FARMACIA, 2008, Vol.LVI, 4
371
KINETIC MODELING OF HYDRATION
HYDROPHILIC MATRICES WITH
DICLOFENAC SODIUM ON BASIS OF
HYDROXYPROPYL METHYLCELLULOSE
AND XANTHAN GUM
I. KUSAI1*, L.VLASE2, I. TOMUŢĂ2, S.E. LEUCUŢA2
1
Optimisation and Validation Process Departament, Terapia- Ranbaxy,
500632, Cluj-Napoca, Romania
2
Department of Pharmaceutical Technology and Biopharmaceutics
Faculty of Pharmacy, “Iuliu Haţieganu”University of Medicine and
Pharmacy, 13 Emil Isac, 400023, Cluj, Cluj-Napoca, Romania
*
corresponding author: iuliana_kusai@yahoo.com
Abstract
The use of natural matrices containing either Xanthan gum or Hydroxypropyl
methylcellulose, as release-controlling-release agents, was studied. These polymers hydrate
and swell in contact with water and they are used for the preparation of single unit matrix
dosage forms.
The aim of this study was the analysis of hydration kinetics of several
formulations of hydrophilic matrices containing hydroxypropyl methylcellulose and
Xanthan gum, diclofenac sodium loaded. A number of 21 formulations were prepared and
analyzed, which differ by polymer type, the polymers’ moisture effect, the polymers’ratio
(between Hydroxypropyl methylcellulose / Xanthan gum) and also the proportion between
polymers and active drug substance. The degree of hydration was evaluated by a
gravimetric method [1, 2].
By application of various mathematical models, it was possible to quantify and
to describe the mechanism of hydration of different kinds of hydrophilic matrices. The
representative model describing the kinetics of hydration for these matrices was Peppas
model and its characteristic parameters were calculated and analyzed.
Rezumat
Guma xantan sau/şi hidroxipropil metilceluloza pot fi folosite ca şi agenţi de
retardare pentru prepararea matriţelor hidrofile. Aceşti polimeri se hidratează şi se umflă în
contact cu apa, astfel încât pot fi utilizaţi pentru prepararea formelor farmaceutice dozate.
Scopul acestui studiu a fost analiza cineticii de hidratare a matriţelor formate din
diclofenac sodic, hidroxipropil metilceluloză (HPMC) şi gumă xantan (GX). Au fost
preparate şi analizate un număr de 21 formulări, care diferă prin natura polimerilor,
umiditatea polimerilor, raportul între polimeri (hidroxipropil metilceluloză/gumă xantan),
proporţia polimeri–substanţă medicamentoasă. Scopul acestui studiu a fost de a cuantifica
rata de hidratare a preparatelor pe bază de gumă şi hidroxipropil metilceluloză prin
măsurători gravimetrice.
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FARMACIA, 2008, Vol.LVI, 4
Au fost aplicate diferite modele matematice, făcând posibila cuantificarea şi
descrierea mecanismului de hidratare din matriţele de diclofenac sodic. Dintre modelele
matematice empirice, cel care a descris cel mai bine cinetica de hidratare a fost modelul
Pepas. Pentru acest model au fost calculaţi şi analizaţi parametrii caracteristici.





Diclofenac Sodium
Xanthan Gum
Hydroxypropyl Methylcellulose
Matrices
Hydration
INTRODUCTION
It has been shown that drug release from hydrophilic matrices is a
complex interaction between swelling, diffusion and erosion [3]. The
gradual penetration of water produces swelling and forms a hydrated gel
through which the drug has to pass by dissolution and diffusion across the
ever-increasing diffusional pathway length. Swelling has been shown to
follow square root of time kinetics. However, drugs contained in certain
systems are released at rates approaching zero order. It is apparent,
therefore, that other mechanisms, in addition to diffusion, must take place at
the interface between the gel and the surrounding medium. The polymer
chains will gradually disentangle from the interface. This polymer chain
relaxation will increase the rate of drug release by decreasing the diffusional
path length for the drug. It is important to try to quantify the degree of
hydration from matrix surface interfacing with the aqueous dissolution
medium.
The objective of this study was to determine the degree of hydration
by gravimetric method and to characterize the prepared formulations from
the point of view of hydration kinetics [1, 4].
MATERIALS AND METHODS
 Materials
Diclofenacum sodium (Terapia S.A. Romania), Hydroxypropyl
methylcellulose (HPMC) - Methocel K 4M CR (Colorcon Ltd., UK),
Xanthan Gum (Colorcon Ltd., UK), colloidal silicon dioxide - Aerosil
(Terapia S.A. Romania), magnesium stearate (Terapia S.A. Romania).
 Tablets preparation
Tablets were directly compressed using rotation tabletting machine (Ronchi
EA/8) at a compression force about 12 kN.
