PHT 312: Pharmaceutics II

Pharmaceutical Emulsions
 Outlines
•Introduction

•Theoretical Aspects

•Types and Applications

•Emulsion Stability

•Formulation of Emulsion

•Properties of Emulsion and Emulsifiers

 Introduction
• It consists of a two-phase system prepared by
combining two immiscible liquids, one of which is
dispersed uniformly throughout the other.

∙ Internal phase = the dispersed phase,

∙ External phase or dispersion medium = continuous phase.

• The liquid that is dispersed into small
droplets is called the dispersed phase
or internal phase
or discontinuous phase

• The other liquid is the dispersion medium

external phase

continuous phase
A. Two immiscible liquids, not
emulsified.
B. An emulsion of Phase
B dispersed in Phase
A.
C. The unstable emulsion
regressively separates.
D. The surfactant positions
itself on the interfaces
between Phase A and
Phase B, stabilizing the
emulsion.
 Emulsions are unstable because:
the globules of the dispersed liquid tend to coalesce to
form large globules until all of the dispersed globules
have coalesced.

• An emulsifying agent is usually added to the system to

prevent the coalescence of the globules and maintain the
integrity of the individual globules of the dispersed
phase.
• Emulsions tend to have a cloudy appearance, because the
many phase interfaces (the boundary between the phases
is called the interface) scatter light that passes through
the emulsion. Emulsions are unstable and thus do not
form spontaneously. Energy input through shaking,
stirring, homogenizers, or spray processes are needed to
form an emulsion.

• Over time, emulsions tend to revert to the stable state of

oil separated from water. Surface active substances
(surfactants) can increase the kinetic stability of
emulsions greatly so that, once formed, the emulsion
does not change significantly over years of storage.
• A phenomenon is called coalescence, and happens
when small droplets recombine to form bigger ones.
Fluid emulsions can also suffer from creaming, the
migration of one of the substances to the top of the
emulsion.

• Emulsions are part of a more general class of two-

phase systems of matter called colloids. Although the
terms colloid and emulsion are sometimes used
interchangeably, emulsion tends to imply that both the
dispersed and the continuous phase are liquid.
• There are three types of emulsion instability:

1. Flocculation, where the particles form clumps;

2. Creaming, where the particles concentrate towards

the surface of the mixture while staying separated;
and

3. Breaking, where the particles coalesce and form a

layer of liquid.
Emulsifier:
• An emulsifier (or surfactant) is a substance which
stabilizes an emulsion.
• Detergents are another class of surfactant, and will
chemically interact with both oil and water, thus
stabilizing the interface between oil or water
droplets in suspension.
• This principle is exploited in soap to remove grease
for the purpose of cleaning.
• A wide variety of emulsifiers are used in pharmacy
to prepare emulsions such as creams and lotions.
20 ml ampule of 1% propofol emulsion suitable for
intravenous injection.
• When oil is the dispersed phase and an aqueous
solution is the continuous phase, the system is
designated as an oil-in-water (O/W) emulsion.

• Conversely, where water or an aqueous solution is

the dispersed phase and oil or oleaginous material is
the continuous phase, the system is designated as
water-in-oil (W/O) emulsion.
• Oil-in-water (O/W) emulsion used for oral
and intravenous administration .

• Water-in-oil (W/O) emulsion used for

intramuscular injections for a depot effect
(extended release or long acting effect).
• Oil-in-water (O/W) emulsion:

• Water-in-oil (W/O) emulsion:

• Multiple Emulsion Method: multiphase emulsions are
prepared by the solvent evaporation technique by a
three-step emulsification process.

• Aqueous drug solution and oil phase containing

emulsion stabilizers are combined to give a water-in-
oil emulsion (step 1). Later the w/o emulsion is
dispersed in the polymer solution (step 2). The solvent
is evaporated under reduced pressure.

• In other way: preparation of a primary o/w emulsion in

which the ‘oily dispersed phase’ in an organic solution
of the drug and the ‘aqueous continuous phase’ is an
aqueous solution containing chitosan and an
emulsifier (step 1); multiple emulsion formation with a
‘oily outer phase’ (step 2); and finally, cross-linkage
adding a cross-linking agent.
 Hint:
Hydrophobic drugs are prepared
using o/w/o multiple emulsion
method.

Hydrophilic drugs are prepared

using w/o/w multiple emulsion
method.
Why would you want an o/w emulsion instead
of a w/o emulsion for an oral dosage form?

• The continuous water phase would be more palatable to

the mouth and the liquid consistency would be easier to
flow through the mouth and down the throat.

