2. Emulsions
Heterogeneous systems consisting of at least one
immiscible liquid phase intimately dispersed throughout
a second phase in the form of droplets or globule
Dispersed particles range in diameter from 0.1 to 100 mm
At least 2 phases:
Disperse or internal phase
Continuous or external phase
thermodynamically unstable as a result of the excess free
energy associated with the surface of the droplets.
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3. Types of emulsions
There are two types of emulsions:
oil-in-water emulsions(o/w) in which the oil is dispersed
in a water continuous phase
water-in-oil emulsions(w/o) in which water droplets are
dispersed in an oil continuous phase
So-called multiple emulsions have been developed with a view
to delaying the release of an active ingredient
In these types of emulsions three phases are present: the
emulsion has the form W/O/W or O/W/O
Drug present in the innermost phase must now cross two
phase boundaries to reach the external, continuous phase
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4. Pharmaceutical Applications
1. Used to deliver drugs that exhibit a low aqueous
solubility
e.g., in o/w emulsions the therapeutic agent is dissolved
in the internal oil phase
2. Used to mask the taste of therapeutic agents, in which
the drug is dissolved in the internal phase of an o/w
emulsion
The external phase may then be formulated to contain
the appropriate sweetening and flavouring agents
3. Enhanced bioavailability of lipophilic drugs
4. Emulsions are employed for total parenteral nutrition
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5. Disadvantages
Pharmaceutical emulsions are thermodynamically
unstable
therefore must be formulated to stabilize the emulsion
from separation of the two phases
Pharmaceutical emulsions may be difficult to
manufacture
need relatively long technological processes of
manufacturing
which require the use of proper technological operations
and special technological equipment
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6. Determination of emulsion type
The most common are
1. Dilution Test or miscibility tests
The emulsion will only be miscible with liquids that are
miscible with its continuous phase;
2. Conductivity Test
Systems with aqueous continuous phases will readily
conduct electricity, whereas systems with oily
continuous phases will not;
3. Dye-Solubility Test
Water-soluble and oil-soluble dyes are used, one of
which will dissolve in, and color the continuous phase
4. Fluorescence test
oils give fluorescence under UV light, while water
doesn’t Therefore, O/W emulsion shows spotty pattern
while W/O emulsion fluoresces
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8. Theories of emulsification
Several theories have been proposed to explain how
emulsifying agents act in producing the multi-phase
dispersion and in maintaining the stability of the resulting
emulsion
The most prevalent theories are
the surface-tension theory
the oriented-wedge theory, and
the interfacial film theory
In reality, none of the emulsion theories can individually
explain the mechanism by which many and varied
emulsifiers promote emulsion formation and stability.
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9. The surface-tension theory
The force causing each liquid to resist breaking up into
smaller particle is called interfacial tension
the use of surfactants results in a reduction in the
interfacial tension of the two immiscible liquids
reducing the repellent force between the liquids and
diminishing each liquid’s attraction for its own molecules
Thus, surfactants enable large globules to break into
smaller globules, and prevent small globules from
coalescing into larger globules
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10. The oriented-wedge theory
proposes that the surfactant forms monomolecular layers
around the droplets of the internal phase of the emulsion
The theory is based on the assumption that emulsifying
agents orient themselves about and within a liquid relative
to their solubility in that particular liquid
An emulsifying agent, having a greater hydrophilic
character than hydrophobic character, will promote O/W
Conversely, W/O emulsions result with the use of an
emulsifyer that is more hydrophobic than hydrophilic.
i .e the phase in which the emulsifying agent is more
soluble will become the continuous or external phase of
the emulsion
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11. The plastic or interfacial film theory
proposes that emulsifying agent surrounding the droplets
of the internal phase as a thin layer of film adsorbed on
the surface of the drops
The film prevents the contact and coalescing of the
dispersed phase
the tougher and more flexible the film, the greater the
stability of the emulsion.
the formation of an oil in water or a water in oil emulsion
depends on the degree of solubility of the emulsifier in
the two phases
with water soluble agents encouraging o/w emulsions &
oil soluble emulsifiers promoting w/o emulsions.
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12. Emulsifying agents
The process of coalescence can be reduced to insignificant
levels by the addition of the emulsifying agent or emulsifier.
