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Review Article
Mathematical Models of Drug Dissolution: A Review
Ramteke K.H.*1, Dighe P.A*1., Kharat A. R1., Patil S.V2.
PESs Modern College of Pharmacy (for ladies), Moshi, Pune, India
2
Ashokrao Mane College of Pharmacy, Peth-Vadgaon, Kolhapur, India
1
*Corresponding author
Ramteke K.H
Email:
Abstract: When a new solid dosage form is developed, it is very important to study drug release or dissolution. The
quantitative analysis of values obtained in dissolution or release rates is easier when mathematical formulae are used to
describe the process. The mathematical modeling helps to optimize the design of a therapeutic device to yield
information on the efficacy of various release models. In this paper we review the different mathematical models used to
determine the kinetics of drug release from drug delivery systems such as, zero order, first order, Hixson-Crowell,
Higuchi, Weibull, Korsemeyer-Peppas, Hopfenberg, Baker-Lonsdale and Gompertz model.
Keywords: Dissolution, Dissolution models, Drug release kinetics.
.
INTRODUCTION
Drug dissolution is important test used to
evaluate drug release of solid and semisolid dosage
forms. This test is developed for quantification of the
amount and extent of drug release from dosage forms.
The values that are obtained from the dissolution study
can be quantitatively analyzed by using different
mathematical formulae. Because qualitative and
quantitative changes in a formulation may alter release
of drug and in vivo performance, developing tools that
facilitate product development by reducing the
necessity of bio-studies is always desirable. Thus
mathematical models can be developed. This
development requires the comprehension of all
phenomena affecting drug release kinetics and this has a
very important value in the formulation optimization.
The model can be simply thought as a mathematical
metaphor of some aspects of reality. For this
generality, mathematical modeling is widely employed
in different disciplines such as genetics, medicine,
psychology, biology, economy and obviously
engineering and technology [1-6]. Model dependent
methods are based on different mathematical functions,
which describe the dissolution profile. Once a suitable
function has been selected, the dissolution profiles are
evaluated depending on the derived model parameters.
To compare dissolution proles between two drug
products model dependent (curve tting), statistic
analysis and model independent methods can be used.
MATHEMATICAL MODELS
388
Applications:
This relation can be used to describe the drug
dissolution of several types of modied release
pharmaceutical dosage forms, as in the case of some
transdermal systems, as well as matrix tablets with low
soluble drugs, coated forms, osmotic systems, etc [1011].
ln (Qt/Q0) = K1t
or
Or in decimal logarithms:
log Qt = logQ0 + (K1/2.303)------------------(12)
Where, Qt is the amount of drug released in
time t, Q0 is the initial amount of drug in the solution
and K1 is the rst order release constant. The data
obtained are plotted as log cumulative percentage of
drug remaining vs. time which would yield a straight
line with a slope of-K/2.303[13].
Applications:
This relationship can be used to describe the
drug dissolution in pharmaceutical dosage forms such
as those containing water soluble drugs in porous
matrices [14-15].
N. Ahuja, Om Prakash Katare, B. Singh, was
studied dissolution enhancement and mathematical
modelling of drug release of a poorly water-soluble
drug using water-soluble carriers. They studied
dissolution profile of drug by using zero order, first
order and Hixson- Crowell model and they found that
first order model tted well at early time periods.
The table 1 shows the kinetics parameters of different
formulations which from that it is concluded that the
first order model show best results than the other two
[16].
Hixson and Crowell model:
Drug powder that having uniformed size particles,
Hixson and Crowell derived the equation which
expresses rate of dissolution based on cube root of
weight of particles and the radius of particle is not
assumed to be constant.
This is expressed by the equation,
M01/3 - Mt1/3 = t -----------------------------(13)
Where, M0 is the initial amount of drug in the
pharmaceutical dosage form, Mt is remaining amount of
drug in the pharmaceutical dosage form at time t and
is proportionality constant.
The above equation can be rewritten as,
M01/3 - Mt1/3 = K N1/3DCst/------------------(14)
389
constant.
Higuchi describes drug release as a diffusion
process based in the Ficks law, square root time
dependent. The data obtained were plotted as
cumulative percentage drug release versus square root
of time [21-23].
Applications:
This relationship can be used to describe the
drug dissolution from several types of modified release
pharmaceutical dosage forms, as in the case of some
transdermal systems and matrix tablets with water
soluble drugs [24-25].
A. Minhaz, S. Islam, H. Rahman were studied
an In vitro Release of Ketorolac from Extended Release
Capsules. They found the 96.23% release of KT within
8 hrs. They applied different models for kinetic study
(zero-order, first-order and Higuchi's equation).They
found best fit with higher correlation with the Higuchi's
equation for almost all the formulations. The result of
study can be shown in table 3[26].