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FARMACIA, 2008, Vol.LVI, 4
Table I
The formulations of experimental design
No.
Exp.
Diclofenac
sodium
(mg)
Methocel
K4 MCR (mg)
Xanthan
Gum
(mg)
Aerosil
(mg)
Magnesium
Stearate
(mg)
Weight
of tablets
(mg)
N1
N2
N3
N4
N5
N6
N7
N8
N9
N10
N11
N12
N13
N14
N15
N16
N17
N18
N19
N20
N21
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
166.7
333.3
110.0
56.0
83.4
166.7
83.4
166.7
250.0
83.4
250.0
56.0
125.0
125.0
125.0
250.0
500.0
166.6
-
333.3
166.7
56.0
110.0
166.7
83.4
166.7
83.4
250.0
83.4
250.0
110.0
125.0
125.0
125.0
250.0
500.0
166.7
1.2
1.2
0.5
0.5
0.7
0.7
0.7
0.7
1.2
0.5
1.2
0.5
0.7
0.7
0.7
0.7
0.7
1.2
1.2
0.5
0.5
6.0
6.0
2.7
2.7
3.7
3.7
3.7
3.7
6.0
2.7
6.0
2.7
3.7
3.7
3.7
3.7
3.7
6.0
6.0
2.7
2.7
607.2
607.2
269.2
269.2
354.4
354.4
354.4
354.4
607.2
269.2
607.2
269.2
354.4
354.4
354.4
354.4
354.4
607.2
607.2
269.2
269.2
 Hydration test of the tablets
The studies were carried out using a Pharma Test PT-DT7
dissolution tester (PharmaTest, Germania), fitted with six rotating baskets.
The dissolution medium used was 900 ml of distilled water maintained at
37±0.5°C by the constant temperature water bath. Agitation speed 100±1
rpm was used during the experiment. Each basket was thoroughly cleaned,
accurately weighed and weighed again after insertion of a matrix tablet, so
that the accurate weight of each tablet could be calculated. The basket and
tablets were then rotated in the dissolution medium and at regular time
intervals (usually 15, 30, 60, 120, 240, 360 and 480 minutes) the basket was
detached, blotted with absorbents tissue to remove any excess medium on
the basket surface and accurately weighed on a Sartorius analytical balance.
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FARMACIA, 2008, Vol.LVI, 4
 Selecting the mathematical model of analysis
The experimental data were analyzed using four kinetic
mechanistic models as it is shown in table II [5, 6].
Table II
Hydration kinetic models used for the analysis of diclofenacum sodium tablets
Model Kinetic model
Parameters
Equation
M1 Zero order
tlag, tced
1
M2 First order
tlag, k1
2
M3 Higuchi
tlag, k Higuchi
3
M4 Peppas
tlag, k Peppas, n
4
where tlag represents the lag time until the start of a kinetic process; tced is the release time
for zero order kinetics, k represents the release rate constant of a first order kinetic process,
Higuchi or Peppas; the indicatives “1”, “0”, “Higuchi”, “Peppas” associate a parameter
with a certain type of kinetics.
From usual selection criteria (Akaike, Schwartz criteria, and
residual analysis) the Akaike criterion [7] was chosen for distinguishing
among competing models. In this criterion a lower value of the indicator
means a better fit. The fitting method was realized with the WinNonlin [8]
program. On the basis of the Akaike indicator we selected the mathematical
model, which describes the release profile for all the analyzed samples with
the greatest accuracy. The kinetic models for mechanistic models (1-4) were
selected.
Equation 1.
Zero order model
%dissolved=100*t/tced
Equation 2.
First order model
%dissolved=100(1-e-k*t)
Equation 3.
Higuchi model
%dissolved=k*(t)0.5
Equation 4.
Peppas model
%dissolved=k*(t)n
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FARMACIA, 2008, Vol.LVI, 4
RESULTS AND DISCUSSION
The tablets’ increase in weight at various time intervals is shown in
Figure 1.
14.00
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
12.00
10.00
8.00
6.00
4.00
2.00
0.00
0
100
200
300
400
500
600
1
10
11
12
13
2
3
4
5
6
7
8
9
16
17
18
19
20
21
Figure 1
Hydration profiles of the examined formulations
Figures 2 and 3 show a relatively nonlinear increase of the degree
of hydration in time.
For the first order kinetic it is considered that on the last determination
a maximum swelling happens and the percentage are 100%. It is recalculated %
of the swelling at various time intervals. After individual fitting on with first
order kinetics, the experimental data do not fit with the model.