The choice of emulsifying agent is frequently critical in
developing a successful emulsion
Desirable Properties
1. It should be surface active and reduce surface tension to
below 10 dynes/cm
2. Be adsorbed quickly around the dispersed drops as a
condensed, non adherent film that will prevent coalescence
3. Impart to the droplets an adequate electrical potential so that
mutual repulsion occurs
4. Increase the viscosity of the emulsion
5. Be effective in a reasonably low concentration
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13. Emulsifying agents may be classified in accordance with the
type of film they form at the interface between the two phase
or Mechanism of Action
Monomolecular Films
Multimolecular Films
Solid Particle Films
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14. Monomolecular Films
Surface-active agents, which are adsorbed at oil–water
interfaces to form monomolecular films and reduce
interfacial tension
the droplets are surrounded now by a coherent monolayer
that prevents coalescence between approaching droplets.
If the emulsifier forming the monolayer is ionized, the
presence of strongly charged and mutually repelling
droplets increases the stability of the system
With un-ionized, nonionic surface active agents, the
particles may still carry a charge;
this arises from adsorption of a specific ion or ions from
solution
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15. Multimolecular Films
Hydrated lyophilic colloids form multimolecular films
around droplets of dispersed oil
they do not cause an appreciable lowering in surface tension
their efficiency depends on their ability to form strong
coherent multimolecular films.
These act as a coating around the droplets and render them
highly resistant to coalescence, even in the absence of a well
developed surface potential.
Furthermore, any hydrocolloid not adsorbed at the interface
increases the viscosity of the continuous aqueous phase
this enhances emulsion stability.
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16. Solid Particle Films
Small solid particles that are wetted to some degree by both
aqueous and nonaqueous liquid phases act as emulsifying
agents
If the particles are too hydrophilic, they remain in the
aqueous phase;
if too hydrophobic, they are dispersed completely in the
oil phase
A second requirement is that the particles are small in relation
to the droplets of the dispersed phase
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18. Chemical Types
Emulsifying agents also may be classified in terms of their
chemical structure
There is some correlation between this classification and that
based on the mechanism of action
For example, the majority of emulsifiers forming
monomolecular films are synthetic, organic materials.
Most of the emulsifiers that form multimolecular films are
obtained from natural sources and are organic.
A third group is composed of solid particles, invariably
inorganic, that form films composed of finely divided solid
particles
Accordingly, the classification, adopted divides emulsifying
agents into synthetic, natural, and finely dispersed solids
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19. Synthetic Emulsifying Agents
Group of surface-active agents that act as emulsifiers,
may be subdivided into
Anionic
Cationic,
Nonionic
Amphoteric
depending on the charge possessed by the surfactant.
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20. Anionics
dissociate to produce negatively charged ions with surface-
active activity
1. potassium, sodium, and ammonium salts of lauric and oleic
acid are soluble in water and are good O/W emulsifying
agents.
They have a disagreeable taste and are irritating to the
gastrointestinal (GI) tract;
this limits them to emulsions prepared for external use
the emulsifying properties are lost under acidic conditions
Due to the effect of pH on the ionization
Similarly, the emulsifying properties are negated in the
presence of di/trivalent cations
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21. 2. Calcium, magnesium, and aluminum salts of fatty acids
are water insoluble and result in W/O emulsions
3.Amine salts of fatty acids N(CH2CH2OH)3
Form o/w emulsions
Are less irritating than the alkali soaps
Their emulgent properties are pH-dependent and may
be negated in the presence of electrolytes
e.g. triethanolamine stearate
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22. Alkyl sulphates
Used to produce o/w emulsions (in conjunction with a
second non-ionic surfactant of low HLB, i.e. 6).
Fatty alcohols (e.g. cetyl, stearic alcohol) are
frequently used for this purpose.
E.g., sodium lauryl sulphate (Figure) and
triethanolamine lauryl sulphate
Stable over high pH range
Structural formula of sodium lauryl sulphate
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23. 5/2/2024
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Cationic surfactants
These are usually quaternary ammonium
compounds which have a surface-active cation.
Examples include cetrimide and benzalkonium
chloride.
They are used in the preparation of o/w emulsions
for external use and must be in their ionized form
to be effective.
The cationic surfactants also have antimicrobial
activity.
They are primarily used pharmaceutically as
preservatives of topical formulations
Disadvantages:
They are sensitive to anionic surfactants and
drugs.
24. Non-ionic surfactants
The most widely used for the formulation of pharmaceutical
emulsions
They are used to formulate both o/w and w/o emulsions.
