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Content

Emulsions - Basic Intro

Stability of Emulsions

Manufacturing of Emulsions

Excipients used in pharmaceutical emulsions

Tests for Emulsion Type

Pharmaceutical Application

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 EMULSION- BASIC INTRO

 Section contains:
 Introduction
 Advantages and Disadvantages
 Types of emulsions
 Classification of Emulsions
 Theories of emulsification
 Additives for formulation of emulsion

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 What are Emulsions?

Dispersion
System

Emulsion Suspension
is a dispersion in is a two phased
which the dispersed system in which a
phase is composed finely divided solid is
of small globules of dispersed in a
a liquid distributed continuous phase of
throughout a vehicle solid, liquid, or gas.
in which it is
immiscible

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 Emulsions (Definition)
 An emulsion is a
thermodynamically unstable
system consisting of at least two
A.: Two immiscible liquids not
immiscible liquid phases one of emulsified
which is dispersed as globules B.An emulsion of phase B
in the other liquid phase dispersed in Phase A
stabilized by a third substance C.Unstable emulsion slowly
called emulsifying agent. separates.
D. The emulsifying agent
( black film) places it self on
-OR- the interface between phase A
and phase B and stabilizes the
emulsion.

 An emulsion is a dispersion in
which the dispersed phase is
composed of small globules of
a liquid distributed throughout a
vehicle in which it is immiscible.
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 Internal Phase or External Phase
in Emulsions
 The dispersed liquid is
known as the Internal or
Discontinuous phase.
The droplet phase is called
the dispersed phase or
internal phase

 whereas the dispersion

medium is known as
the External or Continuous
phase
The liquid in which droplets
are dispersed is
called the external or
continuous phase.
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 Advantages and Disadvantages
of Emulsions

Advantages Disadvantages

• Used to deliver low aqueous • Thermodynamically unstable

solubility • Difficult to manufacture
• To mask taste
• To Reduce Irritation
• Patients who have difficulty
swallowing solid-dosage
forms.
• Employed for total
parenteral nutrition.

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 Classification of Emulsion

Based on:

Oil in Water 0.2 – 50 mm

(O/W): Oil Macro emulsions
droplets (Kinetically
dispersed in Dispersed Stable)
water phase
0.01 – 0.2 mm
Water in Oil size of Micro emulsions
(W/O): Water Liq. droplets (Thermody-
droplets namically
dispersed in oil Stable)

Based on:

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 Types of Emuslion

Micro
emulsions
Multiple
emulsions Nano emulsions
Simple - thermodynamically
Oil-in-water-in-oil stable optically
emulsions transparent , mixtures
(Macro (O/W/O) of a biphasic oil –water
emulsions) Water-in-oil-in- system stabilized with
water surfactants
Oil-in-water (O/W)
Water-in-oil (W/O) (W/O/W)

- diameter greater than

0.1 μm

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 Theories of Emulsification

Surface Oriented- Interfacial

Tension Wedge Film theory
Theory Theory

mono molecular A film of

layers of emulsifying
emulsifying agent
by lowering of
agents are prevents the
interfacial
curved around contact and
tension
a droplet of the coalescing of
internal phase the dispersed
of the emulsion phase.

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 # Emulsifying Agents
 They are the substances added to an emulsion to prevent the coalescence of
the globules of the dispersed phase. They are also known as emulgents or
emulsifiers.
 They help in formation of emulsion by three mechanisms.
-Reduction in interfacial tension – thermodynamic stabilization
- Formation of a rigid interfacial film – mechanical barrier to coalescence
-Formation of an electrical double layer – electrical barrier to approach
of particles.
 Pharmaceutically acceptable emulsifiers must also :
 Be stable .
 Be compatible with other ingredients .
 Be non – toxic .
 Possess little odor , taste , or color .
 Not interfere with the stability
of efficacy of the active agent .

