Coarse Dispersion Physical Pharmacy

Suspensions
A pharmaceutical suspension is a coarse dispersion in which insoluble solid particles
are dispersed in a liquid medium. The particles have diameters for the most part greater
than 0.1 µm.
If the dispersion has low viscosity Brownian motion is observed.
Interfacial properties of suspended particles
During formulation of suspension, work is done to reduce the size of particles or to
disperse in a continuous phase or medium. This makes the system thermodynamically
unstable. In order to increase stability of suspension particles tends to flocculate. That is
to form light, fluffy conglomerates that are held together by weak van der waals forces.
Caking often occurs by the growth and fusing together of crystals in the precipitates to
produce a solid aggregate.
The formation of any type of agglomerate is taken as a measure of the system tendency
to reach more thermodynamically stable condition. An increase in the work , W , or
surface free energy , ∆G, brought about by dividing the solid into smaller particles and
consequently increasing the total surface area, ∆A, is given by ,

∆G = γSL . ∆A

To approach stable state, the system tends to reduce surface free energy. Equilibrium is
reached when ∆G = 0.
The reduction in surface free energy is accomplished by reduction in interfacial tension
of the system.
The interfacial tension can be reduced by the addition of a wetting agent which get
absorbed on the surface of the suspended particles. The wetting agent is not able to
reduce the interfacial tension to zero and hence a suspension generally possesses a
finite positive interfacial tension as a result of which the suspended particles tend to
flocculate or aggregate.

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Coarse Dispersion Physical Pharmacy

The forces acting on the suspended particles are also affecting the degree of
flocculation in a suspension. Forces of attraction arise from van der waals forces while
forces of repulsion result from the interaction of electric double layer surrounding each
particle, this result in potential energy of attraction and repulsion.

When repulsion energy is high, the potential barrier is also high, and collision of the
particles is opposed. The system remains deflocculated, and when sedimentation is
complete, the particles from a closed packed arrangement with smaller particles filling
the voids between the larger particles. To resuspend and redisperse these particles, it
again necessary to overcome the high potential barrier, this is not achieved by the
agitation. The particle tends to remain strongly attached to each other and form hard
cake. When the particles are flocculated, the energy barrier is still too large to be
surmounted and therefore the particles remain separated by a distance approximately
from 1000 to 2000 Å in the secondary minimum. This distance is sufficient to form the
loosely structured floccules.

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Coarse Dispersion Physical Pharmacy

Flocculation and deflocculating in suspension

The over all charge existing on the suspended particle is the zeta potential and it is a
measurable indication of the potential existing at the surface of a particle. Therefore
flocculation and deflocculation may be considered in terms of zeta potential. When zeta
potential is high , the repulsive forces between two particles exceed the attractive van
der waals forces and the particles remain dispersed. These are then said to be
deflocculated.
The zeta potential can be lowered by the addition of an electrolyte whose charge is
opposite to that of suspended particle. At some concentration of the electrolyte, the
forces of attraction dominate slightly over the electrical forces of repulsion. Under this
condition the particles approach each other and form loose aggregates commonly
called as flocs. Such a suspension is said to be flocculated.
Settling In Suspension
Theory of sedimentation
The velocity of suspension is expressed by stokes’s law:

d 2   s  0  g
v
18 0

Where, ν = terminal velocity in cm/sec

d = diameter of the particle in cm
ρs & ρo = densities of dispersed phase and dispersion medium, respectively.
g = acceleration due to gravity
ηo = viscosity of the dispersion medium in poise
In dilute suspension, the particles do not interfere with one another during
sedimentation, and free settling occurs. In most pharmaceutical suspension that
contains dispersed particles in concentration of 5%, 10%, or more percentages, the
particles exhibit hindered settling. The particles may interfere with one another as they
fall and stokes’s law can not be longer applies.

