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By: Saleem Mansoor
 Definition
 Particle Size
 Composition
 Emulsifying Agent
 Emulsification Equipment
 Types Of Emulsion
 Stability of Emulsions
 Preparation of Emulsion
Definition
An emulsion may be defined as thermodynamically
unstable biphasic system consisting of two immiscible
liquids, one of which (the dispersed phase) is finely and
uniformly dispersed as globules throughout the second
phase (the continuous phase) stabilized with emulsifying
agent.
Particle Size
The particle size of the dispersed phase commonly ranges
from 0.1 to 100 μm.
Composition
 Internal/Discontinuous/Dispersed phase
 External/Continuous phase
 Emulsifying agent
Emulsifying Agent
Emulsifier or surface active agent (SAA) is molecule
which has two parts, one is hydrophilic and the other is
hydrophobic. It should be:
 stable chemically
 non toxic
 non irritant
 suitably low in colour, odour and taste
 inexpensive
Mechanism of emulsifying agent:
Mechanism of action of emulsifying agents depends upon the
formation of film they form at the interface of two phases.
There are three types of films formed by emulsifying agents
Monomolecular films:
Emulsifying agents with stabilizing action form
monolayer at the oil-water interface. This monolayer
prevents coalescence of droplets.
The functions of surface active agents to provide stability
to dispersed droplets are as following:
 Reduction of the interfacial tension.
 Form coherent monolayer to prevent the coalescence of
two droplets when they approach each other.
 Provide surface charge which cause repulsion between
adjust particles.
Multi molecular films:
Multi molecular films around the droplets of dispersed
phase are formed by hydrophilic colloids. They act as
coats around the droplets making them highly resistant
to coalescence. They have the ability of swelling
 Hydrophilic colloids form multi molecular adsorption at
the oil/ water interface. They have low effect on the
surface tension.
 Their main function as emulsion stabilizers is by making
coherent multi-molecular film. This film is strong and
resists the coalescence. They have, also, an auxiliary
effect by increasing the viscosity of dispersion medium.
Solid particle films:
Small solid particles like bentonite, veegum, magnesium
hydroxide, aluminum hydroxide and magnesium
trisilicate, that are wetted to some degree by both oil and
water can act as emulsifying agents. This results from
their being concentrated at the interface, where they
produce a particulate film around the dispersed droplets
to avoid coalescence
 Particles that are wetted preferentially by water from o/w
emulsion, whereas those wetted more by oil form w/o
emulsion
 Note that they are very rare to use and can affect rheology
of the final product
 Size of the particle is very important, larger particles can
lead to coalescence
Emulsification equipments:
Various types of equipments are available for
emulsification on laboratory scale and commercial scale.
Usually equipment for emulsification is selected on the
basis of resulting emulsion.
 Small scale processing: For the laboratory scale or
prescription department emulsification of fixed/volatile
oils, the most frequently used equipments are Wedgwood
or porcelain mortars and pestles.
Shaker mixers/agitators:
In shaker mixers for small scale production, the material in
the container is agitated by oscillator, whereas for large scale
production, the material in the container is agitated by rotary
movement similar to that of ball mills
Propeller mixers:
Large and small scale production of emulsion is often made
conveniently with the help of propellant mixers operating in
suitable mixing container. Propellant mixers are generally
used for low viscosity emulsion preparation and they can be
rotated at a speed of about 8000 RPM.
Turbine mixers:
Turbine mixers are used for mixing the high viscosity
emulsions. They are rotated at a slow rate as compared to the
propellant mixers. They are provided generally in a circular
disc impeller attachment to short straight or curved blades.
Homogenizers:
High pressure homogenizers are provided with a high
pressure pump and homogenizing nozzle. The high
pressure pump raises the pressure up to 50 to 500. During
emulsification, the dispersion of two liquids is carried out
by forcing them through a small orifice at a high pressure
.The rotor/stator assembly of the homogenizer consists of a
rotor with blades and a stator with openings. As the rotor
rotates, a vacuum is created drawing the liquid in and out
of the assembly, resulting in liquid circulation. The size of
the dispersed phase is reduced;
1. Due to the mechanical collision against the walls of
Homogenizer because of high liquid acceleration and
2. Due to the sheer force occurring within the gap between
rotor and stator
Ultrasonifiers:
Their mechanism of work is that the dispersion is forced
through an orifice at a medium pressure of 150 to 350 psi
and is allowed to collide upon a blade.
Ultrasonifiers provide an easy way of agitation for the
laboratory scale preparation of constant and reproducible
oil-in-water (o/w) emulsions
Colloid mills:
Colloid mills are suitable for the preparation of emulsions
on a continuous basis. Due to intense shearing force, the
emulsions produced by colloid mills are of very small
globule size Colloid mills are mostly used for the milling of
solids and for the dispersion of very poorly wetable
suspensions; however, colloid mills are very useful for the
preparation of relatively high viscous emulsions
Whisks/churns:
These are used for emulsion preparation involving the
agitation of emulsion ingredients by blenders fitted in the
container. Sometime, the containers may be fitted with a
jacket if heating/cooling effects are required.
Micro-fluidizers:
For the production of very fine particles, micro-fluidizers
are employed. Micro-fluidizers consist of interaction
chambers with micro-channels. During emulsion
processing, the emulsion is subjected to a high velocity
through the micro-channels of the interaction chamber;
thus, the particles are subjected to high shear, uproar,
collision and cavitations.
General Types of Pharmaceutical Emulsions:
1) Lotions
2) Liniments
3) Creams
4) Ointments
5) Vitamin drops
Emulsions are Divided into:
 Primary emulsion: containing one internal phase, for
example, oil-in-water emulsion (o/w) and water-in-oil
emulsion (w/o).
 Secondary emulsion= multiple-emulsion:
It contains two internal phase, for instance, o/w/o or
w/o/w. It can be used to delay release or to increase the
stability of the active compounds.
Emulsion Type and Means of Detection:
By use of naked eye, it is very difficult to differentiate
between o/w or w/o emulsions. Thus, the four following
methods have been used to identify the type of emulsions.
1) Dilution Test:
based on the solubility of external phase of emulsion.
- o/w emulsion can be diluted with water.
- w/o emulsion cannot be diluted with oil.
Few drops
of emulsion
Few drops
of water Water distribute
uniformly
Water separate
out as layer
O/W emulsion
W/O emulsion
Conductivity Test:
water is good conductor of electricity whereas oil is non-
conductor. Therefore, continuous phase of water runs
electricity more than continuous phase of oil.
Electrode
Bulb
Emulsion
= Bulb glows with O/W
= Bulb doesn’t glow with W/O
Dye-Solubility Test:
 Water-soluble dye will dissolve in the aqueous phase.
 Oil-soluble dye will dissolve in the oil phase.
Fluorescence test:
Oils give fluorescence under UV light, while water doesn’t.
Therefore, O/W emulsion shows spotty pattern while W/O
emulsion fluoresces.