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 Classification of Emulsifiers

1 3
Finely divided solid
Synthetic
Surface active 2 particles
( Particulate film)
agents
( Monomolecular Semi synthetic and
films) natural
Hydrophilic colloids
( Multi-molecular
films)

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 1. Synthetic surface active agents
 Reduce interfacial tension and make the emulsion
thermodynamically more stable.
 To reduce the interfacial tension Oil droplets are
surrounded by a coherent monolayer of the surfactant
which prevents coalescence. If the emulsifier is ionized,
the presence of strong charge may lead to repulsion in
droplets and hence increasing stability. (Zeta
Potential) Adsorbed at oil/water interface to form.
 Form protective
monomolecular film
 Micelle formation

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 Classification of Surfactants

 Cationic
 Dissociated to produce +ly charged ion
 Used as preservative in topical formulations
 Quaternary ammonium compounds
 Nonionic
 The most populr in emulsion (o/w & o/w),
more stable and less toxicity
 Polyoxy ethylene fatty alcohol ethers
C12H25 (OCH2CH2)nOH
 Sorbitan fatty acid esters
 Polyoxyethylene sorbitan fatty acid esters
 Polyoxyethylene polyoxypopylene block
copolymers
 Lanolin alcohols and ethoxylated lanolin
alcohols
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Company Logo
  Anionic
 Cheap , more toxic zan others (Limited use in
topical because of this)
 Dissociated to negatively charged ion
 Soaps
-Mono valent
-Polyvalent
-Organic
 Sulphates
 Sulphonates (CH3(CH2)n CH2SO3 – Na+)

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2. Semi synthetic and natural surface
active agents
 Also known as Hydrocolloid Emulsifying agents
 Provide a protective sheath (Multi-molecular films )around
the droplets
 Impart a charge to the dispersed droplets ( so that they
repel each other, Zeta Potential
 Swell to increase the viscosity of the system ( so that
droplets are less likely to change.)

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 Classification of Hydrocolloidals
 Semisynthetic
Includes mainly cellulose derivatives
like sodium carboxymethyl cellulose, hydroxyl propyl
cellulose and methyl cellulose. They are used for
formulating o/w type of emulsions. They primarily act by
increasing the viscosity of the system. e.g., methyl
cellulose, hydroxypropyl cellulose and sodium carboxy
methyl cellulose.

 Natural
-Plant origin
Polysaccharides
(Acacia, tragacanth, agar, pectin, lecithin)
-Animal origin
Proteins ( Gelatin)
Lecithin
Cholesterol
Wool fat
Egg yolk
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 3. Finely divided solid particles
 Also known as Particulate films
 Form a particulate "film“ around dispersed particles.
 These particles rely on adsorption to interfaces and like
the hydrophilic colloids, function by forming a physical
barrier to coalescence.
 Finely divided solid particles that are wetted to some
degree by both oil and water act as emulsifying agents.
This results from their being concentrated at interface,
where they produce a particulate film around the
dispersed droplets to prevent coalescence.

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 Classification of Particulate films
 Colloidal Clays

• Bentonite,( Al2O3.4SiO2.H2O),
• Veegum ( Magnesium Aluminium silicate)
• Magnesium trisilicate

 Metallic hydroxides

• Magnesium hydroxide
• Aluminium hydroxide

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 # Auxiliary Emulsifiers
 Auxiliary (Secondary) emulsifying agents include those
compounds that are normally incapable themselves of
forming stable emulsion. Their main value lies in their
ability to function as thickening agents and thereby help
stabilize the emulsion.

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 # Antimicrobial Preservatives
The preservative must be :
 Less toxic
 Stable to heat and storage
 Chemically compatible
 Reasonable cost
 Acceptable taste, odor and color.
 Effective against fungus, yeast, bacteria.
 Available in oil and aqueous phase at effective
level concentration.
 Preservative should be in unionized state to
penetrate the bacteria.
 Preservative must no bind to other components
of the emulsion

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 - Examples of Antimicrobial agents
 Acids and acid derivatives - Benzoic acid - Antifungal
agent

 Aldehydes – Formaldehyde - Broad spectrum

 Phenolics - Phenol - Broad spectrum

Cresol
Propyl p-hydroxy benzoate

 Quaternaries -Chlorhexidine and salts - Broad spectrum

Benzalkonium chloride
sCetyl trimethyl ammonium bromide

 Mercurials -Phenyl mercuric acetate - Broad

spectrum

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 Determinants of the type of
emulsion

1. Phase volume of the internal phase;

2. The chemical properties of the film

surrounding the internal phase; and

3. Viscosity of the internal and external

phases

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 The chemical properties of the film
surrounding the internal phase
• surface-active agents that are predominantly
hydrophilic will form o/w emulsions, whereas
predominantly hydrophobic surfactants will
form w/o emulsions
• hydrophile–lipophile balance (HLB)
• High HLB, increased water solubility (3
to 6 creates w/o, sorbitan monooleate (e.g.
Span 80): HLB 4.3)
• HLB between 9 and 16 are used to
produce o/w emulsions (termed o/w
emulsifying agents), polyoxyethylene
sorbitan tristearate (e.g. Tween 65): HLB
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 Phase volume of the internal
phase
• Critical value
• The maximum volume that may be occupied
by the internal phase

• Dependent on Droplet size and shape

• 50% is ideal, but up to 74% it is possible for

o/w and 30 t0 40% for w/o, above this, there
will be coalescence because of compact pack

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 Viscosity of the internal and
external phases
• If the viscosity is high the diffusion of the
surface-active agent to the droplet surface will
be reduced, as viscosity is inversely
proportional to the diffusion coefficient of the
surface-active agents.

