Coarse Dispersions

Introduction to Disperse Systems

• Disperse systems = heterogeneous, two-phase systems.
• Consist of:
• Dispersed phase (particles/droplets)
• Dispersion medium (continuous phase)

Disperse systems are foundational to many pharmaceutical formulations—

suspensions, emulsions, colloids—and their behavior is governed by the
interaction between phases.

Classification Based on Particle Size

Type Particle Size Example
Molecular Dispersion < 1 nm True solutions
Colloidal Dispersion 1 nm – 1 µm Liposomes, micelles
Coarse Dispersion > 1 µm Suspensions, emulsions

Size governs not just the appearance and stability, but also the application and
processing methods for these systems.
O Based on the size of the dispersed phase, dispersed
systems are generally considered as:
a) Molecular dispersions,
b) Colloidal dispersions,
c) Coarse dispersions.

Less than 1 nm 1 nm to 0.5µm greater than 0.5 µm

Ordinary ions polymers Emulsions/suspensions
Molecular Dispersions
• Homogeneous systems
• Particles are at molecular level
• Thermodynamically stable
• Examples: Saline, glucose in water
These are true solutions and form the baseline for understanding more
complex disperse systems.

Coarse Dispersions
• Droplets/particles > 1 µm
• Thermodynamically unstable
• Require stabilizers
• Examples: Oral suspensions, emulsions
These are common in pharmacy, but they require careful formulation to
prevent sedimentation and phase separation.
 Colloidal Dispersions
• Intermediate particle size (1 nm to 1 µm)
• Appear homogeneous but are heterogeneous
• Exhibit unique optical/electrical/rheological properties
• Examples: Blood, colloidal silver
Colloids bridge the gap between true solutions and suspensions—playing
key roles in biological and pharmaceutical systems.

Classification of Colloids
Colloidal systems are best classified into three groups on the basis of the
interaction of the particles, molecules, or ions of the dispersed phase with
the molecules of the dispersion medium.

• Lyophilic colloids
• Lyophobic colloids
• Association (amphiphilic) colloids
Lyophilic Colloids
• “Solvent-loving”
• Spontaneous formation
• Thermodynamically stable
• Increase viscosity
• Examples: Gelatin, chitosan
o Systems containing colloidal particles that interact to an appreciable
extent with the dispersion medium.
o Also known as solvent-loving colloids.
o Owing to their affinity for the dispersion medium, such materials
form colloidal dispersions, or sols, (Sol is the colloidal dispersion of a
solid in liquid or gaseous medium. Sols are fluid.)
o Lyophilic colloidal sols are usually obtained simply by dissolving the
material in the solvent being used.
o For example, the dissolution of acacia or gelatin in water or celluloid
in amyl acetate leads to the formation of a sol.
The various properties of this class of colloids are due to the
attraction between the dispersed phase and the dispersion
medium, which leads to solvation, the attachment of solvent
molecules to the molecules of the dispersed phase.
In the case of hydrophilic colloids, in which water is dispersion
medium, this is termed as hydration.
Most lyophilic colloids are organic molecules, such as
gelatin hydrophilic sols
acacia Produce lyophilic colloids in aqueous
insulin
Albumin dispersion media

rubber lipophilic colloids

polystyrene They form lyophilic colloids in non-
aqueous, organic solvents
Lyophobic Colloids
• “Solvent-hating”
• Thermodynamically unstable
• Require stabilizers
• Aggregation likely without surface treatment
• Examples: Gold, silver colloids
These systems are only kinetically stable and need formulation aids like
surfactants to maintain dispersion.

O These colloids are composed of materials that have little attraction for the
dispersion medium, also called as solvent-hating colloids and they are
hydrophobic
O Their properties differ from those of the lyophilic colloids; primary difference is
due to the absence of a solvent sheath around the particle.
O They are generally composed of inorganic particles dispersed in water, such
as
Gold
Silver
Sulfur
Arsenous sulfide
In contrast to lyophilic colloids, it is necessary to use
special methods to prepare lyophobic colloids.
These are;

 Dispersion methods
coarse particles are reduced in size
 Condensation methods
materials of subcolloidal dimensions are caused to
aggregate into particles within the colloidal size range.
Dispersion
O Mechanical methods
milling and grinding processes can be used, however
their efficiency is low.
O High-intensity ultrasonic generators
they can operate at frequencies in excess of 20.000
cycles per second and ultrasonic waves occur
O Production of an electric arc within a liquid.
Owing to the intense heat generated by the arc, some
of the metal of the electrodes is dispersed as vapor,
which condenses to form colloidal particles.
Condensation
O Supersaturation