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Coarse Dispersion Physical Pharmacy

Effect of Brownian movement

When the size of the dispersed particles is very small such as about 2 to 5 µm ,
Brownian motion sets in. however it depends on the density of the particles and the
density and viscosity of the dispersion medium. The Brownian movement prevents or
reduces sedimentation to a considerable extent at room temperature by keeping the
dispersed material in random motion.
Sedimentation of flocculated particles
When sedimentation studied in flocculated system, it is observed that the flocs tend to
fall together, producing a distinct boundary between the sediment and the supernatant
liquid. The liquid above the sediment is clear because even small particles present in
the system are associated with the flocs. The initial rate of settling of flocculated
particles is determined by the flocs size and the porosity of the aggregated mass. The
rate also depends on compaction and rearrangement processes within the sediment.
The term subsidence is sometimes used to describe settling in flocculated system.
Sedimentation parameter
Two useful parameters are derived from the sedimentation, these are:
(1) Sedimentation volume, V, or height, H.
(2) Degree of flocculation.
The sedimentation volume, F, is defined as the ratio of the final or ultimate volume of the
sediment, Vu, to the original volume of the suspension, V 0, before settling.

Vu
F
V

Sedimentation volume can have the values ranging from less then 1 to greater than 1.
F is normally less than 1. In this case, ultimate volume of sediment is smaller than the
original volume of suspension as shown in figure 2-a, in which F = 0.5. If the volume of
sediment in flocculated suspension equals the original volume of suspension, than F =
1(figure 2-b).
It is possible for F to have values greater than 1 , that means the final volume of
sediment is greater than the original suspension volume. This is because the network of

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Coarse Dispersion Physical Pharmacy

flocs formed in the suspension is so loose and fluffy that the volume they are able to
encompass is greater than the original volume of the suspension (figure 2-c).

The sedimentation volume gives only a qualitative account of flocculation.

A more useful parameter for flocculation is β, the degree of flocculation.
If we consider a suspension that is completely deflocculated, the ultimate volume of the
sediment will be relatively small. Writing this volume as V ∞,

V
F 
V0
F ∞ = sedimentation volume of the deflocculated suspension
The degree of flocculation, β, is defined as the ratio of F to F ∞,

F
F
The degree of flocculation is more fundamental parameter than F because It relates the
volume of flocculated sediment to that in a deflocculated system, so

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Coarse Dispersion Physical Pharmacy

Formulation of suspension
The approaches commonly used in the preparation of physically stable suspension fall
in two categories:
(1) The use of structured vehicle to maintain deflocculated particle in suspension
(2) The application of the principles of flocculation to produce flocs that although
they settle rapidly and easily resuspended with a minimum of agitation.
Optimum physical stability and appearance will be obtained when the suspension is
formulated with the flocculated particles in structured vehicle of hydrophilic colloid type.
When this approach is used the product must be (a) flow readily from the container and
(b) posses a uniform distribution of particles in each dose.
Wetting of particles
This is generally first step during the manufacturing of suspension. The dispersion of an
insoluble powder in vehicle may be may be difficult due to adsorbed air at surface and
minute quantities of grease and other contaminants.
Wetting agent such as polysorbate 80 or dioctyl sodium sulfosuccinate can help to
reduce the interfacial tension between the solid particle and the vehicle. The wetting
agents are generally surfactants which lower the contact angle between the
hydrophobic powder and the vehicle and may give particles a charge leading to a
deflocculated dispersion.
Controlled flocculation
Electrolytes act as a flocculating agent by reducing the electric barrier between the
particles, as evidenced by a decrease in zeta potential and formation of bridge between
adjacent particles so as to link them together in a loosely arranged structure.
For example, bismuth subnitrate in water, the particles possesses a positive charge or
zeta potential. Because of strong force of repulsion between adjacent particles, the
system is peptized or deflocculated and will settle and cake. With the continuous
addition of electrolyte, the zeta potential is reduced to zero, whereupon attraction forces
bring about formation of loose flocs with high sediment volume. This is a controlled
flocculated dispersion which is stable and does not cake.
Surfactants, both ionic and nonionic, have been used to bring about flocculation of
suspended particles. The concentration necessary to achieve this effect would appear

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Coarse Dispersion Physical Pharmacy

to be critical because these compounds can act as wetting agents and deflocculating
agents to achieve dispersion.
Hydrophilic polymers also act as protective colloids and particles coated in this manner
are less prone to cake than are uncoated particles. These polymer exhibit pseudoplastic
flows in solution and this property promote physical stability within suspension. For
example, gelatin exhibits flocculation that depends on the pH and ionic strength of
dispersion medium.