• If the viscosity of one phase is preferentially

increased, there is a greater chance of that
phase being the external phase of the emulsion.

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 STABILITY OF EMULSION

 Section contains:
 Physical Instability
Creaming
Flocculation
Phase Inversion

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 Emulsions are Kinetically Stable!

• Emulsification is not a spontaneous process and hence emulsions have

minimal stability.

• Reasons for instability can be understood from the nature of immiscible

phases and their interfacial properties.

When two immiscible liquids are agitated together

polar (aqueous) and non polar (oil) liquids are mixed together

one of the liquids forms small droplets and gets dispersed in the
other liquid

forms an emulsion.

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 Types - Physical Instability
 Types of Physical instability are:
 Flocculation
 Creaming or sedimentation
 Aggregation or coalescence
 Phase inversion

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 I - Flocculation
• Neighboring globules come closer to each other and form
colonies in the continuous phase. This aggregation of
globules is not clearly visible.
• This is the initial stage that leads to instability.
• Flocculation of the dispersed phase may take place before,
during or after creaming.

•The reversibility of
flocculation depends upon
strength of interaction between
particles as determined by:

a the chemical nature of

emulsifier,
b the phase volume ratio,
c. the concentration of dissolved substances, specially
electrolytes and ionic emulsifiers.

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 • The extent of flocculation of globules depends on
(a) globule size distribution.
(b) charge on the globule surface.
(c) viscosity of the external medium.
(a) Globule size distribution
• Uniform sized globules prevent flocculation.
• This can be achieved by proper size reduction process.

(b) Charge on the globule surface

• A charge on the globules exert repulsive forces with the neighboring
globules.
• This can be achieved by using ionic emulsifying agent, electrolytes etc.

(c) Viscosity of the external medium.

• If the viscosity of the external medium is increased, the globules become
relatively immobile and flocculation can be prevented.
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 • This can be obtained by adding viscosity improving agents (bodying agents
or thickening agents) such as hydrocolloids or waxes.
• Flocs slowly move either upward or downward leading to creaming.
• Flocculation is due to the interaction of attractive and repulsive forces,
whereas creaming is due to density differences in the two phases.

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 II - Creaming
• Creaming is the upward movement of dispersed droplets of
emulsion relative to the continuous phase (due to the
density difference between two phases).

• Creaming is the high concentration of globules at the

top or bottom of the emulsion.

• Droplets larger than 1 mm may settle preferentially to the

top or the bottom under gravitational forces.

• Creaming may also be observed on account of the difference

of individual globules (movement rather than flocs).

• It can be observed by a difference in color shade of the

layers.

• It is a reversible process, i.e., cream can be re-dispersed

easily by agitation, this is possible because the oil globules
are still surrounded by the protective sheath of the
emulsifier.
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 • Creaming results in a lack of uniformity of drug distribution. This leads to
variable dosage. Therefore, the emulsion should be shaken thoroughly
before use.

• Creaming is of two types, upward creaming and downward creaming

• Upward creaming, is due to the dispersed phase is less dense than the
continuous phase. This is normally observed in o/w emulsions. The velocity
of sedimentation becomes negative.

• Downward creaming occurs if the dispersed phase is heavier than the

continuous phase. Due to gravitational pull, the globules settle down. This is
normally observed in w/o emulsions.
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 • Since creaming involves the movement of globules in an emulsion,
Stokes’ law can be applied.

• Creaming is influenced by,

– Globule size
– Viscosity of the dispersion medium
– Difference in the densities of dispersed phase and dispersion medium.

• Creaming can be reduced or prevented by:

1.Reducing the particle size by homogenization. Doubling the diameter of oil

globules increases the creaming rate by a factor of four.
2.Increasing the viscosity of the external phase by adding the thickening
agents such as methyl cellulose tragacanth or sodium alginate.
3.Reducing the difference in the densities between the dispersed phase and
dispersion medium.
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 III- Coalescence (Cracking)

Aggregation, Coalescence, Breaking

• Aggregation : Dispersed particles come together but do not
fuse.
• Coalescence is the process by which emulsified particles
merge with each to form large particles.

