dk3131 02 PDF

2
Analytical Solutions to Mass

Transfer
Lawrence X. Yu*
Glaxo Wellcome Research and Development, Research Triangle Park,
North Carolina
Gordon L. Amidon
The University of Michigan, Ann Arbor, Michigan
I. INTRODUCTION
Mass transfer phenomena exist everywhere in nature and are important in the
pharmaceutical sciences. We may think of drug synthesis; preformulation studies;
dosage form design and manufacture; and drug absorption, distribution, metabolism, and excretion. Mass transfer plays a significant role in each. Mass transfer
is referred to as the movement of molecules caused not only by diffusion but
also by convection [1].
Diffusion is the process by which solute molecules are transported from
one part of a system to another as a result of random molecular motion [2]. It
can be observed with the naked eye when a drop of dye is carefully and slowly
placed at the bottom of a beaker filled with water. At first the colored part is
separated from the clear by a sharp, well-defined boundary. Later the upper part
turns colored, and the color becomes fainter toward the top while the lower part
becomes correspondingly less intensely colored. After sufficient time, the whole
solution has a uniform color. There is evidently, therefore, a net transfer of dye
molecules from the lower part to the upper part of the beaker. The dye molecules
have diffused into the water. This diffusion process is primarily due to random
molecular motion.
* Current affiliation: Food and Drug Administration, Rockville, Maryland.
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Copyright n 2000 by Marcel Dekker, Inc. All Rights Reserved.
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Yu and Amidon
In the example above, if the drop of dye is not carefully placed at the
bottom of the beaker, the water is disturbed and convection currents are set up.
Consequently, it can be observed that the dye is transported to the upper part at
a much faster rate. It generally takes less time for the solution to achieve a uniform
color because of convection caused by external forces.
This chapter provides analytical solutions to mass transfer problems in situations commonly encountered in the pharmaceutical sciences. It deals with diffusion, convection, and generalized mass balance equations that are presented in
typical coordinate systems to permit a wide range of problems to be formulated
and solved. Typical pharmaceutical problems such as membrane diffusion, drug
particle dissolution, and intrinsic dissolution evaluation by rotating disks are used
as examples to illustrate the uses of mass transfer equations.
II. DIFFUSION EQUATIONS

A. Ficks First Law
Fick first recognized the analogy among diffusion, heat conduction, and electrical
conduction and described diffusion on a quantitative basis by adopting the mathematical equations of Fouriers law for heat conduction or Ohms law for electrical
conduction [1]. Ficks first law relates flux of a solute to its concentration gradient, employing a constant of proportionality called a diffusion coefficient or diffusivity:
J Aj AD
c
z
(1)
where J is the total flux, A is the area through which diffusion occurs, j is the flux
per unit area, c is concentration, z is distance, and D is the diffusion coefficient. If
c is given in mg/cm 3, A is in cm 2, z is in cm, t is in sec, and j is given in mg/
(cm 2 sec), D then has units of cm 2 /sec. In some cases, such as diffusion in dilute
(ideal) solutions, D can be reasonably considered as constant, while in others,
such as diffusion in concentrated solutions, D may significantly depend on concentration (Chapter 4 of this book).
Equation (1) is the one-dimensional form of Ficks first law in Cartesian
coordinates. In cylindrical and spherical coordinates, the form of Ficks first law
for radial diffusion is
j D
TM
c
r
(2)
Analytical Solutions to Mass Transfer
25
The negative sign in Ficks first law suggests that diffusion occurs in the opposite
direction to increasing concentration. In other words, diffusion occurs in the direction of decreasing concentration of diffusing molecules.
B.
Ficks Second Law
Ficks first law is a concise mathematical statement; however, it is not directly

applicable to solutions of most pharmaceutical problems. Ficks second law presents a more general and useful equation in resolving most diffusion problems.
Ficks second law can be derived from Ficks first law.
Consider an element of volume of a rectangular box of dimensions dx dy
dz, as shown in Figure 1. It is assumed that diffusion occurs only in the z direction.
At the center (x, y, z) of the box, the concentration is c and the flux is j z . The
rate at which diffusing molecules enter the face at z dz/2 is
Figure 1 Diffusion through a rectangular box of dimensions dx dy dz. It is assumed that

diffusion occurs only in the z direction. At the center (x, y, z) of the box the concentration
is c and the flux is j z . J in is the flux into the box at z dz/2, and J out is the flux out of
the box at z dz/2.
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Yu and Amidon
Jin dx dy j z
dz j z
2 z
(3)
and the rate at which diffusing molecules leave the face at z dz/2 is
Jout dx dy j z
dz j z
2 z
(4)
The net contribution to the rate of accumulation of diffusing molecules in the

element from these two faces is thus equal to
Jin Jout dx dy dz
j z
z
(5)
The rate of accumulation of diffusing molecules in the element is

dx dy dz
c
t
(6)
If neither convection nor chemical reaction occurs within the element, the rate
of accumulation of diffusing molecules is then equal to the net contribution by
diffusion:
dx dy dz
j z
c
dx dy dz
t
z
(7)
or
j z
c
t
z
(8)
Substitution of Ficks first law into Eq. (8) gives

c
2 c
D 2
t
z
(9)
Equation (9) is Ficks second law of diffusion, derived on the assumption

that D is constant. Ficks second law essentially states that the rate of change in
concentration in a volume within the diffusional field is proportional to the rate
of change in the spatial concentration gradient at that point in the field, the proportionality constant being the diffusion coefficient.
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III. CONVECTION AND GENERALIZED MASS BALANCE

