Chapter 7

Pharmaceutical Suspensions
 Pharmaceutical Suspensions
Outline
o Introduction
o Desirable properties
o Classification
o Interfacial properties
o Sedimentation
o Ingredients
o Formulation approaches
o Rheology
o Preparation
o Labeling and storage
 Dispersed system
 A dispersed system is a type of system in which one
substance (the dispersed phase) is distributed throughout
another substance (the continuous phase) in the form of
particles, droplets, or bubbles.
 A dispersed system is a heterogeneous mixture consisting of
two phases:
• A dispersed phase (also called internal phase) — the
substance that is distributed
• A continuous phase (also called external phase) — the
substance in which the dispersed phase is distributed
 Dispersed system
• Dispersed systems
 Are systems which consist of:
• Particulate matter

(dispersed phase)
– It is the component
present in small
proportion and is
just like a solute in a
solution
• Dispersion medium
Dispersion Dispersed
(continuous phase) medium phase
excess and is just like a
–A component
solvent in a solution Suspension
present in Emulsion
Colloids
 Pharmaceutical Suspensions
Introduction
o Suspensions are preparations containing:
• finely divided drug particles (the suspensoid) distributed somewhat
uniformly throughout a vehicle in which the drug exhibits a
minimum degree of solubility.
Suspensoid = dispersed phase = internal phase
Vehicle = dispersion medium = external or continuous phase
o may be presented as:
• ready to-use form, or
• dry powders for suspension (reconstitution)
E.g. many antibiotic drugs (“for Oral Suspension”)
 Pharmaceutical Suspensions
Introduction…
o Depending on particle size of dispersed phase:

• Coarse dispersions (10–50 μm): suspensions and emulsions

• Fine dispersions (0.5–10 μm):Colloidal dispersions (1.0

nm and 0.5 μm) Milk, Soap solution, Gelatin in water
• Suspensions can be administered through

d/t routes:

oral, parental, ophthalmic, aerosol, and topical…

 Pharmaceutical Suspensions
Introduction…
Reasons
o Easier administration: some patients have difficulty of swallowing
o Stability: certain drugs are chemically unstable in solution but stable
when suspended.
o Palatability: disagreeable taste of certain drugs in solution form is
overcome when the drug is administered as an oral suspension.
• Reduced Solubility = Reduced Taste Exposure
E.g. Erythromycin estolate, Chloramphenicol palmitate
o Higher bioavailability:
• Solution > Suspension > Capsule > Compressed Tablet > Coated
tablet
 Pharmaceutical Suspensions
Introduction…
Limitations
o Physical instability: sedimentation can cause problems.
o It is bulky: sufficient care must be taken during handling and
transport.
o It is difficult to formulate
o Uniform and accurate dose can not be achieved unless suspensions
are packed in unit dosage form.
 Pharmaceutical Suspensions
Desirable properties
o An ideal suspension:
• Should settle slowly and should be readily redispersed upon gentle
shaking of the container.
• the particle size of the suspensoid should remain fairly constant
throughout long periods of undisturbed standing.
• physically, chemically, and biologically stable
• the suspension should pour readily and evenly from its
container.
 These properties depend on the nature of the dispersed phase,
the dispersion medium, and pharmaceutical adjuncts.
 Pharmaceutical Suspensions
Classification
o Based on route of administration
• Oral suspension: e.g. Paracetamol suspension, antacids
• Externally applied suspension: e.g. Calamine lotion
• Parenteral suspension: e.g. Penicillin G Benzathine, Insulin Zinc
Suspension
o Based on proportion of solid particles
• Dilute suspension (2 to10%w/v solid): e.g. cortisone acetate
• Concentrated suspension (up to 50%w/v solid): e.g. zinc oxide
suspension
 Pharmaceutical Suspensions
Classification…
o Based on the ease of suspendability:
i. Diffusible suspensions
 Contain light powders (insoluble, or only very
slightly soluble) but after shaking disperse evenly
throughout the vehicle for long enough
• Examples:
 Light Kaolin BP (insoluble in water)
 Light Magnesium Carbonate BP (very slightly soluble)
 Magnesium Trisilicate BP (insoluble)
 Pharmaceutical Suspensions
Classification…
o Based on the ease of suspendability:

ii. In-diffusible suspensions

 contain heavy powders that are insoluble in the
vehicle and on shaking do not disperse evenly throughout
the vehicle long enough.

