Pharmaceutical EMULSIONS
Pharmaceutical EMULSIONS
Pharmaceutical EMULSIONS
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Lesson objectives
At the end of this session you will be able to:
define emulsion dosage forms
recognize pharmaceutical application of emulsions
understand:
– theory of emulsification
– Mechanisms of emulsion stabilization
identify types of emulsion
recognize methods used to distinguish emulsions
identify emulsion formulation components
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Introduction
An emulsion is a thermodynamically unstable system
consisting of two immiscible liquid phases, one of
which is dispersed as globules (the dispersed phase) in
the other liquid phase (the dispersion phase) and
stabilized by the presence of an emulsifying agent.
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Introduction
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Pharmaceutical applications of emulsions
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Pharmaceutical applications of emulsions…
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Theories of emulsification
When two immiscible liquids are agitated together one of the
liquids is dispersed as small droplets in the other, the liquids
separate rapidly into two clearly defined layers.
Because:
Cohesive forces between the molecules of each separate liquid
is greater than adhesive force between the two liquids.
When one liquid is broken into small particles surface
area of the formed globules surface free energy
thermodynamic unstability coalescence (merging together of
droplets)
To prevent coalescence or at least to reduce its rate to negligible
proportions, emulsifying agent is used.
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Theories of emulsification ...cont’d
Surface –active
agents (HLB 3-6
and 8-16)
Emulsifying
agents
Finely divided
Hydrophilic
solid particles
polymers
(clays)
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Mechanisms of emulsion stabilization
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Mechanisms of emulsion stabilization
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Mechanisms of emulsion stabilization
Hydrophilic polymers
Hydrophilic colloids ( e.g., acacia, gelatin) form
multimolecualr films around droplets of dispersed
oil.
However, do not cause an appreciable lowering in
surface tension.
Their use has declined because of large number of
synthetic surface-active agents with well-marked
emulsifying properties.
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Mechanisms of emulsion stabilization...
Hydrophilic polymers…….
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Mechanisms of emulsion stabilization...
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Types of Emulsions...........cont’d
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Microemulsions (colloidal
emulsions)....cont’d
Coarse emulsions contain three components, namely, oil,
water, and surfactant;
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Methods to distinguish o/w and w/o
emulsion types
Miscibility tests with oil or water
The emulsion will only be miscible with liquids that are
miscible with its continuous phase.
Conductivity test
Systems with aqueous continuous phases will readily
conduct electricity, whereas systems with oily continuous
phases will not.
Dye-solubility test
Water soluble dye will dissolve in the aqueous phase of an
emulsion while an oil soluble dye will be taken up by the oil
phase.
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Emulsion Formulation
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Choice of emulsion type……….…..cont’d
Emulsions are most widely used for external
application;
Semisolid emulsions and more fluid preparations
for massage into the skin, liniments
o/w emulsions do not have the greasy texture
and easily washed from skin surfaces.
w/o emulsions have greasy texture and difficult
to be washed off from skin surfaces.
Since w/o emulsions have a greasy texture they
have higher apparent viscosity than o/w
emulsions.
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Choice of emulsion type……....cont’d
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Choice of emulsion type……....cont’d
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Rheology of emulsion
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Viscosity of the continuous phase
can be increased by incorporation of syrup or glycerol
in O/W type.
If oil is continuous phase, then inclusion of paraffin or
waxes will increase its viscosity.
Disadvantage: increase density difference between the
two phases upon change in temp, and accelerate
creaming.
Hydrocolloids also increase the continuous phase
viscosity.
But, they do not have the disadvantage of altering the
density of this phase.
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Viscosity of the continuous phase...
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Choice of oil phase
In many instances the oil phase of an emulsion is
the active agent.
Example: Turpentine oil and benzyl benzoate
(antimicrobial activity) are formulated for external
applications.
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Choice of emulsifying agent
Toxicity and irritancy considerations
At emulsifying conc., ionic emulsifying agents
irritate GIT and have a laxative effect hence not
used in oral emulsions.
