Section 10
Emulsions
By Drs. Pardeep K. Gupta, Clyde M. Ofner and Roger L. Schnaare
Table of Contents
Emulsions.......................................................................................................................................1
Table of Contents .......................................................................................................................1
Introduction and Background ........................................................................................................3
Definitions ..................................................................................................................................3
Types of Emulsions ....................................................................................................................3
Formation of an Emulsion ..........................................................................................................4
Determination of Emulsion Type ................................................................................................4
Miscibility or Dilution Test ......................................................................................................4
Staining or Dye Test...............................................................................................................4
Electrical Conductivity Test....................................................................................................4
Physical State of Emulsions ......................................................................................................5
Pharmaceutical Application of Emulsions .................................................................................5
Formulations ..................................................................................................................................6
Typical Ingredients .....................................................................................................................6
Drug .......................................................................................................................................6
Oil Phase................................................................................................................................6
Aqueous Phase ......................................................................................................................6
Thickening Agents .................................................................................................................6
Sweeteners ............................................................................................................................6
Preservative............................................................................................................................6
Buffer......................................................................................................................................7
Flavor .....................................................................................................................................7
Color.......................................................................................................................................7
Sequestering Agents..............................................................................................................7
Humectants............................................................................................................................7
Antioxidants ...........................................................................................................................7
Emulsifiers..............................................................................................................................7
Guidelines ..................................................................................................................................7
Type of Emulsion Desired ......................................................................................................7
Toxicity ...................................................................................................................................8
Method of Preparation ...........................................................................................................8
Typical Formulas ........................................................................................................................8
Cod Liver Oil Emulsion (polysaccharide emulsifier)...............................................................8
Protective Lotion (divalent soap emulsifier) ...........................................................................8
Benzoyl Benzoate Emulsion (emulsifying wax emulsifier) .....................................................8
Barrier Cream (soap emulsifier) .............................................................................................9
Cold Cream (soap emulsifier).................................................................................................9
1
All Purpose Cream (synthetic surfactant emulsifier)..............................................................9
Emulsifiers ....................................................................................................................................10
Natural Products ......................................................................................................................10
Polysaccharides ...................................................................................................................10
Sterols ..................................................................................................................................10
Phospholipids ......................................................................................................................10
Surfactants...............................................................................................................................10
Anionic Surfactants..............................................................................................................11
Soaps ...............................................................................................................................11
Detergents........................................................................................................................11
Cationic Surfactants ............................................................................................................11
Nonionic Surfactants ...........................................................................................................11
Finely Divided Solids................................................................................................................12
Methods to Prepare Emulsions....................................................................................................13
Classical Gum Methods...........................................................................................................13
Dry Gum Method .................................................................................................................13
Wet Gum Method.................................................................................................................13
“In Situ” Soap Method .............................................................................................................13
Lime Water/Vegetable Oil Emulsions...................................................................................13
Other Soaps .........................................................................................................................13
With Synthetic Surfactants ......................................................................................................13
Required HLB of the Oil Phase............................................................................................14
HLB of Surfactant Mixtures .................................................................................................14
Emulsion Stability.........................................................................................................................15
Sedimentation or Creaming .....................................................................................................15
Factors - Stoke’s Law ..........................................................................................................15
Droplet Size......................................................................................................................15
Density Difference ............................................................................................................15
The Gravitational Constant, g ..........................................................................................15
Viscosity ...........................................................................................................................15
Breaking or Cracking ...............................................................................................................16
Thermodynamics of Emulsions....................................................................................................17
Microemulsions ............................................................................................................................18
References ...................................................................................................................................19
Selected Readings .......................................................................................................................19
2
Introduction and Background
dispersion is suspended is the dispersion
medium or the continuous or external phase.
For example, if olive oil is shaken with water,
it breaks up into small globules and
becomes dispersed in water. In this case
the oil is the internal phase, and water is
the external phase.
Definitions
Emulsions are pharmaceutical preparations
consisting of at least two immiscible liquids.
Due to the lack of mutual solubility, one
liquid is dispersed as tiny droplets in the
other liquid to form an emulsion. Therefore,
emulsions belong to the group of preparations known as disperse systems.
The dispersed particles or globules can
range in size from less than 1 µm up to
100 µm. An emulsion is rarely a monodisperse system, e.g., all the particles are
rarely of the same size. A typical emulsion
contains a distribution of many sizes,
making it a polydisperse system.
The USP also defines several dosage forms
that are essentially emulsions but historically
are referred to by other names. For example;
Lotions are fluid emulsions or
suspensions intended for external
application.
Types of Emulsions
Creams are viscous liquid or semi-solid
emulsions of either an oil-in-water
(O/W) or the water-in-oil (W/O) type.
They are ordinarily used topically. The
term cream is applied most frequently
to soft, cosmetically acceptable types
of preparations.
Based on the nature of the internal (or external) phase, emulsions are of two types; oilin-water (O/W) and water-in-oil (W/O). In an
O/W type the oil phase is dispersed in the
aqueous phase, while the opposite is true
in W/O emulsions. Figure 1 depicts these
two types of emulsions.