Examples: Aspirin BP, Calamine BP, Zinc Oxide BP

 Pharmaceutical Suspensions
Classification…
o Based on size of solid particles
• Coarse suspensions: suspended particle sizes of 1 to 100 µm
• Colloidal suspensions: suspended particle sizes of 1 nm to 1 µm.
• Nano suspensions: suspended particle sizes of < 1 nm
o Based on Electrokinetic Nature of solid particles
• Flocculated suspension
• Deflocculated suspension
 Pharmaceutical Suspensions
Interfacial properties
Zeta potential, or ζ
o Zeta potential is a measure of the magnitude of the electrostatic
or charge repulsion/attraction between particles and is
one of the fundamental parameters known to affect stability.
o Zeta potential is a scientific term used to describe the electric
potential at the boundary layer between the surface of a particle
and the surrounding fluid.
 High zeta potential (positive or negative) → strong repulsion
between particles → stable suspension (less aggregation).
 Low zeta potential (near 0 mV) → weak repulsion →
flocculation or aggregation.
 Pharmaceutical Suspensions
Interfacial properties
Zeta potential, or ζ
o if the zeta potential is reduced below a certain value,
the attractive forces exceed the repulsive forces, and the
particles come together.
 this phenomenon is known as flocculation
(opposite is deflocculation.
the system is flocculated (the opposite is
deflocculated).
o Thus the phenomenon of flocculation and deflocculation depends
on zeta potential carried by particles.
 Pharmaceutical Suspensions
Interfacial properties…
Flocculated systems
o In flocculated suspensions,
• zeta potential is lower than critical values.
• The week Vander walls force greater than the repulsion,
force
 as a result the attractive forces > repulsive forces
 this leads to flocculation (formation of
flocs (loose aggregates)). (between distance 10-
20nm)
• the formed flocs will cause increase in sedimentation rate
due to increase in size of sedimenting particles.
• hence, flocculated suspensions sediment more rapidly.
 Pharmaceutical Suspensions
Interfacial properties…
Deflocculated systems
o In deflocculated suspensions,
• zeta potential is higher than critical value (30mV) so that the
repulsive forces dominate the attractive forces.
• particles remain suspended for a long period of time, and only a
small portion of the solid is found in the sediment due to the force of
gravity.
• individual particles are settling.
• Sedimentation height(volume) is very low
• rate of sedimentation is slow, which prevents entrapping of liquid
medium which makes it difficult to re-disperse by agitation.
this phenomenon is called ‘caking’ or ‘claying’.
 Pharmaceutical Suspensions
Interfacial properties…
Flocculated Deflocculated
1. Particles form loose aggregates and 1. Particles exist as separate entities
form a network like structure
2. Rate of sedimentation is high 2. Rate of sedimentation is slow
3. Sediment is rapidly formed 3. Sediment is slowly formed
4. Sediment is loosely packed and 4. Sediment is very closely packed
doesn’t form a hard cake and a hard cake is formed
5. Sediment is easy to redisperse 5. Sediment is difficult to
6. Suspension is not pleasing in redisperse
appearance 6. Suspension is pleasing in
7. The floccules stick to the sides of the appearance
bottle 7. They don’t stick to the sides of the
bottle
 Pharmaceutical Suspensions
Sedimentation parameters
Sedimentation rate
o The various factors involved in the rate of settling of the particles of

𝑑 2 𝑖 − 𝑒
a suspension are embodied in the equation of Stokes law.
= 𝑑
𝑥
𝑑 𝑔 18
Where, 𝑡
• dx/dt is the rate of settling
• d is the diameter of the particles
• i is the density of the particle
• e is the density of the medium
• g is the gravitational constant, and
•  is the viscosity of the medium
 Pharmaceutical Suspensions
Sedimentation…
Sedimentation rate…
o Factors to be adjusted to enhance the physical stability of a suspension:
• Particle size: a decrease in particle size by a factor of 10 results in a
reduction in the rate of settling by a factor of 100.
• density and viscosity of the medium:
 using other vehicles (e.g. glycerin:  = 400 cP;  = 1.25 g/mL)
 adding viscosity enhancers
Limitations of Stock’s law:
• particles are uniform, perfectly spherical in a very dilute conc.
• no turbulence, collision with other particles, and
• no chemical or physical attraction or affinity for the dispersion
medium
 Pharmaceutical Suspensions
Sedimentation…
Sedimentation volume
o is the ratio of the equilibrium volume of the sediment, Vu, to the
total volume of the suspension , Vo
𝑭= 𝑽𝒖
= 𝑯𝒖
𝑽𝟎 𝑯𝟎
o F has values ranging from less than one to greater than one.
o When Vu < Vo F<1
• When Vu = Vo, F =1, flocculation equilibrium, shows
no sedimentation (no clear supernatant on standing).
 Pharmaceutical Suspensions
Sedimentation…
Sedimentation volume…

Deflocculated suspension: F∞ = 0.15; Flocculated suspension: F = 0.75; β = 5.0.

• When Vu > Vo, F>1

– Sediment volume is greater than the original volume due to

the network of flocs formed in the suspension is so
loose and fluffy that the volume they encompass is
greater than the original volume of the suspension.

– needs extra vehicle to contain the sediment when F > 1

2/20/2023 22
2/20/2023 23
 Pharmaceutical Suspensions
Sedimentation…
Degree of flocculation
o degree of flocculation, , is a better parameter for comparing
flocculated systems.
o it relates the sedimentation volume of the flocculated suspension, F,
to the sedimentation volume of the suspension when deflocculated,
F.
= 𝑭𝒖
𝑭
o shows the increased sediment volume resulting from
flocculation.
• if, for example,  has a value of 5.0
• the minimum value of ß is 1, when flocculated suspension sedimentation
volume is equal to the sedimentation volume of deflocculated
suspension.
o formulations with larger values of  are selected if the aim is
Example 1:
Determine the sedimentation volume of a 2.5% w/v suspension of
paracetamol in water. The initial volume of the suspension was 100 mL
while the final volume of the sediment was found to be 44 mL. If the
degree of flocculation is 1.5, what is the deflocculated sedimentation
volume?

