Journal of Membrane Science, 7 (1980) 241-253

Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands

MODELLING OF DRUG DIFFUSION

POLYMERIC SYSTEMS*

NIKOLAOS A. PEPPAS, ROBERT

THROUGH

GURNY**,

241

SWELLABLE

ERIC DOELKER**

and PIERRE

BURI**

School of Chemical Engineering, Purdue University, West Lafayette, IN 47907 (U.S.A.)

and **Laboratoire
de Pharmacie Galenique, Section de Pharmacie, UniversitL de Genkve
(Switzerland)
(Received May 2, 1980; accepted June 4, 1980)

Summary
A drug diffusion model for the case of diffusion of an initially uniformly distributed
drug through a polymeric matrix is presented and solved. Drug diffusion from a single
surface is analyzed for the case of countercurrent diffusion of a solvent which is thermodynamically compatible with the polymer. Due to swelling, considerable volume expansion
is observed leading to a moving-boundary diffusion problem. Drug concentration profiles
within the polymer and drug release rates can be determined. The results are in agreement
with experimental data obtained for the system of KC1 distributed in hydrophilic hydroxypropyl methyl cellulose matrices, in the form of tablets.

Introduction

In recent years polymeric materials have found a variety of uses in the

release of drugs at a controlled rate El]. Drugs can be distributed in a polymeric
matrix either as a dispersion or in solution [Z] and they can be released from
insoluble matrices, through fixed membranes, or through swellable hydrophilic polymers [ 31. Frequently, the desired release profile of the active agent
must follow a specific time-function, such as Lzero-order, exponential, etc.
[ 41. In a.llcases, knowledge of the release mechanism, expected release rates,
and expected behavior is important. Therefore, mathematical modelling of
drug release processes through polymers is of considerable importance in the
prediction of the diffusion behavior and in the investigation of polymeric
structural parameters which may affect the diffusion process.
Simple and sophisticated models of drug diffusion through a variety of
polymeric systems have appeared in the literature in the last twenty years.
Depending on the assumptions of the mathematical analysis, these models can
predict the behavior of either individual sustained-release systems or classes
of drug-loaded polymeric matrices. A thorough analysis of these models by
*Paper presented at the Symposium Controlled-Release
March 27,198O.
0376-7388/80/0000-0000/$02.50

Membranes, Houston, Texas,

1980 Elsevier Scientific Publishing Company

242

one of the authors is presented elsewhere [ 51. Emphasis in mathematical

modelling of drug diffusion is placed on the prediction of the concentration
profiles of the drug in the polymer matrix and on the time-dependent release
rates from the polymer/solvent interface.
A simple mathematical model for the prediction of diffusion of a drug
suspended in a polymeric matrix above its solubility limit was presented by
Higuchi [ 61. The model has been extended to a variety of geometric shapes
and boundary conditions by Roseman and Higuchi [7], Paul and McSpadden
[ 81, and Baker and Lonsdale [ 91. Recently a comprehensive analysis and extension of these models has been presented by Lee [lo], whereas various
computer-aided parameter fitting techniques have been discussed by Fu et
al. [ll] and Cobby [12].
Modelling of erodible release systems has been discussed by Hopfenberg
[ 131, while Cooney [ 14,151 has considered dissolution of the polymeric
matrix with various rate-limiting steps, to derive simple drug release expressions.
Although these models describe to some extent the diffusion process
through specific drug/polymer systems, little information is available on
countercurrent solvent diffusion and its effect on the concentration profiles
in a continuously swelling polymeric matrix. As pointed out by Peppas [ 161,
although most of these models have been developed for diffusion (migration)
of additives through polymers, they are applicable to drug release polymeric
systems as well. Rudolph [ 171 and Frisch [ 181 examined Fickian diffusion
and release of a diffusing species with countercurrent solvent diffusion and
polymer swelling at constant volume. Diffusion and dissolution with
anomalous non-Fickian diffusion mechanisms was treated by Tu [ 191.
Despite these recent developments, mathematical modelling of specific
modes of drug diffusion, especially when the polymer swells and countercurrent diffusion of solvent is important, is not available.
Mathematical modelling
Here we present a simple model for the diffusion of an initially homogeneously distributed drug in a polymeric matrix in the form of a tablet. The
drug may be dispersed or dissolved in the polymer matrix. The tablet is placed
in a dissolution medium which exhibits good thermodynamic compatibility
with the polymer, so that a polymeric gel phase is progressively formed due
to the presence of the swelling agent. Typical polymeric materials behaving
according to this model are hydrophilic polymers in contact with water.
Consider a polymer matrix P with homogeneously distributed drug A at
initial concentration Alo (Fig. 1). This polymer is placed in contact with a
swelling agent S and diffusion of A occurs, while countercurrent diffusion of
S into the polymeric matrix leads to the formation of a gel-like swollen layer.
A moving front separating the polymer from the gel phase is observed. Due
to polymer swelling, considerable volume expansion is also observed. The

