Dispersed Systems

DISPERSED SYSTEMS
1. COLLOIDS
2. SUSPENSION
3. EMULSION

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Learning Objectives
• Demonstrate knowledge on the classification and properties of coarse
dispersions

• Classify dispersed systems based on the phases of the components and

based on the size of the dispersed particles

• Apply knowledge of the parameters involved in dispersion destabilization to

recognize and solve dosage form problems
 DISPERSED SYSTEMS

Consist of particulate matter, known as dispersed phase, distributed throughout a

continuous or dispersion medium

Liquid of solid phase dispersed in an external liquid phase

DISPERSED PHASE
may range in size from particles of atomic and molecular dimensions to particles whose
size is measured in millimeters

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 CLASSIFICATION OF DISPERSED SYSTEMS BASED ON PARTICLE SIZE
CLASS PARTICLE SIZE CHARACTERISTICS EXAMPLES
MOLECULAR < 1 nm Invisible in electron microscope Oxygen molecules, ordinary
DISPERSION Pass through ultrafilter and semipermeable ions, glucose
membrane
Undergo rapid diffusion
COLLOIDAL 1 nm – 0.5 μm Not resolved by ordinary microscope Colloidal silver sols, natural
DISPERSION Visible in electron microscope and synthetic polymers,
Pass through filter paper cheese, butter, jelly, paint,
Do not pass semipermeable membrane milk, shaving creams
Diffuse very slowly
COARSE > 0.5 μm Visible under microscope Grains of sand, most
DISPERSION Do not pass through normal filter paper pharmaceutical emulsions and
Do not dialyze through semipermeable suspensions, red blood cells
membrane
Do not diffuse

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 DISPERSE SYSTEMS

COLLOIDS

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 COLLOIDS

‘colloid’ Greek work kola (glue)

- Coined from the impression that colloidal substances were amorphous or glue-like
rather than crystalline forms of matter

Thomas Graham (1861) : first recognized

Wolfgang Ostwald: described colloids as world of neglected dimensions

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 TYPES OF COLLOIDAL DISPERSIONS ACCORDING TO STATE OF PHASES

DISPERSION MEDIUM DISPERSED PHASE COLLOID TYPE EXAMPLES

SOLID SOLID solid sol pearls, opals

SOLID LIQUID solid emulsion cheese, butter

SOLID GAS solid foam pumice, marshmallow

LIQUID SOLID sol, gel jelly, paint

LIQUID LIQUID emulsion milk, mayonnaise

whipped cream, shaving

LIDUID GAS foam
cream

GAS SOLID solid aerosols smoke, dust

GAS LIQUID liquid aerosols clouds, mist, fog

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 CLASSIFICATION OF COLLOIDAL DISPERSIONS
LYOPHILIC AND LYOPHOBIC
1. Hydrophilic
1. Macromolecular dispersions or Colloid Solution: solvate by their medium
but their size places them in the colloidal range
• [proteins such as albumin and gelatin; polysaccharides such as natural gums and
semisynthetic cellulose derivatives; albumin or hydroxyethyl starch IV]
2. Crystalloid Solutions: true solutions of smaller molecules such as
electrolytes
• [sodium chloride or lactated Ringer’s solution]
2. Hydrophobic
1. Do not have enough surface hydrophilicity to enable them to interact well
with water
2. (-) tendency to aggregate in an aqueous environment
• [milk, IV lipid emulsions, nanocrystal suspensions]

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 CLASSIFICATION OF COLLOIDAL DISPERSIONS
ASSOCIATION COLLOIDS
• Formed by the association of dissolves molecules of a substance to create
particles of colloidal dimensions
• [surfactant micelle, liposomes, microemulsions
• Microemulsion
• Dispersion of oil droplets in water (or water-in-oil)
• Differ from conventional emulsions in that the droplets are much smaller
• Dispersions are transparent
• Considered thermodynamically stable
• Self-emulsifying
• Oil + surfactant + co-surfactant (4-7 chain alcohol)

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 CLASSIFICATION OF COLLOIDAL DISPERSIONS
COARSE DISPERSIONS
• Emulsion
• Mixtures of immiscible liquids in which one phase is dispersed as droplets
within another phase
• o/w: oral
• w/o: topical

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 CLASSIFICATION OF COLLOIDAL DISPERSIONS
COARSE DISPERSIONS
• Suspension
• Coarse dispersions where drug crystals are suspended in a medium in which
they are insoluble