Example 2:
A 200 mL of suspension of a drug in water was made and the final volume
of the sediment was found to be 60 mL. Calculate the sedimentation
volume and deflocculated sedimentation volume if the degree of
flocculation is found to be 1.3.

2/20/2023 25
 Pharmaceutical Suspensions
Ingredients
o Suspending agent: form colloidal dispersion with water and increase
the viscosity of the continuous phase.
• Preferred suspending agents are those that give thixotropy to the
media such as Xanthan gum, Carageenan, Na CMC.
o Wetting agent (surfactants; HLB value of 7-9): increase wettability
• alcohol, glycerin, and propylene glycol may be used sometimes in
the initial stages to disperse
o Buffers: control the pH: acetate, phosphate, citrate, carbonate
o Osmotic agents: added to render osmotic pressure comparable to
biological fluids: NaCl, mannitol, dextrose
 Pharmaceutical Suspensions
Ingredients…
o Preservatives: to prevent microbial contamination: Benzalkonium
chloride, Benzoic acid, Butyl paraben
o Flavoring and coloring agents: added to increase patient
acceptance: Anise oil, Thyme oil, Titanium dioxide (white),
Brilliant blue (blue), Indigo
carmine(blue), Amaranth (red)
o Sweetening Agents: sucrose, sorbitol, sodium saccharin, Aspartame
o Humectants: prevent evaporation of water: propylene glycol ,
glycerol
o Antioxidant: prevent oxidation: ascorbic acid, Sodium bi sulfite,
BHT, BHA
 Pharmaceutical Suspensions
Formulation approaches
o Three approaches: depending on whether the suspension
is flocculated or deflocculated.

Using structured vehicle

Controlled flocculation

Combination of both of the methods

 Pharmaceutical Suspensions
Formulation approaches…
Structured vehicles
o are also called thickening or suspending agents.
o are aqueous solutions of natural and synthetic polymers
o are used to increase the viscosity of the suspension.
o they entrap and reduce the sedimentation of suspended particles.
E.g. methyl cellulose, sodium carboxy methyl cellulose, acacia, gelatin
and tragacanth, bentonite, carbomer
Caution: too much viscosity is not required as it causes:
• Difficulty of shaking
• difficulty in pouring and administration.
• may affect drug absorption since they adsorb on the surface of
particle and suppress the dissolution rate.
 Pharmaceutical Suspensions
F o r m u la t io n a p p r o aches…
Con tr o l le d fl o c cu l a ti o n

o Controlled flocculation of particles is obtained by adding flocculating

agents:
• Electrolytes: are probably the most widely used flocculating agents.
 act by reducing the electrical forces of repulsion between particles,
thereby allowing the particles to form the loose flocs.
 Cationic (for organic substances) or anionic electrolytes (for
minerals)
• Surfactants: Ionic detergents can produce flocculation by
neutralization of the charges on the surface of the drug particle.
• Polymers: generally less well understood than flocculation by
electrolytes
their successful use as flocculants may require trial and error in order
to identify optimal selection of a polymer and an appropriate
concentration.
 Pharmaceutical Suspensions
Formulation approaches…
Flocculation in structured vehicles
o Sometimes suspending agents can be added to flocculated
suspension to retard sedimentation (if F is not close or equal to 1).
o Examples of these agents are: Carboxymethylcellulose (CMC),
Carbopol, Veegum, tragacanth, and bentonite have been
employed, either alone or in combination.
o all the structured vehicles in common use are hydrophilic
colloids.
 Pharmaceutical Suspensions
Formulation approaches…
Particles

Addition of wetting agent and dispersion medium

Uniform dispersion of deflocculated particles

Addition of Addition of
Addition of structured
flocculating agent flocculating agent
vehicle

Flocculated
suspension
Deflocculated suspension in Flocculated suspension Addition of structured
structured vehicle as a final as a final product vehicle
product
Flocculated suspension in
structured vehicle as a final
Alternative approaches to the formulation of suspensions product
 Pharmaceutical Suspensions
Preparation
o Small scale preparation of suspensions:

Step 1:
o the insoluble materials are ground (or)
levigated in the mortar to a smooth paste
with a vehicle containing the wetting
agent.
Step 2:
o all soluble ingredients are dissolved in
same portion of the vehicle and added to
the smooth paste to step1 to get slurry.
 Pharmaceutical Suspensions
Preparation…
Step 3: the slurry is transformed to a graduated cylinder, the mortar is
rinsed with successive portion of the vehicle.
Step 4:
o decide whether the solids are suspended in a structured vehicle or
flocculated and then suspended
o add the vehicle containing the suspending agent/ flocculating
agent
o make up the dispersion to the final volume.
WORK DONE!
 Pharmaceutical Suspensions
Rheology
o An ideal pharmaceutical suspension would exhibit thixotropic
properties
o A high apparent viscosity at low rates of shear during storage