Stability of emulsions
A very important parameter for emulsion products is their
stability;
The instability of emulsion may be classified into four
phenomenon:
 Flocculation
 creaming
 coalescence and breaking
 Phase inversion
Flocculation:
It is the association of small emulsion particles to form large aggregate
which is redispersable upon shaking. It is a reversible process in which the
droplets remain intact. Flocculation is considered as the precursor of
coalescence. This is because the presence of excess surfactant in the
continuous phase of an emulsion can lead to flocculation of emulsion
droplets. The flocculation of emulsion droplets by excess surfactant occurs
because of the so called "depletion effect". The depletion mechanism can
be explained as, a system containing excess surfactant in the form of
micelles, when the dispersed emulsion droplets approach each other to
distances closer than the diameter of the surfactant micelles, segregation
of micelles from the inter-particle space that occurs because of the loss in
configurational entropy of the micelles. This phenomenon results in an
attractive force between the droplets due to the lowering of osmotic
pressure in the region between the droplets, and accordingly, flocculation
of droplets occur.
Creaming:
Creaming is the phenomenon in which the dispersed phase
separates out, forming a layer on the top of the continuous phase.
It is notable that in creaming, the dispersed phase remains in
globules state so that it can be re-dispersed on shaking. Creaming
can be minimized if the viscosity of the continuous phase is
increased.
O/W emulsions generally face upward creaming when the
globules of the dispersed phase are less dense than the continuous
phase. In contrast, W/O emulsions face downward creaming when
the globules of the dispersed phase are denser than the continuous
phase.
Coalescence (synonyms: breaking or cracking):
A more subtle type of emulsion instability, coalescence occurs when the
mechanical or electrical barrier is insufficient to prevent the formation of
progressively larger droplets. Stabilization against coalescence may be
achieved by the addition of high boiling point or high molecular weight
components to the continuous phase. Newman (1914) and Schulman and
Cockbain (1940) experimentally concluded that W/O emulsions are
formed only when the film of emulsifying agent in the interface is
uncharged and rigid as a result of complex formation. They were of the
view that a W/O emulsion cannot be stabilized against flocculation by
charge on the dispersed phase of water droplets, because an electric
diffuse layer cannot be built up as oil being a nonionizing medium. A
surface potential considerably higher than 25 mv is not sufficient to
stabilize the droplets of dispersed phase with a radius ≥1 μ against
flocculation. This is because of the high sedimentation velocities
Stability of W/O emulsions against coalescence
According to Newman (1914) and Schulman and Cockbain (1940) a
charged film is not able to prevent coalescence, because due to the
repulsion between emulsifying molecules in the interface, no interlinked
solid thick film can be formed
Phase inversion:
In this w/o is converted to o/w and vice versa.
METHODS OF PREPARATION OF EMULSIONS
Emulsification process
Milk is a natural emulsion, which consists of fatty globules
surrounded by a layer of casein, suspended in water. The
theory of emulsification is based on the study of milk. When a
pharmaceutical emulsion is to be prepared the principal
consideration is the same as that of milk
General method
Generally, an O/W emulsion is prepared by dividing the oily
phase completely into minute globules surrounding each
globule with an envelope of emulsifying agent and finally
suspends the globules in the aqueous phase. Conversely, the
W/O emulsion is prepared by dividing aqueous phase
completely into minute globules surrounding each globule
with an envelope of emulsifying agent and finally suspending
the globules in the oily phase
1) Continental and dry gum method
Extemporaneously emulsions are usually made by
continental or dry gum method. In this method, the emulsion
is prepared by mixing the emulsifying agent (usually acacia)
with the oil which is then mixed with the aqueous phase.
Continental and dry gum methods differ in the proportion of
constituents:
4 : 2 : 1
oil : water: gum
Primary Emulsifier is triturated with the oil in perfectly dry
porcelain mortar
2 parts of water are added at once triturate immediately,
rapidly and continuously (until get a cracking sound).
2) Wet gum method
In this method, the proportion of the constituents is same as those
used in the dry gum method; the only difference is the method of
preparation. Here, the mucilage of the emulsifying agent (usually
acacia) is formed. The oil is then added to the mucilage drop by
drop with continuous trituration.
3) Bottle or Forbes Bottle Method
Extemporaneous preparation for volatile oils or oil with low
viscosity gum + 2 parts of oil (dry bottle) shake water (volume
equal to oil)is added in portions and shake.
4) Beaker Method
Oil phase: heated about 5-10 degree above the highest melting
point of ingredient (water bath) Water phase: heated to the same
temperature of Oil phase (water bath) Add internal phase into
external phase, mix, constant agitation being provided throughout
the time of addition
Caution: - not to heat the phase above 85 degree- rate of cooling
determining the final texture and consistency.
5) Phase inversion method
In this method, the aqueous phase is first added to the oil
phase so as to form a W/O emulsion. At the inversion point,
the addition of more water results in the inversion of
emulsion which gives rise to an O/W emulsion.
6) Membrane emulsification method
It is a method, which is based on a novel concept of
generating droplets “drop by drop” to produce emulsion.
Here, a pressure is applied direct to the dispersed phase
which seeps through a porous membrane into the continuous
phase and in this way the droplets formed are then detached
from the membrane surface due to the relative shear motion
between the continuous phase and membrane surface.
THEORIES OF EMULSIFICATION
The most well-known theories include surface tension theory, the oriented wedge
theory and the interfacial film theory.
Surface tension theory
In accordance to surface tension theory of emulsification, the emulsifying agents
cause a reduction in the interfacial tension of the two immiscible liquids, reducing
the repellent force between the liquids and withdrawing the attraction of liquids
for their own molecules. In this way, the surfactants convert large globules into
small ones and avoid small globules from coalescing into large ones.
The oriented Wedge theory of emulsions
According to this theory the oil-like or non- polar ends of the emulsifying agents
turn towards the oil and the polar ends towards the polar liquid. The oriented
Wedge theory of emulsions indicates that if the non-polar end of the emulsifying
agent is smaller, the emulsion will be oil-in water (o/w) and if the polar end is
smaller, the emulsion will be water-in-oil (W/O)
The interfacial film theory
The interfacial film theory suggests that the emulsifying agents make an interface
between the two immiscible phases of the emulsion, surrounding the droplets of
the internal phase as a thin film. This film prevents the coalescence of the
dispersed phase.
Types of emulsion
1. MACRO EMULSIONS
A. Parenteral emulsions
B. Water-in-oil emulsions.
C. Oil- in-in-water /oral emulsions
D. Radio opaque
E. Fluorocarbon emulsion
2. MICRO EMULSION
3. NANO EMULSION
4. MULTIPLE EMULSION
5.GEL EMULSION
1) Macro Emulsions :
These emulsions comprise four possible types:
I - “oil-in-water” (O/W),
II- “water-in-oil” (W/O),
III-“water-in-water” (W/W), and
IV- “Oil-in-oil” (O/O).
Emulsions of the W/W type are formed from aqueous solutions of
mixtures of incompatible polymers. They include systems
containing polysaccharides, synthetic polymers, and proteins.
The O/O emulsions consist of incompatible organic solvents
stabilized by block copolymers with residues of differing
solubilities in the two components.
The O/W emulsions are administered orally as well as parenterally,
W/O emulsions are used mainly as diffusion barrier depots when
given intramuscularly.
