SPECIALIZED

PHARMACEUTICAL
EMULSIONS

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 Disperse System

 A disperse system is defined as a

heterogeneous, two-phase system in which
the internal (dispersed, discontinuous) phase
is distributed or dispersed within the
continuous (external) phase or vehicle.
 Various pharmaceutical systems are
included in this with the internal and external
phases being gases, liquids, or solids.
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 Classification
 Disperse systems can be classified in
various ways.
I. Classification based on the physical
state of the two constituent phases.
 The dispersed phase and the dispersion
medium can be solids, liquids, or gases.
 Pharmaceutically most important are
suspensions, emulsions, and aerosols.
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 A suspension is a solid-liquid dispersion, for
example, a solid drug that is dispersed within a
liquid being a poor solvent for the drug.
 An emulsion is a liquid-liquid dispersion in
which the two phases are either completely
immiscible or saturated with each other.
 In the case of aerosols, either a liquid (e.g.,
drug solution) or a solid (e.g., fine drug
particles) are dispersed within a gaseous
phase. 5
II. Classification system is based on the size of
the dispersed particles within the dispersion
medium.
 Particles of dispersed phase vary – large
particles visible to the naked eye, particles
in the colloidal size range, and particles of
atomic and molecular dimensions.
 The three classes are distinguished as;
molecular, colloidal, and coarse dispersions.
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 Molecular dispersions are homogeneous in
character and form true solutions.
 Colloidal dispersions are intermediate in size
between true solutions and coarse dispersions.
 “colloidal” systems – in which particle size is from
1 to 1000 nm e.g., Nanoparticles.
 Dispersions containing dispersed phase of 10 to
50 mm in size, are “coarse dispersions,” which
include most pharmaceutical suspensions and
emulsions.
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 EMULSIONS
 It is 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 (the continuous phase) stabilized by
presence of emulsifying agent.
 Particle diameter of dispersed phase (Internal
phase) ranges from 0.25 to 10 um.

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 Types Of Emulsions:

1. Oil in water emulsions (O/W)

2. Water in oil emulsions (W/O)

3. Multiple emulsions (O/W/O) or (W/O/W)

4. Microemulsions
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 Microemulsions
 Clear, stable, liquid mixtures of oil, water
and surfactant, frequently in combination
with a cosurfactant.
 In contrast to ordinary emulsion,
microemulsions form upon simple mixing
of the components and do not require the
high shear conditions generally used in the
formation of ordinary emulsions.
 The two basic types of microemulsions are
(o/w) and (w/o).
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 Unlike the common macroemulsion in
that:
1. Appear as clear transparent solution.
2. Diameter of internal phase droplets
ranged between 10-200nm.
3. Thermodynamically stable.

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 Pharmaceutical Applications
 Patient acceptance is most important reason
for use.
 Oils and drugs having an objectionable taste
or texture can be made more palatable for
oral administration by formulating into
emulsions, particularly in the case of infants,
children, and elderly.
 Easily swallowed and flexibly dosed
compared with solid dosage forms.
 Small particle size of the drug present in
disperse systems results in a large specific
surface area.
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 Higher rate of drug dissolution and possibly
a superior bioavailability compared with
solid dosage forms containing larger drug
particles.
 Importance in the case of poorly soluble
drugs.
 Mineral oil-based laxatives, oil-soluble
vitamins, vegetable oils, high-fat nutritive
preparations for enteral feeding, and certain
drugs such as valproic acid are formulated
frequently in an oil-in-water (o/w) emulsion
form. 20
 With topically applied emulsions, the formulation
scientist can control the viscosity, appearance,
and degree of greasiness of cosmetic and
dermatologic products.
 o/w emulsions are most useful as water-
washable bases, whereas water-in-oil (w/o)
emulsions are used widely for the treatment of
dry skin and emollient applications to provide an
occlusive effect.

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 Theory of emulsification
 Tension at interface.
 Large area of interfacial contact.
 High interfacial free energy – reduction
of interfacial area.
i. Droplets assume spherical shape.
ii. Coalescence.
(From Book)

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 Droplet stabilization
1. Lowering of interfacial tension
2. Prevention of Coalescence.

 Surface Active agents.

 Reduce surface tension and act as
barrier to coalescence.

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Mechanisms of emulsifying agents

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Electrical Repulsion

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Prediction of type of emulsion
1. Amphiphile.

2. Polar portion of emulsifier more strong.

3. Even at 20-30% water – w/o formation

when water added to oil.
4. Viscosity of external phase.