• To reduce sedimentation or preferably remain permanently

suspended.
o At higher rates of shear (shaking) of the product to be poured
easily from the container.
o For external use,

• spread easily with out excessive rubbing

• should not be so fluid that it runs off the skin surface.
 Pharmaceutical Suspensions
Rheology…
o For injection
• the product should pass easily through a hypodermic needle.
o In a flocculated system, it may not be sufficient to prevent rapid
settling.
 suspending agents may be used to increase the
apparent viscosity of the system.
o Fluids may have:
• Pseudoplastic
• Plastic
• Thixotropic behavior
 Pharmaceutical Suspensions
Rheology…
o No shear during storage
o High shear is encountered when the container is shaken and the
product is poured from the bottle.
o Pseudoplastic substances: tragacanth, sodium alginate, and
NaCMC
o Thixotropic: bentonite
o Mixture of bentonite and CMC: shows both pseudoplastic and
thixotropic characteristics.
 Such a combination should produce an excellent suspending
medium.
 Pharmaceutical Suspensions
Packaging
o Pharmaceutical suspensions for oral use are generally packed in wide
mouth container having adequate space above the liquid to ensure proper
mixing.

o Generally glass and various grades of plastics are used in packaging

of suspension

o Parenteral suspensions are packed in either glass ampoules or vials.

 Pharmaceutical Suspensions
Labeling and Storage
Labeling:
o Shake well before use
o Do not freeze
o Protect from direct light (for light sensitive drugs)
o In case of dry suspensions powder the specified amount of vehicle
to be mixed may indicated clearly on label.
Storage:
o Stored at controlled temperature from 20-25 0C
o Suspensions should be stored in cool place but should not be kept in
a refrigerator
 Chapter 8

Pharmaceutical Emulsions

Emulsifi
er
 Pharmaceutical Emulsions
Outline
o Introduction
o Theories of emulsification
o Formulation
o Preparation of emulsion
o Emulsion type determination
o Physical instabilities
o Chemical instability
o Microbial instability
o Pharmaceutical applications
 Pharmaceutical Emulsions
Introduction
o An emulsion is a dispersion in which the dispersed phase is composed
of small globules of a liquid distributed throughout a vehicle in
which it is immiscible.
o the dispersed phase is the internal phase, and
o the dispersion medium is the external or continuous phase.
o Oil-in-water (o/w): emulsions with an oleaginous internal phase and an
aqueous external phase.
o Water-in-oil (w/o): emulsions with an aqueous internal phase and an
oleaginous external phase.
 Pharmaceutical Emulsions
Introduction…
o the continuous phase is miscible with like solvents.
 an o/w emulsion may be diluted or extended with water or an aqueous
preparation, and
 a w/o emulsion, may be diluted with an oleaginous or oil-miscible
liquid.
o to prepare a stable emulsion, a third phase, an emulsifying agent,
is necessary.
o Depending on their constituents, the viscosity of emulsions can vary
greatly.
👉Liquids: may be employed orally, topically, or parenterally
👉Semisolids: may be applied topically (certain lotions, liniments,
creams, ointments)
 Pharmaceutical Emulsions
Introduction…

(a) o/w and (b) w/o emulsions

o For oral administration, o/w emulsions are used while for external use,
both o/w and w/o systems can be employed.
o Semisolid emulsions are termed as creams
• O/W creams are less greasy and are easily washable after application.
• W/O creams are greasy, with high apparent viscosity
 have an occlusive effect and are therefore preferred as
moisturizing lotions.
 Pharmaceutical Emulsions
Introduction…
o O/W emulsions are administered by all the major parenteral routes
o W/O emulsions:

• are generally reserved for IM or SC administration where sustained

release is required.
• drug action is prolonged because the drug has to diffuse from the
aqueous dispersed phase through the oil-continuous
environment to reach the tissue fluids.
• are generally of high viscosity: difficult to inject
 Pharmaceutical Emulsions
Introduction…

Multiple emulsions

o are emulsions whose disperse phase contains droplets of another

phase

• an oil droplet enclosing a water droplet may be suspended in water

to form a water-in-oil-in water emulsion (w/o/w)

Use:

as delayed-action drug delivery systems (o/w/o)

lower the viscosity of w/o emulsion (w/o/w)

 Pharmaceutical Emulsions
Introduction…

Classification

o Depending on the size of the droplet:

• Coarse emulsions: 5-20 micro meter

• Micro emulsions: 6-100 nanometer

• Nano emulsions: ˂100 nanometer

 Pharmaceutical Emulsions
Theories of emulsification
o 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
o The most prevalent theories:

• surface-tension theory
• oriented-wedge theory, and
• interfacial film theory
 Pharmaceutical Emulsions
Theories of emulsification: Surface tension theory

o When the liquid is in contact with a second liquid in which it is

insoluble and immiscible, the force causing each liquid to
resist breaking up into smaller particles is called interfacial
tension.
o Substances that reduce this resistance encourage a liquid to break up
into smaller drops or particles.