Depending on their end use, emulsions vary considerably in
their composition, structure, and properties. Rheologically,
for example, emulsions range from Newtonian and non-
Newtonian liquids, including thixotropic systems, to gel-like
solids. Surfactants are necessary in formulating stable
emulsions of low viscosity and may be of low or high
molecular weight. The surface activity of low molecular
weight surfactants is sensitive to the composition of both
phases of the system, and it is necessary to have a range of
surfactants to match the hydrophilic-lipophilic balance (HLB)
of a particular surfactant to the emulsion composition
A. Parenteral Emulsions:
“Emulsions that are injected in the body for the purpose of mitigation,
cure and diagnosis of a disease is known as Parenteral emulsions”
Uses
 Injectable emulsions are used mainly for
 Lipids or lipid-soluble materials.
 nutritional purposes
 delivery of vaccines,
 as drug carriers
 Diagnostic agents.
Preparation of Parenteral Emulsions:
Parenteral emulsions are subject to two important constraints:
 particle size and
 Sterilization.
For intravenous emulsions, the particle size cannot be greater than 5µm
without risking emboli in the capillaries. Average particle size for fat
emulsions is less than 1µm
Method of preparation
Step1.
Uniform particle size is achieved by homogenization at high temperatures
under high pressure in homogenizer.
Step2.
The resulting homogenized product is then autoclaved at 110°C for 40 min.
Parenteral emulsions may be sterilized by filtration, provided the particle
size is small enough to pass the filter. Sterilization of individual
components and aseptic assembly is also feasible.
Application:
 Parenteral nutrition:
A major application of lipid emulsions is the delivery of fat in parenteral
nutrition. Fat is a concentrated source of energy and can supply essential
fatty acids.
 Carriers for drugs and as targeted delivery systems
The close resemblance of fat emulsion particles to chylomicrons, the
natural emulsion particles that transport ingested lipophiles such as
triglycerides into the lymphatic and circulatory systems, suggests that fat
emulsions can be used as carriers for drugs and as targeted delivery
systems.
 Prolonged release of drug
Emulsions can affect the metabolism of the drug, which can in turn affect
clearance of the particles from the blood. Positive prolonged release effects
have, however, been noted for progesterone and corticosteroids.
 Increased bioavailability
Intralipid has been used to incorporate valinomycin, an antitumor agent
and it was found that a 20-fold lower dose was sufficient to produce the
same effects as an aqueous suspension.
 Decreased toxicity
Amphotericin B administered as a lipid emulsion, in comparison with a
5% aqueous dextrose solution, gave a lower incidence of fever and
nephrotoxicity and was as effective.
Stability:
Instability of fat emulsions can arise from changes in particle size of
the oil droplets leading to creaming and coalescence, or from
changes in pH, hydrolysis of emulsifier, or oxidation of the oil.
Emulsions cause enhanced stability furnished by a non-aqueous
environment. Many drugs, including barbituric acid, diazepam, and
anesthetics, have been dissolved in the oil phase and administered
by all parenteral routes.
 B. Oil in water emulsion
“If the oil droplets are dispersed throughout the aqueous phase, the emulsion is
termed oil-in-water (O/W) with the help of emulsifying agent”.
Fats or oils for oral administration, either as medicaments in their own
right, or as vehicles for oil soluble drugs, are always formulated as oil in
water (O/W) emulsions.
Characteristics
 They are non greasy
 easily removable from the skin surface and
 they are used externally to provide cooling effect
 Used internally to also mask the bitter taste of oil.
 Water soluble drugs are more quickly released from O/W emulsion.
 O/W emulsion give a positive conductivity test as water
 External phase is a good conductor of electricity.
 The particle size of the dispersed phase commonly ranges from 0.1 to
100 µm
 Emulsifier stabilizes the system by forming a thin film and they is
present around the globules of dispersed phase
C. Water in oil emulsion
“A system in which the water is dispersed as globules in the oil
continuous phase with the help of emulsifying agent is termed
water-in-oil emulsion (W/O)”.
Characteristics
 Water-in-oil emulsions will have an occlusive effect by hydrating
the stratum corneum and inhibiting evaporation of eccrine
secretions.
 It do not give positive conductivity tests
 the external phase which is a poor conductor of electricity W/O
emulsion is also useful for cleansing the skin of oil soluble dirt
 they are greasy in texture although there greasy texture is not
always cosmetically acceptable
D. Radio opaque Emulsions
The substance which emits such radiation is called
radioactive and the process is called as radioactivity. For
therapeutic and diagnostic purposes they are referred as
‘Radiopharmaceuticals’. All radio opaque are not radio-
pharmaceutical unless they contain a radio isotope in their
structure or formula. The element like uranium, radium,
cobalt, phosphorous, iodine etc. are called radioactive
elements.
Development of nano-particulate systems exhibiting long
circulation times in the blood pool, loaded with X-ray
contrasting compounds, to be used as blood pool contrast
agents in computed tomography.
RADIO OPAQUE CONTRAST MEDIA:
Any agent or compound administrated to a patient to improve
the visualization of an organ or tissue is called a contrast
agent.
Certain inorganic agents like iodine or barium salts can act as
radio contrast media, by absorbing at soft tissues and these
tissues becomes capable of absorbing X-rays. The barium
sulphate salt is given to identify of ulcer in G.I.T. whenever
ulcer is formed, broken mucosa retains barium sulphate and
this spot (ulcer) is identified with the help of X-ray film. X-
rays are electromagnetic radiations of short wavelength and
have high penetrating power. The electrons of high atomic
number element can interact with X-rays. The relative
difference between the light and dark areas on a radiographic
image reflects is called radiographic contrast.
D. Flourocarbon emulsion:
The discovery that animals can survive breathing oxygen-saturated
silicones and certain perfluorinated liquids such as the isomers of
perfluorotetrahydrofuran (FC-75) suggested that such inert
substances might be useful as intravascular O2 and CO2 transporting
agents.
These are chemically inert synthetic molecules & are composed of
fluorine & carbon & have ability to dissolve many gases e.g O2, CO2
etc.
Mechanism Of Drug Release: After i.v administration, droplets of these
are taken up by reticulo-endothelial system, after which they are
broken down & are taken into blood from where droplets are
transported into lungs and excreted via inhalation. At present there is
no metabolism in humans.
 Applications:
 They are clinically evaluated as “Artificial oxygen carriers”.
 In future they will be used in the concept of ANH i.e acute normovalaemic
haemodilution, means it is used to augment oxygen delivery during
surgery.
 These are also used in treatment of diseases with compromised tissue
oxygenation such as cerebral ischemia, MI, emergency, trauma etc.
2) MICROEMULSION
Hoar and Schulman used the term micro emulsion (ME) in 1943 to
define a transparent system obtained by titrating a turbid oil - in -
water (o/w) emulsion with a medium chain alcohol, namely hexanol.
Since then the term has been used to describe systems comprising a
non polar component, an aqueous component, a surfactant, and a co-
surfactant. While a co-surfactant is usually present, a ME can be
formulated without a co-surfactant that is, using a single surfactant. It
is important to point out that the term ME was (and occasionally is)
used in the literature to describe various liquid crystalline systems
(lamellar, hexagonal, and cubic), surfactant systems (micelles and
reverse micelles), and even coarse emulsions that are micronized using
external energy (sub micrometer emulsions).
To avoid such confusion, Danielsson and Lindmann proposed the
following definition:
“Microemulsion is defined as a system of water, oil and amphiphile
which is optically isotropic and a thermodynamically stable liquid
solution.”