Cationic surfactants are toxic even at lower
concentrations and limited to only external use.
Anionic alkali soaps often have a high pH and are
thus unsuitable for broken skin cause irritation.
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Choice of emulsifying agent…
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Classification of emulsifying agents
Emulsifying agents
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Naturally occurring materials and their
derivatives
Polysaccharides
Acacia
Acacia is a polysaccharide gum soluble in water.
Acacia stabilizes o/w emulsions by forming a strong
multimolecular film round each oil globule.
Because of its low viscosity, creaming will occur readily.
Therefore a suspending agent such as tragacanth or sodium
alginate can also be included.
Because of its sticky nature the use of acacia is limited to
products for internal use.
It is necessary to preserve acacia emulsions against microbial
attack by use of suitable preservatives. 31
Naturally occurring materials...
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Naturally occurring materials…
Gelatin
It is a protein which has been used for many years
as an emulsifying agent.
It forms o/w type of emulsion.
Lecithin
Lecithin is an emulsifier obtained from both plant
( e.g., soya bean) and animal (e.g., egg yolk).
It is composed of variety of phosphatides
The primary component of most lecithins is
phosphatidylcholine .
Purified lecithins obtained from soyabean and egg yolk
are the principal emulsifiers for intravenous fat
emulsions. 33
Phosphatidylcholine
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Finely divided solids (clays, minerals)
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Cellulose derivatives
include methylcellulose and carmellose sodium
(sodium carboxymethylcellulose)
They form o/w type of emulsion.
They are also called auxiliary emulsifying agents.
Because they alone are not capable of forming stable
emulsions.
Their main value lies in their ability to function as
thickening agents (suspending agents) and thereby
help stabilize the emulsion.
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Cellulose derivatives ...cont’d
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Sterol-containing substances
Sterol-containing substances such as Beeswax, wool fat and
wool alcohols are also used as emulsifying agents.
Beeswax
It is used mainly in cosmetic creams of both o/w and w/o
type in conjunction with borax.
Beeswax alone is used as a stabilizer for w/o creams.
Wool fat (anhydrous lanolin)
Consists chiefly of normal fatty alcohols, fatty acid esters of
cholesterol, and other sterols.
It forms w/o emulsions and it can also be incorporated for
its emollient properties.
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Sterol-containing substances
Cholesterol
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Wool fat
Has high water absorbing properties
But some individuals exhibit sensitization to Wool
fat.
It is not widely used because of its characteristic
odour and the need to incorporate antioxidants.
It can be used as an emulsion stabilizer with
primary emulsifying agents.
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Disadvantages of naturally occurring
materials and their derivatives
Show batch-to-batch variation in composition and
hence in emulsifying properties,
Susceptible to bacterial or mould growth
Not suitable for products requiring a long
shelf-life
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Synthetic surface active agents
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Anionic surfactants
Dissociate to form negatively charged anions that
are responsible for their emulsifying ability
They are widely used because of their cheapness.
Because of their toxicity only used for externally
applied preparations
Anionic surfactants
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Amine soaps
A number of amines form salts with fatty acids.
The most important of those used is based on
triethanolamine N(CH2CH2OH)3 .
It is widely used in both pharmaceutical and cosmetic
products.
These emulsifiers favor formation of o/w emulsions.
Their alkalinity is considerably lower than that of
alkali soaps.
They are also less irritating than alkali soaps.
They are also incompatible with acids and high
concentrations of salts.
Their use is limited to external applications.
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Alkyl sulfates
The alkyl sulfates have the general formula ROSO3M+,
where R represents a hydrocarbon chain and M+ is
usually sodium or triethanolamine.
An example is sodium lauryl sulphate, which is
widely used to produce o/w emulsions.
Sodium lauryl sulphate has high water solubility.
Because of its high water solubility and inability to
form condensed films, used in conjunction with a
non-ionic oil-soluble emulsifying agent.