• surface-active (surfactant) substances lower this tension

 Pharmaceutical Emulsions
Theories of emulsification: Surface tension theory…

o This theory assumes:

• the use of surfactants as emulsifiers and stabilizers:

lowers the interfacial tension of the two immiscible liquids

 reduces the repellent force between the liquids and

diminishes each liquid’s attraction for its own molecules.
 facilitate the breaking up of large globules into
smaller ones, which then have a lesser tendency to reunite
or coalesce.
 Pharmaceutical Emulsions
Theories of emulsification: Oriented-wedge theory
o 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.
• In a system containing two immiscible liquids, the emulsifying
agent is preferentially soluble in one of the two liquids
and becomes more embedded with that phase relative to the
other.
• Many surfactants have a hydrophilic portion and a lipophilic
portion
 Hence, the molecules position or orient themselves into each
phase.
 Pharmaceutical Emulsions
Theories of emulsification: Oriented-wedge theory…
o the wedge shape theory proposes that emulsifiers surround either
oil globules or water globules depending on:
• the shape and size of the molecules
• their solubility characteristics, and,
• thus, their orientation

o emulsifying agent, having a greater hydrophilic character

than hydrophobic character, will promote o/w emulsions.
o w/o emulsions result with the use of an emulsifier that is
more hydrophobic.
 Pharmaceutical Emulsions
Theories of emulsification: Interfacial film theory
o This theory proposes that the emulsifier forms an interface between the
oil and water.
• this film surrounds 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 pliable the film, the greater
the stability of the emulsion.
• Naturally, the surfactant must be available to coat the entire surface
of each drop of internal phase.
o the formation of an o/w or a w/o emulsion depends on the degree
of solubility of the emulsifier in the two phases
Similar to the oriented wedge theory,.
 Pharmaceutical Emulsions
Theories of emulsification…
Which theory best explains a given emulsion?
o None of the emulsion theories, in reality, can individually explain the
mechanism by which the many and varied emulsifiers promote emulsion
formation and stability.
 even within a given emulsion system, more than one of the theories of
emulsification are applicable.
o For instance,

• reducing the interfacial tension is critical during initial formation of an

emulsion
• but the formation of a protective wedge of molecules or
film of emulsifier is equally important for continued emulsion
stability.
 Pharmaceutical Emulsions
Formulation
o When two immiscible liquids are mixed, shaken together or
mechanically agitated both phases tend to form droplets of various
sizes.
o The surface free energy (sum of intermolecular interaction) of the
system, which is dependent on both total surface area and
interfacial tension is raised by the increase in surface area
produced during dispersion.
• Thus, the system becomes thermodynamically unstable, which
results in coalescence of these droplets
o If agitation ceases, coalescence will continue until complete phase
separation, the state of minimum free energy, is reached
 Pharmaceutical Emulsions
Formulation…

o Hence, emulsifying agents are included to prevent coalescence

of emulsion.

• Surfactants’ adsorption at the oil-water interface form

monomolecular films

• Presence of the surfactant monolayer at the surface of the

droplet reduces the possibility of collisions

this helps to maintain the particles in a dispersed

state
 Pharmaceutical Emulsions
Formulation…
o Emulsifiers can be grouped into three groups:

1) surface active agents

2) natural (macromolecular) polymers, and
3) finely divided solids.
o The choice of surfactant depends on its solubility to the phases
o In general, the phase in which the emulsifier is most soluble becomes
the continuous phase
• Hydrophilic surfactants (HLB:9-12)  o/w emulsions
• Lipophilic surfactants (HLB:3-6)  w/o emulsions
 Pharmaceutical Emulsions
Formulation…
Surface active agents
o Surfactants, or amphiphiles, reduce interfacial tension because of their
adsorption at the oil-water interface to form monomolecular films.
• the dispersed droplets are surrounded by a coherent monolayer.
 helps prevent coalescence between two
droplets as they approach one another.
 ideally, such a film should be flexible so that it is
capable of reforming rapidly if broken or disturbed.
o the presence of a surface charge, which will cause repulsion
between adjacent particles, is an additional effect promoting
stability.
 Pharmaceutical Emulsions
Formulation…
Surface active agents…
• Sorbitan esters (Spans): are mixtures of partial esters of sorbitol and its
mono- and dianhydrides with fatty acid.
 they are generally insoluble in
water. Chemical name Commercial HLB
 they are used as w/o emulsifiers name
and as wetting agents. Sorbitan laurate Span 20 8.6
Sorbitan palmitate Span 40 6.7
Sorbitan stearate Span 60 4.7
Sorbitan tristearate Span 65 2.1
Sorbitan oleate Span 80 4.3
Sorbitan trioleate Span 85 1.8
 Pharmaceutical Emulsions
Formulation…
Surface active agents…
• Polysorbates (Tweens): are complex mixtures of partial fatty acid esters of
sorbitol and its mono- and di-anhydrides copolymerized with approximately
20 moles (usually) of ethylene oxide for each mole of sorbitol and its
anhydrides.
 they are generally miscible with water.
 they are used
Chemical as o/w emulsifiers.
name Commercial name HLB
Polyoxyethylene (20) sorbitan laurate Polysorbate (Tween) 20 16.7
Polyoxyethylene (20) sorbitan palmitate Polysorbate (Tween) 40 15.6
Polyoxyethylene (20) sorbitan stearate Polysorbate (Tween) 60 14.9
Polyoxyethylene (20) sorbitan tristearate Polysorbate (Tween) 65 10.5
Polyoxyethylene (20) sorbitan oleate Polysorbate (Tween) 80 15
Polyoxyethylene (20) sorbitan trioleate Polysorbate (Tween) 85 11
 Pharmaceutical Emulsions
Formulation…
Surface active agents…
Required HLB
Required HLB for Required HLB
Ingredients Ingredients
O/W for O/W
Cottonseed oil 6–7 Carbon tetrachloride 16
Petrolatum 8 Lauric acid 16
Mineral oil 10-12 Oleic acid 17
Methyl silicone 11 Required
Ingredients Required
Carnauba wax 12-14 emulsion HLB for O/W HLB for
W/O
Lauryl alcohol 14
Beeswax 9–11 5
Castor oil 14
Paraffin wax 10 4
Kerosene 12-14
Mineral oil 10–12 5–6
Cetyl alcohol 13-16
Lanolin, 12–14 8
Stearyl alcohol 15-16 anhydrous
 Pharmaceutical Emulsions
Formulation…
Surface active agents…
Required HLB…
o Mixtures of surfactants with higher and lower (than required) HLB
values give more stable emulsions than single surfactants.
o HLB of surfactant mixtures can be calculated as:
HLBmixture = 𝑓HLBA + 1−𝑓 HLBB
Where, f is fraction of A and (l - f ) is fraction of B.
E.g. calculate the proportion of Span 60 (HLB = 4.7) and Tween 80 (HLB =