Controlled flocculation in structured vehicle

Although the controlled flocculated approach is capable of fulfilling the desired physical
chemical requisites of a pharmaceutical suspension, the product can look unsightly if F,
sedimentation volume, is not close or equal to 1.
This can lead to incompatibilities, depending on the initial particle change and the
charge carried by the flocculating agent and suspending agent.
For example, suppose we prepare dispersions of positively charged particles that is
then flocculated by the addition of the correct concentration of an anionic electrolyte
such as monobasic potassium phosphate. We flocculate a suspension of negatively
charged particles with a cationic electrolyte, the subsequent addition of a hydrocolloid

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Coarse Dispersion Physical Pharmacy

may result in an incompatible product, as evidenced by the formation of an unsightly

stringy mass that has little or no suspending action and it settles rapidly.

Under this circumstance, it becomes necessary to use a protective colloid to change the
sign on the particle from negative to positive.
Rheologic consideration
The principles of rheology can be applied to study of the following factor:
 The viscosity of suspension as it affects the settling of dispersed particles.
 When the container is shaken and when the product is poured from the bottle,
the change in flow properties of the suspension
 The spreading qualities of the lotion when it is applied to an affected area.
Rheologic considerations are also important in the manufacture of suspension.
The shear that occurs in suspension in storage is due to the settling of suspended
particles but this force is negligible. When the container is shaken and the product is
poured from the bottle, high shearing rate is observed. Ideal suspending agent have
high viscosity at negligible shear during storage of suspension and should have low
viscosity at high shearing rate. It should be free flowing during agitation, pouring and
spreading.
A suspending agent that is thixotropic as well as pseudoplastic should prove to be
useful because it forms gel on standing and becomes fluid when disturbed.
For example, a combination of bentonite and sodium carboxymethylcellulose.

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Coarse Dispersion Physical Pharmacy

EMULSION
An emulsion is a thermodynamically unstable system consisting of at least two
immiscible liquid phases, one of which is dispersed as globules (the dispersed phase) in
the other liquid phase (continuous phase), stabilized by the presence of emulsifying
agent. The emulsified systems range from lotions of relatively low viscosity to ointments
and cream, which are semisolid in nature.
The particle diameter of dispersed phase generally extends from about 0.1 to 10 µm,
although particle diameters as small as 0.01 µm and as large as 100 µm are not
uncommon in some preparation.
Types of Emulsions
In emulsion one liquid phase is essentially polar or aqueous, where as the other is
relatively non polar or an oil.
When oil phase is dispersed as globules throughout in aqueous continuous phase , the
system is referred as oil-in-water (o/w) emulsion.
When aqueous phase is dispersed as globules throughout in oil continuous phase, the
system is referred as water-in- oil (w /o) emulsion.
Externally applied emulsions may be o/w or w/o.
The o/w emulsion employing the following emulsifiers:
Nonionic surfactants, acacia, tragacanth, gelatin, sodium lauryl sulphate,
triethanolamine stearate, monovalent soaps such as sodium oleate and self emulsifying
glyceryl monostearate
The pharmaceutical w/o emulsion employing the following emulsifiers:
Polyvalent soaps such as calcium palmitate, sorbitan esters (spans), cholesterol and
wool fat.
Methods of detection of Emulsions
1. A small quantity of a water soluble dye such as methylene blue or brilliant blue
FCF may be dusted on the surface of the emulsion, if water is the external
phase, the dye will dissolve and uniformly diffuse throughout the water. If the
emulsion is of w/o type, the particles of the dye will lie in clumps on the surface.
2. A second method involves dilution of the emulsion with water. If the emulsion
mixes freely with the water, it is of the o/w type.