EQUATIONS
In many diffusion problems of practical importance in the pharmaceutical sciences, such as intrinsic dissolution studies and drug release from solid dosage
forms, the medium under consideration is not at rest. In addition to concentration
changes due to diffusion, there are concentration changes by convection. External
forces, such as pressure gradients and temperature differences, can cause convective flows. Although convection can also be caused by diffusion itself, our discussion is limited to convection caused by external forces, since convection produced
by diffusion is negligible (less than 10%) for most pharmaceutical problems.
We restrict our derivation to the one-dimensional case. The flux caused by
diffusion alone can be described by Ficks first law:
j z D
c
z
(10)
If there is an external force acting in the same direction on solute molecules, the
velocity of these molecules is v z and the resulting flux is cv z . Therefore, the total
flux, n z , due to both diffusion and convection is
n z j z cv z
(11)
With this equation, we can now discuss a generalized mass balance equation.
We still use Figure 1 to show the derivation. Based on Eq. (5), the net contribution
by diffusion and convection now becomes
(n z ) in (n z ) out dx dy dz
n z
z
(12)
The rate of accumulation of solute molecules in the element is still

dx dy dz
c
t
(13)
In addition, reaction is considered. The rate of production of solute molecules by homogeneous reaction is
dx dy dz R
(14)
where R is the rate per unit volume of a homogeneous chemical reaction producing solute. From mass balance (the rate of accumulation net contribution by
diffusion and convection rate of production), we have
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Yu and Amidon
dx dy dz
n z
c
dx dy dz
dx dy dz R
t
z
(15)
or
n z
c
R
t
z
(16)
Substitution of Eq. (11) into Eq. (16) yields
j z (cv z )
c
R
t
z
z
(17)
If the velocity and the diffusion coefficient are constant, combining Eq. (17) with
Ficks first law, Eq. (1), gives
c
c
2 c
vz
D 2R
t
z
z
(18)
This is a generalized mass balance equation in one dimension. If diffusion and

convection occur in other directions, the generalized mass balance equation becomes
c
c
c
c
2 c 2 c 2 c
vx
vy
vz
D
2 2 R
t
x
y
z
x 2
y
z
(19)
In vectorial notation, the generalized equation can be written as

c
v c D 2 c R
t
(20)
where
i
j
k
x
y
z
(21)
2
2
2
2 2
2
x
y
z
(22)
and
A generalized mass balance equation in other coordinate systems is sometimes useful. In the cylindrical system, Eq. (19) becomes
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29
c
c
1 c
c
1
c
1 2 c 2 c
vr v
vz D
r
2 2 2 R
t
r
r
z
r r r
r
z
(23)
and in the spherical coordinate system, Eq. (19) becomes

c
c
1 c
1 c
vr v
v
t
r
r
r sin
D
r1 r r cr r sin1 sin c r sin1 c R

2
(24)
IV. MEMBRANE DIFFUSION

In the previous section, we detailed diffusion equations and generalized mass
balance equations. We now turn to their practical uses in the pharmaceutical
sciences. Mass transport problems can be classified as steady or unsteady.
In steady mass transport there is no change of concentration with time [3], characterized mathematically by
c
0
t
(25)
In contrast, unsteady mass transport means that there exists a concentration

change with time, depicted mathematically by
c
0
t
(26)
Membrane transport represents a major application of mass transport theory

in the pharmaceutical sciences [4]. Since convection is not generally involved,
we will use Ficks first and second laws to find flux and concentration across
membranes in this section. We begin with the discussion of steady diffusion
across a thin film and a membrane with or without aqueous diffusion resistance,
followed by steady diffusion across the skin, and conclude this section with unsteady membrane diffusion and membrane diffusion with reaction.
A.
Steady Diffusion Across a Thin Film
Figure 2 illustrates steady diffusion across a thin film of thickness h. The solutions
on both sides of the film are dilute, so the diffusion coefficient can be considered
constant. The solute molecules diffuse from the well-mixed higher concentration
c 1 to the well-mixed lower concentration c 2 . The concentrations on both sides of
the film are kept constant. After sufficient time, a steady state is reached in which
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Yu and Amidon
Figure 2 Diffusion across a thin film. The solute molecules diffuse from the well-mixed
higher concentration c 1 to the well-mixed lower concentration c 2 . The concentrations on
both sides of the film are kept constant. At steady state, the concentrations remain constant
at all points in the film. The concentration profile inside the film is linear, and the flux is
constant.
the concentrations remain constant at all points of the film, as shown in Figure
2. The one-dimensional form of Ficks second law is applicable:
c
2 c
D 2
t
z
(27)
At steady state,
D
2 c
0
z 2
(28)
Integrating this equation twice yields

c A Bz
(29)
where A and B are integration constants. For the problem considered here, we
have two boundary conditions
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z 0,
c c1
(30)
z h,
c c2
(31)
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Substitution of these two boundary conditions into the general solution yields A
and B, resulting in the following concentration profile across the film:
c c 1 (c 2 c 1 )
z
h
(32)
This equation shows that the concentration changes linearly from c 1 to c 2 through
the film. The flux is the same across all sections of the film and is given by
j
D
(c 1 c 2 )
h
(33)
The term h/D is often called the diffusional resistance, denoted by R. The flux
equation, therefore, can be written as
j
c1 c2
R
(34)
Steady diffusion across a thin film is mathematically straightforward but

physically subtle. Dissolution film theory, suggested initially by Nernst and Brunner, is essentially based on steady diffusion across a thin film.
B.
Steady Diffusion Across a Membrane
Figure 3 shows a steady diffusion across a membrane. As in the previous case,

the membrane separates two well-mixed dilute solutions, and the diffusion coefficient Dm is assumed constant. However, unlike the film, the membrane has different physicochemical characteristics than the solvent. As a result, the diffusing
solute molecules may preferentially partition into the membrane or the solvent.
As before, applying Ficks second law to diffusion across a membrane, we
have
Dm
2 cm
0
z 2
(35)
where subscript m is referred to the membrane throughout this chapter. The