HLBmixture = 4.7x + 1 − x ∗ 15
15.0) required to prepare mixture surfactant with HLB value of 10.

x = 0.485 (fraction of Span 60) and 1-x = 0.515 (fraction of Tween 80)
 Pharmaceutical Emulsions
Formulation…
Surface active agents…
Required HLB…
o When more than one oils are used, Required HLB values for the

𝑊𝑡 𝑜𝑓 𝑜𝑖𝑙 ∗ 𝑅𝐻𝐿𝐵
emulsion can be calculated as:
RHLBmix =
𝑊𝑎𝑙𝑙 𝑜𝑖𝑙𝑠
E.g. the following formula is required to prepare O/W emulsion.
Beeswax…….15g
Ingredient RHLB
Lanolin………10g
Beeswax 15/50 × 9 = 2.70
Paraffin………20g
Lanolin 10/50 × 12 = 2.40
Cetyl alcohol…5g Paraffin 20/50 × 10 = 4.00
What should be total Cetyl alcohol 5/50 × 15 = 1.50
RHLB for this emulsion? Total RHLB = 10.60
 Pharmaceutical Emulsions
Formulation…
Surface active agents…
Required HLB…
How much of surfactant is sufficient?
o amount of surfactant is determined based on formulation studies.
o But, the minimum amount of surfactant mixture (Qs) can be estimated
as:
6(  4
𝑠

Qs = ) +𝑄
10 − 0.5𝑅𝐻𝐿𝐵 10000
Where, s is the density of the surfactant mixture,  is the density of the
dispersed phase, and Q is the percentage of the continuous phase of the
emulsion.
 Pharmaceutical Emulsions
Formulation…
Natural (Macromolecular) polymers
 Multimolecular adsorption and film formation
• Hydrated lyophilic colloids:
 can be regarded as surface active, but they differ from
synthetic surfactant.
• they do not cause an appreciable lowering of interfacial
tension, and
• they form a multi-rather than a monomolecular film at the
interface.
• their action as emulsifying agents is due mainly to the latter effect
because the films thus formed are strong and resist coalescence.
 the significant increase in the viscosity of the dispersion
medium could also improve stability.
 Pharmaceutical Emulsions
Formulation…
Solid particle adsorption
o Finely powdered solid particles which 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 so as to prevent coalescence.