• This type of closed packing induces

greater cohesion which leads to coalescence.
• It is Irreversible
• In this process, the emulsifier film around the globules is
destroyed to a certain extent. This step can be recognized by
increased globule size and reduced number of globules.

• Coalescence is observed due to:

 Insufficient amount of the emulsifying agent.
 Altered partitioning of the emulsifying agent.
 Incompatibilities between emulsifying agents.
 Incorrect selection of emulsifying agents.
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 Presence of incompatible excipients, A
Temperature, Microbial Spoilage 36
 • Phase volume ratio of an emulsion has a secondary
influence on the stability of the product and
represents the relative volume of water to oil in
emulsion.
• The major factor to prevent coalescence is the
mechanical strength of the interfacial film.

• Breaking:
• Breaking is the destroying of the film surrounding
the particles.
• Separation of the internal phase from the external
phase is called breaking of the emulsion.
• This is indicated by complete separation of oil and
aqueous phases, is an irreversible process, i.e.,
simple mixing fails. It is to re-suspend the globules
into an uniform emulsion.
• In breaking, the protective sheath around the
globules is completely destroyed and oil tends to
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coalesce.
 IV- Phase Inversion
• This involves the change of emulsion type from o/w to w/o or vice versa.
• Related with phase volume (Critical Value)
• When we intend to prepare one type of emulsion say o/w, and if the final
emulsion turns out to be w/o, it can be termed as a sign of instability.

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 MANUFACTURING OF EMULSION

 Section contains:
 Extemporaneous Methods
 Large Scale Methods

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 Extemporaneous Methods
Emulsification process can be carried out by four methods
mainly:

4 parts (volumes) of oil

2 parts of water
1 part of gum 4:2:1 method Dry Gum Method
4 parts (volumes) of oil
2 parts of water
1 part of gum Wet Gum Method
emulsion from volatile oils or
oleaginous substance of low
viscosity. powdered acacia +
2 parts of oil Forbes Bottle Method
hand homogenizer, which
forces the emulsion
through a very small
orifice, reducing the
dispersed droplet size to
Auxiliary Method
about 5 microns or less

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 Large Scale Methods

Physical parameters affecting the droplet size distribution ,

viscosity, and stability of emulsion:

 Location of the emulsifier,

 method of incorporation of the phases,
 the rates of addition ,
 the temperature of each phase and
 the rate of cooling after mixing of the phases considerably

Energy may be supplied in the form of:

 Heat
 Homogenization
 Agitation

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 Heat :
 Emulsification by vaporization
 Emulsification by phase inversion
 Low energy emulsification

Mechanical equipment for emulsification (Agitation)

Equipements

Agitators

Mechanical Propeller Colloid Ultra-

stirrers mixers mills sonifiers

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  Mechanical Stirrers

 An emulsion may be stirred

by means of various impellers
mounted on shafts, which are
placed directly into the
system to be emulsified.

 This is used for mixing,

suspending, milling,
dispersing, disintegrating
solids etc. & reduces batch
time. It consists of stator and
rotor assembly. The rotor
rotates inside the stator
assembly which is fixed with
three tie rods to the motor.

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  Propeller Mixers

 Simple top entering propeller mixers are adequate

for routine development work in the laboratory and
production.

 The degree of agitation is controlled by propeller

rotation but the pattern of liquid flow and resultant
efficiency of mixing are controlled by the type of
impeller, its position in the container, the presence
of baffles, and the general shape of the container.
These stirrers can not be used when :
vigorous agitation is needed,
extremely small droplets are needed.

 Foaming at high shear rates must be avoided.

 These mixers may have paddle blades, counter

rotating blades or planetary blades .
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 Major Types…
Turbine Type Mixers Homogenizers
 If more vigorous agitation is  In homogenizers the dispersion
required or viscosity is more , of two liquids is achieved by
forcing their mixture through a
turbine type mixers can be small inlet orifice at big
used. pressures.
 Homogenizers can be made
with more than one emulsifying
stage, and it is possible to
recycle the emulsion through
the homogenizer more than one
time.
 Homogenizers raise the temp.
of the emulsion, hence cooling
may be required.
 It can be used when a
reasonably mono disperse
emulsion of small droplet size (
1 nm) is required.
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  Colloid Mills

 They operate on principle of high shear

which is normally generated between
rotor and stator of the mill.
 Colloid mill consists of a fixed stator
plate and a high speed rotating rotator
plea.
 Material drawn or pumped through an
adjustable gap set between the rotor and
stator is homogenized by the physical
action and he centrifugal force is created
by high rotation of the rotor which
operates within 0.005 to0.010 inch of the
stator.

