International Journal of Pharmaceutics, 57 (1989) 169-172 169

Elsevier

IJP 01940

A simple equation for the description of solute release.

III. Coupling of diffusion and relaxation

N i k o l a o s A. P e p p a s a n d J e n n i f e r J. Sahlin
School of Chemical Engineering. Purdue Unioersity, West Lafayette, IN 47907 (U.S.A.)
(Received 21 May 1989)
(Accepted 30 June 1989)

Key words: Modeling; Zero-order release; Diffusion; Relaxation; Case-II transport

Summary

The exponential expression of solute release from polymeric devices can be written in terms of the release mechanism's diffusional
and relaxational contributions. The general form of this equation's exponent is related to the geometric shape of the releasing device
through its aspect ratio. A methodologyis presented for general analysis of the release behavior of controlled release systems using a
coupled diffusion/relaxation model.

Introduction shown that two competing release mechanisms, a

In previous publications of this series (Ritger
and Peppas, 1987a, b) we indicated that a simple
exponential expression of the form of Eqn. 1 can
be used to analyze the controlled release behavior
of various pharmaceutical and other systems.
M,
=kt"
M~
In this equation, Mr~Moo is the fraction of drug
released, k is the kinetic constant (with units of
T -~), t is the release time and n is the diffusional
exponent for drug release.
We have explained before that this equation
can be used to analyze the first 60% of a release
curve, regardless of geometric shape. We have also
Fickian diffusional release and a Case-II relaxa-
tional release, are the limits of this phenomenon
(Sinclair and Peppas, 1984; Peppas, 1985).
Fickian diffusional release occurs by the usual
molecular diffusion of the drug due to a chemical
potential gradient. Case-II relaxational release is
the drug transport mechanism associated with
stresses and state-transition in hydrophilic glassy
(1)
polymers which swell in water or biological fluids.
Table 1 describes the limits of this analysis. Re-
gardless of the geometric device used, the value of
the exponent for Case-II transport mechanism is
twice that of pure Fickian diffusional mechanism.
This observation will be used below.
Development

Following a heuristic approach first developed

Correspondence: N.A. Peppas, School of Chemical Engineer- by Alfrey et al. (1966) for the case of solvent
ing, Purdue University, West Lafayette, IN 47907, U.S.A. transport in a polymer, the two p h e n o m e n a con-
0378-5173/89/$03.50 © 1989 Elsevier Science Publishers B.V. (Biomedical Division)
170

TABLE 1 has two regions when the exponent is constant.

Diffusion exponent and solute release mechanism For the aspect ratio, 2a/l, varying from 10 -1 to
102:
Diffusion exponent ( m ) Mechanism
Film Cylinder Sphere [ 0.45 for 2a/l < 0.1
0.50 0.45 0.43 Fickian m=~0.50 for 2a/l>lO0 (3)
diffusion
0.50 < m 0.45 < m 0.43 < m Anomalous
Eqn. 2 can be rewritten as
< 1.00 < 0.89 < 0.85 transport
1.00 0.89 0.85 Case-II
transport
Mt =k'tm 1 + ~ 1' ]
m] (4)
Moo
trolling the release can be considered as additive. The percentage of drug release due to the Fickian
Therefore, we may write mechanism, F, is clearly calculated as:

Mt = k l lm -t-k2 t2m (2) F= 1 (5)

M~ k2 m
1 + --~t
where the first term of the right-hand side is the
Fickian contribution, the second term being the which leads to the ratio of relaxational over Fickian
Case-II relaxational contribution. The coefficient contributions as:
m is the purely Fickian diffusion exponent for a
device of any geometrical shape which exhibits
R = --k2t m (6)
controlled release (see Table 1). F k1
In a previous publication, this coefficient was
given for any shape, including cylinders, tablets
Therefore, Eqns. 2 and 4 indicate that solute
and films, by a diagram (Fig. 1) which can be
release from any device, irrespective of its geomet-
easily fitted by a cubic spline. The curve of Fig. 1
ric shape, can be written in terms of a Fickian and
a relaxational contribution. If the Fickian contri-
0.5~5 bution can be expressed as a function of t m, then
the relaxational contribution can, be expressed as a
• 0.500
function of t 2m. By comparison of Eqns. 1 and 2,
it is concluded that m = n when the relaxational
e
mechanism is negligible.
o o.475

'~ o.45o Simulation and D i s c u s s i o n

t
o
To investigate the importance of the two mech-
o.4~5
anisms in the overall release behavior, we ex-
13 amined the release profiles for various values of k 1
0.400 I ....... I . , ,,,,, . i. . . . . . . . I , , * ,,,,, I , , ,,,*J and k 2. Fig. 2 indicates the fraction of drug
10-" 10 -t 10 ° lO t 10 s lO s released, Mt/M~, from a tablet with m = 0.47 for
Aspeot l~ettio. 2a/~ the case when k 1 = 0 . 1 min -0"47 and k 2 =0.01
m i n -0"94, and the case of k 1 = 0.01 m i n -0"47 and
Fig. 1. Variation of the Fickian diffusional exponent, m, with
the aspect ratio, 2a/l, where 2a is the diameter and I is the k 2 = 0.1 rain -0'94. The release profiles are signifi-
thickness (height) of the device. cantly different, those corresponding to the sec-
 171

i .00 1.00
/ /~.S''f [z,
sl,s \ 3

/ / , S/ o
0.75 2/ -0 0 . 7 5
o
,/// g
/// h
/
/// 0
\ 0.50 // 1 0.50
//
:: / o
- 1,,
/ /
0.25 0.25
:./ ii
i' o 1