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 Formation of emulsions
• Spontaneous.
• Dispersion method.
i. Breaking internal phase into droplets.
ii. Stabilizing them in external phase.
iii. Carry out these steps before intetrnal
phase coalesce.
 Step ii and iii time and temp dependent.

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 1- Physical Parameters
1. Heat

2. PIT

3. Timing

4. Low energy emulsification.

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 Chemical Parameters
 Difficult to designate a general approach or
set of rules in selecting components and their
amounts to formulate.
 Sometimes some oils, emulsifiers and other
ingredients need to be avoided and
sometimes need to be used exclusively.
i. Experience
ii. Personal taste
iii. Trial and error
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1. Chemical stability
2. Safety
3. Lipid Phase
4. Phase ratio
5. Emulsifying agents
6. Formulation consideration
7. Antimicrobial preservative
8. Antioxidant
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 1- Chemical stability
 Chemical inertness an absolute
requirement.
i. Soap as an emulsifier at pH 5 or less.
ii. Easily hydrolyzable ester in acidic/basic
emulsion.
iii. Lipids getting oxidized.
 Chemical nature of all constituents be
understood before selection.
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 2- Safety
 Safety and toxicological clearance of all
components is an absolute requirement.
i. Toxicological information from suppliers.
ii. Scientific literature
iii. Regulatory agencies
 Still an enormous choice of emulsion
ingredients. (differ in cost and ability to
yield a product).
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 3- Lipid Phase
 Material and relative amount depend on
the ultimate use of product.
 Wide variety of lipids (natural/synthetic).
 Drug distributes on the basis of o/w
partition coefficient.
 Absorption depends on its solubility.
 Not be so soluble in vehicle that it
prevents the penetration.
 Feel of emulsion.
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 4- Phase ratio
 The solubility of the active ingredient, must
be present at Pharmacologically effective
level.
 Desired consistency. (Fluid emulsions – low
% of internal phase, heavier emulsions –
high % internal phase).

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 5- Emulsifying agents
1. Surfactants
2. Finely divided solids
3. Hydrophilic colloids

 Required shelf life

 Type
 Cost

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 (i) - Surfactants
 Huge number available
 Selected on intuitive knowledge of hydrophilic
& lipophilic behavior and type produced. (N.I)
 HLB system by Griffin in 1947/1949.
 Determined experimentally from structural
formula.
 Correlate with HLB required.
-

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 Simple arithmetic only polyoxyethylene
ethers.
 Oil sol. – low HLB and water sol. – High.
 HLB required calculate by trial and error.
 Mostly combination of emulsifiers used, –
weighted average of individual surfactant
HLB values.

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 (ii) - Finely divided solids
 Auxiliary emulsifiers.
 Polar inorganic solids – heavy metal
hydroxides, clays, pigments.
 Polar solids – Carbon or
glyceryltristearate.

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 (iii)- Hydrophilic colloids

• Polymers that are water-sensitive.

(thickening agents)
• Natural and synthetic clays.
• Increasing the viscosity.

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6- Formulation consideration
• Consistency and flow.
• Lipid phase, phase vol. ratio and
surfactants.

7- Antimicrobial Preservatives

8- Antioxidants

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 Mechanical equipments for
Emulsification
• Formation of an emulsion may involve a single
step or a number of consecutive steps, depending
on the nature of the starting material and the
method used to create it.
• Disperse the various ingredients into the phase in
which they are most soluble.
• Oil-soluble ingredients are usually mixed with the
oil, whereas water-soluble ingredients are usually
mixed with the water.
• The intensity and duration of the mixing process
depend on the time required to solvate and
uniformly distribute the ingredients. 50
• If the lipid phase contains any crystalline
material, it is necessary to warm it to a
temperature where all the fat melts prior to
homogenization.
• Otherwise it is difficult, if not impossible, to
create a stable emulsion.
• Breaking up of internal phase into droplets
depends on use of force and require
agitation.
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• The process of converting two immiscible liquids
into an emulsion is known as homogenization, and
a mechanical device designed to carry out this
process is called a homogenizer.
• To distinguish between the natures of the starting
materials, it is convenient to divide homogenization
into two categories.
• The creation of an emulsion directly from two
separate liquids will be defined as primary
homogenization, whereas the reduction in size of
the droplets in an existing emulsion will be defined
as secondary homogenization. 52
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• When a liquid jet of one liquid is
introduced under pressure into other, the
stream of liquid is broken into droplets.
Factors involved are;
i. Nozzle diameter.
ii. Speed of liquid injected.
iii. Density and viscosity of injected liquid.
iv. Interfacial tension b/w liquids.
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• Similarly when a liquid is allowed to flow
into another liquid that is being
continuously agitated, breakdown of liquid
into droplets occur.
• After the initial breakdown into droplets,
the continuous turbulence causes
deformation of droplets and results in
further reduction in droplet size.

