PR 1102 Physical Pharmacy

Kang Lifeng
lkang@nus.edu.sg
Disperse System
Disperse System
Dispersed phase
Continuous phase
Interface
Disperse System
Disperse systems consist of particulate matter
(dispersed phase) distributed throughout a
continuous medium
Dispersed material ranges in size, from molecular
dimensions to particles of millimeters
Many biological drugs that have been discovered are
macromolecules that exist in colloidal systems (e.g.
proteins and DNA).
Nanoparticulate systems are also emerging for
improved drug delivery.
Classification by State
a Continuous phase
Gas Liquid Solid
D
i
s
p
e
r
s
e
d

p
h
a
s
e
Gas Nil Foam Solid foam
Liquid Liquid aerosol Emulsion Gel
Solid Sold aerosol Suspension Solid sol
Classification by Particle Size
Class
Particle size
Characteristics of system Examples
Molecular
dispersion
< 10
-9
m Particles invisible in electron
microscope; pass through semi-
permeable membrane; undergo rapid
diffusion
Glucose
injections,
tinctures
Colloidal
dispersion
10
-9
to
10
-7
m
Particles not resolved by ordinary light
microscope although may be detected
under ultra-microscope; pass through
filter paper but do not pass semi-
permeable membrane; diffuse very
slowly
Micro-
emulsions, nano-
particles
Coarse
dispersion
> 10
-7
m Particles visible under microscope; do
not pass through filter paper or semi-
permeable membrane; particles do
not diffuse
Some emulsions
and suspensions
Dispersion Stability
Interactions Between Particles and Medium
Particle movement
Gravitational forces
Drag forces
Dispersed phase
and the continuous
phase interactions
Brownian Motion
Spontaneous, irregular zig-zag movement of
particles because of random collisions with
molecules .
t-timeD-diffusion coefficient; r-average
displacement
Reynolds Number
Re
vr

=
r is the radius of a sphere
v is the velocity of the sphere
is the density of the liquid
is the viscosity of the liquid
Reynolds number measures the relative
importance of inertia and viscosity
For particles on a colloidal scale, Re is small

Stokess Law
6
d
F rv t =
r is the radius of a sphere
v is the velocity of the sphere
is the viscosity of the liquid
F
d
is the drag force
Stokes law is derived from the NavierStokes
equations for small Reynolds numbers.

Einsteins Relation
k
B
is the Boltzmanns constant
D is the diffusion coefficient
T is the temperature
k
drag
is the drag coefficient
B
drag
k T
D
k
=
Stokes-Einstein Equation
If we know the diffusion coefficient D, then
the size of the particle can be estimated by
the Stokes-Einstein equation.
B
drag
k T
D
k
=
6
d drag
F rv k v t = =
6
B
k T
D
r t
=
Rate of Sedimentation
To calculate v when the gravitational and
drag forces are balanced
Smaller particles and higher viscosities give
smaller sedimentation rate
3 3 3
4 4 4
3 3 3
g solid Liquid
F r g r g r g t t t = = A
3
4
6
3
rv r g t t = A
6
d
F rv t =
2
2
9
r g
v
t
t
A
=
One Example: Suppositories
Suppository bases include cocoa butter,
glycerinated gelatin, hydrogenated vegetable
oils, polyethylene glycols
Cocoa butter melt to incorporate fine particles
and then cool in molds. It is a colloid-coarse
disperse system and particles may sediment
Copper sulphate suppository preparation
process: Grind coarse powders, melt base and
incorporate the find powders
Interactions Between Particles
Inter-particle forces
DLVO theory
Zeta potential
Dispersed phase interactions
DLVO Theory
Deryagin-Landau and Verwey-Overbeck
The stability of a particle in solution depends on
its total potential energy function
DLVO Theory
V
T
is the total potential energy
V
A
is the van der Waals attractive energy
V
R
is the electrical repulsive energy
V
S
is the potential energy due to the solvent. It
usually only makes a marginal contribution to
the total potential energy
T A R S
V V V V = + +
Van der Waals Attractive Forces
2
12
A
A
V
d t
=
A is a constant and d is the particle separation
distance. If a repulsion mechanism does not
exist then flocculation will eventually take
place.
Electrostatic Repulsive Forces V
R
2
2
kd
R
V r e tc

=
r is the particle radius, k is a function of the
ionic composition and is the zeta potential

Colloid Stability Mechanism

To Increase Repulsive Forces V
R
Steric repulsion - this involves polymers added
to the system adsorbing onto the particle
surface and preventing the particle surfaces
coming into close contact and at those
separations the van der Waals forces are too
weak to cause the particles to adhere
Electrostatic or charge stabilization - this is the
effect on particle interaction due to the
distribution of charged species in the system
Charged Particle and Zeta Potential
Stern layer
Negatively charged particle
Diffuse Layer
Diffuse layer
Slipping Plane
Hydrodynamic plane
of shear (slipping
plane)
Zeta Potential
Zeta Potential
The zeta potential is the electrical potential at
the hydrodynamic plane of shear
It depends not only on the particle surface but
also on the dispersant
It can be affected by small changes in the pH
or ionic strength of the medium
Particles interact according the magnitude of
the zeta potential, not their surface charge
Therefore, it can be used to predict stability
Significance of Zeta Potential
If all the particles have a large negative or
positive zeta potential they will repel each
other and there is dispersion stability
If the particles have low zeta potential values
then there is no force to prevent particles
coming together and there is dispersion
instability
The dividing line of stable and instable zeta
potential is +30 mV or -30mV
Factors Affecting Zeta Potential
Changes in the pH of the sample
The conductivity of the medium
(concentration and type of salt)
pH Effects on Bovine Serum Albumin
(BSA) Zeta Potential
Stable
Stable
Unstable
Z
e
t
a

P
o
t
e
n
t
i
a
l

(
m
V
)
pH
The rule of thumb of stability +/- 30 mV.
Conductivity Effects on BSA Zeta Potential
Z
e
t
a

P
o
t
e
n
t
i
a
l

(
m
V
)
Concentration (Log(mol/l)
An Example of Liposome
Plasmids Cationic liposome
Plasmid - cationic liposome complex
Liposome Complex Zeta-potential
Molar ratio of Plasmid and liposome
Z
e
t
a

P
o
t
e
n
t
i
a
l

(
m
V
)
P
a
r
t
i
c
l
e

d
i
a
m
e
t
e
r
(
n
m
)
PEG-coated Liposome
PEG Liposome complex
Liposome
Polyethylene glycol (PEG)
Z
e
t
a

P
o
t
e
n
t
i
a
l

(
m
V
)
Ratio of PEG2000
PEG-coated Liposome Zeta-potential
If an electric field is applied across a sample,
charged particles suspended in the mdeium
are attracted towards the electrode of
opposite charge
The particles move with a velocity depends
on: (i)Field strength, (ii) dielectric constant of
medium and (iii) viscosity of the medium and
(iv) zeta potential.
Parameters (i)-(iii) are know, so zeta potential
can be determined
Measure Zeta-potential