+

Diffusion phenomena, Drug

release and dissolution
PhD candidate : Haithem N. Aldeen
Department of Pharmaceutics
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Diffusion
• Diffusion: is a process of mass transfer of
individual molecules of a substance as a
result of random molecular motion.
• The driving force for diffusion is usually the
concentration gradient.
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 Molecular diffusion or permeation through nonporous media depends

on the solubility of the permeating molecules in the bulk membrane

 The passage of a substance through solvent-filled pores of a membrane

and is influenced by the relative size of the penetrating molecules and
the diameter and shape of the pores

 Diffusion or permeation through polymer strands with branching

and intersecting channels. Depending on the size and shape of the
diffusing molecules, they may pass through the tortuous pores
formed by the overlapping strands of polymer. If it is too large for
such channel transport, the diffusant may dissolve in the polymer
matrix and pass through the film by simple diffusion.
+
+ Drug Absorption and Elimination

Passage of Drugs Through Membranes

 Passive diffusion

 Transcellular diffusion (through the lipoidal bilayer of cells)

 Paracellular diffusion (passage through aqueous channels)

 Using membrane transporters

 Facilitated diffusion (energy independent)

 Active transport  (energy dependent)

+
Membrane Transport Mechanisms
I. Passive Transport

 Diffusion- simple movement from regions of high concentration to low

concentration

 Osmosis- diffusion of water across a semi-permeable membrane

 Facilitated diffusion- protein transporters which assist in diffusion

+

Elementary Drug Release

+ Osmosis

The diffusion of water across a selectively permeable membrane.

 
Water moves from a high concentration of water (less salt or sugar dissolved
in it) to a low concentration of water (more salt or sugar dissolved in it). 
This means that water would cross a selectively permeable membrane from a
dilute solution (less dissolved in it) to a concentrated solution (more
dissolved in it).
+
Ultrafiltration and Dialysis

 Ultrafiltration is used to separate colloidal

particles and macromolecules by the use of a
membrane.

 Hydraulic pressure is used to force the solvent

through the membrane, whereas the
microporous membrane prevents the passage
of large solute molecules
 Fick’s laws of diffusion

 Fick’s first law: The amount, M, of material flowing through a

unit cross section, S, of a barrier in unit time, t, is known as the
flux, J:
dM
J equation (1)

The flux, in turn, is proportional to the

S  dt
concentration gradient, dC/dx:
dC
Where: J is flux (g/cm .sec)
2
J  D equation (2)
M is the amount of material flowing (g) dx
S is cross sectional area of flow (cm2)
t is time (sec)
D is the diffusion coefficient of the drug in cm2/sec
dC/ dx is the concentration gradient
C concentration in (g/cm3)
X distance in cm of movement perpendicular to the surface of the barrier
+
 Fick’s first law
dM dC
J J  D Rate of diffusion through unit area
S  dt dx

• The negative sign of equation signifies that diffusion occurs in a

direction opposite to that of increasing concentration.
• That is, diffusion occurs in the direction of decreasing concentration
of diffusant; thus, the flux is always a positive quantity.
• The diffusion coefficient, D it does not ordinarily remain constant.
• D is affected by concentration, temperature, pressure, solvent
properties, and the chemical nature of the diffusant.
• Therefore, D is referred to more correctly as a diffusion coefficient
rather than as a constant.
+
One often wants to examine the rate of
change of diffusant concentration at a point in
the system. An equation for mass transport
that emphasizes the change in concentration
with time at a definite location rather than the
mass diffusing across a unit area of barrier in
unit time is known as Fick's second law.

The concentration, C, in a particular volume

element changes only as a result of net flow of
diffusing molecules into or out of the region. A
difference in concentration results from a
difference in input and output.
 Fick’s laws of diffusion
Fick’s second law:
The concentration of diffusant in the volume element changes with time, that is, ΔC/Δt, as
the flux or amount diffusing changes with distance, ΔJ/Δx, in the x direction

dC dJ
 Where: J is flux (g/cm2.sec)
M is the amount of material
dt dx flowing (g)
dC
Differentiating the equation J  D S is cross sectional area of
flow (cm2)
2 dx
dJ d C t is time (sec)
 D 2 D is the diffusion coefficient of
dx dx the drug in cm2/sec
dC/ dx is the concentration
2 gradient (g/cm4)
dC d C C is concentration
D 2
dt dx
change in concentration of diffusant with time at any distance
 Fick’s laws of diffusion
 Flux: is the rate of flow of molecules across a given surface.
 Flux is in the direction of decreasing concentration.
 Flux is always a positive quantity
 Flux
equal zero (diffusion stop) when the concentration
gradient equal zero.