boundary conditions are the membrane concentrations at z 0 and z h m , which
are unknown. However, the membrane concentrations at the surfaces can be related to the solution concentrations by the partition coefficient provided that equilibrium exists at the interfaces of the membrane and the solutions. The boundary
conditions, therefore, can be written as
z 0,
z hm,
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c m Kc 1
c m Kc 2
(36)
(37)
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Yu and Amidon
Figure 3 Diffusion across a membrane. The solute molecules diffuse from the wellmixed higher concentration c 1 to the well-mixed lower concentration c 2 . Equilibrium is
assumed at the interfaces of membrane and solutions. The concentrations on both sides
of the membrane are kept constant. At steady state, the concentrations cm remain constant
at all points in the membrane. The concentration profile inside the membrane is linear,
and the flux is constant.
where K is the partition coefficient. Solving Eq. (35) with the boundary conditions
of Eqs. (36) and (37) results in the concentration profile
c m Kc 1 K(c 2 c 1 )
z
hm
(38)
and the flux

j
KD m
(c 1 c 2 )
hm
(39)
The term KD m /h m is often referred to as the permeability coefficient [1]. The

concentrations c 1 and c 2 are assumed to be independent of time in Eqs. (36) and
(37). This may experimentally imply that the volume of the membrane is negligible compared to that of solutions on either side of the membrane. Practically,
neither these concentrations nor the concentration gradient is exactly constant.
In diffusion or Caco-2 cell experiments, for example, a solution of higher concentration is initially placed in the donor compartment and a solution of lower concentration is placed in the receptor compartment. Even after sufficient time, the
concentration will still fall in the donor compartment and rise in the receptor
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33
compartment. Therefore, we are not actually dealing with a steady state in the
strict sense of the word, but rather a quasi-steady state. The premise of a steady
state is approximately satisfied. Such an approximation will not cause a serious
error, however.
In general, it is easier to measure the permeability coefficient than the partition coefficient, diffusion coefficient, and membrane thickness. Once permeability is measured, it is difficult to separate the contributions of the individual variables. We often see permeability coefficients being reported in the literature
instead of the more fundamental partition coefficient and diffusion coefficient
being reported separately.
C.
Steady Diffusion Across a Membrane with Aqueous

Diffusion Layers
In the example above, the solutions are assumed to be well stirred and mixed; the
aqueous resistance is negligible, and the membrane is the only transport barrier.
However, in any real case, the solutions on both sides of the membrane become
less and less stirred as they approach the surface of the membrane. The aqueous
diffusion resistance, therefore, very often needs to be considered. For example,
for very highly permeable drugs, the resistance to absorption from the gastrointestinal tract is mainly aqueous diffusion. In the section, we give a general solution
to steady diffusion across a membrane with aqueous diffusion resistance [5].
A stagnant diffusion layer is often assumed to approximate the effect of
aqueous transport resistance. Figure 4 shows a membrane with a diffusion layer
on each side. The bulk solutions are assumed to be well mixed and therefore of
uniform concentrations c b1 and c b2 . Adjacent to the membrane is a stagnant diffusion layer in which a concentration gradient of the solute may exist between the
well-mixed bulk solution and the membrane surface; the concentrations change
from c b1 to c s1 for solution 1 and from c b2 to c s2 for solution 2. The membrane
surface concentrations are c m1 and c m2 . The membrane has thickness h m , and the
aqueous diffusion layers have thickness h 1 and h 2 .
Applying the concentration profile of Eq. (32) obtained from a thin film
to both aqueous diffusion layers at steady state, we have
z
h1
z h1 hm
c 2 c s2 (c b2 c s2 )
h2
c 1 c b1 (c s1 c b1 )
(40)
(41)
Similarly, applying the concentration profile of Eq. (38) to membrane diffusion

gives
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Yu and Amidon
Figure 4 Diffusion across a membrane with aqueous diffusional layers. c b1 and c b2 are
the concentrations of bulk solutions 1 and 2, respectively. The thicknesses of the aqueous
diffusion layers are h 1 and h 2 . The membrane has a thickness of h m . Equilibrium is assumed
at the interfaces of the membrane and the aqueous diffusion layers. At steady state, the
concentrations remain constant at all points in the membrane and in the aqueous diffusion
layers. The concentration profiles inside the membrane and aqueous diffusion layers are
linear, and the flux is constant.
c m Kc s1 K(c s2 c s1 )
z h1
hm
(42)
In Eqs. (40)(42), c b1 and c b2 are experimentally measurable and the aqueous diffusion layer thickness can be estimated theoretically. Therefore, the only
unknowns are the solute concentrations at the interfaces, c s1 and c s2 . Their estimation is shown below.
The steady flux across each aqueous diffusion layer is
j1
D
(c b1 c s1 )
h1
(43)
j2
D
(c s2 c b2 )
h2
(44)
The steady flux across the membrane is

jm
TM
KD m
(c s1 c s2 )
hm
(45)
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At steady state, the flux of solute across each diffusion layer or membrane must
be the same; therefore,
j1 jm j2
(46)
Solving Eqs. (43)(46), the solute concentration at each interface is given by

c s1
(Dh m KD m h 2 ) c b1 KD m h 1 c b2
Dh m KD m (h 1 h 2 )
(47)
c s2
KD m h 2 c b1 (Dh m KD m h 1 ) c b2
(48)
and
Substituting Eqs. (47) and (48) into Eq. (45) yields

j1 jm j2
KDD m (c b1 c b2 )
(49)
Very often, we may see in the literature that flux is expressed as

j Peff (c b1 c b2 )
c b1 c b2
R tot
(50)
where Peff is called the effective permeability coefficient and R tot is the total resistance. The product of Peff and R tot is equal to 1.
Let
P1
1
D
,
R1 h 1
Pm
KD m
1
,
Rm
hm
P2
1
D
R2
h2
(51)
Comparing Eqs. (49) and (50) yields

R tot R 1 R m R 2
(52)
1
1
1
1
Peff P1 Pm P2
(53)
or
Equation (52) shows an important property of diffusion across barriers in

series: The diffusional resistance is additive. Therefore, in the case of diffusion
involving n barriers in series, the total resistance can be calculated as
R tot R 1 R 2 R n
(54)
The corresponding flux can still be calculated by using Eq. (50).