Microemulsions are emulsions with
extremely small droplet sizes and usually
require a high concentration of surfactant
for stability. They can also be regarded
as isotropic, swollen micellar systems.
Figure 1: Representation of Two Types
of Emulsions
Multiple emulsions are emulsions that
have been emulsified a second time,
consequently containing three phases.
They may be water-in-oil-in-water
(W/O/W) or oil-in-water-in-oil (O/W/O).
O/W Emulsion
(water black)
W/O Emulsion
(oil white)
When two immiscible phases are shaken
together, either type of emulsion can result.
However, this result is not random, but is
dependent primarily on two factors; most
importantly the type of emulsifier used and
secondly the relative ratio of the aqueous
and oil phases (phase volume ratio). The
emulsifiers and their role in the type of
emulsion are discussed in detail later in
this chapter.
Fluid emulsions are generally composed
of discrete, observable liquid droplets in
a fluid media, while semi-solid emulsions
generally have a complex, more
disorganized structure.
The liquid which is dispersed as droplets is
called as the dispersed, discontinuous or
internal phase, and the liquid in which the
3
The time required for this process is
determined by kinetics.
In terms of the phase volume ratio, the
percent of the internal phase is generally
less than 50%, although emulsions can
have internal phase volume percent as high
as 75%. Uniform spheres, when packed in
a rhombohedral geometry occupy approximately 75% of the total volume. Phase
volumes higher than 75% require that the
droplets of dispersed phase be distorted
into geometric shapes other than perfect
spheres. Although it is rare to find emulsions
with higher than 75% internal volume, phase
volumes of over 90% have been reported
in literature.
Determination of Emulsion Type
Several tests can be used to determine
whether a given emulsion is an O/W or W/O
type. These are as follows:
Miscibility or Dilution Test
This method is based on the fact that an
emulsion can be diluted freely with a liquid
of the same kind as its external phase.
Typically, a small amount of the emulsion is
added to a relatively large volume of water
and the mixture is stirred. If the emulsion
disperses in water, it is considered to be
an O/W type emulsion. If, however, the
emulsion remains undispersed, it is a W/O
type emulsion.
Formation of an Emulsion
When two immiscible liquids are placed
in contact with each other, they form two
separate layers. The liquid with higher
density forms the lower layer and the one
with lower density forms the upper layer.
When this two-layer system is shaken
vigorously, one of the layers disperses in
the other liquid forming an unstable emulsion. If left unstirred, the dispersed phase
comes together and coalesces into larger
drops until the layers become separate
again. If no other ingredient is added, this
process of separation is usually complete
in a matter of a few minutes to a few hours.
Therefore, a liquid dispersion is inherently
an unstable system.
Staining or Dye Test
This test is based on the fact that if a dye is
added to an emulsion and the dye is soluble
only in the internal phase, the emulsion
contains colored droplets dispersed in
the colorless external phase. This can be
confirmed by observing a drop of emulsion
under a low power microscope. An example
of such a dye is scarlet red, which is an oil
soluble dye. When added to an O/W type
emulsion, followed by observation under
the microscope, bright red colored oil drops
in an aqueous phase can be seen clearly.
However, when an emulsifier is present in
the system, it reduces the interfacial tension
between the two liquids and forms a
physical barrier between droplets, hence
lowers the total energy of the system
(see discussion on Thermodynamics of
Emulsions), thereby reducing the tendency
of the droplets to come together and
coalesce. Consequently, the globules of
the internal phase may remain intact for
long periods of time, forming a “stable”
emulsion. It should be noted, however,
that even with an emulsifier, an emulsion
is a thermodynamically unstable system
and will eventually revert to bulk phases.
Electrical Conductivity Test
This test is based on the fact that only
the aqueous phase can conduct electrical
current. Thus, when a voltage is applied
across a liquid, a significant amount of
electrical current will flow only when the
path of the current is through a continuous
aqueous phase. Since oil is a non-conductor
of electricity, when tested for conductivity,
a W/O type emulsion will show insignificant
current flow.
4
Often times a single test may not be conclusive. In such circumstances, more than one
test may need to be carried out to confirm
the emulsion type.
also makes it easy to rinse off the
residual dose from the mouth and
does not leave an oily taste. Mineral
oil and cod liver oil are emulsified
for this reason.
Physical State of Emulsions
• To improve the absorption of poorly
soluble drugs. Oil soluble drugs may
not be soluble enough to be absorbed
efficiently. An example of such a drug
is cyclosporin, which is dispensed as
a microemulsion.
Most emulsions are either liquid or semisolid at room temperature. In general, due to
their high viscosity, the semi-solid emulsions
are relatively more physically stable. Liquid
emulsions are more commonly compounded
for internal use, while semisolids are usually
for external use or for use in body cavities
(rectal or vaginal).
• To deliver nutrients and vitamins by
intravenous injection. Intralipid is an
emulsion product for administering
an oil by the IV route.
Other terms commonly used to describe
emulsions are lotion and cream. The term
lotion refers to a disperse system that flows
freely under the force of gravity. A cream is
a product that does not flow freely under the
force of gravity. It should be noted, however,
that these terms are meaningful only when
the product is at room temperature. A cream
product may behave like a lotion with a
temperature increase of a few degrees.