Weibull model:
The Weibull equation can be applied to almost
all kinds of dissolution curves [27-28]. If applied to
dissolution of pharmaceutical dosage form, this
equation expresses the accumulation of fraction of drug
in solution and is given by equation:
M = M0 [1-e-(t-T/a)b] --------------------------(18)
Where, M is the amount of drug dissolved as a
function of time t. M0 is total amount of drug being
released. T accounts for the lag time measured as a
result of the dissolution process. Parameter a denotes
a scale parameter that describes the time dependence,
while b describes the shape of the dissolution curve
progression. For b = 1, the shape of the curve
corresponds exactly to the shape of an exponential
profile with the constant k = 1/a (equation 19).
M = M0 (1 e-k (t-T) --------------------------(19)
If b has a higher value than 1, the shape of
the curve gets sigmoidal with a turning point, whereas
390
= 2 ( 2t )2 +
n
n=1 (1)
n
2 Dt
(24)
= 2 ( 2t )2 = a 2 --------------------------------(25)
k t n
= 1 1 C 0a
0 0
-------------------------------(27)
f1 = 2 1 1 M t
2
3
Mt
M
3D KC
r 20
t-----(32)
f1 = 2 1 1 M t
2
3
Mt
M
= kt -------------(33)
f1 = 2 1 1 M t
2
3
Mt
M
3D m C ms
r 20 C 0
t ----(29)
Applications:
This equation has been used to the
linearization of release data from several formulations
of microcapsules or microspheres [50-51].
S. K. Singh, J. Dodge, M. J. Durrani were
studied the release of drug from controlled release
pellets coated with an experimental latex. They were
study the kinetics of release by applying different
models (Higuchi, First order, Hixon- crowell, Baker Lonsdale), but they were found that Baker- Lonsdale
model provide a best correlation from the results, given
in table 7[52].
Gompertz model:
Dissolution profile of pharmaceutical dosage
form can also been described by Gompertz model,
expressed by equation:
X t = Xmax exp[ e log t ]------------------------(34)
Where X(t) = percent dissolved at time t
divided by 100; Xmax = maximum dissolution;
determines the undissolved proportion at time t = 1 and
described as location or scale parameter; = dissolution
rate per unit of time described as shape parameter. This
model has a steep increase in the beginning and
converges slowly to the asymptotic maximal dissolution
[53-56].
t----(30)
Applications:
The Gompertz model is more useful for
comparing the release profiles of drugs having good
solubility and intermediate release rate [56].
f1 = 2 1 1 M t
2
3
Mt =
3D C
r 20 C 0
392
Table 1: Statistical parameters of various formulations obtained after tting the drug release data
to various release kinetic models; shows first order model is best fitted [16].
Sr.
No.
Formulation
1
2
3
4
5
6
7
8
9
10
Pure RFX
RCA50%
RCA25%
RCA10%
RNA50%
RNA25%
RNA10%
RU50%
RU25%
RU10%
Sr. No.
Name
BronchoRetard 500
BronchoRetard 200
Theodur 300
Lasma 300
Paddle
0.006
r = 0.996
n = 24
0.005
r = 0.997
n = 28
0.003
r = 0.995
n = 26
0.003
r = 0.996
n = 25
Table 3: Kinetic parameters of the release curve showing best fit with higher correlation
with the Higuchi's equation for almost all the formulations [26].
Sr. no.
1
2
3
4
5
6
7
8
Formulation
F1
F2
F3
F4
F5
F6
F7
F8
r2 (Zero order)
r2 (First order)
0.94
0.93
0.93
0.96
0.95
0.92
0.97
0.93
0.93
0.88
0.95
0.81
0.93
0.87
0.92
0.82
r2, correlation coefficient
r2(Higuchi)
0.98
0.98
0.99
0.99
0.95
0.92
0.96
0.95
393
na
250
100
50
0.45 n
0.45 < n < 0.89
0.89
n > 0.89
Fickian diffusion
Non-Fickian transport
Case II transport
Super case II transport
t - 0.5
t n-1
Zero order release
t n1
Tablet shape
Triangle (half of side length)
Cylinder (radius)
Half-sphere (radius)
r2, correlation coefficient
r2
0.993
0.924
0.981
N
4
2
1
Table 7: Release kinetic parameters showing best fit with higher correlation with the Baker-Lonsdale equation
[52].
Sr. No.
1
2
3
4
Dissolution model
Higuchi
First order
Hixson-Crowell cube root law
Baker Lonsdale
r2
0.9819
0.8403
0.7175
0.9984
Table 8: Comparison of calculated parameters and their R2 using the modied Gompertz model on a mixture of
three isomers and the single substrata [57]
Initial concentration (mg l-1)
27
40
80
CONCLUSION:
The review represents the mathematical
models for the study of dissolution. From this study it is
found that these dissolution mathematical models are
necessary to study the release mechanism of drug from
Chemicals
DMI
DMT
DMP
DMI
DMT
DMP
DMI
DMT
DMP
R2
0.9999
0.9998
0.9995
0.9999
0.9997
0.9929
0.9998
0.9944
0.9931
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
396