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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. 1PES’s Modern College of Pharmacy (for ladies), Moshi, Pune,
India 2Ashokrao 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 Noyes–Whitney 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 Noyes–Whitney equation by
multiplying both terms of equation by V and making K
equal to k1V. Comparing these terms, the following
relation is obtained:
assumed to be constant.
This is expressed by the equation,
M01/3 - Mt1/3 = κ t ----------------------------- (13)
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 κ
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/δ------------------ (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, δ is the porosity of the
D is diffusion coefficient, Cs is solubility in the matrix, τ is the tortuisity of the matrix and Q, A, Cs and
equilibrium at experience temperature and δ 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 Fick’s 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 concentration This relationship can be used to describe the
minus the cube root of percent remained, as a function drug dissolution from several types of modified release
of time. The results as shown in table 2 indicates that a pharmaceutical dosage forms, as in the case of some
linear relationship was obtained in all cases [19]. transdermal systems and matrix tablets with water
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 show under perfect sink conditions, the following initial and
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) = polymer–water interface. The solution equation under
(- a ln M- M0 / M0 )1/b + T------------------------ (20) these conditions was proposed initially by Crank
(1975):
The equation (18) may rearrange into
1
(24)
M D
1
t t
nδ
logarithmic form,
∞
=2( ) 2
− + n=1 (−1)
n
2
M∞
δ
log[-ln(1- m)] = b log (t- Ti) - log a ------- (21)
2 2 Dt
(25)
M D
t t
=2( ) =a
M∞
δ
ordinate value (1/a) at time t=1. The parameter, a, can
be replaced by the more informative dissolution time, Then, if the diffusion is the main drug release
Td, that is defined by a= (Td) d and is read from the mechanism, a graphic representing the drug amount
graph as the time value corresponding to the ordinate - released, in the referred conditions, versus the square
ln (1- m) = 1. Since -ln (1 - m) = 1 is equivalent to root of time should originate a straight line. Under some
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
dissolved amount of drug versus the logarithm of time
Mt
(26)
= a n -----------------------------------------------
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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 ε 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 ε = ε0 + KC0 -----------------------------------(31)
slabs, spheres and infinite cylinders displaying
heterogeneous erosion [42-43]. The drug release was Where ε0 is the initial porosity and K is the
expressed by equation: drug specific volume. If ε0 is small, Eq. (30) can be
Mt
=1− 1− (27) k0 t
n
-------------------------------
rearranged as:
2
M C a
∞ 0 0
3 Mt Mt 3D KC
f = 1−1− − = − t-----(32)
the pharmaceutical dosage form is exhausted, M t /M∞ is Hence, the Baker-Lonsdale model could be
the fraction of drug dissolved, k0 is the erosion rate given by equation:
constant, C is the initial concentration of drug in the
2
M M
3
f= 1−1− 3
− = kt -------------(33)
3 Mt Mt 3Dm C ms
X t = Xmax exp[−α eβ log t]------------------------(34)
f = 1−1− 3
− = − t ----(29)
1 2
M
∞ M
∞ 2
r0 C0
Where X(t) = percent dissolved at time t
divided by 100; Xmax = maximum dissolution; α
Where Mt is the drug released amount at time t
determines the undissolved proportion at time t = 1 and
and M∞ is the amount of drug released at an infinite
described as location or scale parameter; β = dissolution
time, Dm is the diffusion coefficient, Cms is the drug rate per unit of time described as shape parameter. This
solubility in the matrix, r0 is the radius of the spherical model has a steep increase in the beginning and
matrix and C0 is the initial concentration of drug in the converges slowly to the asymptotic maximal dissolution
matrix [45]. [53-56].
3 Mt 3 Mt 3D C
f = 1−1− − = − t----(30)
Where Df is the diffusion coefficient, Cfs is the transformation of dimethyl phthalate, dimethyl
drug solubility in the liquid surrounding the matrix, τ is
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Ramteke KH et al., Sch. Acad. J. Pharm., 2014; 3(5):388-396
isophthalate and dimethyl terephthalate by profile of process by using modified 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 fitting 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].
393
Ramteke KH et al., Sch. Acad. J. Pharm., 2014; 3(5):388-396
a Weibull analysis
n 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 8: Comparison of calculated parameters and their R2 using the modified 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
for drug release from controlled release dosage 44. Wilbert S, Viness P, Michael PD, Alvaro MV,
forms. J. Pharm. Pharmacol., 1980; 32: 580–2. Sandy V, Riaz AK; AAPS Pharm. Sci. Tech.,
31. Langenbucher F, Linearization of dissolution rate 2004; 5: 18.
curves by the Weibull distribution. J. Pharm. 45. Seki T, Kawaguchi T, Endoh H, Ishikawa K, Juni
Pharmacol., 1988; 24: 979-81. K, Nakano M; Controlled release of 3,5-diester
32. Goldsmith JA, Randall N, Ross SD; On methods prodrugs of 5-fluoro-2-deoxyuridine from poly-
of expressing dissolution rate data. J. Pharm. L-lactic acid microspheres. J. Pharm. Sci., 1980;
Pharmacol., 1978; 30: 347-9. 79: 985–7.