• To serve as a vehicle for the topical
administration of a variety of drugs.
The physical state of the final product is also
influenced by its intended use. For example
suntan lotions are dispensed as lotions
instead of creams because they need to
be applied on large body surface. Lotion
form makes it easy to pour and spread the
product. For application over a small portion
of skin, a cream is the preferred form of an
emulsion.
Pharmaceutical Applications of Emulsions
There are several reasons for formulation
of a product as an emulsion. These include
the following:
• To disguise the taste or smell of oils or
oil soluble drugs. These emulsions are
normally O/W types with the aqueous
phase containing sweeteners and
flavoring agents to mask the poor
taste of oils. An O/W type of emulsion
5
Formulations
cover the taste of the drug and other
ingredients. Sorbitol, corn syrup and
sucrose are used at relatively high concentrations and also contribute to the viscosity
of the suspension. Other sweetening agents
such as sodium saccharin and aspartame,
used in relatively low concentrations, do
not affect the overall viscosity. See Table 4,
Typical Sweetening Agents in Section 9 of
this manual.
Typical Ingredients
Drug
The oil phase may constitute the active
drug, e.g., mineral oil or castor oil emulsified
as an O/W emulsion for oral administration.
Alternately, a drug can be dissolved or
dispersed in either the oil or aqueous phase
of an emulsion which serves as the vehicle.
This mode of drug incorporation can be
used for oral and/or topical administration.
Preservative
Preservatives are required in most emulsions
because thickening (suspending) agents,
emulsifiers and sweeteners are good growth
media for microorganisms. As with suspensions, many preservatives are ionic, such as
sodium benzoate, and may interact and bind
or complex with other emulsion ingredients.
In addition, preservatives with appreciable
lipid or oil solubility may partition into the
oil phase. Preservatives that are bound or
dissolved in the oil phase are generally not
active.
Oil Phase
The oil phase of an emulsion can be
composed of a variety of oils, vegetable or
mineral oil depending on the intended use.
The consistency of the oil phase can be
altered by the addition of waxes, such as
beeswax or paraffin wax, or waxy solids,
such as fatty alcohols, acids, or esters,
e.g., cetyl alcohol, stearic acid, or glycerol
monostearate. These solids typically are
miscible with various oils when melted.
The concentration of preservative needed
to provide an effective concentration in the
aqueous phase when the preservative partitions into the oil phase and is solubilized by
the emulsifier (surfactant) can be calculated
by1:
Caq = [Ctot (+ 1)]/[(Kp+ (S Kb + 1)]
Aqueous Phase
The aqueous phase is composed of the
water soluble components in a formulation,
including preservatives, flavors, colors,
buffers and thickening agents.
Thickening Agents
where: Caq is the concentration in the
aqueous phase needed for
preservative activity
Ctot is the total concentration of
preservative in the emulsion
is the phase volume ratio, i.e.,
the ratio of the oil to aqueous
phases
Kp is the oil/water partition
coefficient of the preservative
S is the surfactant concentration
Kb is the binding constant of the
preservative with the surfactant
Thickening agents are materials added to
an emulsion to increase viscosity and retard
sedimentation. These include most of the
materials classified as suspending agents.
See Table 2, Typical Suspending Agents in
Section 9 of this manual.
Sweeteners
Sweeteners are added to emulsions to
produce a more palatable preparation, to
6
The equation shows that the effective
concentration in the aqueous phase will
always be a fraction of the total
concentration.
and sorbitol.
Antioxidants
Antioxidants are often added to prevent
oxidation of vegetable oils and/or the active
drug.
Solvents such as alcohol, glycerin and
propylene glycol are often used as a
preservative at concentrations approaching
10%. See Table 5, Typical Preservatives in
Section 9 of this manual.
Table 1. Typical Antioxidants
Buffer
Many chemical buffer systems have been
used in emulsions to control the pH. The
optimal pH is chosen to ensure activity of
the emulsifier, control stability of the drug
and to ensure compatibility and stability
of other ingredients.
Flavor
Emulsifiers
Flavoring agents enhance patient acceptance of the product, which is particularly
important for pediatric patients.
Emulsifiers are substances that have the
ability to concentrate at the surface of a
liquid or interface of two liquids, many of
them reducing the surface or interfacial
tension. Those emulsifiers that reduce
surface tension are also called surfactants.
Emulsifiers in general are discussed in
more detail in a later section of this chapter.
Color
Colorants are intended to provide a more
aesthetic appearance to the final product.
Emulsions are generally not colored with
the exception of some topical products.
Guidelines
Sequestering Agents
Before selecting a formula for an emulsion,
one needs to consider several factors.
These are listed below.
Sequestering agents may be necessary to
bind metal ions in order to control oxidative
degradation of either the drug or other
ingredients.
Type of Emulsion Desired
Since O/W emulsions are more pleasant
to touch and swallow, they are generally
preferred. Preparations for internal use
are almost always O/W type products.
Externally used emulsions may be of either
type. Creams and lotions that are used
primarily to provide oil to the skin need to
be W/O due to high concentration of oils
in these preparations.