Generally one water-soluble and the other oil-soluble are
employed to ensure the formation of a stable interfacial film
around the surface of the droplets of the disperse phase
Are more stable than ionic surfactants in the presence of
electrolyte and/or changes in pH
the hydrophobic portion of the molecule is composed of a
fatty acid or fatty alcohol
the hydrophilic portion is composed of an alcohol or ethylene
glycol moieties.
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25. 1. Sorbitan esters (e.g. Span series)
produced by the esterification of one or more of the
hydroxyl groups of sorbitan with either lauric, oleic, palmitic
or stearic acids
They exhibits lipophilic properties and tends to form w/o
emulsions.
however, when combined with the polysorbates , both o/w
and w/o emulsions may be formulated
structure of sorbitan monostearate 5/2/2024
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26. 2. Polyoxyethylene fatty acid derivatives of the sorbitan
esters (e.g. Tween series)
prepared by forming polyoxyethylene esters of the sorbitan
esters
emulsifying properties of the molecules in this series may
be modified by altering the number of oxyethylene
(OCH2CH2) groups and the type of fatty acid (denoted as R
in Figure)
are used to form o/w or w/o emulsions in combination with
a second surface-active agent, e.g. sorbitan esters, cetyl
alcohol, glyceryl monostearate, to ensure emulsion stability.
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27. These have the general formula:
where R represents a fatty acid chain
The emulsifying properties of this series are
tolerant of changes in electrolyte concentration
and pH.
Generally they are non-toxic and are used in both
parenteral and non-parenteral emulsions
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28. Polyoxyethylene alkyl ethers
These are ethers formed between polyethylene glycol and a
range of fatty alcohols (lauryl, oleyl, myristyl, cetyl, stearyl)
Two commercial series of these compounds are Cremophor
and Brij
The physicochemical properties may be modified by altering
the length of polyoxyethylene group and the length of the
aliphatic chain (denoted as x and y in Figure)
They are used as emulsifying agents for both o/w and w/o
emulsions
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29. Polyoxyethylene fatty acid esters
These are a series of polyoxyethylene derivatives of
fatty acids.
The most commonly used derivatives are the stearate
derivatives
The surface-active properties of these compounds may
be modified by varying the length of the oxyethylene
substituent and by mono- or di esterification of the
acid,
They are frequently combined with stearyl alcohol
(or related fatty alcohols) in the formulation of o/w
emulsions.
The emulsifying properties are tolerant of the presence
of strong electrolytes 5/2/2024
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30. Fatty alcohols
Examples include cetyl alcohol and stearyl alcohol
In addition, cetostearyl alcohol (a mixture of cetyl
(20–35%) and stearyl (50–70%) alcohols
Fatty alcohols are generally used in combination
with more hydrophilic surfactants to produce stable
o/w emulsions
When used alone, fatty alcohols act as w/o
emulsifiers
Furthermore, the addition of these to a hydrophobic
base will increase the water absorption properties
of the formulation
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1.
CH3(CH2)14CH2OH
2.
CH3(CH2)16CH2OH
31. Amphoteric surfactants
These are compounds that possess both positively
and negatively charged groups (cationic at low pH
values and anionic at high pH values).
The emulsifying properties are reduced as the pH
approaches the isoelectric point (the pH at which it
has zero net charge) of the surface-active agent.
The most commonly used amphoteric surface-active
agent is lecithin
Lecithin is used in emulsions (for intravenous and
intramuscular administration) and creams, in which it
acts as an o/w emulsifying agent
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32. Structural formula for lecithin (R1 and
R2 refer to either identical or different
fatty acids) 5/2/2024
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33. Natural Emulsifying Agents
Acacia is a carbohydrate gum that is soluble in water and
forms O/W emulsions.
Emulsions prepared with acacia are stable over a wide pH
range
Gelatin, a protein, has been used for many years as an
emulsifying agent
Lecithin is an emulsifier obtained from both plant (e.g.,
soybean) and animal (e.g., egg yolk) sources and is
composed of various phosphatides
Purified lecithins from soy or egg yolk are the principal
emulsifiers for intravenous fat emulsions.
Disadvantage; batch to batch variation ,susceptible to
bacterial and mold growth, and susceptible to
electrolytes 5/2/2024
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34. Finely Dispersed Solids
Finely divided solid particles 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 prevent coalescence
Additionally, most of them swell in the dispersing medium
resulting in an enhanced viscosity.