• By dispersing a foul tasting or smelling drug in the oil

phase, your taste buds and your sense of smell will be
unaware of the agent passing by.

• In addition, in the o/w emulsion the manufacturer can

add sweeteners and flavors to the continuous phase
which will be experienced by the taste buds as the
medication passes over them.
Advantages of emulsions over other liquid
forms:

1- The unpleasant taste or odor of an oil can be

masked partially or wholly, by emulsification

2- The solubility of many drugs is increased when they

are incorporated into emulsions

3- The stability of many drugs which are unstable in

aqueous solutions is increased when incorporated
into an emulsion
4- Prolonged drug action and increased bioavailability
are often obtained when drugs are incorporated into
emulsions

5- The appearance of oleaginous materials intended for

topical applications is usually improved when
formulated in an emulsified form
 Emulsion Stability
• Flocculation and Coalescence:

if no protective barrier is present at the

interface, or if very low surface coverage
by emulsifier exists, emulsion droplets
rapidly aggregate and coalesce. Even
though coverage sufficient to prevent
coalescence may exist, however, a
relatively weak particle-particle
interaction known as flocculation may
occur. Flocculation is differentiated from
coalescence primarily by the fact that the
interfacial film remains intact and that
aggregation may be reserved.
 Emulsion Stability
• Flocculation and Coalescence (…cont.):

While flocculation (aggregation) is the

clumping together of particles, coalescence is
the fusing of the agglomerates into a large
drop, or drops.

Coalescence is usually rapid when two

Immiscible liquids are shaken together, since
there is no large energy barrier to prevent
fusion of drops or reformation of the original
bulk phases.
 Emulsion Stability
• Flocculation and Coalescence (…cont.):

When an emulsifying agent is added to

the system, flocculation still may occur
but coalescence is reduced to an extent
depending on the efficacy of the
emulsifying agent to form a stable,
coherent interfacial film. It is therefore
possible to prepare emulsions that are
flocculated, yet which do not coalesce.
 Emulsion Stability
• An emulsion is considered unstable if:

a. The internal phase tends to form globule

aggregates

b. Large globules rise to the top (cream) or fall

to the bottom to form a concentrated layer
of emulsified internal phase globules

c. If the emulsion breaks (coalescence of the

internal phase globules into a distinct
phase). In other words, the separation of the
internal phase from the emulsion, and the
emulsion is described being cracked or
broken.
 Emulsion Stability
• What causes an emulsion to break?
The globules coalesce due to too little emulsifying agent in
the first place or possibly due to degradation of the emulsifying
agents by chemical or enzymatic (from microbes or other
sources) means. Sterility isn't necessary with oral emulsions,
but destruction of the microbes can improve the physical
stability of emulsion formulations.

Fungistatic preservatives are generally included because fungi

(molds and yeasts) are more likely to contaminate emulsions
than are bacteria.
 Emulsion Stability
• What causes an emulsion to break?
Methylparaben and propylparaben are frequently used to serve this
function. Alcohol at 12-15%, based on the aqueous volume, is
frequently added to oral o/w emulsions for preservation.

Care must be taken to protect emulsions against extremes of cold

and heat. Freezing and thawing causes a coarsening of an
emulsion and sometimes causes breaking. Excessive heat has
the same effect.

Light-resistant containers which can seal tightly should be used to

protect the emulsion from photolysis and oxidation. Chemical
antioxidants are usually employed.
 Emulsion Stability
• In light of these considerations, the instability of
pharmaceutical emulsions may be classified as follows:

• Flocculation and creaming

• Coalescence and breaking

• Miscellaneous physical and chemical changes

• Phase inversion
 Emulsion Stability
• Creaming and Stokes’ Law:

• Those factors that find importance in the creaming of

an emulsion are related by Stokes’ Law. The
limitations of this equation to actual systems have been
discussed previously for pharmaceutical suspensions,
and these apply equally to emulsified systems.
 Emulsion Stability
• Creaming and Stokes’ Law (…cont.)

• Analysis of the equation shows that if the dispersed

phase is less dense than the continuous phase, which is
generally the case in the o/w emulsions, the velocity
of sedimentation becomes negative, that is, an upward
creaming results. If the internal phase is heavier than
the external phase, the globules settle, a phenomenon
customarily noted in w/o emulsions in which the
internal aqueous phase is more dense than the
continuous oil phase. This effect may be referred to as
creaming in a downward direction. The diameter of
globules is seen to be a major factor in determining the
rate of creaming.
 Formulation of Emulsion
• It is difficult to designate a general approach
and set of rules for selecting the materials, and
their amounts, required to formulate a desired
product.