Humectants
Humectants are water soluble polyols that
prevent or hinder the loss of water from
semi-solid emulsions, i.e., topical creams.
They also contribute to the solvent properties of the aqueous phase and contribute
to the sweetness of oral preparations. The
most common are glycerin, propylene glycol
7
Protective Lotion (divalent soap emulsifier)
Toxicity
Most emulsifiers are not suitable for internal
use. For orally given emulsions, acacia is
commonly used as an emulsifying agent.
Taste is another factor in selection of
ingredients. In this regard, most polysaccharides are tasteless and, hence, suitable
from a taste standpoint.
Method of Preparation
Preparation
Soaps and acacia are excellent for
extemporaneous preparations. While soaps
allow the preparation to be made by simply
mixing the ingredients and shaking, acacia
can be used in a pestle and mortar to
prepare emulsions.
1. Mix the two powders in a mortar and triturate
well, taking care that all the lumps and large
particles have been reduced.
2. Then add oil slowly with constant trituration until
all the oil has been added. Triturate to form a
smooth paste.
3. Then add the limewater and triturate briskly to
form the emulsion.
Typical Formulas
Note: The emulsifier, calcium oleate (from
limewater and olive oil), preferentially forms
O/W emulsions.
Cod Liver Oil Emulsion (polysaccharide
emulsifier)
Benzyl Benzoate Emulsion (emulsifying
wax emulsifier)
Preparation
Preparation
1. Add benzyl benzoate to the wax in a beaker
and heat in a water bath until the wax melts
and the temperature reaches 60°C.
2. In a separate beaker, add an appropriate volume
of water and heat to the same temperature.
3. Add the water to the oil phase with continuous
stirring.
4. Continue to stir until the mixture begins to
thicken and cools to room temperature.
1. Using a ratio of 4:2:1 for oil, water and gums
(both combined), prepare a primary emulsion by
dry gum method. (See Methods to Prepare
Emulsions on page 13.)
2. Dilute with water to a flowable consistency and
pour in a measuring device.
3. Add alcohol diluted with equal volume of water,
followed by the benzaldehyde and saccharin
sodium.
4. Dilute to volume (200 mL) with water
8
Barrier Cream (soap emulsifier)
All Purpose Cream (synthetic surfactant
emulsifier)
Preparation
Preparation
1. Mix the paraffins, cetostearyl alcohol and
stearic acid in a beaker and heat in a water
bath to about 60°C.
2. Heat water and chlorocresol together to the
same temperature.
3. Add the aqueous phase to the oil phase and
stir until congealed and cooled to room
temperature.
1. Melt the sorbitan monostearate and stearic
acid in the liquid paraffin and cool to 60°C.
2. Mix the sorbitol solution, preservatives,
polysorbate 60 and water and heat to the
temperature of the oil mixture.
3. Add the aqueous solution to the oil phase and
stir until it has congealed and cooled to room
temperature.
Note: The emulsifier is triethanolamine stearate
formed in situ.
Note: Propylene glycol serves as a solvent for
the preservatives.
Cold Cream (soap emulsifier)
Preparation
1. Mix and melt the wax and paraffin together.
2. Dissolve borax in water and heat both containers
on a water bath to 70°C.
3. Add the aqueous phase to the oil phase and
stir until it has congealed and cooled to room
temperature.
Note: The fatty acid in white beeswax reacts with
borax (sodium borate) to make a sodium soap
which acts as an W/O type emulsifier.
9
Emulsifiers
There are of basically three types of
emulsifiers: natural products, surface
active agents (surfactants), and finely
divided solids. Based on whether a stable
emulsion can be produced, emulsifiers are
also classified either as primary emulsifying
agents which produce stable emulsions by
themselves, or secondary emulsifying agents
(stabilizers) which help primary emulsifiers
to form a more stable emulsion.
A common problem with sterol-containing
emulsifiers is that being complex mixtures
of natural substances, they are prone to
variability in their quality and, hence,
performance. Also, these agents usually
contain some degree of an odor, which
varies with the purity and source. Some
semi-synthetic substitutes are available
that seek to overcome some of the
problems associated with these agents.
Natural Products
Phospholipids
Polysaccharides
Lecithin is very hydrophilic in nature and
produces O/W emulsions. However, it is
prone to microbial attack and tends to
oxidize and darken readily.
Examples of polysaccharides include acacia,
tragacanth, sodium alginate, pectin and agar.
The advantage these agents offer is that
being biocompatible, they can be used in
emulsions for internal use. Acacia is perhaps
the most widely used among these. It is an
excellent emulsifying agent for emulsions
intended for oral use and yields preparations
that are stable and elegant.
Table 2. Typical Emulsifying Agents
Type
Natural
Polysaccharides
Phospholipids
Sterols
Surfactants
Anionic
Other polysaccharides are generally
secondary emulsifying agents. Tragacanth
in solution produces a mucilage with high
viscosity and is used to thicken acacia
emulsions; alginate, pectin and agar also
work by increasing viscosity and as such
are not used as primary emulsifiers.