It is interesting to examine two limits of Eq. (49). First, when the mem-
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Yu and Amidon
branes diffusional resistance is much greater than the total aqueous resistance
(that is, R m R 1 R 2 by a factor of at least 10), the rate-determining step is
the diffusion across the membrane: R tot R m h m /KD m . Consequently, Eq. (49)
is reduced to
j
c b1 c b2 c b1 c b2 KD m
(c b1 c b2 )
R tot
Rm
hm
(55)
which is identical to Eq. (39), where only membrane diffusion is considered.

Second, when the aqueous diffusion layer resistance is much greater than the
membranes diffusional resistance (that is, R 1 R 2 R m by a factor of at least
10), the rate-determining step becomes the diffusion across the aqueous diffusion
layers: R tot R 1 R 2 (h 1 h 2 )/D. Equation (49) is then reduced to
j
D
(c b1 c b2 )
h1 h2
(56)
which is similar to Eq. (33), where diffusion across a thin film is considered.
D. Steady Diffusion in Parallel

The section discusses diffusion across a number of diffusion barriers in parallel.
Diffusion across the skin represents one of the best examples to illustrate steady
diffusion involving two or more independent diffusional pathways in parallel [6].
When a drug is applied topically to the skin, it will partition into either
the stratum corneum or the sebum-filled ducts of the pilosebaceous glands. Two
principal diffusion routes are then employed for drug absorption; one is the transepidermal route involving diffusion across the stratum corneum, and the other is
the transfollicular route involving diffusion through the follicular pore. The solute
molecules from either route finally reach the viable epidermal and dermal points
of entry. A concentration gradient is established across the skin up to the outer
reaches of the skins microcirculation, where the solute is swept away by the
capillary blood flow and distributed throughout the body. A critical factor in
transdermal delivery is the rate at which the solute molecules reach the systemic
circulation.
First, consider the transepidermal (TE) route. The solute molecules diffuse
across the stratum corneum and the viable tissues located above the capillary
bed. Considering the stratum corneum and the viable tissues as two diffusion
barriers in series, the total resistance is given by
R TE R m1TE R m2TE
TM
h m1TE
h m 2TE
D m1TE K m1TE D m 2TE
(57)
37
where the subscripts m1 and m2 refer to the stratum corneum and the viable
tissues, respectively. The flux by the transepidermal route is
j TE
f TE
R TE
(c b1 c b2 ) f TE PTE (c b1 c b2 )
(58)
where f TE is the fractional area of this route, which is virtually equal to 1.0 since
this route constitutes the bulk of the area available for diffusion. Similarly, for
the transfollicular (TF) route, the drug molecules diffuse through sebaceous pores
and viable tissues. The total transfollicular resistance is given by
R TF R m1TF R m 2TF
h m1TF
h m2TF
D m1TF K m1TF
D m2TF
(59)
The corresponding flux by the transfollicular route is given by

j TF
f TF
R TF
(c b1 c b2 ) fTF PTF (c b1 c b2 )
(60)
Thus, the overall flux by both transepidermal and transfollicular routes is

j j TE j TF ( f TE PTE f TF PTF )(c b1 c b2 )
(61)
In terms of the effective permeability or the total resistance, we have

Peff f TE PTE f TF PTF
(62)
f TE
f TF
1
R tot R TE R TF
(63)
or
Equation (63) shows that, unlike diffusion in series, the total diffusional resistance for diffusion in parallel is no longer additive. For diffusion in series, the
total diffusional resistance is higher than any individual resistance, whereas for
diffusion in parallel, the total diffusional resistance is between the minimum and
maximum individual resistances.
E.
Unsteady Diffusion into a Semi-Infinite Membrane
We have discussed steady diffusion across a membrane with or without aqueous

diffusion resistance. If the membrane is extremely thick or if solute diffusion in
the membrane is extremely slow, the membrane may behave as if it is almost
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Yu and Amidon
impermeable. In this case, diffusion on one side will not affect the other. As a
result, the impermeable membrane acts like a semi-infinite slab. We want to determine the flux and the concentration profile when one side of the membrane is
subject to a concentration increase [1].
Figure 5 shows the diffusion of a solute into such an impermeable membrane. The membrane initially contains no solute. At time zero, the concentration
of the solute at z 0 is suddenly increased to c 1 and maintained at this level.
Equilibrium is assumed at the interface of the solution and the membrane. Therefore, the corresponding membrane concentration at z 0 is Kc 1 . Since the membrane is impermeable, the concentration on the other side will not be affected
by the change at z 0 and will still be free of solute. This abrupt increase
produces a time-dependent concentration profile as the solute penetrates into the
membrane. If the solution is assumed to be dilute, Ficks second law Eq. (9) is
applicable:
c m
2 cm
Dm
t
z 2
(64)
Figure 5 Diffusion into a semi-infinite membrane. The membrane initially contains no

solute. At time zero, the concentration of the solution at z 0 is suddenly increased to
and maintained at c 1 . This abrupt increase produces time-dependent concentration profiles
as the solute penetrates into the membrane.
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The initial condition is

t 0,
cm 0
z 0,
(65)
The boundary conditions are

t 0,
t 0,
c m Kc 1
cm 0
z 0,
z ,
(66)
(67)
Let
(68)
4D m t
Equation (64) then becomes

d 2 cm
dc m
2
0
2
d
d
(69)
and the initial and boundary conditions, Eqs. (65)(67), become