• Although there are obvious situations in which

certain oils, emulsifiers, and other ingredients
must be avoided or used exclusively, decisions
of such a specific nature are made ultimately
on the basis of the experience and personal
tastes of the emulsion formulator, and
considerable trial and error.
 Properties of emulsions
• A). Oil Phase and Water Phase: the materials
making up the oil portion of an emulsion and their
relative amounts are determined primarily by the
ultimate use of the product, the optional toxicity of
the oil, consistency desired, and the possible
chemical incompatibilities with other ingredients.

• For pharmaceutical and cosmetics products, the oil

phase is restricted to various grades of mineral oil; a
number of edible vegetable oils, such as those
derived from corn, peanuts, sesame, and olives; and
semi-solid and solid substances such as petroleum,
lanolin, beeswax, and long chain acids and alcohols.
 Properties of emulsions
• A). Oil Phase and Water Phase:

• Isopropyl and myristate, a clear viscous liquid, is also a

popular ingredient used in dermatological and cosmetic
formulations.

• Chemical decomposition of vegetable oils and mineral

oil by means of oxidation is common problem that has
to be considered, particularly for those systems that
must be subjected to heat.
 Properties of emulsions
• B). Phase Volume Ratio:

• For fluid emulsions it has been suggested that a 40

to 60 percent internal phase volume produces
acceptable emulsions with minimal difficulty.

• The use of lower percentages makes it difficult to

avoid creaming and sedimentation unless the
external phase viscosity is increased by the addition
of suitable substances, e.g. hydrophilic colloids.
 Properties of emulsions
• C). Emulsifying agent:

• an emulsifier functions and operationally defined as a

stabilizer of the droplet form (globules) of the internal
phase.

• On the basis of their structure, emulsifiers (wetting agents or

surfactants) may be described as molecules comprising both
hydrophilic (oleophobic) and hydrophobic (oleophilic)
portions.

• For this reason, this group of compounds is frequently called

amphiphilic (i.e. water- and oil-loving).
 Desired features of emulsifier
• It must be compatible with the other components in the formulation,
which means it must not interfere with the chemical stability of
each of the components or with the therapeutic efficacy of the drug.

• It must be stable in the preparation itself. If it decomposes or

degrades, what good is it?

• The agent must be nontoxic.

• It should not possess an unacceptable odor, taste or color.

• It must assist in the formation of and continue to support the

emulsified system throughout the shelf-life of the product.

• 6. The cost of emulsifiers

 Desired features of emulsifier
Emulsifying agents, in general, assist in the formation
of emulsion by three mechanisms:

• A. Reduction of interfacial tension (thermodynamic

stabilization).

• B. Formation of a rigid interfacial film (mechanical

barrier to coalescence).

• C. Formation of an electrical double layer (electrical

barrier to approach of particles).
 Types of emulsifier
Carbohydrates: naturally occurring agents such as
acacia, tragacanth, agar, and pectin.

• These agents generally help to produce o/w

emulsions.

• Acacia is probably the most common emulsifier for

extemporaneous preparations. It is an acidic
polysaccharide.

• These agents are also called hydrophilic colloids.

They influence an emulsion by increasing the
viscosity of the aqueous phase.
 Types of emulsifier
Macromolecules such as proteins:

• Naturally occurring agents such as gelatin, egg white

and casein, which also help to produce o/w
emulsions.

2. They are not very popular since they form thin

emulsions, but more importantly because they
decompose rapidly which results in a broken
emulsion.
 Types of emulsifier
High molecular weight alcohols:

such as stearyl alcohol (18 carbons) and cetyl alcohol (16

carbons).

Finely divided solids:

such as bentonite, magnesium hydroxide or aluminum

hydroxide. They have shown to be good emulsifiers
alone and in combination with surfactants and/or
macromolecules.
 Types of emulsifier
Important Note:

All these emulsifiers have in

common the ability to accumulate
at the oil-water interface,
as well as the tendency to influence
the degree of particle flocculation,
and hence the viscosity of
the emulsion.
 Types of emulsifier
Important Note:

The major requirement of a potential emulsifying agent is that it

readily form a film a round each droplet of dispersed material.

The main purpose of this film, which can be a monolayer, a multilayer,

or a collection of small particles adsorbed around the interface, is to
form a barrier which prevents the coalescence of droplets that come
into contact with one another.