ROTOR AND
STATOR

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  Ultrasonifiers
 Ultrasonic energy s used to produce
pharmaceutical emulsions.
 These transduced piezoelectric
devices have limited output and are
expensive.
 They are useful for laboratory
preparation of emulsions of
moderate viscosity and extremely
low particle size.
 Commercial equipment is based n
principle of Pohlmn liquid whistle.
The dispersion is forced through an
orifice at modest pressure and is
allowed to impinge on a blade. The
pressure range is from 150-350 psi .
This pressure causes blade to
vibrate rapidly to produce an
ultrasonic note. When the system
reaches a steady state, a cavitational
field is generated at the leading edge
of the blade and the pressure
fluctuations of approx. 60 tones psi
can be achieved in commercial
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 TESTS FOR EMULSION TYPE

Emulsion Type and Means of Detection

Dilution
Refractive index
Conductivity Tests measurement

Dye-solubility Filter paper

Emulsion Type (W/O or O/W emulsions)

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 Dilution Test
 In this test the emulsion is diluted either with oil or water. If the
emulsion is o/w type and it is diluted with water, it will remain stable
as water is the dispersion medium" but if it is diluted with oil, the
emulsion will break as oil and water are not miscible with each
other. Oil in water emulsion can easily be diluted with an aqueous
solvent whereas water in oil emulsion can be diluted with a oily
liquid.

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 Conductivity Test

 The basic principle of this test is

that water is a good conductor of
electricity. Therefore in case of o/w
emulsion, this test will be positive
as water is the external phase.

‘In this test, an assembly is

used in which a pair of
electrodes connected to an
electric bulb is dipped into an
emulsion. If the emulsion is
o/w type, the electric bulb
glows.’

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 Dye-Solubility Test
 In this test an emulsion is mixed with a water soluble dye (amaranth)
and observed under the microscope. If the continuous phase
appears red, it means that the emulsion is o/w type as water is in the
external phase and the dye will dissolve in it to give color. If the
scattered globules appear red and continuous phase colorless, then
it is w/o type. Similarly if an oil soluble dye (Scarlet red C or Sudan
III) is added to an emulsion and the continuous phase appears red,
then it is w/o emulsion.

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 Ref. Index & Filter paper Test
Fluorescence Test:

 If an emulsion on exposure to ultra-

violet radiations shows continuous
fluorescence under microscope,
then it is w/o type and if it shows
only spotty fluorescence, then it is
o/w type.

Cobalt Chloride Test:

 When a filter paper soaked in

cobalt chloride solution is dipped in
to an emulsion and dried, it turns
from blue to pink, indicating that the
emulsion is o/w type.

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 PHARMACEUTICAL APPLICATIONS
Emulsions can be used for following dosage forms:
Emulsions are used for administering drugs orally due to following
reasons :
Oil a.More palatable : Objectionable taste or texture of medicinal agents
gets masked.
Products b.Better absorption : Due to small globule size, the medicinal agent gets
absorbed faster.

a. I/V route :
Lipid nutrients are emulsified and given to patients by i/v rout. Such
O/W emulsions have particle size less than 100 nm.
b. Depot injections :
Parenteral W/o emulsions are used to disperse water soluble antigenic materials
in mineral oil for i/m depot injection.

O/W emulsions are more acceptable as water washable

drug bases for cosmetic purposes.
Topical W/O emulsions are used for treatment of dry skin.
Products Emulsions have following advantages when used for topical
purpose:
a. Patient acceptance
b. washable character,
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Acceptable A 53
d. Less greasiness.
 Excipients used in pharmaceutical
emulsions
• Emulsifying agent
• Vehicle
• Aqueous (Usually purified water) and oil
phase (vegetable oils, e.g. cottonseed oil,
arachis oil, almond oil)
• Alternative non-aqueous phases;
• petrolatum and mineral oil
• Used as internal or external phase

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 • Isopropyl myristate
• Used as internal or external phase
• Antioxidants
• To enhance stability of the API and the oil
phase, not to oxidize
• flavours and sweeteners
• viscosity modifiers
• preservatives

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