Structure and formation of microemulsion systems
A ME system can be one of three types depending on the
composition:
 Oil in water (o/w ME), in which water is the continuous medium;
 Water in oil (w/o ME), in which oil is the continuous medium, and
 Water - and - oil bicontinuous ME, in which almost equal amounts
of water and oil exist.
Phase Behavior:
The phase behavior of simple micro-emulsion systems comprising
oil, water and surfactant can be studied with the aid of ternary
phase diagram (at fixed pressure and temperature) in which each
corner of the diagram represents 100% concentration of the
particular component.
The relative amounts of these three components can be represented
in a ternary phase diagram. Gibbs phase diagrams can be used to
show the influence of changes in the volume fractions of the
different phases on the phase behavior of the system.
Hypothetical Phase Regions of Micro Emulsion Systems:
From above figure, we can see that,
 With high oil concentration surfactant forms reverse micelles
capable of solubilizing water molecules in their hydrophilic
interior.
 Continued addition of water in this system may result in the
formation of W/O microemulsion in which water exists as
droplets surrounded and stabilized by interfacial layer of the
surfactant / co-surfactant mixture.
 At a limiting water content, the isotropic clear region changes
to a turbid, birefringent one.
 Upon further dilution with water, a liquid crystalline region
may be formed in which the water is sandwiched between
surfactant double layers.
 Finally, as amount of water increases, this lamellar structure
will break down and water will form a continuous phase
containing droplets of oil stabilized by a surfactant / co-
surfactant (O/W microemulsions)
Applications:
1- Oral Drug Delivery :
Examples include Sendimmune neural which is commercial name for
Cyclosporin A.
Other examples include Paclitaxel & Simvastatin.
2- Transdermal Drug Delivery :
A diverse range of drug molecules such as ketoprofen, apomorphine, estradiol,
lidocaine, indomethacin and diclofenac, prostaglandin E 1 were incorporated
as ME.
3- Parenteral Drug Delivery :
Flubiprofen o/w ME systems were prepared and evaluated as vehicles for
parenteral drug delivery. These systems were formulated using POE 20
sorbitan mono- laurate (Tween 20) as the surfactant.
4- Ocular Drug Delivery :
Nanoemulsion is a type of emulsion sized between 20-200 nm with narrow
distributions. They are transparent or translucent with a bluish coloration. So,
the definition is different from that of sub-micron emulsions.
3) NANOEMULSIONS
Nanoemulsion is a type of emulsion sized
between 20-200 nm with narrow distributions.
These are very small sized as compared to simple
emulsions. The high pressure of 25000 to 40,000
psi is required for its formulation as compared to
simple emulsions which require 500 to 5000
psipressure.
These are thermodynamically unstable but
kinetically stable so they require high mechanical
energy for their preparation supplied from high
pressure homogenisers, microfluidizers, etc.
Applications of nano Emulsions:
1. Drug and gene delivery
2. Enhancement of skin permeation
3. Extended drug release
4. Antimicrobial activity
5. Medical applications:
 Parenteral route (propofol and diazepam)
 Ocular route (pilocarpine hydrochloride)
 Nasal route (peptide and vaccine)
 Topical route
4) MULTIPLE EMULSIONS
Multiple emulsions are also known as emulsions of emulsions,
liquid membrane system or double emulsion. The two major types
of multiple emulsions are the w/o/w and o/w/o double emulsions.
The most common multiple emulsions are of W/O/W types which
are widely used for pharmaceutical purposes.
Formulation:
Modified Two Steps Emulsification:
 In step 1→ water phase is added into oil + surfactant mixture with
low HLB → homogenization done at 9500 rpm/min for 15 min →
w/o emulsion is prepared.
 In step 2→w/o emulsion is added into water +surfactant with high
HLB → mechanical stirring done at 600 rpm/min for 30 min
→w/o/w multiple emulsion.
Phase Inversion Technique (One Step Technique):
An increase in volume concentration of dispersed phase
may cause an increase in the phase volume ratio, which
subsequently leads the formation of multiple emulsions. The
method typically involves the addition of an aqueous phase
containing the hydrophilic emulsifier [Tween 80] to an oil phase
consisted of liquid paraffin and containing lipophillic emulsifier
(Span80). A well-defined volume of oil phase is placed in a vessel of
pin mixer. An aqueous solution of emulsifier is then introduced
successively to the oil phase in the vessel at a rate of 5 ml/min,
while the pin mixer rotates steadily at 88 rpm at room temperature.
When volume fraction of the aqueous solution of hydrophilic
emulsifier exceeds 0.7, the continuous oil phase is substituted by
the aqueous phase containing a number of vesicular globules
among the simple oil droplets, leading to phase inversion and
formation of W/O/W multiple emulsion.
Application of multiple emulsions:
1) Multiple emulsions in cancer therapy
2) Vaccine/vaccine adjuvant
3) Oxygen substitute
4) Multiple emulsions in diabetes
Surfactant-coated insulin was dispersed in the oil by
ultra-sonification, this dispersion was mixed with the outer water phase
with a homogenizer.
5) As antidiabetic
Multiple emulsions of chloroquine, an anti-malarial agent has been
successfully prepared and had been found to mask the bitter taste
efficiently. Taste masking of chlorpromazine, an antipsychotic drug has
also been reported by multiple emulsions.
6) Drug over dosage treatment
This system could be utilized for the over dosage treatment by utilizing the
difference in the pH. For example Barbiturates, salicylates etc.
5) GEL EMULSIONS:
Gellified emulsions (Emulsion in gel) have emerged as one of the most intere
sting topical drug delivery and have dual control i.e as emulsion & as a gel.
Emulgel is emulsions, either of the O/W or W/O type, which are gelled by
addition of a gelling agent. Examples are antifungal agents.
This antifungal agent is Itraconazole, which has both antifungal and antibact
erial properties. It is applied locally in mild uncomplicated dermatophyte an
d other cutaneous infections.
Gellified Emulsion is stable one and better vehicle for hydrophobic or
Water insoluble drugs.
Oil/water emulsions are most useful as water washable drug bases and for ge
neral cosmetic purposes, while water/oil emulsions are employed more widel
y for the treatment of dry skin and emollient.
Preparation of gellified emulsion:
The Gel in formulations were prepared by dispersing Carbopol 934
(thickner and suspending agent)
in purified water with constant stirring at a moderate speed then
the pH are adjusted to 6 to 6.5 using Tri Ethanol Amine (TEA). The
oil phase of the emulsion wereprepared by dissolving Span 20 in
light liquid paraffin while the aqueous phase was prepared by
dissolving Tween 20 in purified water. Methyl and Propyl paraben
was dissolved in propylene glycol whereas drug (Itraconazole)
is dissolved in ethanol and both solutions was mixed with the aqueous
phase. Both the oily and aqueous phases were separately heated to
70° to 80°C; then the oily phase are added to the aqueous phase
with continuous stirring until cooled to room temperature.
And add Glutaraldehyde(as a sterilant) during of mixing of gel
and emulsion in 1:1 and to obtain the Gellified Emulsion.
Rheology & stability of emulsion:
Rheological properties are affected by both conc. & temp. Stability
of gel emulsion at room temperature is increased by addition of
NACl.