0,
c m Kc 1
(70)
cm 0
(71)
where Eq. (70) is transformed from Eq. (66) and Eq. (71) is transformed from
either Eq. (65) or Eq. (67). Integrating Eq. (69) twice gives
cm A
eu du B
2
(72)
where A and B are integration constants. Applying the boundary conditions Eqs.
(70) and (71) to Eq. (72) yields
A
Kc 1
2Kc 1
B Kc 1
(73)
Substitution of A and B into Eq. (72) gives

c m Kc 1 erfc() Kc 1 [1 erf()]
(74)
where erf() is the error function, which by definition is

erf()
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eu du
2
(75)
40
Yu and Amidon
The flux is
j D m
c m
Dm
z2
Kc 1 exp
t
4D m t
(76)
Note that, unlike the steady-state case, the flux in the semi-infinite membrane
decreases with increasing time and distance. The flux at the interface is
j | z0
Dm
Kc 1
t
(77)
It may be appropriate here to introduce film theory. As mentioned in reference to the steady diffusion across a thin film, we often hypothesize a film called
an unstirred layer to account for the aqueous diffusion resistance to mass
transfer. Film theory is valuable not only because of its simplicity but also because of its practical utility. However, the thickness of the film is often difficult
to determine. In the following, we try to answer the question, What does the
thickness of the film represent?
If we assume that the thickness of the aqueous film is , the diffusional
flux across the film is
j | z0
Dm
c1
(78)
Coupling Eq. (77) with Eq. (78) gives

D m t
(79)
Note that K 1 and D m becomes D in aqueous media. Equation (79) suggests

that under steady-state conditions the thickness of the film is a function of time.
The tangent equation of the concentration curve at z 0 is
c c1
c
z
(80)
(81)
z0
or
c c1
c1
Dt
The z-axis intercept is

z Dt
(82)
Therefore, the film thickness is the z-axis intercept of the tangent curve of the
concentration profile. The calculated thickness of the aqueous diffusion layer is
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41
Table 1 Calculated Thickness

of the Aqueous Diffusion
Layer Based on Eq. (82),
Assuming a Diffusion
Coefficient of 5 106 cm 2 /sec
Time (sec)
Film
thickness
(m)
0.1
1
10
30
60
120
13
40
125
217
307
434
given in Table 1, assuming that the diffusion coefficient is 5 106 cm 2 /sec.

Table 1 shows that the film thickness increases significantly with time. This occurs partly due to our assumption of impermeability.
F.
Unsteady Diffusion Across a Membrane
In this section we want to discuss unsteady diffusion across a permeable membrane. In other words, we are interested in how concentration and flux change
before reaching the steady state discussed in Section IV.B. The membrane is
initially free of solute. At time zero, the concentrations on both sides of the membrane are increased, to c 1 and c 2 . Equilibrium between the solution and the membrane interface is assumed; therefore, the corresponding concentrations on the
membrane surfaces are Kc 1 and Kc 2 . Ficks second law is still applicable:
c m
2 cm
Dm
t
z 2
(83)
with the following initial and boundary conditions

t 0,
0 z h,
t 0,
z 0,
t 0,
z hm,
cm 0
c m Kc 1
c m Kc 2
(84)
(85)
(86)
This problem can be solved by the method of separation of variables. The details
can be found in Jost [3]. The final solution is
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Yu and Amidon
c m Kc 1 K(c 2 c 1 )
2
n1
z
hm
Kc 2 (1) n Kc 1
Dm n2 2 t
nz
sin
exp
n
hm
h 2m
(87)
The flux across the interface z h is given by Ficks first law,

j D m
c m
z
2D m
hm
zh
n1
KD m (c 1 c 2 )
hm
Dm n2 2 t
[Kc 1 (1) Kc 2 ]exp
h 2m
n
(88)
The concentration profiles are shown in Figure 6. As time approaches infinity,

the term involving the exponential vanishes and the diffusion process approaches
the steady state; Eqs. (87) and (88) are then reduced to the steady concentration
profile, Eq. (38), and flux, Eq. (39).
By integrating the flux with respect to time, we obtain the cumulative mass
of diffusing solute molecules per unit area:
Figure 6 Unsteady diffusion across a membrane. The membrane is initially free of

solute. At time zero, the concentrations on the two sides of the membrane are increased
to and maintained at c 1 and c 2 . The solute penetrates into the membrane from both sides,
resulting in time-dependent concentration profiles within the membrane.
TM
43
KD m (c 1 c 2 )t
hm
2h m
2
n1
Kc 1 (1) n Kc 2
Dm n2 2 t
1 exp
2
n
h 2m
(89)
If c 1 c 2 , Eq. (89) is then reduced to

M
KD m c 1 t h m Kc 1 2h m Kc 1
hm
6
2
n1
Dm n2 2 t
(1) n
exp
2
n
h 2m
(90)
When time approaches infinity, the cumulative mass approaches a linear function
of time:
M
h2
KD m c 1
t m
hm
6D m
(91)
Equation (91) represents the situation where the permeation has attained a steady
state so that the amount penetrating per unit time is constant.
In addition, the straight line expressed by Eq. (91) has an intercept on the
time axis of
tL
h 2m
6D m
(92)
This intercept is referred to as the lag time [4], and it provides a means for
estimating the diffusion coefficient provided the membrane thickness is known
and with the assumption that other time-dependent processes, such as membrane
hydration, do not occur during the lag phase.
G.
Effect of Reaction on Membrane Diffusion
A biologically important factor affecting drug absorption is drug metabolism or