0.0 I I I I 0.0 I I I
0 10 20 ~0 40 50 o 50 100 150 200
t (mln) Release Time, t (rain)
Fig. 2. Fraction of drug released, M,/Moo for a tablet with Fig. 4. Fickian release fraction, F, from a thin film with
m = 0.47, as a function of release time, t. (Curve 1) k~ = 0.1 m = 0.5, as a function of release time, t, when k 1 = 0.2 rain -°5,
rain -0"47, k 2 = 0.01 rain-°'94; (curve 2) k 1 = 0.01 rain -0"47, (Curve 1) k 2 = 0.1 min-1; (curve 2) k 2 = 0.01 min-1; (curve
k 2 = 0.1 rain -°'94. 3) k 2 = 0.001 rain -1.

ond set of k~ and k e being more linear with time,

nism from measurement of k 1 and k 2. For these
indicating a relaxational mechanism that pre-
reasons, Eqn. 5 or 6 must be used. Fig. 4 indicates
dominates. In Fig. 3 it is seen that as the magni-
the Fickian release fraction, F, from thin films
tude of k~ increases (while k 2 is kept constant),
( m - 0.5) as a function of the relaxational con-
the diffusional mechanism predominates.
stant k 2. Indeed, as k 2 decreases, the Fickian
It is not possible to give an exact answer as to
fraction of drug released becomes larger, ap-
the importance of the Fickian or Case-II mecha-

1,00 1.00

/
" /
//
r~

O.75 I
I /
/
//
/
/
o

o
#
0.75

3 2t 1 k
~* / ,/ e
\ 0.50 -/// E 0.50
:i" / ,,
o
/
0.25

o 1

0.0 0.0 I I I
o lO 20 30 40 50 0 50 10o 1t5o ~oo
t (rain) Release Time, t (rain)
Fig. 3. Fraction of drug released, Mr~Moo, from a tablet with Fig. 5. Fickian release fraction, F, from a tablet with m = 0.47,
m = 0.47, as a function of release time, t, when k 2 = 0.01 as a function of release time, t, when k 1 = 0.2 min -°'47. (Curve
rain -°'94. (Curve 1) k 1 =0.1 rain-°47; (curve 2) kl= 0.2 1) k 2 = 0.1 rain-°'94; (curve 2) k 2 = 0.01 rain-°94; (curve 3)
rain-°47; (curve 3) k 1 = 0.3 min -°'47. k 2 = 0.001 rain -°'94.
172

proaching 100%. A similar behavior can be ob- Acknowledgement

tained for release from tablets (Fig. 5).
Based on this analysis, the following methodol-
This work was supported b y a grant from the
ogy is proposed for analysis of the release mecha-
National Science Foundation.
nism using a coupled d i f f u s i o n / r e l a x a t i o n model:

(i) calculate the aspect ratio ( d i a m e t e r / t h i c k -

ness) of the device tested;
(ii) determine m from Eqn. 3 or from Fig. 1;
(iii) plot the experimental release data and fit the References
first 60% to Eqn. 2;
(iv) calculate k 1 and k2; and Alfrey, T., Jr, Gurnee, E.F. and Lloyd, W.G., Diffusion in
(v) use Eqn. 5 to determine the percentage of glassy polymers. J. Polym. Sci., C12 (1966) 249-261.
Fickian and relaxational drug release. Peppas, N.A., Analysis of Fickian and non-Fickian drug re-
lease from polymers. Pharm. Acta Helo., 60 (1985) 110-111.
Ritger, P.L. and Peppas, N.A., A simple equation for descrip-
tion of solute release. I. Fickian and non-Fickian release
Conclusions from non-sweUable devices in the form of slabs, spheres,
cylinders or discs. J. Controlled Release, 5 (1987a) 23-36.
The previous analysis indicates that it is possi- Ritger, P.L. and Peppas, N.A., A simple equation for descrip-
ble to calculate the a p p r o x i m a t e contributions of tion of solute release. II. Fickian and anomalous release
from swellable devices. J. Controlled Release, 5 (1987b)
the diffusional and relaxational mechanisms in an
37-42.
anomalous solute release process by fitting the Sinclair, G.W. and Peppas, N.A., Analysis of non-Fickian
data to a heuristic model containing both phe- transport in polymers using a simplified exponential ex-
nomena. pression. J. Membrane Sci., 17 (1984) 329-331.