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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.
1
PESs Modern College of Pharmacy (for ladies), Moshi, Pune, India
2
Ashokrao Mane College of Pharmacy, Peth-Vadgaon, Kolhapur, India
*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. .
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Ramteke KH et al., Sch. Acad. J. Pharm., 2014; 3(5):388-396
To study the release kinetics, data obtained (sink conditions), it is possible to use this last equation
from in vitro drug release studies were plotted as that, after integration, will become:
cumulative amount of drug released versus time [8-9]. W = VCs (1 e-kt) -----------------------------(10)
Where, D is the solute diffusion coefficient in The table 1 shows the kinetics parameters of different
the dissolution media, V is the liquid dissolution formulations which from that it is concluded that the
volume and h is the width of the diffusion layer. Hixson first order model show best results than the other two
and Crowell adapted the NoyesWhitney equation in [16].
the following manner:
dW/ dt = KS(Cs -C) ------------------------- (7) Hixson and Crowell model:
Drug powder that having uniformed size particles,
Where, W is the amount of solute in solution at Hixson and Crowell derived the equation which
time t, dW/dt is the passage rate of the solute into expresses rate of dissolution based on cube root of
solution in time t and K is a constant. This last equation weight of particles and the radius of particle is not
is obtained from the NoyesWhitney equation by assumed to be constant.
multiplying both terms of equation by V and making K This is expressed by the equation,
equal to k1V. Comparing these terms, the following M01/3 - Mt1/3 = t -----------------------------(13)
relation is obtained:
K = D/h ---------------------------------------(8) Where, M0 is the initial amount of drug in the
pharmaceutical dosage form, Mt is remaining amount of
In this manner, Hixson and Crowell equation (eq.7) can drug in the pharmaceutical dosage form at time t and
be written as: is proportionality constant.
dW/ dt = KS/V (VCs-W) = k (VCs-W)-------(9)
The above equation can be rewritten as,
Where, k = k1S. If one pharmaceutical dosage M01/3 - Mt1/3 = K N1/3DCst/------------------(14)
form with constant area is studied in ideal conditions
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Ramteke KH et al., Sch. Acad. J. Pharm., 2014; 3(5):388-396
Where K is a constant related to the surface, Where, D is the diffusion coefficient of the
shape and density of particle, N is number of particles, drug molecule in the solvent, is the porosity of the
D is diffusion coefficient, Cs is solubility in the matrix, is the tortuisity of the matrix and Q, A, Cs and
equilibrium at experience temperature and is thickness t have the meaning assigned above.
of diffusion layer.
Tortuisity is defined as the dimensions of
To study the release kinetics, data obtained from in radius and branching of the pores and canals in the
vitro drug release studies were plotted as cube root of matrix and the Porosity is function of matrix that exist
drug percentage remaining in matrix versus time [17]. as pores or channels from which liquid penetrate inside
for release of drug from granular matrix. In a general
Applications: way it is possible to simplify the Higuchi model as:
This is applies to different pharmaceutical f t = Q = KH t --------------------------------(17)
dosage form such as tablets, where the dissolution
occurs in planes which are parallel to the drug surface if Where, KH is the Higuchi dissolution
the tablet dimensions diminish proportionally, in such a constant.
way that the initial geometrical form keeps constant all
the time [18]. Higuchi describes drug release as a diffusion
process based in the Ficks law, square root time
I. Jalal, E. Zmaily and N. Najib was studied dependent. The data obtained were plotted as
dissolution kinetics of commercially available cumulative percentage drug release versus square root
controlled-release theophylline preparations by using of time [21-23].
Hixson and Crowell model. The dissolution data are
plotted in accordance with the Hixson-Crowell cube Applications:
root law, i.e. the cube root of the initial This relationship can be used to describe the
concentration minus the cube root of percent drug dissolution from several types of modified release
remained, as a function of time. The results as shown pharmaceutical dosage forms, as in the case of some
in table 2 indicates that a linear relationship was transdermal systems and matrix tablets with water
obtained in all cases [19]. soluble drugs [24-25].