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Coarse Dispersion Physical Pharmacy

3. In other test, a pair of electrodes connected to an external electric source and

immersed in the emulsion. If the external phase is water, a current will pass
through the emulsion and can be deflect a voltmeter needle or cause light in
circuit to glow. If the oil is the external phase, the emulsion fails to carry the
current.
Theory of Emulsification
When a liquid is broken into small particles, the interfacial area of globules constitutes a
surface that is enormous compared to surface area of the original liquid. The increase in
energy associated with the enormous surface is sufficient to make the system
thermodynamically unstable; hence the droplets have a tendency to coalesce.
To prevent coalescence or to reduce its rate it is necessary to introduce an emulsifying
agent that will form a film around the dispersed globules.
Emulsifying agents can be divided into three groups as follows:
a) Surface active agents, which are adsorbed at oil-water interface to form
monomolecular films and reduce interfacial tension.
b) Hydrophilic colloids, which form multi-molecular film around the dispersed
droplets of oil in an o/w emulsion.
c) Finely divided solid particles, which are absorbed at the interface between two
immiscible liquid phases and form to a film of particles around the dispersed
globules.
Monomolecular adsorption
Surfactants are substances containing both hydrophilic and lipophilic regions in their
molecular structure. These act by getting adsorbed at the oil-water interface in such a
way that the lipophilic non-polar groups are oriented towards oil while the hydrophilic
polar groups are oriented towards the water thus forming a stable film. This film act as a
mechanical barrier to coalescence of the globules of the dispersed phase. A good
emulsifying agent also reduces the interfacial tension which turn reduces the surface
free energy and hence the tendency for coalescence. An additional effect promoting
stability is the presence of surface charge which will cause repulsion between adjacent
particles.

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Coarse Dispersion Physical Pharmacy

The type of emulsion produced depends on the HLB of the emulsifier. For example, o/w
emulsion is formed when the HLB of emulsifier is in the range of 9 to12 whereas w/o
emulsion is formed when range is 3 to 6. Tweens which have high HLB value gives o/w
emulsions and spans which have low HLB value gives w/o emulsions.
The type of emulsion formed is a function of relative solubility of the emulsifier. The
phase in which the emulsifier is more soluble becomes the continuous phase. This is
referred to as Bancroft’s rule. Thus, an emulsifying agent with high HLB is preferentially
soluble in water and results in the formation of o/w emulsion. An emulsifying agent with
low HLB is soluble in oil and results in w/o emulsion.
Multimolecular adsorption and film formation
Hydrated lyophilic colloids are used as emulsifying agents. They differ from the
synthetic surface active agent in that:
a) They do not cause an appreciable lowering of interfacial tension.
b) They form a multi molecular film rather then monomolecular film at the interface.
Their action as emulsifying agent is due to the formation of Multimolecular film because
the film formed is strong and resist the coalescence. An auxiliary effect is the increase in
the viscosity of the dispersion medium. They tend to promote the formation of o*w
emulsions because the emulsifying agents form Multimolecular film around the droplets.
Solid particle adsorption
Finely divided solid particles that are wetted by to some degree by both oil and water
can act as a emulsifying agents. This results from their being concentrated at the
interface, where they produce a particulate film around the dispersed droplets so as to
prevent coalescence.
Powder that are wetted with water forms o/w emulsions whereas those wetted by oil
forms w/o emulsions.

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Coarse Dispersion Physical Pharmacy

Physical stability of emulsions

The stability of a pharmaceutical emulsion is characterized by the absence of
coalescence of the internal phase, absence of creaming and maintenance of elegance
with respect to appearance, odor, color, and other physical properties.
Another phenomenon important in the preparation of emulsion is phase inversion, which
can be an aid or a detriment in emulsion technology. Phase inversion involves the
change of emulsion type from o/w to w/o or vice-versa. The instability of pharmaceutical
emulsion may be classified as follows:
1. Flocculation and creaming
2. Coalescence and breaking
3. Miscellaneous physical and chemical changes
4. Phase inversion
1. Creaming and flocculation
Creaming is a phenomenon characterized by accumulation of droplets of the dispersed
phase at the top of the emulsion. The rate of creaming is governed by stokes’s law:

d 2   s  0  g
v
18 0

Where, ν = terminal velocity in cm/sec

d = diameter of the particle in cm
ρs & ρo = densities of dispersed phase and dispersion medium, respectively.
g = acceleration due to gravity
ηo = viscosity of the dispersion medium in poise
If the dispersed phase is less dense than the continuous phase, which is generally the
case in o/w emulsions, the velocity of sedimentation becomes negative that is called
upward creaming. If the internal phase is heavier than the external phase, the globules
settle, a phenomenon observed in w/o emulsion in which the internal aqueous phase is
denser than the continuous oil phase. This effect can be referred as downward
creaming.

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Coarse Dispersion Physical Pharmacy

The greater the difference between the density of the two phases, the larger the oil
globules, and the less viscous the external phase, the greater is the rate of creaming.
By increasing the force of gravity through centrifugation, the rate of creaming can also
be increased.
Diameter of the globules is seen to be a major factor in determining the rate of
creaming. Doubling the diameter of the oil globules increases the creaming rate by a
factor of four.
The rate of creaming is reduced by following different ways:
a) The viscosity of the external phase can be increased without exceeding the limits
of acceptable consistency by adding a viscosity improver or thickening agent as
tragacanth, sodium alginate or methylcellulose.
b) The particle size of the globules can be reduced by homogenization.
c) Minimizing the difference in the density of two phases. This is difficult since the
density changes with temperature and agents required to increase density of the
oil phase such as bromophorm, carbon tetrachloride, etc. are toxic for internal
use.
2. Coalescence and breaking
A few globules tend to fuse with each other and form bigger globules. In this process,
the emulsifier film around the globules is destroyed to certain extent. This step can be
recognized by increased globule size and reduced number of globules. Coalescence is
followed by creaming stage. Coalescence is observed due to:
 Insufficient amount of the emulsifying agent.
 Altered partitioning of the emulsifying agent.
 Incompatibilities between emulsifying agents.
Phase volume ratio represents the relative volume of water to oil in an emulsion. At right
ratio (>74% of oil to water), globules are closely packed, wherein small globules occupy
the void spaces between bigger globules. Thus, globules get compressed and become
irregular in shape, which leads to fusion of adjacent globules.

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Coarse Dispersion Physical Pharmacy

Breaking
This is indicated by complete separation of oil and aqueous phase phases. It is
irreversible process, i.e., simple mixing fails to resuspend the globules into an uniform
emulsion. In breaking, the protective film around the globules is completely destroyed.
3. Phase inversion
Phase inversion simply means by change in type of emulsion during the manufacturing
of emulsion. For example, an o/w emulsion stabilized with sodium stearate can be
inverted into the w/o type by addition of calcium chloride.
Inversion can also produced by alteration in phase volume ratio. In the manufacturing of
emulsion, one can mix an o/w emulsifier with an oil and then add small amount of water,
a w/o emulsion is produced by agitation. Since water volume is less, it forms w/o
emulsion. But when more water is added slowly, phase inversion occurs and an o/w
emulsion is produced.
Pharmaceutical application of the emulsions
1. An o/w emulsion is a convenient way of orally administrating water insoluble
liquids, especially when dispersed phase have unpleasant taste. More significant
in contemporary pharmacy is the observation that some oil soluble vitamins are
absorbed more completely when emulsified than when administered orally as oily
solution.
2. The use of intravenous emulsion has been observed as a means of maintaining
debilitated patients who are unable to assimilate materials administered orally.
When the emulsion is administered intravenously, the droplets are normally
rapidly taken up by the cells of reticuloendothelial system.
3. Radiopaque emulsions have found application as diagnostic agent in x-ray
examinations.
4. Emulsions are widely used in pharmaceutical and cosmetic products for external
use. This is particularly so with dermatologic and cosmetic lotion and creams.
5. Emulsion is used in aerosols to produce foams. Propellant that forms the
dispersed liquid phase within the container vaporizes when emulsion is
discharged from the container. This results in rapid formation of foam.

Faculty of Pharmacy Tejas B Patel DDU