3 – 5 μm Pulmonary inhalation suspensions (for deep lung penetration)

(lower end)
(upper end) Oral suspensions
< 100 μm Dermatologicals (to minimize palpability)
< 10 μm Ophthalmics (to minimize palpability and facilitate dissolution)

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PHYSICAL STABILITY OF DISPERSED SYSTEMS
DISPERSION UNIFORMITY

BROWNIAN MOTION
↓ Temperature ↓ Brownian Motion
↑ Particle Size ↓ Brownian Motion
↑ Viscosity ↓ Brownian Motion

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 STOKES’ EQUATION
Derived for an ideal situation in which uniform, perfectly spherical particles in very dilute
..
suspension settle without producing turbulence, without colliding with other particles of
the suspensoid, and without chemical or physical attraction or affinity for the dispersion
medium
𝑑𝑥 𝑑 2 𝜌𝑖 − 𝑝𝑒 𝑔
=
𝑑𝑡 18𝜂
dx/dt Rate of settling
d Diameter of the particles
ρi Density of the particle
ρe Density of the medium
g Gravitational constant
η Viscosity of the medium 14
 STOKES’ EQUATION

dx/dt Rate of settling

𝑑𝑥 𝑑2 𝜌𝑖 − 𝑝𝑒 𝑔 d Diameter of the particles
= ρi Density of the particle
𝑑𝑡 18𝜂
ρe Density of the medium
g Gravitational constant
η Viscosity of the medium

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 STOKES’ EQUATION
A powder has a density of 1.3 gg/cc and an average particle diameter of 2.5 μg (assuming
..
the particles to be spheres). According to Stokes’ equation, this powder will settle in
water (viscosity of 1 cP assumed) at this rate:
−4 2
𝑑𝑥 (2.5 𝑥 10 ) 1.3 − 1.0 980
= = 1.02𝑥10 − 4𝑐𝑚/𝑠
𝑑𝑡 18𝑥 0.01
If particle size of the powder is reduced to 0.25μm and water is still used as the dispersion
medium, the powder will now settle at this rate:
−5 2
𝑑𝑥 (2.5 𝑥 10 ) 1.3 − 1.0 980
= = 1.02𝑥10 − 6𝑐𝑚/𝑠
𝑑𝑡 18𝑥 0.01

↓factor of 10 ↓102
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 STOKES’ EQUATION
If a different dispersion medium, such as glycerin is used, a further decrease in settling
..
will result. Glycerin has a density of 1.25 g/mL and viscosity of 400 cP. The large particle
size powder will settle at this rate:
−4 2
𝑑𝑥 (2.5 𝑥 10 ) 1.3 − 1.25 980
= = 4.25𝑥10 − 8𝑐𝑚/𝑠
𝑑𝑡 18𝑥 4
The smaller particle size (0.25μm) powder will not settle at this rate

𝑑𝑥 (2.5 𝑥 10−5 )2 1.3 − 1.25 980

= = 4.25𝑥10 − 10𝑐𝑚/𝑠
𝑑𝑡 18𝑥 4

A change in dispersion medium results in the greatest change

in the rate of settling particles
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 PHYSICAL STABILITY OF DISPERSED SYSTEMS
DISPERSION UNIFORMITY

GRAVITATIONAL FORCES
*FOR PARTICLES LARGER THAN COLLOIDAL DIMENSIONS (INCLUDE AGGREGATES OF COLLOIDAL PARTICLES)
↑ Particle Size ↑ Sedimentation rate
↑ viscosity ↓ sedimentation rate
↑ ρ1 – ρ2 ↑ sedimentation rate

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 PHYSICAL STABILITY OF DISPERSED SYSTEMS
DISPERSION PARTICLE GROWTH
Aggregation and its consequences (reversible or irreversible)
• Particles at the surface (interfacial molecules) will possess a lesser overall
binding energy, which corresponds to a positive surface energy

↑ # of particles at
↓Particle Size ↑ Surface Area
interface
↑ Free Energy

If particle size decreases, free energy increases driving particles to aggregate

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 PHYSICAL STABILITY OF DISPERSED SYSTEMS
DISPERSION PARTICLE GROWTH
Aggregation and its consequences (reversible or irreversible)
• Particles at the surface (interfacial molecules) will possess a lesser overall
binding energy, which corresponds to a positive surface energy

↑ # of particles at
↓Particle Size ↑ Surface Area
interface
↑ Free Energy

If particle size decreases, free energy increases driving particles to aggregate

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 EMULSION STABILITY

AGGREGATION of droplets

Irreversible uniting of
droplets COALESCENCE

Complete phase
separation BREAKING

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 SUSPENSION STABILITY

AGGREGATION of crystals

Permanent uniting of crystals

CAKING

If attractive forces between particles dominate over repulsive forces, particles

may aggregate.
But, if repulsive forces dominate, then aggregation can be prevented unless those
forces are overcome.