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• Various types of equipments available can
be divided into following categories;
1. Mechanical stirrers.
2. Homogenizers.
3. Ultrasonifiers.
4. Colloid mills.
5. Micro fluidization.
6. Membrane Homogenizers.
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 Selection of equipment
• Mechanical requirements of preparation and problems
to scale-up to production size need to be addressed.
• One of the most important point is the degree of shear
and turbulence required.
• Agitation required depends on;
i. Total volume of liquid.
ii. Viscosity of the system.
iii. Interfacial tension at oil-water interface.
(ii, iii – emulsion type, phase ratio, type and conc. of
emulsifiers).
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1- Mechanical Stirrers (High-Speed Blenders)
• High-speed blenders are the most
commonly used method for directly
homogenizing oil and aqueous phases.
• The liquids to be homogenized are placed
in a suitable vessel which may contain as
little as a few cubic centimeters or as much
as several cubic meters of liquid, and are
then agitated by a stirrer which rotates at
high speeds (typically 20 to 2000 rev min–
1).
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• Stirred by various impellers mounted on shafts
placed directly into the system.
• Simple top-entering propeller mixers enough for
lab and production scale if low viscosity
emulsion.
• For vigorous agitation and moderate viscosity –
turbine mixers are used.
• Agitation is controlled by speed of impeller
rotation, but pattern of liquid flow and mixing
efficiency is controlled by type of impeller, its
positioning, presence of baffles and container59
shape.
• Blending generally leads to an increase in the
temperature of an emulsion because some of
the mechanical energy is converted into heat.
• If any of the ingredients in the emulsion are
sensitive to heat, it may be necessary to control
the temperature of the vessel during
homogenization.
• Also not suited if very small droplets required
or foaming at high shear rates need to be
avoided.
• Droplets produced by a high-speed blender
range between about 2 and 10 μm in diameter.
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 2-High-Pressure Valve Homogenizers
• Mixture is forced though a small inlet orifice at
high pressure to obtain small size droplets.
• A pump that raises the pressure of dispersion
to 500-5000psi and an orifice through which
the fluid impinges on the homogenizing valve
held in place on the valve seat by spring.
• When pressure builds up the spring is
compressed and some dispersion escapes
b/w valve and valve seat.
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• Experiences a combination of intense shear,
cavitational, and turbulent flow conditions which
cause the larger droplets to be broken down into
smaller ones.
• spring-loaded valves so that the gap through which
the emulsion passes can be varied.
• Decreasing the gap size increases the pressure drop
across the valve, which causes a greater degree of
droplet disruption and smaller droplets to be
produced.
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• narrowing the gap increases the energy
input required to form an emulsion, thereby
increasing manufacturing costs.
• Can be built to pass through homogenizer
multiple times.
• Variable design.
• Temp is raised so cooling required.
• Monodisperse emulsion of low particle size
(1nm).
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3-Ultrasonic Homogenizers (Ultrasonifiers)
• Utilizes high-intensity ultrasonic waves
which generate intense shear and pressure
gradients within a material that disrupt the
droplets mainly due to cavitational effects.

• A stream of fluid is made to pass through an

orifice at modest pressure (150-350psi) and
impinge on a sharp-edged blade, which
causes the blade to rapidly vibrate.

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• Thus generating an intense ultrasonic field
that breaks up any droplets in its immediate
vicinity due to a combination of cavitation,
shear, and turbulence.