o Powders that are wetted preferentially by water form o/w

emulsion, whereas those more easily wetted by oil form w/o
emulsions.
 Pharmaceutical Emulsions
Formulation…
Table: Emulsifying agents derived from natural products and finely divided solids
 Pharmaceutical Emulsions
Formulation…
Other ingredients
o Antioxidants: butylated hydroxy toulene (BHT) and butylated
hydroxyanisole (BHA)
o Humectants: propylene glycol, glycerol, and sorbitol are often added
to dermatological preparations
o Preservatives: benzoic acid, parahydroxybenzoic acid esters,
phenoxyethanol, Chloroform Water
• W/O emulsions are less susceptible to attack than O/W
emulsions
 because the aqueous continuous external phase can produce ideal
conditions for the growth of bacteria, moulds and fungi.
 Pharmaceutical Emulsions
Formulation…
Other ingredients: Preservatives
o Bacteria can degrade nonionic and anionic emulsifying agents,
glycerin, vegetable gums (as thickeners).
• this results in phase separation, gas and odor formation,
discoloration, changes in rheological properties
o Two phase system: adequate concentration of preservative should be
available in water phase as bacteria mainly grow in aqueous phase
 Therefore, preservative should:
• strongly partition in favor of water
• be in its un-ionized form to penetrate bacterial membrane
• not be bound to other components of the emulsion
 Pharmaceutical Emulsions
Preparation methods
o Emulsions may be prepared in different methods
o Small scale
• a mortar and pestle, a mechanical blender, a homogenizer.
• three main methods of Emulsion Preparation
1. Continental or dry gum method
2. English or wet gum method
3. Bottle method
o Large scale
• Colloid mills, high-pressure homogenizers,
microfluidizers, ultrasonic homogenizers may be used to
prepare an emulsion.
 Pharmaceutical Emulsions
Preparation methods: Dry gum method
o is also referred to as the 4:2:1 (O:W:G) or continental method
Oil - 4 parts by volume
Aqueous phase - 2 parts by volume
Gum - 1 part by weight
o The preparation of an emulsion has two main components:
• Preparation of a concentrate called the ‘primary emulsion’.
• Dilution of the concentrate.
o The proportions are important when making the primary emulsion, to
prevent the emulsion breaking down on dilution or storage.
o NB: 4:2:1 is used for fixed oils while 3:2:1 for mineral oils
 Pharmaceutical Emulsions
Preparation methods: Dry gum method…
E.g What quantities of oil, water, and gum would be required to produce
100 mL of a 20% emulsion of a fixed oil?
o For a 20% emulsion 20mL of the oil in 100mL of emulsion would
be required.
• 4 parts would be equivalent to 20mL of oil.
• 2 parts would be equivalent to 10mL aqueous phase.
• 1 part would be equivalent to 5 g of gum.
o The formula for the primary emulsion would therefore be:
Fixed oil ………... 20 mL
Aqueous phase …. 10 mL
Gum …………….. 5 g
 Pharmaceutical Emulsions
Preparation methods: Dry gum method…

E.g. What quantities of oil, water, and gum would be required

to produce 200 mL of 30% v/v Cod liver oil emulsion?

• 60mL of Cod Liver Oil BP is required, therefore 4 parts

60mL.

• Two parts would be equivalent to 30 ml aqueous phase.

• 1 part would be equivalent to 15 g of gum

o The formula for the primary emulsion would therefore be:
Cod Liver oil …. …60 mL
Aqueous phase …. .30 mL
Gum ………………15 g
 Pharmaceutical Emulsions
Preparation methods: Dry gum method…
Procedure
1.The acacia or O/W emulsifier is triturated with the oil in a dry
mortar, until uniformly mixed.
2. The two parts of water are added all at once.
• Then the mixture is triturated immediately, rapidly and
continuously until the primary emulsion is formed
( 3 min)
 the end point of the preparation could be
noticed when a creamy white and crackling sound or
‘clicking’ sound is observed.
 Pharmaceutical Emulsions
Preparation methods: Dry gum method…
Procedure…
3. Other liquid ingredients that are soluble in the external phase may
then be added.
4. Solid substances such as active ingredient, preservatives,
colorants, and flavoring agent usually dissolved in water then added
to an emulsion.
5. 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.
6. Finally make up to final volume with water
 Pharmaceutical Emulsions
Preparation methods: Wet gum method
o also called English method

o the same proportion of water, gum and oil is used but the process
is different.

o more difficult to use, but produces a more stable product.

o produces O/W emulsion.

 Pharmaceutical Emulsions
Preparation methods: Wet gum method…
Steps:
1. Triturating of acacia with water in a mortar.
2. The oil is added slowly in portions, triturating continuously.
3. The mixture is triturated for several minutes to form the primary
emulsion.
4. Additional water can be added after the primary emulsion is
prepared
5. Other substances may be added.
6. Finally make up to final volume with water.
 Pharmaceutical Emulsions
Preparation methods: Bottle method
o Another variant of the Continental Method
o it is used for volatile oils or oleaginous substances of low viscosity.
1. The powder acacia is placed in a dry bottle.
2. Four parts of oil is then added.
3. The bottle is then capped and shaken.
4. Water is then added immediately in portions, and shaken until
primary emulsion is formed.
6. Additional water can be added after the primary emulsion is
prepared.
5. The other ingredients are added.
6. Finally QS with water to final volume.
 Pharmaceutical Emulsions
Emulsion type determination
o Dye (staining) test
• A small quantity of a water soluble dye such as methylene blue
or amaranth (red) may be dusted on the surface of the
emulsion.
 o/w emulsion: the dye will dissolve and uniformly diffuse
throughout the water.
 w/o emulsion: the particles of dye will lie in clumps on
the surface
o Dilution (miscibility) test:
• dilution of the emulsion with water or oil
 o/w emulsion: the emulsion mixes freely with water
 w/o emulsion: is miscible with oil
 Pharmaceutical Emulsions
Emulsion type determination…
o Conductivity:
• a pair of electrodes connected to an external electric source and
immersed in the emulsion.
 o/w emulsion: a current will pass through the
emulsion and can be made to deflect a voltmeter needle or
cause a light in the circuit to glow.
w/o emulsion: the emulsion fails to transmit the current.
o Fluorescence:
• When oils are exposed to UV rays, they fluoresce.
 o/w emulsion exhibit spotty pattern and w/o
emulsion fluoresce throughout the field.
 Pharmaceutical Emulsions
Emulsion type determination…

o Direction of creaming:

• As oils are lower in density than water:

w/o: droplets will sediment

o/w: there will be upward movement/creaming.

