersion medium
Packaging and storage of suspensions
o should be packaged in wide-mouth containers having
adequate airspace above the liquid to permit
thorough mixing by shaking and ease of pouring
o should be stored in tight containers protected from
freezing, excessive heat, and light
o suspensions should be shaken before each use to
ensure a uniform distribution of solid in the vehicle
and thereby uniform and proper dosage

Suspension

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Pharmaceutical

o Suspensions are heterogeneous systems containing

o The internal (dispersed) phase

is made up of particulate matter, which is

practically insoluble in the external phase

o The external phase (continuous phase or dispersion

o Depending on the routes of administration

o Suspensions are also available as aerosols

which can be applied topically on the skin or

o Topical suspensions can be

o Parenteral preparations can be formulated in an oily

o Suspended particle should not settle rapidly

o Efficient for delivering hydrophobic drugs

o Avoidance of the use of cosolvents

o Masking of unpleasant taste of certain ingredients

E.g. Chloramphenicol suspension and Erythromycin Estolate susp.

o Offer resistance to degradation of drugs due to hydrolysis, oxidation

E.g. Antibiotic suspension

Disadvantages of suspension dosage forms

o The possibility of dose variation

o Requirement of large storage area

Surface Free Energy

1. reducing interfacial tension

2. decreasing the interfacial area

 Ionization of SAA which are already adsorbed at the

concentration of ions in solution

o The suspension, as a whole, is electrically neutral despite the

presence of unequal distribution of charges in the double

 The aggregation of solid particles in suspension

 sedimentation velocity of the particles of a

o Viscosity of the medium can be increased in order to

 Stokes’ equation was derived for an ideal situation in which

uniform, perfectly spherical particles in a very dilute

suspension (NMT 2% solids) settle without

 colliding with other particles of the dispersed phase, and

 chemical or physical attraction or affinity for the dispersion

 Stokes’ equation does not apply precisely to the usual

o A deflocculated system has a zeta potential higher

o they will not form hard cake like deflocculated

o The extent of flocculation of a system can be

assessed by sedimentation parameters

o Two important sedimentation parameters are

sedimentation volume and degree of flocculation

The sedimentation volume (F)

 The value of F normally ranges from 0 to 1

o The sedimentation volume of the deflocculated

E.g If β = 4 what does it indicate?

it implies flocculated suspension creates 4 times more sediment

o The approach used in the preparation of physically

Wetting of the particles

o Poor wetting of hydrophobic powders materials

where θ is the contact angle

γ is the interfacial tension between the different phases, solid

o Surfactants with HLB value b/n 7 and 9 can function

 Commonly used surfactants as wetting agents for

oral use are polysorbates and sorbitan esters

 SDS (sodium dodecyl sulfate) is an example of a

surfactant that is used externally

 Parenteral preparation may contain polysorbates,

some of the poloxamers, and lecithin