Cationic
Nonionic
Examples
Acacia
Lecithin
Cholesterol
Soaps
Potassium laurate
Triethanolamine stearate
Alkyl sulfates
Sodium lauryl sulfate
Quaternary ammonium compounds
Benzalkonium chloride
Sorbitan fatty acid esters
Polyoxythylene sorbitan fatty acid esters
Finely Divided Solids
Colloidal clays
Bentonite
Metallic hydroxides Magnesium hydroxide
Sterols
Examples of sterols as emulsifiers are
cholesterol and various fatty acid esters
of cholesterol. Cholesterol itself is a very
efficient emulsifier and produces W/O type
emulsions. Consequently, its use is limited
to topical preparations such as Hydrophilic
Petrolatum USP which readily absorbs water
forming a W/O cream. Woolfat or lanolin
contains a considerable amount of cholesterol esters and can absorb up to 50% of
its own weight of water.
Emulsion
Type Formed
O/W
O/W
W/O
O/W
O/W
O/W
–
W/O
O/W
Depends on
phase volume
ratio
Surfactants
Surfactants or surface active agents are
molecules that consist of two distinct parts,
a hydrophobic tail and a hydrophilic head
group. They are generally classified based
on the hydrophilic properties of the head
group (ionic charge, polarity, etc.). Since the
hydrophobic chains do not vary much in
their properties, the nature of surfactants
is dependent mainly on the head group
structure.
10
Figure 3: Typical Surfactant Structure
Lipophilic Tail
However, the unacceptable effects of soaps
on the mucosal membranes and unpleasant
taste make them unsuitable for oral
preparations.
Soaps of divalent ions such as calcium and
magnesium are W/O type emulsifiers. Use
of limewater (calcium hydroxide solution)
in the presence of some fatty acid, such as
oleic acid, is common in many preparations.
Calcium ion in the limewater reacts with the
fatty acid of the oil to make the soap in situ.
Hydrophilic Head
Based primarily on the head group, they are
classified as follows:
Anionic Surfactants
Detergents
These contain a relatively large anionic
head group with a small cation to balance
the charge.
These emulsifiers are characterized by
a sulfate or sulfonate polar head group.
Typical among these is sodium lauryl sulfate.
In general, they are strong electrolytes as
opposed to the soaps and, as such, are
much more stable in the presence of acids
and added electrolytes. They are widely
used in topical cream formulas.
Soaps
Alkali metal and ammonia soaps are
examples of such surfactants. These include
sodium, potassium or ammonium salts of
long chain fatty acids, such as oleic or
stearic acids. They produce O/W type
emulsions. The surfactant may be
prepared in situ by mixing the fatty acid
and a base along with other ingredients.
Cationic Surfactants
These surfactants contain a positively
charged head group; the most commonly
used fall under the category of quaternary
ammonium salts. They produce O/W type
emulsions, but by themselves are poor
emulsifiers. Due to charge interactions,
these agents are not compatible with
anionic surfactants. They are most often
used as antibacterials.
Often, vegetable oils that contain some
fraction of free fatty acids can be emulsified
directly by adding water and alkali base.
The alkali forms soap with the fatty acid
fraction and helps emulsify the remaining
oil. Emulsions prepared with these surfactants are very sensitive to low pH values.
Addition of acids can revert the soap back
to the free fatty acid and break the emulsion.
Nonionic Surfactants
This group of emulsifiers, which numbers
in the hundreds, contain a polyoxyethylene
chain as the polar head group. They are
nonionic and, thus, are compatible with ionic
compounds and are less susceptible to pH
changes. There are several such surfactants
official in the USP/NF, typified by sorbitan
monooleate (a partial ester of lauric acid
with sorbitol), polysorbate 80 (polyoxyethylene 20 sorbitan monooleate) which contains
20 oxyethylene units copolymerized sorbitan
Amine soaps consist of an amine, such as
triethanolamine, in the presence of a fatty
acid. These surfactants are viscous solutions
and produce O/W type emulsions. They
offer the advantage that the final pH of the
preparations is generally close to neutral,
and, therefore, allows their use on skin for
extended periods of time.
11
Table 3. Typical HLB Numbers
of Emulsifiers
monooleate) and polyoxyl 40 stearate
(a mixture of stearic acid esters with mixed
poloxyethylene diols equivalent to about
40 oxyethylene units).
The large number of nonionic emulsifiers
results from the large number of possible
combinations of various alkyl groups with
polyoxyethylene chains of varying lengths.
Compounds with saturated and/or large
alkyl groups, such as stearyl, tend to be
solids or semisolids while oleyl (also large,
but unsaturated) compounds tend to be
liquids. Also, the longer the polyoxyethylene
chain, the higher the melting point.
Finely Divided Solids
Finely divided solids function as emulsifiers
because of their small particle size. Fine
particles tend to concentrate at a liquidliquid interface, depending on their
wetability, and form a particulate film
around the dispersed droplets. They are
seldom used as the primary emulsifier.
To characterize such a large number of
compounds, they are each assigned an HLB
number. The HLB number or hydrophilelipophile balance, is a measure of the relative
hydrophilic vs lipophilic character of the
molecule as determined by the relative size
of the polyoxyethylene chain vs the alkyl
group. HLB numbers range from 0 for a
pure hydrocarbon to 20 for a pure polyoxyethylene chain. Some typical values
are listed in Table 3.