Diffusion coefficient also called diffusivity. It is affected by:

 Chemical nature of the diffusant drug.
 Solvent properties.
 Temperature
 Pressure
 Concentration
+ Steady state condition
 With time the concentration of the diffusant molecule in the barrier
increases gradually until it reaches a steady state condition.

 At the steady state at each there no change in the concentration of

the diffusant with time inside the barrier.

dC d 2C
D 2 0
dt dx
2
d C
2
0
dx
dC C
  constant
dx x
+

2
dC d C
D 2 0
dt dx
Concentration will not be rigidly constant, but rather is likely to vary slightly with
time, and then dC/dt is not exactly zero. The conditions are referred to as a
quasistationary state, and little error is introduced by assuming steady state
under these conditions.
 Diffusion Through Membranes
+ Steady state diffusion through a thin film with thickness =h

dC d 2C
D 2 0
dt dx
Integrating the equation using the conditions that at z = 0, C= C1 and at z = h,
C = C2 yields the
following equation:

dC
J  D
dx
C1 C 2
J D
h
+ Steady state diffusion through a thin film
with thickness =h
C1  C 2
JD
h
h
 R Where: R is diffusional resistance
D
C1  C 2
J
R

dM dC
J J  D
S  dt dx
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 Membrane permeability
+

 The membrane can have a partition

coefficient that affects the concentration of
the diffusant inside it.

 Therefore the concentration inside the

membrane is a function of the
concentration at the boundary and the
partition coefficient of the membrane.
 Membrane permeability
+
dM C1 C 2
J D
S  dt h
C1 : Conc. in the memb. at the donor sid
C2 : Conc. in the memb. at the receptor side

C1 C 2
K 
Cd Cr
dM Cd  Cr
 DSK Rate of transport
dt h
 Cr  0 Sink conditions cr=0
dM Cd
 DSK
dt h

Cumulative amount of drug released through membrane??

 Membrane permeability
+
Sink Conditions
 Sink Conditions : concentration of Cr is zero
 When? Rate of exit of drug > rate of entry
(no accumulation)

dM Cd  Cr
 DSK
dt h
 Cr  0
dM Cd
 DSK
dt h
+ Membrane permeability

h
dM Cd R
 DSK D
dt h Where: R is diffusional resistance

DK 1 Where P is the permeability of the

P  membrane in cm/sec.

h R P = permeability coefficient
dM (cm/s)
 PSCd
dt
+ Membrane permeability

dM
 PSCd
dt
Cd  constant
M  PSCd  t M: is the amount of diffusant that passes
through the membrane after time t.

Cumulative amount of drug released through membrane

+
Diffusion
Zero-order process

M  PSCd  t

- Amount of drug transported is constant over time

- Only if Cd does not change
- Diffusion of drug from transdermal patch
+ Diffusion
First-order transport

 dM
If the donor conc. changes with time,
 PSCd
dt
Md
Cd 
Vd

PS
log Cd t  log Cd (0)  t
2.303Vd
PS
ln Cdt  ln Cd (0)  t
Vd
(Cd)t : donor conc. at any time
(Cd)0 : initial donor conc.
Vd : volume of the donor compartment (mL)
 Dissolution rate
+

Zero order dissolution

under sink condition

First order dissolution under

Conc. of dissolved drug

non-sink condition

Time
+
Burst effect

 In many of the controlled release formulations, immediately upon

placement in the release medium, an initial large bolus of drug is
released before the release rate reaches a stable profile. This
phenomenon is typically referred to as ‘burst release.’

 Initial release of drug into receptor side is at a higher rate than the
steady-state release rate
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Lag time, Burst effects

 Lag time : time of molecules saturating the membrane

tL = h2 / 6D
h : membrane thickness (cm)
D : diffusion coefficient (cm2/s)

dM Cd DSKCd
 DSK M  t
dt h h
h
M
DSKCd
(t  t L ) tL 
h 6P
+
Lag time, Burst effect

 Burst effect : time of initial rapid release of drug

tB = h2 / 3D
h : membrane thickness (cm)
D : diffusion coefficient (cm2/s)

dM Cd DSKCd
 DSK M  t h
dt h h tB 
M
DSKCd
(t  t B ) 3P
h
+ Multilayer Diffusion
 Diffusion across biologic barriers

 The passage of gaseous or liquid solutes through the walls of

containers and plastic packaging materials

 The passage of a topically applied drug from its vehicle through the
lipoidal and lower hydrous layers of the skin.
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Multilayer Diffusion
+ Multilayer Diffusion
Di K i 1 hi
Pi  Ri   
hi Pi Di K i

The total resistance, R

1 1 1 1
R  R1  R2  .......  Rn    ..... 
P P1 P2 Pn
The total permeability for the two layers

D1 K1 D2 K 2
P
h1 D2 K 2  h2 D1 K1
+ Procedures and Apparatus For Assessing Drug Diffusion
+ Thank you for
listening