• Can be used for the continuous production of

emulsions, it can generate very small droplets
(lab scale), and it is more energy efficient
than high-pressure valve homogenizers.
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 4-Colloid Mills
• To homogenize medium- and high viscosity
liquids.
• The liquids to be homogenized are fed into the
colloid mill in the form of a coarse emulsion,
rather than as separate oil and aqueous phases.
• Because it is much more efficient at reducing the
size of the droplets in a preexisting emulsion
(secondary homogenization) than at
homogenizing two separate phases (primary
homogenization).
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• Liquid fed into the homogenizer and flows
through a narrow gap between two disks:
• the rotor (a rotating disk) and the stator (a
static disk).
• The rapid rotation of the rotor generates a
shear stress in the gap which causes the
larger droplets to be broken down into
smaller ones.
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• The intensity of the shear stresses can
be altered by
i. varying the thickness of the gap between
the rotor and stator (from about 50 to
1000 μm).
ii. varying the rotation speed (from about
1000 to 20,000 rev min–1)
iii. or by using disks that have roughened
surfaces or interlocking teeth.
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• Droplet disruption can also be enhanced by
increasing the length of time the emulsion
spends in the colloid mill, either by decreasing
the flow rate or by passing the emulsion through
the device a number of times.
• Colloid mills are more suitable for homogenizing
intermediate- and high-viscosity fluids than high-
pressure valve or ultrasonic homogenizers.

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• Typically, they can be used to produce
emulsions with droplet diameters between
about 1 and 5 μm.
• Operate on the principle of high shear,
developed b/w the rotor and stator.
• Can be used for Comminution of solids,
dispersion of suspensions having poorly
wetted solids and viscous emulsions.
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 5- Microfluidization
• Technique which is capable of creating
emulsions with extremely small droplet sizes
directly from the individual oil and aqueous
phases.
• Separate streams of the oil and aqueous
phases are accelerated to a high velocity and
then made to simultaneously impinge on a
surface, which causes them to be intermingled
with each other and broken up into droplets.

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• Extremely small emulsion droplets can be
produced by recirculating an emulsion
through the microfluidizer a number of
times.

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 6- Membrane Homogenizers
• Emulsion is formed by forcing one immiscible liquid
into another through a glass membrane which
contains a uniform pore size.
• The size of the droplets formed depends on the
diameter of the pores in the membrane and the
interfacial tensions between the oil and water
phases.
• Membranes can be manufactured with different pore
diameters so that emulsions with different droplet
sizes can be produced.
• The membrane must be sufficiently strong so that it
is not broken by the pressures applied to the fluids
during homogenization.
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• The membrane technique can be used as
either a batch or a continuous process.
• Ability to produce emulsions with very
narrow droplet size distributions and the
fact that they are highly energy efficient
because much less energy is lost due to
viscous dissipation.
• Emulsions with mean droplet sizes
between about 0.3 and 10 μm can be
produced using this technique.
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 Emulsion Stability
• “Emulsion stability” refers to the ability of an
emulsion to resist changes in its properties over
time – the more stable the emulsion, the more
slowly its properties change.
• An emulsion may become unstable due to a
number of different types of physical and chemical
processes.
• In addition to the physical and chemical processes
there are also various biochemical, and
microbiological processes that can also affect their
shelf life and quality.
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• Crucial to be clear about which of these
mechanisms are important in the system
under consideration.

• Physical instability results in an alteration in

the spatial distribution or structural
organization of the molecules, whereas
chemical instability results in an alteration in
the chemical structure of the molecules.

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• Creaming, flocculation, coalescence, partial
coalescence, phase inversion, and Ostwald
ripening are examples of physical instability.
• Oxidation and hydrolysis are common
examples of chemical instability.

• On purely thermodynamic grounds the

emulsions are physically unstable.
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• Stable emulsion was defined as, “the
emulsion that would maintain the same
number of sizes of particles of the
dispersed phase per unit volume of
weight of the continuous phase.”
• In considering the “stability” of an emulsion,
it is extremely important to distinguish
between its thermodynamic stability and its
kinetic stability.
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• Thermodynamics tells us whether or not a given
process will occur, whereas kinetics tells us the
rate at which it will proceed if it does occur.
• Emulsions are thermodynamically unstable
systems and will eventually break down if they
are left long enough.
• Differences in kinetic stability are largely
responsible for the diverse range of properties
exhibited by different emulsions.

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• Free energy change associated with emulsion
formation determines whether or not an emulsion is
thermodynamically stable, but it does not give any
indication of the rate at which the properties of an
emulsion change with time, the type of changes
which occur, or the physical mechanism(s)
responsible for these changes.
• Information about the time dependence of emulsion
stability is particularly important for products which
retain their desirable properties for a sufficiently
long time under a variety of different environmental
conditions.
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• Scientists are usually more interested in the
kinetic stability of emulsions, rather than their
thermodynamic stability.
• An emulsion which creams up or creams down
may sill be acceptable as long as it can be
reconstituted by modest shaking.
• Stability therefore is defined on the objective
basis rather than subjective.
• To describe the Subjective evaluation of stability
a term Shelf life is used.