Supersaturation can be provided by a change in

solvent system or reduction in temperature.
O Chemical reactions

Hydrolysis, oxidation or double decomposition can be

used. Bu double decomposition an undissolved salt can
be formed. (Such as colloidal silver chloride)
Preparation of Lyophilic Colloids
• Spontaneous formation
• Hydrophilic macromolecules (e.g., methylcellulose, gums)
• Requires only mixing
These are easy to prepare and form the basis for gels, thickeners, and
stabilizers.
Preparation of Lyophobic Colloids
1. Condensation Methods
1. Chemical reactions (e.g., AgNO₃ + KI → AgI colloid)
2. Change in solvent
2. Dispersion Methods
1. Ultrasonication
2. Colloid milling
• Ultrasonicator: Cavitation leads to particle size reduction
• Colloid mill: Shear force applied between rotor-stator
Lyophobic colloids require more energy or chemical means for formation and
need stabilizers to remain stable.
Comparison of Lyophilic vs Lyophobic Colloids

Property Lyophilic Colloids Lyophobic Colloids

Affinity for Dispersion
High (solvent-loving) Low (solvent-hating)
Medium
Thermodynamically
Stability Thermodynamically stable
unstable
Requires special
Formation Spontaneous
preparation methods
Stable in presence of Easily precipitated by
Effect of Electrolytes
electrolytes electrolytes
Viscosity Increases significantly Little or no change
Gold, sulfur, ferric
Examples Gelatin, acacia, starch
hydroxide
Association Colloids (Micelles)
• Formed by amphiphilic molecules (e.g. surfactants)
• Self-assemble above critical micelle concentration (CMC)
• Micellar solubilization improves drug solubility
These systems are important for solubilizing hydrophobic drugs in aqueous
media.

Association colloids: (a) spherical micelle, (b) cylindrical micelle,

(c) microtubular micelle, (d) flattened disc-shaped micelle.
o When present in a liquid medium at low concentrations, the
amphiphiles exist separately and are of such a size as to be
subcolloidal.
o As the concentration is increased, aggregation, occurs over a
narrow concentration range.
o These aggregates, which may contain 50 or more monomers,
are called Micelles. Because the diameter of each micelle is
of the order of 50Å, micelles lie within the size range we have
designated as colloidal. The concentration of monomer at
which micelles form is termed the critical micelle
concentration (CMC).
o The number of monomers that aggregate to form micelle is
known as the aggregation number of the micelle.
Properties of Colloidal Systems
A. Optical Properties of Colloids
 The Faraday-Tyndall Effect
 Light Scattering

B. Kinetic Properties of Colloids

 Brownian Motion
 Diffusion
 Osmotic pressure
 Sedimentation
 Viscosity
C. Electrical Properties of Colloids
 Electric double layer
 Nernst and Zeta potential
 The Faraday-Tyndall Effect

 When a strong beam of light is passed through a colloidal

sol, a visible cone, resulting from the scattering of light by
the colloidal particles, is formed. This is the Faraday-
Tyndall
 An intense light beam is passed through the sol against a
dark background at right angles to the plane of
observation, and, although the particles cannot be seen
directly, the bright spots corresponding to particles can be
observed and counted.
 The ultramicroscope/electron-microscope can be used to
examine the light points responsible for the Tyndall cone.
Electron microscope resolution is about 0.5 nm (5 Å)
Light Scattering
 This property depends on the Faraday-Tyndall effect
 It is used for determining the molecular weight of
colloids.
 It can also be used to obtain information on the shape
and size of these particles.
 Scattering can be described in terms of turbidity ().

Turbidity
is fractional decrease in intensity due to scattering as the
incident light passes through 1 cm of solution.

 At a given concentration of dispersed phase, the

turbidity is
proportional to the molecular weight of the lyophilic
colloid.
The molecular weight of the colloid can be obtained from the
following equation:

 : the turbidity (cm-1)

c : the concentration of solute in g/cm3 of solution,
M : weight-average molecular weight (g/mol or dalton),
B : interaction constant
H : constant for a particular system

n : refractive index
c : concentration (g/cm3)
λ : wavelength (cm-1)
dn/dc : change in refractive index
with concentration
N : Avogadro’s number.
Kinetic Properties of Colloids
Grouped under this heading are several properties of
colloidal systems that relate to the motion of particles
with respect to the dispersion medium.
The motion may be,
- thermally induced Brownian movement
Diffusion
Osmosis
- gravitationally induced Sedimentation
- applied externally Viscosity
 Brownian Motion

 It describes the random movement of colloidal particles

and may be observed with particles at about 5 µm.
 It was explained as resulting from the bombardment of
the particles by the molecules of the dispersion medium.
 The velocity of the particles increases with decreasing
particle size.
 Increasing the viscosity of the medium decreases and
finally stops the Brownian movement.
  Diffusion

 Particles diffuse spontaneously from a region of higher

concentration to one of lower concentration until the
concentration of the system is uniform throughout.
 Diffusion is a direct result of the Brownian movement.