reaction coincident with diffusion across a membrane. The reaction often produces inactive or less potent products than the parent drug. It is conceivable that
the reaction will also reduce the drug flux into the systemic circulation. We are
interested in the effect of reaction on membrane diffusion.
For simplicity, only an irreversible first-order reaction is considered. We
begin with the generalized mass balance equation in rectangular coordinates with
mass transfer in one dimension:
c m
c m
2cm
vz
Dm 2 k1 cm
t
z
z
TM
(93)
44
Yu and Amidon
The negative sign before the reaction term k 1 c m indicates that the drug is consumed rather than being produced as in the derivation of the generalized mass
balance equation.
We deal with membrane diffusion; no convection is involved (v z 0). We
also assume that the system is at steady state (c m /t 0). The generalized mass
balance equation, therefore, can be reduced to
Dm
2cm
k1 cm 0
z 2
(94)
with the boundary conditions

z 0,
z hm,
c m Kc 1
cm 0
(95)
(96)
A general solution of Eq. (94) is

c m A cosh[ k 1 /D m z] B sinh[ k 1 /D m z]
(97)
Using the boundary conditions to determine the integration constants A and B

yields
sinh[ k 1 /D m (h m z)]
cm
Kc 1
sinh[ k 1 /D m h m ]
(98)
The flux is then

j D m
cosh[ k 1 /D m (h m z)]
dc m
Kc 1 D m k 1
dz
(99)
In order to understand the effect of reaction on membrane diffusion, we

use the membrane without reaction as a reference. The corresponding flux [Eq.
(39), where c 2 is equal to zero] is
j0
KD m c 1
hm
(100)
Therefore, we have the ratio of steady flux with reaction to steady flux without
reaction across a membrane:
j
j0
TM
h m k 1 /D m
cosh[ k 1 /D m (h m z)]
(101)
45
At z 0, the flux ratio becomes

j| z0
j0
h m k 1 /D m coth[ k 1 /D m h m ]
(102)
and at z h m , the flux ratio is

j| zhm
j0
h m k 1 /D m
(103)
These two equations represent the effect of reaction on membrane diffusion.

Two limits are instructive. First, when the reaction is very slow and k 1 is
close to zero or h m k 1 /D m 1, Eqs. (102) and (103) become
j| z0
j0
(104)
and
j| zhm
j0
(105)
These results suggest that the effect of reaction is insignificant when the reaction is relatively slow. Second, when the reaction is fast, k 1 is large or or
h m k 1 /D m 1. As a result,
j| z0
j0
h m k 1 /D m 1
(106)
and
j| zhm
j0
(107)
Therefore, when the reaction is fast, the rate of solute entry into the membrane
is significantly increased. But the solute flux leaving the membrane (e.g., entering
the systemic circulation in the case of drug absorption) is nearly zero, since most
of the solute is consumed in the reaction (metabolism).
V.
DIFFUSION IN A CYLINDER
Membrane diffusion represents over 80% of the diffusion problems of pharmaceutical interest. Membrane diffusion may be called diffusion in a plane sheet,
since it involves one-dimensional diffusion in a medium bounded by two parallel
TM
46
Yu and Amidon
planes. In this and the next section, we discuss diffusion in a cylinder and a
sphere. Diffusion in a cylinder is less common in the pharmaceutical sciences;
however, we discuss it briefly for the sake of completeness.
Consider a long circular cylinder in which a solute diffuses radially. The
concentration is a function of radial position (r) and time (t). In the case of constant diffusion coefficient, the diffusion equation is
c D
c
r
t
r r
r
(108)
If the cylinder is hollow with inner and outer radii r1 and r2 , at steady state we
have
D
c
r
0,
r r r
r1 r r2
(109)
The general solution is

c A B ln r
(110)
where A and B are integration constants. If the surface at r r1 has a constant

concentration c 1 and the surface at r r2 has a constant concentration c 2 , the
boundary conditions are then
r r1 ,
c c1
(111)
r r2 ,
c c2
(112)
Using the boundary conditions to determine the constants A and B, we have

c
c 1 ln(r2 /r) c 2 ln(r/r1)

ln(r2 /r1)
(113)
The flux can still be obtained from Ficks first law:

j D
c D(c 1 c 2 )
r
r ln(r2 /r1)
(114)
Note that, unlike steady flux in a membrane, steady flux in a hollow cylinder is
a function of radius. However, the total flux per unit length is constant:
J 2rj
TM
2D(c 1 c 2 )
ln(r2 /r1)
(115)
47
VI. DISSOLUTION OF A SPHERE

Diffusion in a sphere may be more common than that in a cylinder in the pharmaceutical sciences. The example we may think of is the dissolution of a spherical
particle. Since convection is normally involved in solute particle dissolution in
reality, the dissolution rate estimated by considering only diffusion often underestimates experimental values. Nevertheless, we use it as an example to illustrate
the solution of the differential equations describing diffusion in the spherical
coordinate system [1].
A sphere is assumed to be a poorly soluble solute particle and therefore to
have a constant radius r0 . However, the solid solute quickly dissolves, so the
concentration on the surface of the sphere is equal to its solubility. Also, we
assume we have a large volume of dissolution medium so that the bulk concentration is very low compared to the solubility (sink condition). The diffusion equation for a constant diffusion coefficient in a spherical coordinate system is
c
2 c 2 c
D
t
r 2
r r
(116)
At steady state, we have
2 c 2 c
0
r 2
r r
(117)
with boundary conditions

r r0 ,
c cs
(118)
r r0 ,
c0
(119)
where c s is the solubility of solute. A general solution of Eq. (117) is

cB
A
r
(120)
Using the boundary conditions to determine the integration constants A and B,

we have the concentration profile
c
TM
r0
cs
r
(121)
48
Yu and Amidon
The steady dissolution flux is

j | rr0 D
c
r
rr0
D
cs
r0
(122)
The total amount of solute dissolved from time 0 to time t is