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Ramteke KH et al., Sch. Acad. J. Pharm., 2014; 3(5):388-396
the shape of the curve with b lower than 1 would under perfect sink conditions, the following initial and
show a steeper increase than the one with b = 1. boundary conditions can be assumed:
t=0 -d / 2 < x < d/2 c = c0
The time, when 50% (w/w) and 90% (w/w) of t>0 x=d/2 c = c1
drug being in each formulation was released, was
calculated using the inverse function of the Weibull Where c0 is the initial drug concentration in the
equation: device and c1 is the concentration of drug at the
t(50% resp. 90% dissolved) = polymerwater interface. The solution equation under
(- a ln M- M0 / M0 )1/b + T------------------------(20) these conditions was proposed initially by Crank
(1975):
1
The equation (18) may rearrange into Mt D
= 2 ( 2t )2 +
1 n n
M 2 n=1 (1)
2 Dt
(24)
logarithmic form,
log[-ln(1- m)] = b log (t- Ti) - log a -------(21)
A sufficiently accurate expression can be
From this equation a linear relation can be obtained for small values of t since the second term of
obtained for a loglog plot of -ln (1-m) versus time, t. Eq. (24) disappears and then it becomes:
1 1
Mt D
The shape parameter (b) is obtained from the slope of = 2 ( 2t )2 = a 2 --------------------------------(25)
M
the line and the scale parameter, a, is estimated from the
ordinate value (1/a) at time t=1. The parameter, a, can
Then, if the diffusion is the main drug release
be replaced by the more informative dissolution time,
mechanism, a graphic representing the drug amount
Td, that is dened by a= (Td) d and is read from the
released, in the referred conditions, versus the square
graph as the time value corresponding to the ordinate -
root of time should originate a straight line. Under some
ln (1- m) = 1. Since -ln (1 - m) = 1 is equivalent to
experimental situations the release mechanism deviates
m=0.632, Td represents the time interval necessary to
from the Ficks equation, following an anomalous
dissolve or release 63.2% of the drug present in the
behavior (non-Fickian)[34-38]. In these cases a more
pharmaceutical dosage form. To pharmaceuticals
generic equation can be used:
systems following this model, the logarithm of the Mt
dissolved amount of drug versus the logarithm of time = a n -----------------------------------------------(26)
M
plot will be linear [29-30].
n value is used to characterize different
Applications: release for cylindrical shaped matrices; and it is
The Weibull model is more useful for describe in table 5. For the case of cylindrical tablets,
comparing the release profiles of matrix type drug 0.45 n corresponds to a Fickian diffusion mechanism,
delivery [31-32]. 0.45 < n < 0.89 to non-Fickian transport, n = 0.89 to
Case II (relaxational) transport, and n > 0.89 to super
Kevin J. Carroll, M.Sc. was done the analysis of case II transport[39-40]. To find out the exponent of n
survival data arising in clinical trial by using Weibull the portion of the release curve, where Mt/ M < 0.6
model. He found that Weibull analysis allows direct should only be used. To study the release kinetics, data
assessment and quantication of proportionality, or lack obtained from in vitro drug release studies were plotted
thereof and also Weibull analysis offers the opportunity as log cumulative percentage drug release versus log
to predict how data might mature over time, something time.
that is of great interest within oncology trials, especially
where a series of interim analyses are planned. The Applications:
result can be shown in table 4[33]. This equation has been used to the
linearization of release data from several formulations
Korsemeyer- peppas model: of microcapsules or microspheres.
Korsemeyer et al. (1983) derived a simple
relationship which described drug release from a HY Karasulu, G Ertana, T Kose were studied
polymeric system equation. theophylline release from different geometrical erodible
ft = Ktn --------------------------------------(22) tablets. They follow the Korsemeyer- peppas model for
the study and found the good results as given in table 6.
Where, ft is fraction of drug released at time t, They were also studied change in geometry of tablets
k is release rate constant and n is the release exponent. by calculating n values for each tablet, and are found
The drug diffusion from a controlled release polymeric to be 4, 2 and 1 for the triangular, cylindrical and half-
system with the form of a plane sheet, of thickness spherical tablets respectively [41].