 According to Fick’s first law;

the amount of substance (dq) diffusing in time (dt) across a plane
of area (S) is directly proportional to the change of concentration
(dc) with distance traveled (dx).
Stokes-Einstein equation
 If the colloidal particles can be assumed to be approximately
spherical, the following equation can be used to obtain the
radius of the particle and the particle weight or molecular
weight:

D: diffusion coefficient (obtained from

Fick’s law) R: molar gas constant,
T: absolute temperature,
η: viscosity of the solvent,
r: radius of the spherical particle,
N: Avogadro’s number.
The measured diffusion coefficient can be used to obtain the
molecular weight of approximately spherical molecules, such
as egg albumin and hemoglobin, by use of the below
equation:

M: molecular weight
ν : the partial specific volume
(approximately equal to the volume in cm3 of 1 g of the solute, as
obtained from density measurements)
Analysis of these equations allows us to formulate the
following three main rules of diffusion:

a) The velocity of the molecules increases with decreasing

particle size,
b) The velocity of the molecules increases with increasing
temperature, and
c) The velocity of the molecules decreases with
increasing viscosity of the medium.
  Osmotic Pressure

The osmotic pressure of a dilute colloidal solution is

described by the Van’t Hoff Equation:

Π: osmotic pressure
c: molar concentration of solute.
R: molar gas constant,
T: absolute temperature,

This equation can be used to calculate the molecular weight of a

colloid in a dilute solution.

For very dilute solutions, the equation can

be converted as:

Here, Cg is the grams of solute per liter of

solution, and M is the molecular weight,
 Sedimentation

The velocity, V, of sedimentation of spherical

particles having a density, ρ, in a medium of
density ρ0 and a viscosity η0 is given by Stoke’s
Law:

where is the acceleration due to gravity. If the

particles are subjected only to the force of gravity,
than the lower size limit of particles obeying
Stokes’s equation is about 0.5 m.
 This is because Brownian movement becomes significant
and tends to offset sedimentation due to gravity and
promotes mixing instead.

 Consequently, a stronger force must be applied to bring

about the sedimentation of colloidal particles in a
quantitative and measurable manner.

 This is accomplished by use of the ultracentrifuge which

can produce a force one million times that of gravity.
 Viscosity

 Viscosity is an expression of the resistance to the flow of

a system under applied stress.
 The more viscous a liquid is, the greater is the applied
force required to make it flow at a particular rate.
 Viscosity studies also provide information regarding the
shape of the particles in solution.
 Einstein developed an equation of flow applicable to
dilute colloidal dispersions of spherical particles,
namely,
In this equation, which is based on
hydrodynamic theory, η0 is the viscosity of the
dispersion medium, and η is the viscosity of the
dispersion when the volume fraction of colloidal
particles present is Φ.

The volume fraction is defined as the volume of

the particles divided by the total volume of the
dispersion. Both η0 and η can be determined using
a capillary viscometer.
 Electrical Properties of Colloids
Particles dispersed in liquid media may become charged
mainly in 3 ways:
1. selective adsorption of a particular ionic species present in
solution. Examples:
- an ion added to the solution
- the hydronium or hydroxyl ion of pure water
2. charges on particles arise from ionization of groups (such as
COOH) that may be situated at the surface of the particle.
In this case, the charge is a function of pK and pH.
3. difference in dielectric constant between the particle and
its dispersion medium could cause a the charge on a
particle surface
  The Electric Double Layer

• Consider a solid surface in contact with a polar solution

containing ions, (for example, electrolyte solution).
• Let us suppose that some of the cations are adsorbed
onto the surface, giving it a positive charge (aa’ layer).

• Anions in the solution will attract to

the positively charged surface by
electric forces (bb’ layer) that also
serve to repel the approach of any
further cations once the initial
adsorption is complete.
As a result, an equilibrium situation is
set up in which some of the excess
anions approach the surface, whereas
the remainder are distributed in
decreasing amounts as one proceeds
away from the charged surface.
aa` is the surface of the solid. The
adsorbed ions give the surface positive
charge. potential-determining ions.

bb` layer is a region of tightly bound

solvent molecules, together with some
negative ions.

 In the region cc`, there is an excess of negative ions.

 Beyond cc`, the distribution of ions is uniform and electric
neutrality is obtained (dd’ layer)
 Thus, the electric distribution at the interface is equivalent
to a double layer of charge, the first layer (aa’ to bb’)
tightly bound and a second layer (from bb’ to cc’) that is
more diffuse.
 The so-called diffuse double layer, therefore, extends
Electrothermodynamic (Nernst) Potential, E,
• The potential at the solid surface
aa’ due to the potential-
determining ions is defined as the
difference in potential between
the actual surface and the
electroneutral region of the
solution.