Ionic surfactants, such as sodium lauryl
sulfate, were not included in the original
definition of the HLB system but have been
included as the HLB system was developed.
The HLB number of 40 for sodium lauryl
sulfate is outside of the range of 0 to 20
and simply means that sodium lauryl sulfate
is much more soluble or hydrophilic than
a pure polyoxyethylene chain.
12
Methods to Prepare Emulsions
The method for preparing an emulsion
depends on the kind of surfactant used
and can be summarized as follows:
Lime Water/Vegetable Oil Emulsions
Forms W/O emulsions based on the
following reaction.
Classical Gum Methods
Oleic acid
These methods are based on the formation
of a primary emulsion using all of the oil in
the formula, a gum such as acacia, and
water in a 4-2-1 ratio for fixed oils. Other
gums and volatile oils are used in other
ratios. Following formation of the primary
emulsion, other additives are added with
enough water to adjust to volume.
Ca(OH)2
+
(from olive oil)
=
(from lime water)
Ca oleate
(soap)
Other Soaps
Stearic acid
NaOH
+
(in oil phase)
Dry Gum Method
Stearic acid
+
The primary emulsion is formed by mixing
the entire amount of oil with the gum, adding
the water required for the primary emulsion
all at once and mixing vigorously until a
thick and sticky emulsion results.
(in oil phase)
=
(in aqueous phase)
Sodium stearate
(soap)
Triethanolamine Triethanolamine stearate
=
(in aqueous phase)
(soap)
Simple mixing and shaking is sufficient if
the fatty acid is a liquid. Typically the oil
and aqueous phase are mixed together and
subjected to high shear to prepare a W/O
emulsion. If waxes or waxy solids are part
of the oil phase, then both the oil and
aqueous phase must be heated to a
temperature above the melting point of
the waxes. Homogenization must be done
at high temperature while the oil phase is
still liquid. Stirring must continue until the
emulsion congeals and reaches room
temperature. This method is generally
used for emulsions that are semisolid
at room temperature.
Wet Gum Method
In this method the order of addition of
ingredients differs in forming the primary
emulsion. Acacia and water are mixed
thoroughly to form a thick mucilage.
Then the oil phase is added slowly with
vigorous mixing.
In Situ Soap Method
Soap as the emulsifier is formed in situ as
a chemical reaction between a fatty acid
in the oil phase and a base in the aqueous
phase. The emulsion type will depend on
the type of soap formed.
With Synthetic Surfactants
Basically the formula is divided into an
oil phase and an aqueous phase with the
ingredients dissolved in their proper phases
(oil or water). The surfactant(s) is added to
the phase in which it is most soluble. The
oil phase is then added to the aqueous
phase with mixing, and the coarse mixture
passed through an homogenizer.
13
(4.7)+(5- )(15.6) = 10(5)
When waxes or waxy solids are included in
the formulation, the use of heat is necessary,
as described above.
4.7 + 78.0- 15.6 = 10(5)
10.9 = 28
Required HLB of the Oil Phase.
= 2.57 and 5- = 2.43
It has been found that various oils and lipid
materials form stable emulsions with
surfactants that have a certain HLB value.
This HLB value is called the required HLB
of the oil or lipid. Theoretically, any surfactant with the required HLB would produce
a stable emulsion with the indicated oil or
lipid. Some examples are given in Table 4.
Thus a mixture of 2.57 g of sorbitan
monooleate and 2.43 g of polysorbate 80
would have a HLB of 10.
Griffin2 described an experimental approach for the
formulation of emulsions using synthetic emulsifiers.
1. Group the ingredients on the basis of their
solubilities in the aqueous and oil phases.
2. Determine the type of emulsion required and
calculate an approximate required HLB value.
3. Blend a low HLB emulsifier and a high HLB
emulsifier to the required HLB.
4. Dissolve the oil soluble ingredients and the low
HLB emulsifier in the oil phase. Heat, if necessary,
to approximately 5 to 10° over the melting point
of the highest melting ingredient or to a maximum
temperature of 70 to 80°C.
5. Dissolve the water soluble ingredients (except
acids and salts) in a sufficient quantity of water.
6. Heat the aqueous phase to a temperature which
is 3 to 5° higher than that of the oil phase.
7. Add the aqueous phase to the oil phase with
suitable agitation.
8. If acids or salts are employed, dissolve them in
water and add the solution to the cold emulsion.
9. Examine the emulsion and make adjustments in
the formulation if the product is unstable. It may
be necessary to add more emulsifier, change to
an emulsifier with a slightly higher or lower HLB
value or to use an emulsifier with different
chemical characteristics.
Table 4. Required HLB Values for Typical
Oils and Lipids
HLB of Surfactant Mixtures
It may be difficult to find a surfactant with
the exact HLB number required for a given
oil phase in an emulsion. Fortunately, the
HLB numbers have been shown to be
additive for a mixture of surfactants. Thus,
if one required a surfactant with a HLB of
10, one could use a mixture of sorbitan
monooleate (HLB = 4.7) and polysorbate
80 (HLB = 15.6). Such a mixture can be
calculated on the basis of a simple weighted
average as follows.