Applications:
Uses include;
1- These are used as antifungals to treat topical fungal infections e.g
itraconazol, miconazol nitrate emulsified gel.
2-Terbinafin emulsion gel is an under eye emulsion gel & is used for:
 Moisturising effect
 Provide comfort to delicate eye
 For skin repair
 To get rid of skin circles
 Provide protection against excessive dehydration.
Specialized pharmaceutical emulsions

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Specialized pharmaceutical emulsions

  • 2.  Definition  Particle Size  Composition  Emulsifying Agent  Emulsification Equipment  Types Of Emulsion  Stability of Emulsions  Preparation of Emulsion
  • 3. Definition An emulsion may be defined as thermodynamically unstable biphasic system consisting of two immiscible liquids, one of which (the dispersed phase) is finely and uniformly dispersed as globules throughout the second phase (the continuous phase) stabilized with emulsifying agent. Particle Size The particle size of the dispersed phase commonly ranges from 0.1 to 100 μm.
  • 4.
  • 5. Composition  Internal/Discontinuous/Dispersed phase  External/Continuous phase  Emulsifying agent Emulsifying Agent Emulsifier or surface active agent (SAA) is molecule which has two parts, one is hydrophilic and the other is hydrophobic. It should be:  stable chemically  non toxic  non irritant  suitably low in colour, odour and taste  inexpensive
  • 6. Mechanism of emulsifying agent: Mechanism of action of emulsifying agents depends upon the formation of film they form at the interface of two phases. There are three types of films formed by emulsifying agents Monomolecular films: Emulsifying agents with stabilizing action form monolayer at the oil-water interface. This monolayer prevents coalescence of droplets. The functions of surface active agents to provide stability to dispersed droplets are as following:  Reduction of the interfacial tension.  Form coherent monolayer to prevent the coalescence of two droplets when they approach each other.  Provide surface charge which cause repulsion between adjust particles.
  • 7. Multi molecular films: Multi molecular films around the droplets of dispersed phase are formed by hydrophilic colloids. They act as coats around the droplets making them highly resistant to coalescence. They have the ability of swelling  Hydrophilic colloids form multi molecular adsorption at the oil/ water interface. They have low effect on the surface tension.  Their main function as emulsion stabilizers is by making coherent multi-molecular film. This film is strong and resists the coalescence. They have, also, an auxiliary effect by increasing the viscosity of dispersion medium.
  • 8. Solid particle films: Small solid particles like bentonite, veegum, magnesium hydroxide, aluminum hydroxide and magnesium trisilicate, that are wetted to some degree by both oil and water can act as emulsifying agents. This results from their being concentrated at the interface, where they produce a particulate film around the dispersed droplets to avoid coalescence  Particles that are wetted preferentially by water from o/w emulsion, whereas those wetted more by oil form w/o emulsion  Note that they are very rare to use and can affect rheology of the final product  Size of the particle is very important, larger particles can lead to coalescence
  • 9. Emulsification equipments: Various types of equipments are available for emulsification on laboratory scale and commercial scale. Usually equipment for emulsification is selected on the basis of resulting emulsion.  Small scale processing: For the laboratory scale or prescription department emulsification of fixed/volatile oils, the most frequently used equipments are Wedgwood or porcelain mortars and pestles.
  • 10. Shaker mixers/agitators: In shaker mixers for small scale production, the material in the container is agitated by oscillator, whereas for large scale production, the material in the container is agitated by rotary movement similar to that of ball mills Propeller mixers: Large and small scale production of emulsion is often made conveniently with the help of propellant mixers operating in suitable mixing container. Propellant mixers are generally used for low viscosity emulsion preparation and they can be rotated at a speed of about 8000 RPM. Turbine mixers: Turbine mixers are used for mixing the high viscosity emulsions. They are rotated at a slow rate as compared to the propellant mixers. They are provided generally in a circular disc impeller attachment to short straight or curved blades.
  • 11. Homogenizers: High pressure homogenizers are provided with a high pressure pump and homogenizing nozzle. The high pressure pump raises the pressure up to 50 to 500. During emulsification, the dispersion of two liquids is carried out by forcing them through a small orifice at a high pressure .The rotor/stator assembly of the homogenizer consists of a rotor with blades and a stator with openings. As the rotor rotates, a vacuum is created drawing the liquid in and out of the assembly, resulting in liquid circulation. The size of the dispersed phase is reduced; 1. Due to the mechanical collision against the walls of Homogenizer because of high liquid acceleration and 2. Due to the sheer force occurring within the gap between rotor and stator
  • 12. Ultrasonifiers: Their mechanism of work is that the dispersion is forced through an orifice at a medium pressure of 150 to 350 psi and is allowed to collide upon a blade. Ultrasonifiers provide an easy way of agitation for the laboratory scale preparation of constant and reproducible oil-in-water (o/w) emulsions Colloid mills: Colloid mills are suitable for the preparation of emulsions on a continuous basis. Due to intense shearing force, the emulsions produced by colloid mills are of very small globule size Colloid mills are mostly used for the milling of solids and for the dispersion of very poorly wetable suspensions; however, colloid mills are very useful for the preparation of relatively high viscous emulsions
  • 13. Whisks/churns: These are used for emulsion preparation involving the agitation of emulsion ingredients by blenders fitted in the container. Sometime, the containers may be fitted with a jacket if heating/cooling effects are required. Micro-fluidizers: For the production of very fine particles, micro-fluidizers are employed. Micro-fluidizers consist of interaction chambers with micro-channels. During emulsion processing, the emulsion is subjected to a high velocity through the micro-channels of the interaction chamber; thus, the particles are subjected to high shear, uproar, collision and cavitations.
  • 14. General Types of Pharmaceutical Emulsions: 1) Lotions 2) Liniments 3) Creams 4) Ointments 5) Vitamin drops
  • 15. Emulsions are Divided into:  Primary emulsion: containing one internal phase, for example, oil-in-water emulsion (o/w) and water-in-oil emulsion (w/o).  Secondary emulsion= multiple-emulsion: It contains two internal phase, for instance, o/w/o or w/o/w. It can be used to delay release or to increase the stability of the active compounds.
  • 16. Emulsion Type and Means of Detection: By use of naked eye, it is very difficult to differentiate between o/w or w/o emulsions. Thus, the four following methods have been used to identify the type of emulsions. 1) Dilution Test: based on the solubility of external phase of emulsion. - o/w emulsion can be diluted with water. - w/o emulsion cannot be diluted with oil. Few drops of emulsion Few drops of water Water distribute uniformly Water separate out as layer O/W emulsion W/O emulsion
  • 17. Conductivity Test: water is good conductor of electricity whereas oil is non- conductor. Therefore, continuous phase of water runs electricity more than continuous phase of oil. Electrode Bulb Emulsion = Bulb glows with O/W = Bulb doesn’t glow with W/O
  • 18. Dye-Solubility Test:  Water-soluble dye will dissolve in the aqueous phase.  Oil-soluble dye will dissolve in the oil phase. Fluorescence test: Oils give fluorescence under UV light, while water doesn’t. Therefore, O/W emulsion shows spotty pattern while W/O emulsion fluoresces.