Electrokinetic, or Zeta,
Potential, ζ.
• The potential located at the shear
plane bb` is defined as the
difference in potential between the
surface of the tightly bound layer
(shear plane) and the
electroneutral region of the
Stability of Colloid Systems
• The presence and magnitude, or absence, of a charge on a
colloidal particle is an important factor in the stability of
colloidal systems.
• Stabilization is accomplished essentially by two means:
1. providing the dispersed particles with an electric
charge
2. surrounding each particle with a protective solvent
sheath that prevents mutual adherence when the
particles collide as a result of Brownian movement.
(This second effect is significant only in the case of
lyophilic sols.)
• A lyophobic sol is thermodynamically unstable. The particles in such
sols are stabilized only by the presence of electric charges on their
surfaces. The like charges produce a repulsion that prevents the
coagulation of the particles.
• The addition of a small amount of electrolyte to a lyophobic sol
tends to stabilize the system by imparting a charge to the particles.

• Addition of electrolyte beyond that necessary for maximum

adsorption on the particles, however, sometimes results in the
accumulation of opposite ions and reduces the zeta potential below
its critical value.
• The critical potential for finely dispersed oil droplets in water (oil
hydrosol) is about 40 millivolts, this high value signifying relatively
great instability.
• The critical zeta potential of a gold sol is nearly zero, which suggests
that the particles require only a minute charge for stabilization;
hence, they exhibit marked stability against added electrolytes.
 DLVO Theory
According to this approach, the forces on colloidal particles in a
dispersion are due to
• electrostatic repulsion and
• London-type Van der Walls attraction.
These forces result in potential energies of repulsion, VR, and
attraction, VA, between particles; together with the curve for the
composite potential energy, VT.
• There is an attraction near the origin
and a high potential barrier of
repulsion at moderate distances. A
secondary trough of attraction (or
minimum) is sometimes observed at
longer distances of separation
between particles.
• The presence of a secondary
minimum is significant in the
controlled flocculation of coarse
dispersions.
Lyophilic and amphiphilic colloids are thermodynamically
stable and exist in true solution so that the system constitutes
a single phase.

The addition of an electrolyte to a lyophilic colloid in moderate

amounts does not result in coagulation, as was evident with
lyophobic colloids.

If sufficient salt is added, however, agglomeration and

sedimentation of the particles may result. This
phenomenon is referred to as “salting out”.
 Sensitization and Protective Colloidal Action
 The addition of a small amount of hydrophilic or
hydrophobic colloid to a hydrophobic colloid of opposite
charge tends to sensitize or even coagulate the particles
due to a reduction of the zeta potential below the
critical value (usually ± 20-50 mV are optimal ).

 A reduction in the thickness of the ionic layer

surrounding the particles and a decrease in the
coulombic repulsion between the particles can also
result in the instability of the hydrophobic particles.
• The addition of large amounts of the hydrophilic colloid
however, stabilizes the system, the hydrophile being
adsorbed on the hydrophobic particles.
• This phenomenon is known as Protection, and the added
hydrophilic sol is known as a Protective Colloid.
• The protective property is expressed most frequently in
terms of the Gold Number.
• The Gold Number is the minimum weight in milligrams of
the protective colloid (dry weight of dispersed phase)
required to prevent a color change from red to violet in 10
mL of a gold sol on the addition of 1 mL of a 10% solution of
sodium chloride.
Pharmaceutical Applications of Colloids
• Colloids are extensively used for modifying the properties of
pharmaceutical agents. The most common property that is
affected is the solubility of a drug.
• However, colloidal forms of many drugs exhibit
substantially different properties when compared with
traditional forms of these drugs.
• Another important pharmaceutical application of colloids
is their use as drug delivery systems. The most often-used
colloid-type drug delivery systems include hydrogels,
microspheres, microemulsions, liposomes,
• micelles, nanoparticles, nanocrystals
• Certain medicinals have been found to possess
unusual or increased therapeutic properties when
formulated in the colloidal state.
• Colloidal silver chloride, silver iodide, and silver protein are
effective germicides and do not cause irritation that is
characteristic of ionic silver salts.
• Coarsely, powdered sulfur is poorly absorbed when
administered orally, yet the same dose of colloidal sulfur
may be absorbed so completely as to cause a toxic reaction
and even death.
• Colloidal copper has been used in the treatment of cancer,
colloidal gold as a diagnostic agent for paresis and colloidal
mercury for syphilis.