Suppose 5 g of surfactant mixture is
required. Let = the g of sorbitan
monooleate, then 5 = the g of polysorbate
80 required.
14
Emulsion Stability
In addition to chemical degradation of
various components of an emulsion, which
can happen in any liquid preparation,
emulsions are subject to a variety of
physical instabilities.
Density Difference
If the difference in density between the
emulsion droplet and the external phase
can be matched, the creaming rate could
be reduced to zero. This is almost impossible with most oils and waxy solids used in
emulsions.
Sedimentation or Creaming
Factors - Stoke’s Law
The Gravitational Constant, g
Creaming usually occurs in a liquid emulsion
since the particle size is generally greater
than that of a colloidal dispersion. The rate
is described by Stoke’s Law for a single
particle settling in an infinite container
under the force of gravity as follows:
d
dt
where: d/dt
d
2
1
g
=
This parameter is not of much interest since
it can not be controlled or changed unless
in space flight.
Viscosity
d2(2 - 1)g
Viscosity turns out to be the most readily
controllable parameter in affecting the
creaming rate. While the viscosity in
Stoke’s Law refers to the viscosity of the
fluid through which a droplet rises, in reality
the viscosity that controls creaming is the
viscosity of the entire emulsion. Thus,
doubling the viscosity of an emulsion will
decrease the creaming rate by a factor of 2.
18
= the sedimentation rate in
distance/time
= droplet diameter
= droplet density
= emulsion medium density
= acceleration due to gravity
= viscosity of the emulsion
medium
There are three major ways to increase the
viscosity of an emulsion:
Since for most oil phases, 2 < 1, then
sedimentation will be negative, i.e., the oil
droplets will rise forming a creamy white
layer. While Stoke’s Law does not describe
creaming quantitatively in an emulsion, it
does provide a clear collection of factors
and their qualitative influence on creaming.
Droplet Size
Reducing droplet size can have a significant
effect on creaming rate. Since the diameter
is squared in Stoke’s Law, a reduction in size
by ¹⁄₂ will reduce the creaming rate by (¹⁄₂)2
or a factor of 4.
•
Increase the concentration of the internal
phase
•
Increase the viscosity of the internal
phase by adding waxes and waxy
solids to the oil phase.
•
Increase the viscosity of the external
phase by adding a viscosity building
agent. Most of the suspending agents
described in the Suspensions Section
in this manual have been used for this
purpose.
Creaming does not usually occur in a
semi-solid emulsion.
15
Breaking or Cracking
•
This problem arises when the dispersed
globules come together and coalesce to
form larger globules. As this process
continues, the size of the globules increases,
making it easier for them to coalesce. This
eventually leads to separation of the oil and
water phases. For cracking to occur, the
barrier that normally holds globules apart
has to break down. Some of the factors
that contribute to cracking are as follows:
Cracking is the most serious kind of physical
instability of an emulsion. Cracking of an
emulsion usually renders it useless. In
creams, the problem of cracking may show
up as tearing. This is a process where one
phase separates and appears like drops on
top of the cream.
•
Insufficient or wrong kind of emulsifier in
the system.
•
Addition of ingredients that inactivate the
emulsifier. Incompatible ingredients may
show their effect over a period of time.
An example of such an incompatibility
will be to use large anions in the
presence of cationic emulsifier.
•
Presence of hardness in water. The
calcium and magnesium present in hard
water can replace a part of the alkali
soap with divalent soap. Since these
soaps form different kinds of emulsions,
phase inversion usually takes place.
•
Low viscosity of the emulsion
•
Exposure to high temperatures can also
accelerate the process of coalescence.
This is due to the fact that at an elevated
temperature, the collisions between the
globules can overcome the barrier to
coalescence, thereby increasing the
chance that a contact between two
particles will lead to their fusion.
Temperature may have an adverse effect
on the activity of emulsifiers, particularly
if these are proteinaceous in nature.
However, this usually happens at temperatures higher than 50°C. Conversely, a
reduction in temperature to the point that
the aqueous phase freezes also will break
the emulsion.
An excessive amount of the internal
phase makes an emulsion inherently less
stable because there is a greater chance
of globules coming together.
The basic difference between creaming
and cracking is that the globules in creaming
do not coalesce to form larger particles.
Therefore, creaming is a less serious
problem and most preparations that show
creaming can be shaken to redisperse the
internal phase to its original state. A common example of creaming is the formation of
cream on top of whole milk due to collection
of emulsified fat of the milk. This problem is
solved by homogenizing the milk to reduce
the particle size of dispersed fat, thereby
reducing the rate at which they travel to
the surface.
16
Thermodynamics of Emulsions
the particles can come together and
flocculate, but still may not coalesce
unless the boundaries of the droplets
break and fusion takes place.