For the film to be an efficient barrier, it should possess some degree of

surface elasticity and should not thin out and rupture when sandwiched
between two droplets. If broken, the film should have the capacity to
reform rapidly.
 Hydrophilic-Lipophilic Balance (HLB) System
• A convenient way to choosing emulsifiers involves the use of
a numerical scale for characterization.

• One such approach assigns to an emulsifier a hydrophile-lipophile

balance value (HLB), which is characteristic of its relative polarity.

• This approach is empirical and essentially no different from choosing a

series of any type of emulsifiers. The advantage of HLB system is that
to a first approximation one can compare any chemical type when both
polar and nonpolar groups are different. With regard to the specific
choice of an emulsifier,

• it has been suggested that surfactants having an HLB value of 3 to 6

should be used for obtaining w/o emulsions, whereas values of 8 to 18
are suitable for forming o/w emulsions.
 Hydrophilic-Lipophilic Balance (HLB) System
• Surfactants are characterized according to the
"balance" between the hydrophilic ("water-
loving") and lipophilic ("oil-loving") portions of
their molecules.

• The hydrophilic-lipophilic balance (HLB) number

indicates the polarity of the molecules in an
arbitrary range of 1-40, with the most commonly
used emulsifiers having a value between 1 and 20.

• The HLB number increases with increasing

hydrophilicity.
 Hydrophilic-Lipophilic Balance (HLB) System
• According to the HLB number, surfactants may be utilized for
different purposes:

Function HLB Range

Antifoaming agent 1 to 3
Emulsifier, water-in-oil 3 to 6
Wetting agent 7 to 9
Emulsifier, oil-in-water 8 to 18
Detergent 13 to 15
Solubilizer 15 to 20
 Hydrophilic-Lipophilic Balance (HLB) System
• The desired HLB numbers can also be achieved by
mixing lipophilic and hydrophilic surfactants. The
overall HLB value of the mixture is calculated as the
sum of the fraction * individual HLB.

• Example: A mixture of 30% Span 80 (HLB=4.3) and

70% Tween 80 (HLB=15) has an overall HLB value
of:
HLB=(0.3 * 4.3) + (0.7 * 15)=11.8.
 Methods of Preparation
• A mortar and pestle is employed frequently in the
extemporaneous preparation of emulsions. It is not a
very efficient technique and is not used on a large
scale. The types of equipment available for preparing
emulsions can be divided into four categories:

• (1) mechanical stirring

• (2) homogenizers
• (3) colloid mills
• (4) ultrasonifiers
 Methods of Preparation
Mechanical Stirring:

• An emulsion may be stirred by means of various

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

• The degree of agitation is controlled by the speed

of impeller rotation, but the patterns of liquid flow
and the resultant efficiency of mixing are
controlled by the type of impeller, its position in
the container, the presence of baffler, and the
general shape of the container.
 Methods of Preparation
Homogenization:

• A homogenizer can be used to produce fine

droplets by first compressing the liquids to high
pressure and then allowing them to escape
gradually past a flat disc held by a strong spring.

• The high shearing stresses produced at pressure

ranging from 500-5000 p.s.i. can produce
extremely fine particles, the size depending on the
viscosity and the interfacial tension of a system.
 Methods of Preparation
Colloid Mills:

• The colloid mills is used primarily for the reduction of

solid particle size and for the dispersion of suspensions
containing poorly wetted solids.

• Such a machine often is used when viscous emulsions are

to be prepared or when other methods are not available.

• The combination of rotator high speed, which produces

extremely high rates of shear, usually results in evolving
heat.
 Methods of Preparation
Ultrasonification:

• The system works very well with fluid of moderate

viscosity, giving extremely fine particle size in
convenient.

• This technique is designed for commercial scale

production of pharmaceutical emulsions.
 Pharmaceutical Applications
• Oral, rectal and topical administration of
oils and oils-soluble drugs.

• Intramuscular injections of some water-

soluble vaccines to provide slow release
and therefore a greater antibody response
and longer lasting immunity.

• Total parenteral nutrition (TPN) makes use

of an emulsion formulations. Sterile oil-in-
water emulsions are used to deliver oily
nutrients intravenously to patients, using
non-toxic emulsifying agents.
 Identification of Emulsion Type
• Miscibility Tests: an emulsion will mix
with a liquid that is miscible with the
continuous phase. Therefore an o/w
emulsion is miscible with water, a w/o
emulsion with an oil.

• Conductivity Measurement: systems

with an aqueous continuous phase will
conduct electricity, whilst systems with an
oily continuous phase will not.

• Staining Tests: filter paper soaked in

cobalt chloride solution and allowed to dry
turns from blue to pink on exposure to
stable o/w emulsions.