  • 19. Stability of emulsions A very important parameter for emulsion products is their stability; The instability of emulsion may be classified into four phenomenon:  Flocculation  creaming  coalescence and breaking  Phase inversion
  • 20. Flocculation: It is the association of small emulsion particles to form large aggregate which is redispersable upon shaking. It is a reversible process in which the droplets remain intact. Flocculation is considered as the precursor of coalescence. This is because the presence of excess surfactant in the continuous phase of an emulsion can lead to flocculation of emulsion droplets. The flocculation of emulsion droplets by excess surfactant occurs because of the so called "depletion effect". The depletion mechanism can be explained as, a system containing excess surfactant in the form of micelles, when the dispersed emulsion droplets approach each other to distances closer than the diameter of the surfactant micelles, segregation of micelles from the inter-particle space that occurs because of the loss in configurational entropy of the micelles. This phenomenon results in an attractive force between the droplets due to the lowering of osmotic pressure in the region between the droplets, and accordingly, flocculation of droplets occur.
  • 21. Creaming: Creaming is the phenomenon in which the dispersed phase separates out, forming a layer on the top of the continuous phase. It is notable that in creaming, the dispersed phase remains in globules state so that it can be re-dispersed on shaking. Creaming can be minimized if the viscosity of the continuous phase is increased. O/W emulsions generally face upward creaming when the globules of the dispersed phase are less dense than the continuous phase. In contrast, W/O emulsions face downward creaming when the globules of the dispersed phase are denser than the continuous phase.
  • 22. Coalescence (synonyms: breaking or cracking): A more subtle type of emulsion instability, coalescence occurs when the mechanical or electrical barrier is insufficient to prevent the formation of progressively larger droplets. Stabilization against coalescence may be achieved by the addition of high boiling point or high molecular weight components to the continuous phase. Newman (1914) and Schulman and Cockbain (1940) experimentally concluded that W/O emulsions are formed only when the film of emulsifying agent in the interface is uncharged and rigid as a result of complex formation. They were of the view that a W/O emulsion cannot be stabilized against flocculation by charge on the dispersed phase of water droplets, because an electric diffuse layer cannot be built up as oil being a nonionizing medium. A surface potential considerably higher than 25 mv is not sufficient to stabilize the droplets of dispersed phase with a radius ≥1 μ against flocculation. This is because of the high sedimentation velocities Stability of W/O emulsions against coalescence According to Newman (1914) and Schulman and Cockbain (1940) a charged film is not able to prevent coalescence, because due to the repulsion between emulsifying molecules in the interface, no interlinked solid thick film can be formed
  • 23. Phase inversion: In this w/o is converted to o/w and vice versa.
  • 24. METHODS OF PREPARATION OF EMULSIONS Emulsification process Milk is a natural emulsion, which consists of fatty globules surrounded by a layer of casein, suspended in water. The theory of emulsification is based on the study of milk. When a pharmaceutical emulsion is to be prepared the principal consideration is the same as that of milk General method Generally, an O/W emulsion is prepared by dividing the oily phase completely into minute globules surrounding each globule with an envelope of emulsifying agent and finally suspends the globules in the aqueous phase. Conversely, the W/O emulsion is prepared by dividing aqueous phase completely into minute globules surrounding each globule with an envelope of emulsifying agent and finally suspending the globules in the oily phase
  • 25. 1) Continental and dry gum method Extemporaneously emulsions are usually made by continental or dry gum method. In this method, the emulsion is prepared by mixing the emulsifying agent (usually acacia) with the oil which is then mixed with the aqueous phase. Continental and dry gum methods differ in the proportion of constituents: 4 : 2 : 1 oil : water: gum Primary Emulsifier is triturated with the oil in perfectly dry porcelain mortar 2 parts of water are added at once triturate immediately, rapidly and continuously (until get a cracking sound).
  • 26. 2) Wet gum method In this method, the proportion of the constituents is same as those used in the dry gum method; the only difference is the method of preparation. Here, the mucilage of the emulsifying agent (usually acacia) is formed. The oil is then added to the mucilage drop by drop with continuous trituration. 3) Bottle or Forbes Bottle Method Extemporaneous preparation for volatile oils or oil with low viscosity gum + 2 parts of oil (dry bottle) shake water (volume equal to oil)is added in portions and shake. 4) Beaker Method Oil phase: heated about 5-10 degree above the highest melting point of ingredient (water bath) Water phase: heated to the same temperature of Oil phase (water bath) Add internal phase into external phase, mix, constant agitation being provided throughout the time of addition Caution: - not to heat the phase above 85 degree- rate of cooling determining the final texture and consistency.
  • 27. 5) Phase inversion method In this method, the aqueous phase is first added to the oil phase so as to form a W/O emulsion. At the inversion point, the addition of more water results in the inversion of emulsion which gives rise to an O/W emulsion. 6) Membrane emulsification method It is a method, which is based on a novel concept of generating droplets “drop by drop” to produce emulsion. Here, a pressure is applied direct to the dispersed phase which seeps through a porous membrane into the continuous phase and in this way the droplets formed are then detached from the membrane surface due to the relative shear motion between the continuous phase and membrane surface.
  • 28. THEORIES OF EMULSIFICATION The most well-known theories include surface tension theory, the oriented wedge theory and the interfacial film theory. Surface tension theory In accordance to surface tension theory of emulsification, the emulsifying agents cause a reduction in the interfacial tension of the two immiscible liquids, reducing the repellent force between the liquids and withdrawing the attraction of liquids for their own molecules. In this way, the surfactants convert large globules into small ones and avoid small globules from coalescing into large ones. The oriented Wedge theory of emulsions According to this theory the oil-like or non- polar ends of the emulsifying agents turn towards the oil and the polar ends towards the polar liquid. The oriented Wedge theory of emulsions indicates that if the non-polar end of the emulsifying agent is smaller, the emulsion will be oil-in water (o/w) and if the polar end is smaller, the emulsion will be water-in-oil (W/O) The interfacial film theory The interfacial film theory suggests that the emulsifying agents make an interface between the two immiscible phases of the emulsion, surrounding the droplets of the internal phase as a thin film. This film prevents the coalescence of the dispersed phase.
  • 29. Types of emulsion 1. MACRO EMULSIONS A. Parenteral emulsions B. Water-in-oil emulsions. C. Oil- in-in-water /oral emulsions D. Radio opaque E. Fluorocarbon emulsion 2. MICRO EMULSION 3. NANO EMULSION 4. MULTIPLE EMULSION 5.GEL EMULSION
  • 30. 1) Macro Emulsions : These emulsions comprise four possible types: I - “oil-in-water” (O/W), II- “water-in-oil” (W/O), III-“water-in-water” (W/W), and IV- “Oil-in-oil” (O/O). Emulsions of the W/W type are formed from aqueous solutions of mixtures of incompatible polymers. They include systems containing polysaccharides, synthetic polymers, and proteins. The O/O emulsions consist of incompatible organic solvents stabilized by block copolymers with residues of differing solubilities in the two components. The O/W emulsions are administered orally as well as parenterally, W/O emulsions are used mainly as diffusion barrier depots when given intramuscularly.