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Sulfonates
Sulfonates are a class of compounds in which the
sulfur atom is connected directly to the carbon atom
giving the general formula: RSO3 M+
They are much less widely used as emulgents.
Materials of this class include sodium
dioctylsulphosuccinate, and are more often used for
their detergency.
Sodium dioctylsulphosuccinate
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Cationic surfactants
The surface activity in the cationic group resides in
the positively charged ion.
The pH of an emulsion prepared with a cationic
emulsion lies in the pH 4 to 6 ranges.
Because this includes the normal pH of skin, they are
used in anti-infective products such as lotions and
creams.
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Cationic surfactants...
Because of toxicity of cationic surfactants they tend
to be used only for formulation of antiseptic cream.
They alone produce poor emulsions but if used with
non-ionic oil-soluble auxiliary emulgents such as
cetostearyl alcohol they will form stable emulsions.
The most important group of cationic emulgents
consists of the quaternary ammonium compounds.
An example is cetyltrimethyl-ammonium bromide
(cetrimide) CH3 (CH2)14 CH2N+(CH3)3Br-.
Cationic emulsifiers should not be used with anionic
emulsifiers.
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Nonionic surfactants
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Nonionic surfactants…
Advantages of non-ionic surfactants
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Nonionic surfactants…
Most non-ionic surfactants are based upon:
A fatty acid or alcohol (usually with 12-18 carbon
atoms), the hydrocarbon chain of which provides
the hydrophobic moiety.
An alcohol (-OH) and/or ethylene oxide groups
(-OCH2CH2-), provide hydrophilic part of the molecule.
By varying the relative proportions of the
hydrophilic and hydrophobic groupings many
different products can be obtained.
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Nonionic surfactants…
Hydrophobic parts tend to migrate into the oil phase.
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Glycerol esters
For example, Glyceryl monostearate (an ester of
glycerol and stearic acid ) C17H35COOCH2CHOHCH2OH
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Sorbitan esters (Spans®)
These are produced by the esterification of one or
more of the hydroxyl groups of sorbitan with either
lauric acid (C11H23COOH), oleic acid (C17H33COOH),
palmitic acid (C15H31COOH) or stearic acid
(C17H35COOH)
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Polysorbates(Tweens®)...
Polyoxyethylene 20 sorbitan monooleate, for
example, contains 20 oxyethylene groups in the
molecule.
Polysorbates are generally used in combination with
the corresponding sorbitan ester to form a complex
condensed film at the oil/water interface.
Glyceryl monostearate, cetyl or stearyl alcohol or
propylene glycol monostearate, can be incorporated
with polysorbates to produce 'self-emulsifying‘
preparations.
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Higher fatty alcohols
The hexadecyl (cetyl) and octadecyl (stearyl)
members of this series of saturated aliphatic
monohydric alcohols are useful auxiliary emulsifying
agents.
Part of their stabilizing effect comes from their
ability to increase the viscosity of the preparation,
thereby retarding creaming.
Cetyl and stearyl alcohol form complex interfacial
films with hydrophilic surface-active agents such as
sodium lauryl sulphate, and cetrimide to stabilize
o/w emulsions.
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Stabilization of emulsion by the HLB method
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Required HLB value…
Mixture of emulsifiers may
Produce densely packed complex film at oil-water
interface
Increase viscosity of the interfacial emulsifier film
which inhibit thinning at the points of droplet to
droplet contact
Provide more elastic interfacial film which resist
rupture upon collision of emulsion droplets.
The HLB of a mixture of surfactants, consisting of
fraction A (x ) and fraction of B (1 - x), is assumed to
be an algebraic mean of the two HLB numbers:
HLBmix = x HLBA + (1-x) HLB B 62
Preparation of emulsions
The preparation of emulsion requires to reduce the
internal phase into small droplets and disperse them
throughout the external phase.
This can be accomplished by mortar and pestle at
small scale or high-speed homogenizer at large scale.