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 Instability symptoms
• After preparation, time and temp dependent
processes occur to result in its separation.
Following are important processes involved in
instability of emulsions;
1. Creaming/Sedimentation.
2. Flocculation.
3. Coalescence.
4. Ostwald Ripening.
5. Phase Separation.
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 1-Creaming/Sedimentation
• Creaming and sedimentation are both forms
of gravitational separation.
• The droplets in an emulsion have a different
density to that of the liquid which surrounds
them, and so a net gravitational force acts
upon them.
• If the droplets have a lower density than the
surrounding liquid, they have a tendency to
move upward, which is referred to as
creaming.
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• if they have a higher density than the
surrounding liquid, they tend to move
downward, which is referred to as
sedimentation.
• If creaming occurs without any aggregation,
the emulsion can be reconstituted by
shaking/mixing.

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• Despite some short comings Stokes equation is used to
understand this process.
i. Creaming is a function of the square root of the radius of
the droplet – larger particles cream quickly as compared
to smaller.
ii. Larger aggregates formed by coalescence or flocculation
favor creaming while the smaller the particles size of the
emulsion the lower the chances of creaming.
iii. No creaming is possible if specific gravities of the two
phases are equal.
iv. Rate of creaming is inversely proportional to the
viscosity. Increased viscosity of the external phase is
associated with an increased shelf life.
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 Prevention
1. Minimize density difference.
2. Reduce droplet size.
3. Increasing viscosity of the continuous
phase.
4. Increasing droplet concentration.
5. Preventing the droplets from flocculating.

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 2- Flocculation
• Flocculation of dispersed phase may occur
before, during or after creaming.
• Reversible aggregation of droplets of
internal phase in the form of 3 dimensional
clusters.
• Flocculation is the process whereby two or
more droplets come together to form an
aggregate in which the droplets retain their
individual integrity.
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• Flocculation can only occur when the
mechanical or electrical barrier is sufficient
to prevent coalescence.
• The interfacial film and the individual
droplets remain intact.
• Reversibility of the process depends on
strength of the interaction b/w the particles
which are dependent on chemical nature of
emulsifier, phase volume ratio and
concentration of the dissolved substances.
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 Prevention
• Rate at which flocculation proceeds can be
controlled by manipulating the droplet collision
frequency.
• The rate at which droplets encounter each other
in an unstirred emulsion can be reduced by;
i. Increasing the viscosity of the continuous phase.
ii. By regulating the colloidal interactions between
the droplets.
iii. Designing an emulsion in which the repulsive
interactions between the droplets are
significantly greater than the attractive
interactions.
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 3- COALESCENCE
• Two or more liquid droplets merge together to
form a single larger droplet – leads to complete
separation.
• In oil-in-water emulsions, coalescence
eventually leads to the formation of a layer of oil
on top of the material, which is referred to as
oiling off.
• In water-in-oil emulsions, it leads to the
accumulation of water at the bottom of the
material.
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• Occur when the droplets are close to each other
and the interfacial membranes are disrupted.
• Mechanical strength of the interfacial barrier is
the main factor which prevents coalescence.
• Formation of a thick interfacial film from
macromolecules or particulate solids can assure
good shelf life and absence of coalescence.
• Variety of gums and proteins are used as
auxiliary emulsifiers or sometimes even as
primary emulsifiers.

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 Prevention
• Coalescence rate can be decreased by
i. Reducing the length of time that droplets are in
close contact.
ii. Decreasing their collision frequency.
iii. Ensuring that they do not flocculate, and
preventing them from forming a concentrated
layer at the top (or bottom) of an emulsion due
to creaming (or sedimentation).
iv. By prevention of membrane disruption.
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 4- OSTWALD RIPENING
• Ostwald ripening is the process whereby
large droplets grow at the expense of
smaller ones because of mass transport of
dispersed phase from one droplet to
another through the intervening
continuous phase.
• Important in oil-in-water emulsions which
contain more water-soluble lipids.

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 5- PHASE INVERSION
• Phase inversion is the process whereby a
system changes from an oil-in-water emulsion to
a water-in-oil emulsion or vice versa,
• Phase inversion is usually triggered by some
alteration in the composition or environmental
conditions of an emulsion (e.g., dispersed-phase
volume fraction, emulsifier type, emulsifier
concentration, solvent conditions, temperature,
or mechanical agitation).

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