AD
c dt
ct
AD
r
r
t
(123)
where A is the surface area of a spherical particle and equal to 4r 2. Equation

(123) shows a linear relationship between the amount dissolved and the solubility.
It must be pointed out, however, that the size of the spherical solute particle is
assumed to remain constant.
Now we want to determine the time to reach the steady state. To answer
this question, we return to the mass balance equation, Eq. (116), subject to the
following initial and boundary conditions:
t 0,
t 0,
r r0 ,
r r0 ,
c0
c cs
(124)
(125)
t 0,
r ,
c0
(126)
Let
u cr
(127)
Equation (116) then becomes

2 u
u
D 2
t
r
(128)
with the modified initial and boundary conditions

t 0,
t 0,
r r0 ,
r r0 ,
u0
u r0 c s
(129)
(130)
t 0,
r ,
u0
(131)
Equation (128) with the initial and boundary conditions of Eqs. (129)(131) is
very similar to the model equations for diffusion in a semi-infinite membrane
[Eqs. (64)(67)]. The concentration profile is
c
TM
r r0
r0 c s
r r0 r0 c s
erfc
1 erf
r
r
4Dt
4Dt
(132)
49
The flux is then

j
Dc s
r0
1
r0
Dt
(133)
A comparison of Eq. (133) with Eq. (123) suggests that the term r0 / Dt is due
to the effect of the unsteady state. It can be used to estimate the time to achieve
steady state. For example, if r0 0.01 cm and D 5 106 cm 2 /sec, then it
will take about 43 min for the term r0 / Dt to become equal to 0.05, significantly
less than 1.
VII. INTRINSIC DISSOLUTION

The intrinsic dissolution rate is the rate of mass transfer from the solid phase to
the liquid phase. Information on the intrinsic dissolution rate is important in early
drug product development. It has been suggested that drugs with intrinsic dissolution rates of less than 0.1 mg/(min cm 2 ) will have dissolution ratelimited
absorption, while drugs with intrinsic dissolution rates greater than 0.1 mg/
(min cm 2 ) are unlikely to have dissolution rate problems.
The intrinsic dissolution rate is usually evaluated by using a rotated disk
method (Fig. 7). The pure powdered solute is compressed in a die under high
pressure, in the absence of any excipients. The resulting nondisintegrating disk
is then transferred to a dissolution cell which has sufficient volume to maintain
sink conditions. The die is rotated at a certain speed, and the rate of drug dissolution is then measured.
We solve this problem by using a generalized mass balance equation in
cylindrical coordinates, centered on the disk:
c v c
c
c
vr
vz
t
r
r
z
D
c
1 c
c
r
r
r r r
r
z z
(134)
At steady state, the concentration does not change with time. It is recognized
that the concentration profile is angularly symmetrical; the concentration, therefore, does not change with . We also assume that the disk is infinitely wide so
that the concentration is a function of z only. This assumption can be justified
since the diameter of the solute loaded is usually much smaller than that of the
disk. Also, no production of drug occurs during dissolution testing. Consequently,
Eq. (134) can be reduced to
TM
50
Yu and Amidon
Figure 7 Rotating disk to evaluate the intrinsic dissolution rate of compounds. The
amount of drug dissolving per unit area is the same everywhere on the disk surface. This
simplification makes the disk a powerful experimental tool in drug discovery and development.
vz
dc
d2c
D 2
dz
dz
(135)
subject to the boundary conditions

z 0,
z ,
c cs
c0
(136)
(137)
where c s is the saturated concentration or solubility of the solute. Note that v z is

not a constant; it is a function of z. Therefore, we have to find v z before we can
integrate Eq. (135) to have the concentration profile. The finding of v z is a problem
in fluid mechanics detailed by Levich [7]. The expression for v z is
vz
0.51 3/2 z 2
1/2
(138)
where is the angular velocity of the rotating disk and is the kinematic viscosity of the dissolution medium. Combining Eqs. (135) and (138), we have
TM
0.51 3/2 z 2 dc d 2 c
2
D 1/2 dz
dz
(139)
51
Integrating Eq. (139) once gives
dc
3/2 z 3
A exp
dz
5.88 D 1/2
(140)
and a second integration results in
exp 5.88 Dz
z
cA
3/2 3
1/2
dz B
(141)
where A and B are integration constants. Subsitution of the boundary conditions,

Eqs. (136) and (137), gives
exp 5.88 Dz
dz
exp 5.88 Dz dz
z
c
1
cs
3/2 3
1/2
(142)
3/2 3
1/2
where
exp
3/2 z 3
1.81 D 1/3 1/6
dz
5.88 D 1/2
1/2
1/2 z
exp
1.81 D 1/3 1/6
1.61 D 1/3 1/6

1/2
1/2 z
1.81 D 1/3 1/6
(143)
Therefore, Eq. (142) becomes

0.62 1/2
c
1 1/3 1/6
cs
D
exp
3/2 z 3
dz
5.88 D 1/2
(144)
Equation (144) is the concentration profile as a function of the distance