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 DISPERSE SYSTEMS

SUSPENSION

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 SUSPENSION

Preparations containing finely divided drug particles (suspensoid), distributed somewhat

uniformly throughout a vehicle in which the drug exhibits a minimum degree of solubility

AVAILABLE AS:
• Ready to use form “Oral Suspension”
• Dry powders intended for suspension in liquid vehicles
• For drugs that are unstable if maintained for extended periods in the presence of an aqueous vehicle,
ex: antibiotic drugs “for Oral Suspension”

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 REASONS FOR SUSPENSIONS

• Drugs that are chemically unstable in solution but stable when suspended
• Patients who prefer liquid form over solid form, difficulty in swallowing
• Drugs with disagreeable taste in solution

Example – ERYTHROMYCIN ESTOLATE

Less water-soluble ester form of erythromycin used to prepare a palatable liquid dosage form of erythromycin
Erythromycin Estolate Oral Suspension, USP

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 DESIRABLE QUALITIES

1. A properly prepared pharmaceutical suspension should settle slowly and should be

readily redispersed upon gentle shaking of the container.

2. The particle size of the suspensoid should remain fairly constant throughout long
periods of undisturbed standing.

3. The suspension should pour readily and evenly from its container.

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 CLASSIFICATION OF SUSPENSIONS
FLOCCULATED
aggregation of particles in a flocculated
suspension will lead to a much more rapid rate
of sedimentation because each unit is
composed of many individual particles, larger.
The intentional formation of a less rigid or loose
aggregation of the particles held together by
weak bonds is method to prevent caking – floc
or a floccule
floccules have porous loose structure and the
dispersion medium can flow through them during
sedimentation;can entrap a large amount of the
liquid phase; the volume of the final sediment
will still be large and will easily be redispersed
by moderate agitation
Although flocs settle more rapidly than individual
discrete particles, flocculated particles forming a
type of lattice that resists complete settling and
thus are less prone to compaction and cake
formation than unflocculated particles
DEFLOCCULATED
dispersed particles remain as discrete separated
units and settling will be slow
the supernatant of this suspension will continue
to remain cloudy for an appreciable time after
shaking, due to the very slow settling rate of the
smallest particles in the product
the slow rate of settling prevents the entrapment
of liquid within the sediment, which thus
becomes compacted and can be very difficult to
redisperse
CAKING the most serious of all the physical
stability problems encountered in suspension
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 DISPERSE SYSTEMS

EMULSION

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 EMULSION

A dispersion in which the dispersed phase is composed

of small globules of a liquid distributed throughout a
vehicle in which it is immiscible

Dispersed Phase = Internal Phase

Dispersion Medium = Continuous Phase

Emulsifying Agent
third phase, needed to prepare a stable emulsion

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 REASONS FOR EMULSIONS

• enables pharmacist to prepare relatively stable and homogeneous

mixtures of two immiscible liquids

• permits administration of liquid drug in the form of minute globules

rather than in bulk

• (o/w) permits palatable administration of other wise distasteful oil by

dispersing it in a sweetened, flavored aqueous vehicle

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 THEORIES OF EMULSIFICATION

1. Surface Tension Theory

2. Oriented Wedge Theory
3. Plastic or Interfacial Film Theory

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 TYPES OF EMULSION
EMULSION TYPE INTERNAL PHASE EXTERNAL PHASE
Simple Emulsions (Macro)
Oil-in-water Oleaginous Aqueous
Water-in-oil Aqueous Oleaginous
Multiple Emulsions
Oil-in-water-oil
Water-in-oil-in-water
Micro Emulsions