  • 31. Depending on their end use, emulsions vary considerably in their composition, structure, and properties. Rheologically, for example, emulsions range from Newtonian and non- Newtonian liquids, including thixotropic systems, to gel-like solids. Surfactants are necessary in formulating stable emulsions of low viscosity and may be of low or high molecular weight. The surface activity of low molecular weight surfactants is sensitive to the composition of both phases of the system, and it is necessary to have a range of surfactants to match the hydrophilic-lipophilic balance (HLB) of a particular surfactant to the emulsion composition
  • 32. A. Parenteral Emulsions: “Emulsions that are injected in the body for the purpose of mitigation, cure and diagnosis of a disease is known as Parenteral emulsions” Uses  Injectable emulsions are used mainly for  Lipids or lipid-soluble materials.  nutritional purposes  delivery of vaccines,  as drug carriers  Diagnostic agents.
  • 33. Preparation of Parenteral Emulsions: Parenteral emulsions are subject to two important constraints:  particle size and  Sterilization. For intravenous emulsions, the particle size cannot be greater than 5µm without risking emboli in the capillaries. Average particle size for fat emulsions is less than 1µm Method of preparation Step1. Uniform particle size is achieved by homogenization at high temperatures under high pressure in homogenizer. Step2. The resulting homogenized product is then autoclaved at 110°C for 40 min. Parenteral emulsions may be sterilized by filtration, provided the particle size is small enough to pass the filter. Sterilization of individual components and aseptic assembly is also feasible.
  • 34. Application:  Parenteral nutrition: A major application of lipid emulsions is the delivery of fat in parenteral nutrition. Fat is a concentrated source of energy and can supply essential fatty acids.  Carriers for drugs and as targeted delivery systems The close resemblance of fat emulsion particles to chylomicrons, the natural emulsion particles that transport ingested lipophiles such as triglycerides into the lymphatic and circulatory systems, suggests that fat emulsions can be used as carriers for drugs and as targeted delivery systems.  Prolonged release of drug Emulsions can affect the metabolism of the drug, which can in turn affect clearance of the particles from the blood. Positive prolonged release effects have, however, been noted for progesterone and corticosteroids.
  • 35.  Increased bioavailability Intralipid has been used to incorporate valinomycin, an antitumor agent and it was found that a 20-fold lower dose was sufficient to produce the same effects as an aqueous suspension.  Decreased toxicity Amphotericin B administered as a lipid emulsion, in comparison with a 5% aqueous dextrose solution, gave a lower incidence of fever and nephrotoxicity and was as effective. Stability: Instability of fat emulsions can arise from changes in particle size of the oil droplets leading to creaming and coalescence, or from changes in pH, hydrolysis of emulsifier, or oxidation of the oil. Emulsions cause enhanced stability furnished by a non-aqueous environment. Many drugs, including barbituric acid, diazepam, and anesthetics, have been dissolved in the oil phase and administered by all parenteral routes.
  • 36.  B. Oil in water emulsion “If the oil droplets are dispersed throughout the aqueous phase, the emulsion is termed oil-in-water (O/W) with the help of emulsifying agent”. Fats or oils for oral administration, either as medicaments in their own right, or as vehicles for oil soluble drugs, are always formulated as oil in water (O/W) emulsions. Characteristics  They are non greasy  easily removable from the skin surface and  they are used externally to provide cooling effect  Used internally to also mask the bitter taste of oil.  Water soluble drugs are more quickly released from O/W emulsion.  O/W emulsion give a positive conductivity test as water  External phase is a good conductor of electricity.  The particle size of the dispersed phase commonly ranges from 0.1 to 100 µm  Emulsifier stabilizes the system by forming a thin film and they is present around the globules of dispersed phase
  • 37. C. Water in oil emulsion “A system in which the water is dispersed as globules in the oil continuous phase with the help of emulsifying agent is termed water-in-oil emulsion (W/O)”. Characteristics  Water-in-oil emulsions will have an occlusive effect by hydrating the stratum corneum and inhibiting evaporation of eccrine secretions.  It do not give positive conductivity tests  the external phase which is a poor conductor of electricity W/O emulsion is also useful for cleansing the skin of oil soluble dirt  they are greasy in texture although there greasy texture is not always cosmetically acceptable
  • 38. D. Radio opaque Emulsions The substance which emits such radiation is called radioactive and the process is called as radioactivity. For therapeutic and diagnostic purposes they are referred as ‘Radiopharmaceuticals’. All radio opaque are not radio- pharmaceutical unless they contain a radio isotope in their structure or formula. The element like uranium, radium, cobalt, phosphorous, iodine etc. are called radioactive elements. Development of nano-particulate systems exhibiting long circulation times in the blood pool, loaded with X-ray contrasting compounds, to be used as blood pool contrast agents in computed tomography.
  • 39. RADIO OPAQUE CONTRAST MEDIA: Any agent or compound administrated to a patient to improve the visualization of an organ or tissue is called a contrast agent. Certain inorganic agents like iodine or barium salts can act as radio contrast media, by absorbing at soft tissues and these tissues becomes capable of absorbing X-rays. The barium sulphate salt is given to identify of ulcer in G.I.T. whenever ulcer is formed, broken mucosa retains barium sulphate and this spot (ulcer) is identified with the help of X-ray film. X- rays are electromagnetic radiations of short wavelength and have high penetrating power. The electrons of high atomic number element can interact with X-rays. The relative difference between the light and dark areas on a radiographic image reflects is called radiographic contrast.
  • 40. D. Flourocarbon emulsion: The discovery that animals can survive breathing oxygen-saturated silicones and certain perfluorinated liquids such as the isomers of perfluorotetrahydrofuran (FC-75) suggested that such inert substances might be useful as intravascular O2 and CO2 transporting agents. These are chemically inert synthetic molecules & are composed of fluorine & carbon & have ability to dissolve many gases e.g O2, CO2 etc. Mechanism Of Drug Release: After i.v administration, droplets of these are taken up by reticulo-endothelial system, after which they are broken down & are taken into blood from where droplets are transported into lungs and excreted via inhalation. At present there is no metabolism in humans.  Applications:  They are clinically evaluated as “Artificial oxygen carriers”.  In future they will be used in the concept of ANH i.e acute normovalaemic haemodilution, means it is used to augment oxygen delivery during surgery.  These are also used in treatment of diseases with compromised tissue oxygenation such as cerebral ischemia, MI, emergency, trauma etc.
  • 41. 2) MICROEMULSION Hoar and Schulman used the term micro emulsion (ME) in 1943 to define a transparent system obtained by titrating a turbid oil - in - water (o/w) emulsion with a medium chain alcohol, namely hexanol. Since then the term has been used to describe systems comprising a non polar component, an aqueous component, a surfactant, and a co- surfactant. While a co-surfactant is usually present, a ME can be formulated without a co-surfactant that is, using a single surfactant. It is important to point out that the term ME was (and occasionally is) used in the literature to describe various liquid crystalline systems (lamellar, hexagonal, and cubic), surfactant systems (micelles and reverse micelles), and even coarse emulsions that are micronized using external energy (sub micrometer emulsions). To avoid such confusion, Danielsson and Lindmann proposed the following definition: “Microemulsion is defined as a system of water, oil and amphiphile which is optically isotropic and a thermodynamically stable liquid solution.”