from the disk surface. The diffusion flux (intrinsic dissolution rate) is
j D
TM
c
z
0.62
z0
D 2/3 1/2
cs
1/6
(145)
52
Yu and Amidon
Therefore, the final equation is relatively simple despite the fact that the derivation is complex. Equation (145) shows that the intrinsic dissolution rate depends
on the diffusion coefficient and solubility of the drug, disk rotational speed, and
the viscosity of the dissolution medium. The amount of drug dissolving per unit
area is the same everywhere on the disks surface. This makes the disk a powerful
experimental tool in drug discovery and development.
VIII. SUMMARY
This chapter has introduced Ficks law for dilute solutions and has shown how
this law can be combined with mass balances to calculate concentrations and
fluxes. The mass balances are made on a small rectangular box. When the box
becomes very small, the mass balances become the differential equations used
to solve various pharmaceutical transport problems. Thus, this chapter discussed
many mathematical equations. Although these mathematical equations are tedious, they are essential to each specific application of mass transfer in pharmaceutical systems to be discussed in the rest of this book.
Membrane diffusion illustrates the uses of Ficks first and second laws. We
discussed steady diffusion across a film, a membrane with and without aqueous
diffusion layers, and the skin. We also discussed the unsteady diffusion across
a membrane with and without reaction. The solutions to these diffusion problems
should be useful in practical situations encountered in pharmaceutical sciences,
such as the development of membrane-based controlled-release dosage forms,
selection of packaging materials, and experimental evaluation of absorption potential of new compounds. Diffusion in a cylinder and dissolution of a sphere
show the solutions of the differential equations describing diffusion in cylindrical
and spherical systems. Convection was discussed in the section on intrinsic dissolution. Thus, this chapter covered fundamental mass transfer equations and their
applications in practical situations.
REFERENCES
1. EL Cussler. Diffusion. New York: Cambridge University Press, 1984, pp 18, 24, 32,
33, 4244, 55, 81, 82.
2. J Crank. The Mathematics of Diffusion. 2nd ed. Oxford, UK: Clarendon Press, 1975.
3. W Jost. Diffusion in Solids, Liquids, Gases. New York: Academic Press, 1960, pp 8,
4245.
4. GL Flynn, SH Yalkowsky, TJ Roseman. Mass transfer phenomena and models: Theoretical concepts. J Pharm Sci 63:479510 (1974).
TM

5.
6.
7.
TM
53
GE Amidon, WI Higuchi, NSF Ho. Theoretical and experimental studies of transport

of micelle-solubilized solutes. J Pharm Sci 71:7784 (1982).
GL Flynn. Topical drug absorption and topical pharmaceutical systems. In: GB
Banker, CT Rhodes, eds. Modern Pharmaceutics. New York: Marcel Dekker, 1990,
pp 263326.
VG Levich. Physicochemical Hydrodynamics. Englewood Cliffs, NJ: Prentice-Hall,
1962, pp 3972.

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2

Analytical Solutions to Mass

Copyright n 2000 by Marcel Dekker, Inc. All Rights Reserved.

II. DIFFUSION EQUATIONS

Copyright n 2000 by Marcel Dekker, Inc. All Rights Reserved.

Analytical Solutions to Mass Transfer

Ficks Second Law

Ficks first law is a concise mathematical statement; however, it is not directly

Figure 1 Diffusion through a rectangular box of dimensions dx dy dz. It is assumed that

Copyright n 2000 by Marcel Dekker, Inc. All Rights Reserved.

The net contribution to the rate of accumulation of diffusing molecules in the

The rate of accumulation of diffusing molecules in the element is

Substitution of Ficks first law into Eq. (8) gives

Equation (9) is Ficks second law of diffusion, derived on the assumption

Copyright n 2000 by Marcel Dekker, Inc. All Rights Reserved.

Analytical Solutions to Mass Transfer

III. CONVECTION AND GENERALIZED MASS BALANCE

The rate of accumulation of solute molecules in the element is still

Copyright n 2000 by Marcel Dekker, Inc. All Rights Reserved.

Substitution of Eq. (11) into Eq. (16) yields

This is a generalized mass balance equation in one dimension. If diffusion and

In vectorial notation, the generalized equation can be written as

Copyright n 2000 by Marcel Dekker, Inc. All Rights Reserved.

Analytical Solutions to Mass Transfer

and in the spherical coordinate system, Eq. (19) becomes

r1 r r cr r sin1 sin c r sin1 c R

IV. MEMBRANE DIFFUSION

In contrast, unsteady mass transport means that there exists a concentration

Membrane transport represents a major application of mass transport theory

Steady Diffusion Across a Thin Film

Copyright n 2000 by Marcel Dekker, Inc. All Rights Reserved.

Integrating this equation twice yields

Copyright n 2000 by Marcel Dekker, Inc. All Rights Reserved.

Analytical Solutions to Mass Transfer

Steady diffusion across a thin film is mathematically straightforward but

Steady Diffusion Across a Membrane

Figure 3 shows a steady diffusion across a membrane. As in the previous case,

where subscript m is referred to the membrane throughout this chapter. The

Copyright n 2000 by Marcel Dekker, Inc. All Rights Reserved.

and the flux

The term KD m /h m is often referred to as the permeability coefficient [1]. The

Copyright n 2000 by Marcel Dekker, Inc. All Rights Reserved.

Analytical Solutions to Mass Transfer

Steady Diffusion Across a Membrane with Aqueous

Similarly, applying the concentration profile of Eq. (38) to membrane diffusion

Copyright n 2000 by Marcel Dekker, Inc. All Rights Reserved.

The steady flux across the membrane is

Copyright n 2000 by Marcel Dekker, Inc. All Rights Reserved.

Analytical Solutions to Mass Transfer

Solving Eqs. (43)(46), the solute concentration at each interface is given by

Substituting Eqs. (47) and (48) into Eq. (45) yields

Very often, we may see in the literature that flux is expressed as

Comparing Eqs. (49) and (50) yields

Equation (52) shows an important property of diffusion across barriers in

The corresponding flux can still be calculated by using Eq. (50).

Copyright n 2000 by Marcel Dekker, Inc. All Rights Reserved.

which is identical to Eq. (39), where only membrane diffusion is considered.

D. Steady Diffusion in Parallel

Copyright n 2000 by Marcel Dekker, Inc. All Rights Reserved.

D m1TE K m1TE D m 2TE

Analytical Solutions to Mass Transfer

The corresponding flux by the transfollicular route is given by

Thus, the overall flux by both transepidermal and transfollicular routes is