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MULTIPLE EMULSION

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 TYPE IDENTIFICATION TESTS
VISIBLE RESULT
TEST REAGENT USED
O/W W/O
..
Oil soluble dye (sudan Scarlet globules, clear Scarlet background, clear
red, scarlet red) background globules
DYE TEST
Water soluble dye Clear globules, green Green background, clear
(amaranth green) background globules
Water separate out as a
DILUTION TEST Water to dilute Diluted with water
layer
ELECTRICAL
Bulb and electrode Bulb glows Bulb does not glow
CONDUCTIVITY TEST
FLUORESCENCE TEST UV light Spotty pattern Fluorescence
Cobalt chloride (water
COBALT CHLORIDE TEST soluble) coated filter Blue to pink Pink spots
paper

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HYDROPHILE LIPOPHILE BALANCE

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 HLB SYSTEM

HLB (Hydrophile-Lipophile Balance) is an empirical

expression for the relationship of the hydrophilic
("water-loving") and hydrophobic ("water-hating")
groups of a surfactant

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 HLB SYSTEM

The HLB of an emulsifier is an expression of its

Hydrophile-Lipophile Balance: the balance of the size
and strength of the hydrophilic (water loving or polar)
and the lipophilic (oil loving or non polar) groups of the
emulsifier

All emulsifiers consist of a molecule that combines both

hydrophilic and lipophilic groups

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 HLB SYSTEM

LIPOPHILIC EMULSIFIER: assigned a low HLB number (below 9.0)

HYDROPHILIC EMULSIFIER: assigned a high HLB number (above 11.0)
intermediate: (9-11)

The higher the HLB value, the more water-soluble the surfactant

w/o emulsions require low HLB values

o/w emulsions require higher HLB

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 HLB SYSTEM

The HLB of a blend is an excellent indication of what the emulsifier system

will do, that is, whether it will make an oil-in-water (O/W) emulsion or a
W/O emulsion or act as a solubilizer for some oil

EMULSION TYPE INTERNAL PHASE

3–6 w/o emulsifiers
7–9 Wetting agents
8 – 18 o/w emulsifiers
13 – 16 Detergents
15 – 20 Solubilizers

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 HLB SYSTEM

Wetting agents are surfactants with HLB values of 7 to 9. Wetting agents aid in attaining
intimate contact between solid particles and liquids.

Emulsifying agents are surfactants with HLB values of 3 to 6 or 8 to 18. Emulsifying agents
reduce interfacial tension between oil and water, minimizing surface energy through the
formation of globules.

Detergents are surfactants with HLB values of 13 to 16. Detergents will reduce the surface
tension and aid in wetting the surface and the dirt. The soil will be emulsified, and
foaming generally occurs and a washing away of the dirt.

Solubilizing agents have HLB values of 15 to 20.

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 HLB SYSTEM

When two or more emulsifiers are blended, the resulting HLB of the blend
is easily calculated.

For example, suppose you want to determine the HLB value of a blend
comprising 70% of TWEEN 80 (HLB = 15) and 30% of SPAN 80 (HLB = 4.3).

TWEEN 80 70% x 15.0 = 10.5

SPAN 80 30% x 4.3 = 1.3
HLB of blend = 11.8

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 HLB SYSTEM

If 20 mL of an HLB of 9.0 is required, two surfactants (with HLB values of

8.0 and 12.0) can be blended in a 3:1 ratio.

The following quantities of each will be required:

0.75 × 8.0 = 6.0

0.25 ×12.0 = 3.0
Total HLB = 9.0

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 HLB SYSTEM
RELATIONSHIP TO SOLUBILITY
An emulsifier having a low HLB will tend to be oil-soluble

An emulsifier having a high HLB will tend to be water-soluble

Although, two emulsifiers may have the same HLB and yet exhibit quite
different solubility characteristics

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 HLB SYSTEM
RELATIONSHIP TO SOLUBILITY

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 HLB SYSTEM
REQUIRED HLB FOR INGREDIENT BLENDS
For example, suppose you are making an O/W emulsion textile lubricant. The
product might be 30% mineral spirits, 50% cottonseed oil and 20% chlorinated
paraffin to be emulsified in water. The required HLB of the combination can be
calculated as follows:
Mineral Spirits ..........30% X Req. HLB 14 = 4.2
Cottonseed Oil ..........50% X Req. HLB 6 = 3.0
Chlorinated Paraffin . . 20% X Req. HLB 14 = 2.8
Estimated HLB for emulsifier system ..........10.0
You should check this estimated value with a few exploratory tests in the range of say 9-11, but you
know from this calculation that emulsifier combinations in this range will probably give best
results.

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