243

xp

L(t)

Fig. 1. Drug diffusion in a swellable polymer. A: inert substrate; B: solvent-free polymer;

C: swollen polymeric gel; D: surrounding swelling agent.

phenomenon is treated as pseudo-steady state one-dimensional single-face

diffusion (when the aspect ratio d/Lo is greater than 15). An inert substrate
engulfs the adjacent surfaces of the polymer film.
Diffusion equations can be written for the diffusion of drug A in the
(solvent-free) polymer with concentration A 1 and drug diffusion coefficient
D, ; for the diffusion of A in the gel-like phase with concentration A2 and
drug diffusion coefficient Dz; and for the countercurrent diffusion of swelling
agent S in the gel-like phase with concentration S and diffusion coefficient D,.

aAl
-=
at
aA
---=D2--at

as
-=
at

D,-

a2Al

(1)

ax2

a2A2

(2)

ax2
a2s
D,----ax2

(3)

Initial and boundary conditions for this system are expressed by equations
(4)-(g). These conditions refer to the drug and swelling agent concentrations
and fluxes at x = 0, the inert substrate/polymer interface, at x = x,, the
polymer/gel time-dependent interface, and at x = L, the gel/swelling agent
time-dependent interface.
(4)

A,(x.,t)

= 4(x,,t)

= A,

(5)

244

D,-

aAl

= D*

ax

as(X*,t)

aAz (x,,t)

(6)

8X

(7)

ax

s(L,t)

(8)

= St)

4(&t)

(9)

= -4,

Equations (5) and (6) express the continuity at the polymer/gel interface,
while eqn. (7) shows that the swelling agent diffuses only up to the position
of the time-dependent moving polymer/gel front. Finally, eqns. (8) and (9)
establish the conditions at the gel/swelling agent interface.
Due to volume expansion, a mass balance for the swollen (gel) portion of
the polymer film can be written:

where M, and p are the molecular weight and density of the swelling agent,
respectively. The term M,/p = V is the molar volume of the swelling agent
(cm3/mole).
This mathematical model can be written in dimensionless form using three
dimensionless concentrations, C1, C2, and C3, with respect to the initial drug
concentration A, ,, and constant swelling-agent concentration SO in the surrounding medium; a dimensionless depth g with respect to the initial position
of the polymer/swelling agent interface LO (or the thickness of the film); and
a dimensionless time 7.
C, = Al/A,,,,

Cz = AZ/Al,,,

Cs = S/So,

1; = x/Lo,

r = D1 t/L;

Then the model is rewritten as follows:

ac,
-=-

azc,

a7

ac2

a7=

a62

a2c2
a.g2

ac3 = ~a2c3
--

a a7

at2

(11)
(12)
(13)

with

w0,7)
__a$

(14)

245

ac3(t*,o)

(17)

al;
C,(Z,T) = 1
C,(Z,7)

= 0

and

Here $, and 1 denote the dimensionless position of the two interfaces and
P = M, &IP.
Parameters e and (Yexpress the ratios of diffusion coefficients Dl/Dz and
D JO,, respectively. These ratios are always much smaller than one, usually
in the range of 0.01-0.001 for dissolved drugs, or even smaller for dispersed
systems.
Since e = 0, eqn, (12) can be solved as in a steady-state problem with the
boundary conditions of eqns. (15) and (19) to give:

C,(E) =

c, -

C*(-c- 4,)
(l- -5,)

(1-E)

(21)

* o-t*1

This equation gives the drug concentration profile in the gel layer (i.e. at
{, < .$< 1). Equation (13) gives a similar solution. From eqns. (20) and (13)
with the boundary condition (17) and (18) one also obtains:
I- t* = (I-

(22)

$*)/(I -0)

This expression gives the thickness of the gel layer for various swelling agents.
Equation (11) can be solved under these conditions to give

Cl(c;,T) =

c, + fJ a,exp(-XiT)cos(X,

4)

(23)

n=l

namely, the concentration profile of drug in the solvent-free phase (0 < f < g,),
where
OLn=
Since

(-l)n-

4(1 - C,)

(2n - 1)7r

246

aClG*,7)

at

C 01, exp(-h:T)
n=1

X, sin X, i, = -

2(1-C*)
t*

m
C exp(+)
n=l

one may write (eqn. (16)),

ac,
__ = -ac2 = _ f

at

at

(L *) 5
*

exp(-XiT)

tl=l

f!Zf-

(24)

which will give finally

1-4, - c*u - PI
i*

2e(l-

C,)

1
-

(25)

nFl exP(-AiT)

with h, = (2n- 1)7~/2t,.

Equations (21) through (25) provide the solution of the model. An
interesting simplified expression can be obtained at long times, where the first
term in the summation of eqn. (25) is the dominant one. Then:

l-5,
r=

C*(l - P)
26(1-

C,) * exp(-n2/2t,)

(26)

and eqns. (26) and (22) can be used to easily calculate the position of the
interfaces.
Release rates can be calculated by evaluating the term D2(aC2/ag) at [ = I
through eqn. (24).
Experimental and analytical procedures
Materials

All experiments for the determination of drug concentration profiles in

swellable polymeric systems were carried out with tablets of KC1 in cellulosic
derivatives. Hydroxypropyl methyl cellulose (HPMC) (Methocel K15M, Dow
Chemical Co., nominal viscosity 15000 cp) and KC1 (Ph. Helv. grade) were
sieved, and equal weights of the 63-100 pm fractions were mixed in a Turbula
mixer (Bachofen A.G.) for 10 minutes to form a homogeneous mixture. The
mixture was transferred to a Specac hydraulic press (Kontron A.G.) and
compressed at a force of 50 kN. Typical tablets of 500 mg with diameter of
15 mm and thickness of 2 mm were prepared under a corresponding pressure
of 280 MN/m2. Thus the initial volume of the tablet was calculated as 353.4
mm3 and the initial concentration of the homogeneously distributed drug
wasAl
= 0.707 mg/mm3 or 9.48 X 10e3 mol KCl/cm3. Under these pressure conditions the effective void fraction in the tablet was determined to be
0.119, in close agreement with previously published data [ 201.

247

Dissolution experiments
Studies of the dissolution of KC1 were carried out using the procedure
reported by Salomon [20]. Each tablet was placed in a special Plexiglas holder
D (Fig. 2), and was secured in a cylindrical opening E of the same diameter
as the hydrophilic polymer matrix. The holder was immersed in a release
medium consisting of 0.1 N HCl at 37 +_0.5% and agitation was provided

Fig. 2. Apparatus for dissolution experiment. A-B: sampling system for K analysis; C:
dissolution chamber; D: Plexiglas sample holder; E: location of polymer sample; F: agitation;
G: surrounding medium.

Single-face diffusion of KC1 through the polymer was followed by removing

the swollen tablets E at various intervals and slicing them in a microtome.
After removal from the dissolution medium the tablets were immediately
frozen in dry ice to prevent any further diffusion of KCl. They were coated
with gelatin and sectioned into 250qm thick slices by use of a refrigerated
microtome. Each slice was weighed and frozen at -50C until further analysis.
The average volume of these slices was 44.18 mm3.
Water and polymer content in the swollen tablets were determined by drying
the slices to constant weight, Concentration profiles of KC1 were obtained
through analysis of potassium ions using a flame photometer (Corning 435).