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Preparation of emulsions......cont’d
High-speed homogenizer 64
Preparation of emulsions………..cont’d
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Preparation of emulsions...cont’d
Addition of internal phase to external phase
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Preparation of emulsions...cont’d
Addition of external phase to internal phase (the dry
gum technique ) (4:2:1 method)
4 parts of oil: 2 parts of water: 1 part of surfactant is
used.
In this method, O/W emulsifier (e.g acacia) is
triturated with the oil in dry mortar.
After the oil and emulsifier have been mixed, water is
added all at once, and the mixture is triturated
immediately.
Other ingredients that are soluble in or miscible with
the external phase may then be mixed into the
primary emulsion. 67
Preparation of emulsions...cont’d
Solid substances such as preservatives, stabilizers,
colorants, and any flavor are usually dissolved in a
suitable volume of water (assuming water is external
phase) and added as a solution to the primary
emulsion and mixed.
Mixing both phases after heating
This method is used when waxes or other substances
that require melting are used.
The oil-soluble emulsifying agents (oils and waxes) are
melted and mixed thoroughly.
The water-soluble ingredients dissolved in water are
warmed to a temperature slightly higher than the oil
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phase.
Mixing both phases after heating.... cont’d
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Preparation of emulsions...cont’d
Alternate addition of the two phases to the
emulsifying agent
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Preparation of emulsions...cont’d
Factors which affect the type of emulsion formed:
a. Volume of internal and external phases.
The smaller volume will be the internal phase and the
larger volume will be external phase.
In some cases, internal phases can be more than 50% of the
total volume.
b. Nature of the emulsifying agents
Dominance of polar part of emulsifying agents results in
formation of o/w emulsion.
Dominance of non-polar part results in formation of w/o
emulsion.
Note that polar groups are better barriers than non-polar
groups; therefore, o/w emulsion can be prepared with
more than 50 % of oil phase as an “ internal phase”. 71
Physical instability of emulsions
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Physical instability of emulsions..cont’d
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Physical instability of emulsions...cont’d
Creaming
Is the upward movement of dispersed droplets
relative to the dispersion medium.
A creamed emulsion is inelegant in appearance,
provides the possibility of inaccurate dosage, and
increases the likelihood of coalescence as the
globules are close together in the cream.
Sedimentation
Sedimentation is the downward movement of
dispersed droplets relative to the continuous phase.
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Physical instability of emulsions...cont’d
Factors that influence the rate of sedimentation are
similar to those involved in the sedimentation rate of
particles in suspension formulations.
(Stoke’s equation)
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Physical instability of emulsions...cont’d
Coalescence
Coalescence is the fusion of droplets.
Depends on the structural properties of the
interfacial film.
It decreases the number of droplets and ultimately
leads to separation of the two immiscible
phases breaking (cracking)
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Physical instability of emulsions...cont’d
Flocculation (aggregation)
In flocculation, the dispersed globules come together
but do not fuse.
Caused by alteration of electrical potential and van
der Waals forces on droplets.
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Physical instability of emulsions...cont’d
Breaking( cracking)
Separation of an emulsion into its constituent
phases is termed cracking or breaking .
It is an irreversible process.
When breaking occurs, simple mixing fail to
resuspend the globules in a stable emulsified form.
Because the film surrounding the particles has
been destroyed.
It follows that any agent that will destroy the
interfacial film will break (crack) the emulsion.
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Physical instability of emulsions...cont’d
Factors that cause an emulsion to break/crack:
The addition of a chemical that is incompatible
with the emulsifying agent
Bacterial growth
Temperature change
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Physical instability of emulsions...cont’d
Phase inversion
Phase inversion is the process in which an emulsion
changes from one type to another, say O/W to W/O or vice
versa
The higher the fraction of one phase, the greater likelihood
it will form the external phase.
Factors which contribute phase inversion:
excess amount of internal phase
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END!!!
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