 Pharmaceutical Emulsions
Physical instability

o A stable emulsion may be defined as a system in which the globules:

retain their initial character

remain uniformly distributed throughout the continuous phase

• Different instability problems

• Reversible: such as creaming, sedimentation, and flocculation

• Irreversible: such as coalescence and cracking

 Pharmaceutical Emulsions
Physical instability…

Phase Separation
 Pharmaceutical Emulsions
Physical instability: Creaming
o The disperse phase, according to its density relative to that of
the continuous phase
rises to the top, or
 sinks to the bottom of the emulsion, forming a layer
of more concentrated emulsion.
o Upward creaming:  dispersed phase <  continuous phase (o/w
emulsion), the velocity of the sedimentation becomes
negative.
o Downward creaming:  dispersed phase >  continuous phase (w/o
emulsion), the velocity of the sedimentation becomes positive.
 Pharmaceutical Emulsions
Physical instability: Creaming…
 The rate of creaming can be increased if
the density difference is greater
force of gravity is increased through centrifugation
diameter of the globule is increased
o Creaming is undesirable from a pharmaceutical point of view:
• Creamed emulsion is inelegant in appearance
• Possibility of inaccurate dosage
• Increases the likelihood of coalescence as the globules are close
together in the cream
 Pharmaceutical Emulsions
Physical instability: Creaming…

o Creaming is governed by Stock’s law.

o Rate of sedimentation will be decreased by:

• reduction in the globule size (e.g. by homogenizing the emulsion)

• increasing viscosity of continuous phase (e.g. by using thickening

agents such as tragacanth or methyl cellulose)
• decreasing the density difference between the two phases
 Pharmaceutical Emulsions
Physical instability: Flocculation
o A weak reversible association between emulsion globules separated by
thin films of continuous phase.
• the individual droplets retain their separate identities, but each
floccule or cluster of droplets behaves physically as a
single unit.
• the association arises from the interaction of attractive and
repulsive forces between droplets.
• the cream floccules can be redispersed easily, and a uniform
mixture is reconstituted from a creamed emulsion by agitation.
 b/c the oil globules are still surrounded by a
protective sheath of emulsifying agent.
 Pharmaceutical Emulsions
Physical instability: Coalescence and Breaking
o Coalescence: is the fusion of the droplets, leading to a decrease in their
numbers.
i.e. where dispersed phase droplets merge to form larger droplets.
this may lead to phase separation (breaking or cracking).
o Breaking: the disperse phase coalesces and forms a separate
layer.
• re-dispersion cannot be achieved by shaking and the preparation is
no longer an emulsion.
o Factors:
relative magnitude of forces between droplets
disruption of interface
dehydration, freezing
 Pharmaceutical Emulsions
Physical instability: Coalescence and Breaking…
o Cracking can occur:
• if the oil turns rancid during storage.
• by addition of a chemical that is incompatible with the emulsifying
agent, thus destroying its emulsifying ability.
Eg. Surfactants of opposite ionic charge, (e.g. addition of cetrimide
(cationic) to an emulsion stabilized with sodium oleate (anionic))
o Strategies to reduce coalescence and breaking
adding thickening or gelling agent
increasing thickness of interface
increasing repulsion or reduce attraction
 Pharmaceutical Emulsions
Chemical instability
o Ingredients should be chemically compatible
o Ionic emulsifiers are usually incompatible with materials of opposite
charge
o Precipitation of emulsifiers: by the addition of material in which they
are insoluble
o Changes in pH: breaking of emulsion
o Many of the oils and fats are susceptible to oxidation
 Pharmaceutical Emulsions
Microbial instability
o Growth of MO: is supported by the water component
o Contamination affects the physicochemical properties
• Gas production
• Color and odor change
• Hydrolysis of fats and oils
• pH changes in the aqueous phase
• Breaking of emulsions
Preservative is a must
 Pharmaceutical Emulsions
Microbial instability…
o Desirable features of a preservative
• A wide spectrum of activity: all bacteria, yeast and moulds
• Bactericidal rather than bacteriostatic activity
• Free from toxicity, irritation or sensitization activity
• High water solubility, low oil/water partition coefficient
• Compatible with other ingredients
• Stable and effective over a wide range of pH and temperature
o Benzoic acid, sorbic acid, chlorocresol, methyl paraben and propyl
paraben
 Quizes(10p)

1. Write and explain the three theories of

emulsification.(2.5p)
2. How to prevent creaming?(2p)
3. Enumerate and describe three tests to determine
emulsion.(2.5p)
4. What is the role of emulsifying agent in
emulsion?(1P)
5. What is the difference between W/O and O/W
emulsions?(2p)
Knowledge
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