From a thermodynamic standpoint all
emulsions are unstable systems. This is due
to the fact that dispersion of an insoluble
material in another leads to increase in total
energy of the system. Since every system
tends to spontaneously reduce its energy to
a minimum, all emulsions will tend to separate into two phases with time. However, an
emulsion is considered pharmaceutically
stable if the time scale of instability is long
enough that the system allows dispensing
of a uniform dose over the shelf life of the
product. Most thin emulsions have a shelf
life of one to two years. The shelf life of
semi-solid emulsions may extend many
years.
For the repulsive barrier to be efficient in
preventing globules from passing into the
state of coalescence, it is necessary for the
charge density on each globule to be high.
This implies that the emulsifier should form
a closely packed film at the interface. For
this reason, a higher concentration of
emulsifier leads to a more stable emulsion.
However, once the concentration of
emulsifier is high enough to saturate the
entire interface surface, additional amounts
will not contribute to stability. For this
reason, ionic surfactants with longer
hydrocarbon chains are more effective
as emulsifiers because they form a tight
film at the interface due to their greater
interaction, thus causing a firmer anchorage
in the oil phase.
The basic role of an emulsifier is to allow
dispersion of one phase by reducing the
interfacial tension between the two liquids.
However, no emulsifier can reduce the
interfacial tension to zero (if this were to
happen, solubility would occur). Hence
the tendency of the system to return to
its original state remains.
In mixed emulsifier systems, more than one
surfactant can help create a more complete
film at the interface and contribute positively
to stability. It is common to observe synergistic action among various emulsifiers.
Several models have been used to describe
the relative stability of emulsions. One of
these is the electrical double layer theory.
This theory is based on the fact that
amphipathic nature (one polar end and
one non-polar end) of surface-active agents
causes them to become adsorbed at the
oil-water interface with their charged or polar
groups sticking out in the aqueous phase.
This imparts a net charge, or in the case
of non-ionic surfactants, a high degree of
polarity at the interface. In case of ionic
surfactants, the charge density at the
interface can be very high. This presence of
charges at the interface creates an electrical
double layer around each globule resulting
in an energy barrier near the interface which
must be overcome before two particles can
contact each other. If this barrier is high
enough, the particles will repel each other.
If, however, this barrier is not strong enough,
In W/O systems, the electrical double layer
exists in the internal phase. However, its
effect shows beyond the interface and still
contributes to stability. In general, W/O
systems are less stable than W/O systems.
Most W/O emulsions are formulated as
semi-solids to allow viscosity to aid in
increasing stability.
The double layer theory does not offer a
satisfactory explanation for stability of
emulsions formed with non-ionic surfactants.
The hydrophilic groups of non-ionic
surfactants consist of extended polyoxyethylene chains. This leads to an osmotic
repulsion between droplets similar to the
stabilization and flocculation of suspension
17
ary emulsifiers because the absence of full
charge makes them compatible with most
other emulsifiers.
by polymers. In general, emulsions formed
with non-ionic surfactants are not as stable
as those employing ionic surfactants. Nonionic surfactants are very useful as second-
Microemulsions
containing the surfactant, oil, cosurfactant
and water. One combination of such system
is sodium lauryl sulfate with 1-pentanol as
the cosurfactant. Care has to be taken that
for internally used preparations, both the
surfactant and the cosurfactant have to be
free from toxicity.
Microemulsions are a special class of
emulsions consisting of an oil-water
dispersion in which the particle size and
characteristics of the dispersed are such
that the system is thermodynamically stable
and transparent. This is achieved by combining a surfactant with another molecule
known as a cosurfactant to achieve the
dispersion. Since these systems are
thermodynamically stable, they form
spontaneously when the right proportion
of ingredients is present.
The properties of microemulsions are
intermediate between regular emulsions
and micellar systems that behave very close
to true solutions. The exact nature of the
dispersed particles is not clear, but it is
established that they closely resemble
micelles. Some authors refer to them as
swollen micelles due to their large size.
The size range of micelles is between 25
to 60 Å (angstroms), while the particles in
microemulsions can be as large as 1000 Å.
Since this size is smaller than the wavelength of the light in visible spectrum,
microemulsions appear transparent or
translucent.
Like regular emulsions, microemulsions can
be of O/W or W/O type. The cosurfactant in
these systems is usually a linear alcohol of
medium chain length. One of the requirements of the cosurfactant is that it should
have a small amount of water solubility. This
allows a significant amount of the alcohol to
be present in the water phase. Some authors
believe that the linear alcohols make a link
between water and oil and extend the
boundary between them, hence the formation of large size particles. The film at the
interface is believed to be a mixed layer
18
References
1. Bean HS, Preservatives for
Pharmaceuticals, J. Soc. Cosmet. Sci.
23, 703-20 (1972)
2. Griffin WC, Lynch, MJ and Lathrop LB,
Drug Cosmet. Ind. 101, 41 (1967).
Selected Readings
Remington: The Science and Practice of
Pharmacy, 19th ed, A. R. Gennaro ed, Mack,
Easton PA 1995.
Physical Pharmacy, 4th ed. Martin A. and
Bustamonte P., Lea & Febiger, Phila., 1993.
Pharmaceutical Dosage Forms: Disperse
Systems, Lieberman HA, Rieger MA and
Banker GS, eds. Vols. 1, 2 and 3, Marcel
Dekker, NY., 1996.
19