248

Fig. 3. Apparatus for determination of release rates of KC1 in the dissolution medium.
1: dissolution medium; 2: agitation; 3: tablet holder; 4: pump; 5: conductivity cell; 6:
conductivity meter; 7: recorder; 8,9: thermostated bath.

The release rate of KC1 was also determined by analysis of aliquots obtained
from the medium G (Fig. 2) in a system measuring conductivity
as shown in
Fig. 3.
Diffusion coefficients
The diffusion coefficient
of KC1 in various hydrogels of HPMC was determined as follows. Hydrated matrices of HPMC were prepared by dispersing a
known amount of the polymer in an aqueous solution of KC1 at 90C. The
dispersion was stirred and allowed to cool to about 45C. A fixed volume of
gel (25 cm3) was poured into the diffusion cell E (Space A, Fig. 4) and allowed
to stabilize at 37C. A cellophane membrane B (duPont PD124, void fraction
0.7) was fixed on the jacketed beaker C, filled with 250 ml of distilled water D,
maintained at 37C and stirred with a magnetic rod F at 150 rpm. Aliquots
were taken every 15 minutes for 120 minutes and analyzed for K+.

Fig. 4. Apparatus for KC1 diffusion coefficient determination, A: polymer gel; B: cellophane
membrane; C: jacketed chamber; D: water at 37C; E: diffusion cell; F: stirrer.

249

The amount of KCl, M,, released at time t was divided by the diffusional
surface area S (cross-sectional area of the cell X void fraction), and plotted
against t * [ 21 221. The apparent diffusion coefficient was calculated from
the slope of th; linear portion of this plot according to Higuchi [21] . In some
experiments a 0.01 N HCl solution was used instead of distilled water in
chamber D of Fig. 4. The calculated diffusion coefficient was not significantly
different for both media, within experimental error.
Results and discussion

Drug diffusion through the hydrophilic polymer was accompanied by

countercurrent diffusion of water into the tablet. Considerable swelling and
volume expansion was observed. The position of the moving front, x,, separating the water-free polymer from the swollen hydrophilic matrix could be
observed by visual inspection or with an optical microscope. Figures 5, 6, and
7 present experimental data of the concentration profile of KC1 in the gel
layer of the tablet. Due to experimental limitations of the microtome technique, it was not possible to slice the hard solvent-free polymer in order to
determine the concentration profile in it. Considerable volume expansion
was observed and the thickness of the swollen polymer layer changed from
1.75 mm at 4 hours, to 3 mm at 5 hours, and 5.25 mm at 6 hours. The reported
experimental points are the average of at least three experimental runs.
Experimental results for the concentration profiles of water and KC1 in the
tablet are in agreement with the solution of the proposed model, which is
plotted as the solid curves in Figures 5,6, and 7. All concentrations are expressed in mg/mm3. For the solution of this model, values of the drug diffusion
coefficient of D1 = 10-l* cm*/sec and D2 = 27.3 X 10m6cm*/sec were used. The
diffusion coefficient of the drug in the swollen polymer (gel) phase, DZ is

Thickness

bnm)

Fig. 5. Concentration profiles of KC1 (l), water (2), and HPMC (3) in the gel phase of the
swollen polymer tablet at 4 hours. Thickness is measured from the gel phase/dissolution
medium interface.

250

Thickness

(mm)

Fig. 6. Concentration
profiles of KC1 (l), water (2), and HPMC (3) in the gel phase of the
swollen polymer tablet at 5 hours. Thickness is measured from the gel phase/dissolution

medium interface.

Thickness

(mm)

Fig. 7. Concentration
profiles of KC1 (l), water (2), and HPMC (3) in the gel phase of the
swollen polymer tablet at 6 hours. Thickness is measured from the gel phase/dissolution
medium interface.

a function of concentration of water in the polymer as shown by the experimental data obtained independently (Table 1). However, due to the high water
content in the gel layer we assumed a constant average diffusion coefficient
Dz = 27.3 X lo- cm/sec. The diffusion coefficient of water in the gel phase D,
was taken as lo- cm*/sec.