  • 42. Structure and formation of microemulsion systems A ME system can be one of three types depending on the composition:  Oil in water (o/w ME), in which water is the continuous medium;  Water in oil (w/o ME), in which oil is the continuous medium, and  Water - and - oil bicontinuous ME, in which almost equal amounts of water and oil exist. Phase Behavior: The phase behavior of simple micro-emulsion systems comprising oil, water and surfactant can be studied with the aid of ternary phase diagram (at fixed pressure and temperature) in which each corner of the diagram represents 100% concentration of the particular component. The relative amounts of these three components can be represented in a ternary phase diagram. Gibbs phase diagrams can be used to show the influence of changes in the volume fractions of the different phases on the phase behavior of the system.
  • 43. Hypothetical Phase Regions of Micro Emulsion Systems:
  • 44. From above figure, we can see that,  With high oil concentration surfactant forms reverse micelles capable of solubilizing water molecules in their hydrophilic interior.  Continued addition of water in this system may result in the formation of W/O microemulsion in which water exists as droplets surrounded and stabilized by interfacial layer of the surfactant / co-surfactant mixture.  At a limiting water content, the isotropic clear region changes to a turbid, birefringent one.  Upon further dilution with water, a liquid crystalline region may be formed in which the water is sandwiched between surfactant double layers.  Finally, as amount of water increases, this lamellar structure will break down and water will form a continuous phase containing droplets of oil stabilized by a surfactant / co- surfactant (O/W microemulsions)
  • 45. Applications: 1- Oral Drug Delivery : Examples include Sendimmune neural which is commercial name for Cyclosporin A. Other examples include Paclitaxel & Simvastatin. 2- Transdermal Drug Delivery : A diverse range of drug molecules such as ketoprofen, apomorphine, estradiol, lidocaine, indomethacin and diclofenac, prostaglandin E 1 were incorporated as ME. 3- Parenteral Drug Delivery : Flubiprofen o/w ME systems were prepared and evaluated as vehicles for parenteral drug delivery. These systems were formulated using POE 20 sorbitan mono- laurate (Tween 20) as the surfactant. 4- Ocular Drug Delivery : Nanoemulsion is a type of emulsion sized between 20-200 nm with narrow distributions. They are transparent or translucent with a bluish coloration. So, the definition is different from that of sub-micron emulsions.
  • 46. 3) NANOEMULSIONS Nanoemulsion is a type of emulsion sized between 20-200 nm with narrow distributions. These are very small sized as compared to simple emulsions. The high pressure of 25000 to 40,000 psi is required for its formulation as compared to simple emulsions which require 500 to 5000 psipressure. These are thermodynamically unstable but kinetically stable so they require high mechanical energy for their preparation supplied from high pressure homogenisers, microfluidizers, etc.
  • 47. Applications of nano Emulsions: 1. Drug and gene delivery 2. Enhancement of skin permeation 3. Extended drug release 4. Antimicrobial activity 5. Medical applications:  Parenteral route (propofol and diazepam)  Ocular route (pilocarpine hydrochloride)  Nasal route (peptide and vaccine)  Topical route
  • 48. 4) MULTIPLE EMULSIONS Multiple emulsions are also known as emulsions of emulsions, liquid membrane system or double emulsion. The two major types of multiple emulsions are the w/o/w and o/w/o double emulsions. The most common multiple emulsions are of W/O/W types which are widely used for pharmaceutical purposes. Formulation: Modified Two Steps Emulsification:  In step 1→ water phase is added into oil + surfactant mixture with low HLB → homogenization done at 9500 rpm/min for 15 min → w/o emulsion is prepared.  In step 2→w/o emulsion is added into water +surfactant with high HLB → mechanical stirring done at 600 rpm/min for 30 min →w/o/w multiple emulsion.
  • 49. Phase Inversion Technique (One Step Technique): An increase in volume concentration of dispersed phase may cause an increase in the phase volume ratio, which subsequently leads the formation of multiple emulsions. The method typically involves the addition of an aqueous phase containing the hydrophilic emulsifier [Tween 80] to an oil phase consisted of liquid paraffin and containing lipophillic emulsifier (Span80). A well-defined volume of oil phase is placed in a vessel of pin mixer. An aqueous solution of emulsifier is then introduced successively to the oil phase in the vessel at a rate of 5 ml/min, while the pin mixer rotates steadily at 88 rpm at room temperature. When volume fraction of the aqueous solution of hydrophilic emulsifier exceeds 0.7, the continuous oil phase is substituted by the aqueous phase containing a number of vesicular globules among the simple oil droplets, leading to phase inversion and formation of W/O/W multiple emulsion.
  • 50. Application of multiple emulsions: 1) Multiple emulsions in cancer therapy 2) Vaccine/vaccine adjuvant 3) Oxygen substitute 4) Multiple emulsions in diabetes Surfactant-coated insulin was dispersed in the oil by ultra-sonification, this dispersion was mixed with the outer water phase with a homogenizer. 5) As antidiabetic Multiple emulsions of chloroquine, an anti-malarial agent has been successfully prepared and had been found to mask the bitter taste efficiently. Taste masking of chlorpromazine, an antipsychotic drug has also been reported by multiple emulsions. 6) Drug over dosage treatment This system could be utilized for the over dosage treatment by utilizing the difference in the pH. For example Barbiturates, salicylates etc.
  • 51. 5) GEL EMULSIONS: Gellified emulsions (Emulsion in gel) have emerged as one of the most intere sting topical drug delivery and have dual control i.e as emulsion & as a gel. Emulgel is emulsions, either of the O/W or W/O type, which are gelled by addition of a gelling agent. Examples are antifungal agents. This antifungal agent is Itraconazole, which has both antifungal and antibact erial properties. It is applied locally in mild uncomplicated dermatophyte an d other cutaneous infections. Gellified Emulsion is stable one and better vehicle for hydrophobic or Water insoluble drugs. Oil/water emulsions are most useful as water washable drug bases and for ge neral cosmetic purposes, while water/oil emulsions are employed more widel y for the treatment of dry skin and emollient.
  • 52. Preparation of gellified emulsion: The Gel in formulations were prepared by dispersing Carbopol 934 (thickner and suspending agent) in purified water with constant stirring at a moderate speed then the pH are adjusted to 6 to 6.5 using Tri Ethanol Amine (TEA). The oil phase of the emulsion wereprepared by dissolving Span 20 in light liquid paraffin while the aqueous phase was prepared by dissolving Tween 20 in purified water. Methyl and Propyl paraben was dissolved in propylene glycol whereas drug (Itraconazole) is dissolved in ethanol and both solutions was mixed with the aqueous phase. Both the oily and aqueous phases were separately heated to 70° to 80°C; then the oily phase are added to the aqueous phase with continuous stirring until cooled to room temperature. And add Glutaraldehyde(as a sterilant) during of mixing of gel and emulsion in 1:1 and to obtain the Gellified Emulsion.
  • 53. Rheology & stability of emulsion: Rheological properties are affected by both conc. & temp. Stability of gel emulsion at room temperature is increased by addition of NACl. Applications: Uses include; 1- These are used as antifungals to treat topical fungal infections e.g itraconazol, miconazol nitrate emulsified gel. 2-Terbinafin emulsion gel is an under eye emulsion gel & is used for:  Moisturising effect  Provide comfort to delicate eye  For skin repair  To get rid of skin circles  Provide protection against excessive dehydration.