can be represented by:
c / t = D (2c / x2) -----------------------(23) Hopfenberg model:
Hopfenberg developed a mathematical model
Where D is the drug diffusion coefficient to correlate the drug release from surface eroding
(concentration independent). If drug release occurs polymers so long as the surface area remains constant
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Ramteke KH et al., Sch. Acad. J. Pharm., 2014; 3(5):388-396
during the degradation process. He was analyzed the tortuosity factor of the capillary system and is the
release of drugs from surface-eroding devices with porosity of the matrix. The matrix porosity can be
several geometries and developed a general described by:
mathematical equation describing drug release from = 0 + KC0 -----------------------------------(31)
slabs, spheres and innite cylinders displaying
heterogeneous erosion [42-43]. The drug release was Where 0 is the initial porosity and K is the
expressed by equation: drug specic volume. If 0 is small, Eq. (30) can be
Mt k t n rearranged as:
M
= 1 1 C 0a -------------------------------(27) 2
0 0 3D KC
3 M 3 Mt
f1 = 2 1 1 M t M
= r 20
t-----(32)
where Mt is the amount of drug dissolved in
time t, M is the total amount of drug dissolved when
the pharmaceutical dosage form is exhausted, Mt /M is Hence, the Baker-Lonsdale model could be
the fraction of drug dissolved, k0 is the erosion rate given by equation:
2
constant, C is the initial concentration of drug in the 3
f1 = 2 1 1 M t
M 3
Mt
= kt -------------(33)
matrix and a0 is the initial radius for a sphere or M
cylinder or the half-thickness for a slab. The value of n Where, k is release constant and is corresponds
is 1, 2 and 3 for a slab, cylinder and sphere, to slope.
respectively. A modied form of this model was
developed to accommodate the lag time (l) in the To study the release kinetics, data obtained
beginning of the drug release from the pharmaceutical from in vitro drug release studies were plotted as [d (Mt
dosage form: / M)] / dt with respect to the root of time inverse[45-
Mt
= 1 1 k1 t (t l) n -----------------------(28) 49].
M
Applications:
Where k1 is equal to k0 /C0 a0. This model
This equation has been used to the
assumes that the rate-limiting step of drug release is the
linearization of release data from several formulations
erosion of the matrix itself and that time dependent
of microcapsules or microspheres [50-51].
diffusional resistances internal or external to the
eroding matrix do not inuence it.
S. K. Singh, J. Dodge, M. J. Durrani were
studied the release of drug from controlled release
Applications:
pellets coated with an experimental latex. They were
This model is useful for identification of the
study the kinetics of release by applying different
mechanism of release from the optimized oily- spheres
models (Higuchi, First order, Hixon- crowell, Baker -
using data derived from the composite profile, which
Lonsdale), but they were found that Baker- Lonsdale
displayed site-specific biphasic release kinetics [44].
model provide a best correlation from the results, given
in table 7[52].
Baker-Lonsdale model:
This model was developed by Baker and
Gompertz model:
Lonsdale (1974) from the Higuchi model and described
Dissolution profile of pharmaceutical dosage
the drug release from spherical matrices by using the
form can also been described by Gompertz model,
equation:
2 expressed by equation:
3
f1 = 2 1 1 M t
M 3
Mt
=
3D m C ms
t ----(29) X t = Xmax exp[ e log t ]------------------------(34)
M r 20 C 0
Where Df is the diffusion coefficient, Cfs is the Jiaxi Li, Ji-Dong Gu, Li Pan was studied
drug solubility in the liquid surrounding the matrix, is transformation of dimethyl phthalate, dimethyl
392
Ramteke KH et al., Sch. Acad. J. Pharm., 2014; 3(5):388-396
isophthalate and dimethyl terephthalate by profile of process by using modied Gompertz model,
Rhodococcus rubber Sa and they studied dissolution they found good results as shown in table 8[57].
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].
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].
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Ramteke KH et al., Sch. Acad. J. Pharm., 2014; 3(5):388-396
Weibull analysis
na
HR 5th and 95th percentiles SE (log HR)
0.802 0.681, 0.935 0.0983
250
0.800 0.686, 0.935 0.0955
0.804 0.624, 1.023 0.1516
100
0.801 0.620, 1.024 0.1493
0.782 0.460, 1.334 0.3209
50
0.800 0.494, 1.347 0.3079
a, number per group; HR, Hazard ratio; SE, Standard error.
Table 7: Release kinetic parameters showing best fit with higher correlation with the Baker-Lonsdale equation
[52].
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]
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Ramteke KH et al., Sch. Acad. J. Pharm., 2014; 3(5):388-396
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Ramteke KH et al., Sch. Acad. J. Pharm., 2014; 3(5):388-396
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