Example of agents: bentonite (Al2O3.4SiO2.H2O), veegum
(Magnesium Aluminum Silicate), hectorite, magnesium
hydroxide, aluminum hydroxide and magnesium trisilicate
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35. Bentonite is a white to gray, odorless and tasteless powder
that swells in the presence of water to form a translucent
suspension with a pH of about 9
Depending on the sequence of mixing it is possible to
prepare both O/W and W/O emulsions.
When an O/W emulsion is desired, the bentonite is first
dispersed in water and allowed to hydrate so as to form a
magma.
The oil phase is then added gradually with constant titration.
Because the aqueous phase is always in excess, the O/W
emulsion type is favored.
To prepare a W/O emulsion, the bentonite is first dispersed in
oil; the water is then added gradually
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36. Auxiliary Emulsifying Agents
include those compounds that are normally incapable
themselves of forming stable emulsion.
Their main values lies in their ability to function as
thickening agents and thereby help stabilize the emulsion.
Because these agents have only weak emulsifying
properties, they are always use in combination with other
emulsifiers
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37. The hydrophilic lipophilic balance (HLB) numbering
system
The preference of surfactants for the water or the oil
phase has been quantified using the HLB numbering
system.
The numbering system can be used to identify
surfactants useful for several applications
HLB value & application
1 -3 Anti-foaming agent
3 - 6 W/O emulsifying
agents
7 - 9 Wetting agents
8 - 18 O/W emulsifying
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38. 5/2/2024
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HLB numbering system and emulsifier selection:
Surfactants that orient more of the molecule into a
water continuous phase have HLB numbers between 8
and 18 and will make oil-in-water (o/w) emulsions.
Surfactants that orient more of the molecule into the oil
continuous phase have HLB numbers between 3 and 6
and will make water-in-oil (w/o) emulsions
Surfactants can be blended to produce an optimal HLB.
Surfactants have the potential to cause some irritation
to mucous membranes
Thus, the concentration of surfactant used by the oral
or ophthalmic routes must be relatively low compared
with what is used topically.
Some surfactants can only be used topically
39. Formulation and preparation of emulsions
Methods of emulsion preparation
Continental or dry gum method
English or wet gum method
Bottle or Forbes bottle method
Beaker Method
Types of oils are O:W:G(oil-water-gum)
Fixed oils in ratio of 4:2:1
Mineral oils “ 3:2:1
Volatile oils “ 2:2:1
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40. Continental or dry gum (4:2:1) method
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used to prepare the initial or primary emulsion from
oil, water, and a hydrocolloid or "gum" type
emulsifier (usually acacia)
In a mortar, the 1 part gum (e.g., acacia) is
levigated with the 4 parts oil until the powder is
thoroughly wetted; then the 2 parts water are added
all at once, and the mixture is vigorously and
continually triturated until the primary emulsion
formed is creamy white
Additional water or aqueous solutions may be
incorporated after the primary emulsion is formed.
Solid substances (e.g., active ingredients,
preservatives, color, flavors) are generally dissolved
41. 5/2/2024
41
Oil soluble substance, in small amounts, may be incorporated
directly into the primary emulsion.
Any substance which might reduce the physical stability of
the emulsion, such as alcohol (which may precipitate the
gum) should be added as near to the end of the process as
possible to avoid breaking the emulsion
When all agents have been incorporated, the emulsion
should be transferred to a calibrated vessel, brought to final
volume with water, then homogenized or blended to ensure
uniform distribution of ingredients
42. English or Wet gum method
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In this method, the proportions of oil, water, and
emulsifier are the same (4:2:1), but the order and
techniques of mixing are different.
The 1 part gum is triturated with 2 parts water to
form a mucilage; then the 4 parts oil is added
slowly, in portions, while triturating.
After all the oil is added, the mixture is triturated for
several minutes to form the primary emulsion.
Then other ingredients may be added as in the
continental method.
Generally speaking, the English method is more
difficult to perform successfully, especially with more
viscous oils, but may result in a more stable
emulsion
43. Bottle method
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This method may be used to prepare emulsions of
volatile oils, or oleaginous substances of very low
viscosities.
This method is a variation of the dry gum method.
One part powdered acacia (or other gum) is placed
in a dry bottle and four parts oil are added
The bottle is capped and thoroughly shaken
To this, the required volume of water is added all at
once, and the mixture is shaken thoroughly until the
primary emulsion forms.