33. Kevin J, Carroll MSc, On the use and utility of 46. Jun HW, Lai JW; Preparation and in vitro
the Weibull model in the analysis of survival dissolution tests of egg albumin microcapsules of
data. Controlled clinical trials, 2003; 24: 682- nitrofurantoin. Int. J. Pharm., 1983; 16: 65–77.
701. 47. Chang RK, Price JC, Whithworth CW; Control
34. Harland RS, Gazzaniga A, Sangalli ME, of drug release rates through the use of mixtures
Colombo P, Peppas NA; Drug–polymer matrix of polycaprolactone and cellulose propionate
swelling and dissolution. Pharm. Res., 1988; 5: polymers. Pharm Tech., 1986; 10: 24–33.
488–94. 48. Shukla AJ, Price JC; Effect of drug (core)
35. Ford JL, Mitchell K, Rowe P, Armstrong DJ, particle size on the dissolution of theophylline
Elliott PNC, Rostron C et al; Mathematical from microspheres made from low molecular
modeling of drug release from hydroxyl propyl weight cellulose acetate propionate. Pharm Res.,
methyl cellulose matrices: effect of temperature. 1989; 6: 418–21.
Int. J. Pharm., 1991; 71: 95–104. 49. Bhanja RS, Pal TK; In-vitro release kinetics of
36. Kim H, Fassihi R; Application of binary polymer salbutamol sulphate microcapsules coated with
system in drug release rate modulation 2, both Eudragit RS 100 and Eudragit RL 100.
Influence of formulation variables and Drug Dev. Ind. Pharm., 1994; 20: 375–86.
hydrodynamic conditions on release kinetics. J. 50. Polleto FS, Jager E, Re MI, Guterres SS,
Pharm. Sci., 1997; 86: 323–8. Pohlmann AR; Rate-modulating ... acid model
37. El-Arini SK, Leuenberger H; Dissolution drugs. Int. J. Pharm., 2007; 345: 70.
properties of praziquantel–PVP systems, Pharm. 51. Fuentes G, Lara A, Peon E, Torres M, Lat Am
Acta Helv., 1998; 73: 89–94. Appl Res., 2005; 35: 9.
38. Pillay V, Fassihi R; In vitro release modulation 52. Singh SK, Dodge J, Durrani MJ; Optimization
from crosslinked pellets for site-specific drug and characterization of controlled release pellets
delivery to the gastrointestinal tract I, coated with a an experimental latex: 1 anionic
Comparison of pH-responsive drug release and drugs. Int. J. Pharm., 1995; 125: 243-55.
associated kinetics. J Control Release, 1999; 59: 53. Thawatchai P, Tamotsu K, Garnpimol CR;
29–242. Chitosan citrate as film former: compatibility
39. Riger PL, Peppas NA; A simple equation for with water-soluble anionic dyes and drug
description of solute release II. Fickian and dissolution from coated tablets. Int. J. Pharm.,
anomalous release from swellable devices. J 2000; 198: 97-111.
Control Rel., 1987; 5: 37. 54. Kachrimanis K, Malamataris S; Release of
40. Siepmann J, Peppas NA; Preface: Mathematical ibuprofen from spherical crystal agglomerates
modeling of controlled drug delivery. Adv. Drug and from corresponding compacts. Pharm Sci.,
Deliv. Rev., 2001; 48: 139. 2000; 10: 387-93.
41. Karasulu HY, Ertana G, Kose T; Modeling of 55. Cohen S, Yoshika T, Ukarelli M, Hwang LH,
theophylline release from different geometrical Langer R; Controlled delivery systems for
erodible tablets. Eur. J. Pharm. and Biopharm., proteins based on poly(lactic/glycolic acid)
2000; 49: 177-82. microspheres. Pharm Res., 1991; 8: 713-20.
42. Hopfenberg HB; Controlled Release Polymeric 56. Encyclopedia of biopharmaceutical statistics,
Formulations, Paul DR, Haris FW Eds., (ACS Sheilu Chang Ed., Informa Health Care, New
Symposium Series No. 33), American Chemical York, 2003.
Society, Washington, 1976. 57. Jiaxi Li, Ji-Dong Gu, Li Pan; Transformation of
43. Katzhendler I, Hofman A, Goldberger A, dimethyl phthalate, dimethyl isophthalate and
Friedman M; Modeling of drug release from dimethyl terephthalate by Rhodococcus rubber
erodible tablets. J. Pharm. Sci., 1997; 86: 110–5. Sa and modeling the processes using the
modified Gompertz model. Int. bideterioration
and biodegradation, 2005; 55: 223-32.
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