251
TABLE

Diffusion coefficient of KC1 in highly swollen hydroxypropyl

Weight fraction (%)

Diffusion coefficient,
D,* (cm/sec)

KC1

HPMC

Water

1.0
2.0
3.0
5.0

3.5
6.0
12.0
15.0

95.5
92.0
85.0
80.0

*Mean of 6-12

methyl cellulose at 37C

33.2
25.8
26.6
26.5

x 1O-6 (+- 1.1)

x lo+ (5 0.8)
X 1O-6 (+ 1.7)
x 1O-6 (t 2.4)

determinations.

The concentration profiles of HPMC were determined experimentally. The

dotted curves in Figs. 5-7 represent the best polynomial fitting of these data,
since the proposed model does not predict the polymer concentration profile.
Due to the high water content at the water/polymer interface (above 95%),
it was not possible to analyze the first 250-pm thick samples from the microtoming process. Samples from the slicing procedure at shorter times were also
obtained. However, it was rather difficult to obtain meaningful results from
these samples, due to experimental problems in the microtoming procedure
as a result of the very low mechanical strength of these samples. In all studies
the diffusing quantity of HCl was assumed negligible with respect to water.
Potassium chloride release data from three experimental runs of the same
system are presented in Fig. 8. These data are plotted versus the Square root of
100

,/l,/,,I,

,,I,

,I.,,

.,I.

.
.

SO-.
.i
/

SO-.
2
./-

A.

z-

..

20._
.

l/

I
0
0

II~I/l~~~111,~~~I~II
5
(Time)%

Fig. 8. Release MJM,

IO

15

20

25

) (tr4
of KC1 in dissolution medium at time t. HPMC tablets.

time as predicted by Fickian diffusion. Agreement with the proposed model is

satisfactory over most of the time interval of the release. There is considerable
disagreement in the initial period of the drug release. This deviation is attributed

252
to

the initial porosity of the polymer tablet, which leads to a countercurrent

flux of water into the void space in the matrix. This flux is not predicted by
the present model. Previous studies by Salomon [ZO] have actually shown
the effect of compression force during preparation of the tablets (and therefore the porosity of the sample) on the release rates observed.
In conclusion, the proposed model accurately predicts the concentration
profiles of KC1 and water in a polymeric matrix with simultaneous swelling.
Release rates can also be predicted for most of the time period of the dissolution experiments. Minor deviations from this model can be expected for
industrial preparations which may include additives.
Acknowledgment
The technical assistance of Miss J. Boucherat and Mrs. D, Mordier of the
School of Pharmacy of the University of Geneva is kindly acknowledged.

Notation
A lb

0,

Alo
Cl,

c2

d
D,
D*
D,
i(T)
Lo
L(t)
M,
M, M_
S&t)
t
x
x*(t)

A2

h,

Concentration of drug in solvent-free and gel-like phases,

respectively
Initial concentration of drug
Dimensionless concentrations of drug
Dimensionless concentration of swelling agent
Diameter of tablet
Drug diffusion coefficient in solvent-free polymer
Drug diffusion coefficient in gel-like phase
Diffusion coefficient of swelling agent in gel-like phase
Dimensionless position of gel/swelling agent interface (= L/L,)
Initial thickness of tablet
Position of gel/swelling agent interface
Molecular weight of swelling agent
Weight of released drug at times t and ~0, respectively
Swelling agent concentration
Diffusion time
Position from inert substrate/polymer interface (x = 0)
Position of polymer/gel interface
Diffusivity ratio DJD,
Dimensionless constant M,S,/p
Diffusivity ratio D JDz
Dimensionless position (depth) (= x/L,)
Dimensionless position of polymer/gel interface (= x,/L,)
Density of swelling agent
Dimensionless time (= D 1t/L:)
Mclar volume of swelling agent

253

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