It is important to minimize the initial amount of time
the gum and oil are mixed.
The gum will tend to imbibe the oil, and will become
more waterproof.
44. Preservation of emulsions
The propagation of microorganisms in emulsified products
is supported by one or more of the components present in
the formulation
Thus, bacteria have been shown to degrade nonionic and
anionic emulsifying agents, glycerin, and vegetable gums
present as thickeners, with a consequent deterioration of the
emulsion
Preservatives should be in aqueous phase.
Preservatives should be in unionized state to penetrate
the bacteria
Preservatives must not bind to other components of the
emulsion
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45. Physical stability of emulsions
A stable emulsion may be denned as a system in
which the globules retain their initial character and
remain uniformly distributed throughout the
continuous phase.
The three major phenomena associated with
physical stability are
1. the upward or downward movement of dispersed
droplets relative to the continuous phase, termed
creaming or sedimentation, respectively.
2. the aggregation and possible coalescence of the
dispersed droplets to reform the separate, bulk
phases.
3. Phase inversion, in which an O/W emulsion inverts
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47. Creaming and Sedimentation
Creaming is the upward movement of dispersed droplets
relative to the continuous phase
Sedimentation is the downward movement of particles
This is undesirable in a pharmaceutical product where
homogeneity is essential for the administration of the
correct and uniform dose
Factors that influence the rate of sedimentation or
creaming
the diameter of the suspended droplets
the viscosity of the suspending medium
the d/f in densities b/n the dispersed phase & the
dispersion medium.
A decrease of creaming rate may be achieved by
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48. Aggregation and Coalescence
In aggregation (flocculation) the dispersed droplets come
together but do not fuse.
Coalescence, the complete fusion of droplets, leads to a
decrease in the number of droplets and the ultimate
separation of the two immiscible phases.
Aggregation precedes coalescence in emulsions; however,
coalescence does not necessarily follow from aggregation.
Aggregation is, to some extent, reversible.
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49. 5/2/2024
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Although aggregation is not as serious as coalescence, it will
accelerate creaming or sedimentation,
because the aggregate behaves as a single drop
Aggregation is related to the electrical potential on the
droplets,
But, coalescence depends on the structural properties of the
interfacial film.
Separation of the internal phase from the emulsion is called
breaking
the emulsion is described as being cracked or broken.
This is irreversible, because the protective sheath about the
globules of the internal phase no longer exists
50. Inversion
An emulsion is said to invert when it changes from an
O/W to a W/O emulsion, or vice versa.
Inversion sometimes can be brought about
by the addition of an electrolyte
by changing the phase-volume ratio
Inversion often can be seen when an emulsion, prepared by
heating and mixing the two phases, is being cooled.
This takes place presumably because of the temperature-
dependent changes in the solubilities of the emulsifying
agents
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51. Rheological properties of emulsions
Most emulsions, except dilute ones, exhibit non-
Newtonian flow
the dispersed phase, the continuous phase, and
the emulsifying agent of an emulsion can affect the
rheologic behavior of an emulsion in several ways.
The factors related to the dispersed phase include
the
phase–volume ratio
the particle-size distribution
the viscosity of the internal phase itself
Thus, when volume concentration of the dispersed
phase is low (less than 0.05), the system is
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52. 5/2/2024
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As the volume concentration is increased, the
system becomes more resistant to flow and
exhibits pseudoplastic flow characteristics.
At sufficiently high concentrations, plastic flow
occurs.
When the volume concentration approaches
0.74, inversion may occur, with a marked
change in viscosity
Reduction in mean particle size increases the
viscosity;
The wider the particle size distribution, the
lower is the viscosity when compared with a
53. 5/2/2024
53
The major property of the continuous phase that affects
the flow properties of an emulsion is not, surprisingly,
its own viscosity
the reduction in viscosity with increasing shear may be
due in part to a decrease in the viscosity of the
continuous phase as the distance of separation
between globules is increased.
Another component that may influence the viscosity of
an emulsion is the emulsifying agent.
The type of agent will affect particle flocculation and
interparticle attractions, and these in turn will modify
flow.
In addition, for any one system, the greater the
concentration of emulsifying agent, the higher will be
the viscosity of the product
54. Evaluation of stability of emulsions
a size–frequency analysis of the emulsion from time
to time as the product ages
Other methods are based on accelerating the
separation process, which normally takes place
under storage conditions
These methods employ freezing, thaw– freeze
cycles, & centrifugation
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