100
Formulation N3
90
80
70
60
50
Observed
40
Predicted
30
20
10
0
0
50
100 150 200 250 300 350 400 450 500
Time
Figure 2
First order kinetic fitting of the data for the formulation N3
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FARMACIA, 2008, Vol.LVI, 4
100
Formulation N8
90
80
70
60
50
Observed
40
Predicted
30
20
10
0
0
50
100
150
200
250
300
350
400
450
500
Time
Figure 3
First order kinetic fitting of the data for the formulation N8
There was an increase of relative weight compared to initial weight
for fitting data of Peppas and Higuchi kinetics. In the following tables the
data which were used in mathematic equation no. 3 and no. 4. are shown.
Table III
Relative weight at various time intervals
No.
exp
N1
N2
N3
N4
N5
N6
N7
N8
N9
N10
N11
N12
N13
Relative
weight
at 15
minutes
(mg)
1.42
1.20
1.45
2.40
2.12
1.80
2.44
1.61
1.62
2.28
1.70
2.25
2.02
Relative
weight
at 30
minutes
(mg)
1.93
1.52
2.05
2.92
2.89
2.31
2.88
2.31
2.08
2.84
2.14
3.34
2.61
Relative
weight
at 60
minutes
(mg)
3.05
2.35
3.03
3.70
3.85
2.99
3.76
2.80
2.74
3.65
2.52
4.16
3.21
Relative
weight
at 120
minutes
(mg)
4.38
3.13
3.83
5.44
5.34
3.89
4.63
3.39
3.81
4.88
3.45
5.06
4.60
Relative
weight
at 240
minutes
(mg)
6.83
4.43
5.19
7.30
7.90
5.39
6.82
4.54
5.55
7.01
4.88
6.73
6.28
Relative
weight
at 360
minutes
(mg)
8.63
5.54
5.69
8.56
10.01
6.53
8.38
5.29
7.35
8.24
6.26
7.64
7.51
Relative
weight
at 480
minutes
(mg)
9.50
6.34
6.29
9.06
10.91
7.08
9.27
5.61
8.78
8.75
7.44
8.19
8.30
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FARMACIA, 2008, Vol.LVI, 4
No.
exp
N16
N17
N18
N19
N20
N21
Relative
weight
at 15
minutes
(mg)
1.22
2.27
1.85
0.91
1.75
3.67
Relative
weight
at 30
minutes
(mg)
1.29
2.96
2.62
0.99
2.01
4.48
Relative
weight
at 60
minutes
(mg)
1.60
4.07
3.98
1.64
2.39
5.30
Relative
weight
at 120
minutes
(mg)
1.92
5.73
5.79
1.93
3.11
7.18
Relative
weight
at 240
minutes
(mg)
5.44
9.34
9.72
2.53
3.58
11.33
Relative
weight
at 360
minutes
(mg)
2.75
11.48
11.46
2.75
4.03
12.33
Relative
weight
at 480
minutes
(mg)
2.99
11.44
12.65
2.73
4.32
12.55
After the individual fitting on Higuchi and Peppas models, Akaike
values were calculated for each experimental data.
No. exp
Higuchi
N1
N2
N3
N4
N5
N6
N7
N8
N9
N10
N11
N12
N13
N16
N17
N18
N19
N20
N21
Average
-0.8
-22.8
3.3
5.7
-6.9
-0.2
2.4
5.6
-2.5
3.9
-4.2
11.1
-0.7
1.9
7.2
6.1
0.5
8.8
15.3
1.8
Table IV
The average Akaike values for each kinetic model
Peppas
Akaike lower
Optimum
values
model
-5.9
-5.9
Peppas
-21.0
-22.8
Higuchi
-7.2
-7.2
Peppas
-3.5
-3.5
Peppas
-6.9
Peppas
-5.0
-14.7
Peppas
-14.7
-2.5
-2.5
Peppas
-14.1
Peppas
-14.1
-3.6
-3.6
Peppas
-5.2
-5.2
Peppas
-4.2
Higuchi
-2.6
-8.4
-8.4
Peppas
Peppas
-12.9
-12.9
-21.9
-21.9
Peppas
7.2
Higuchi
9.2
4.5
4.5
Peppas
-9.3
-9.3
Peppas
Peppas
-21.0
-21.0
Peppas
11.4
11.4
-7.0
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FARMACIA, 2008, Vol.LVI, 4
It is clear that in table V, the Peppas model (M4) is the one which
best describes the hydration kinetics for the analyzed samples. For each
pharmaceutical formulation, the values of the constant characteristics of the
Peppas models were calculated, as well as a parameter, which denotes the
precision with which the calculus of the constants is performed (variation
coefficient of the standard error of the determination average).
No. exp
N1
N2
N3
N4
N5
N6
N7
N8
N9
N10
N11
N12
N13
N16
N17
N18
N19
N20
N21
Table V
The values valid for Peppas model parameters
of the examined pharmaceutical formulation
k
n
0,309025
0.559745
0,295385
0.496575
0,583372
0.389035
0.755771
0.407748
0.755771
0.407748
0.516062
0.497414
0.556700
0.413889
0.668246
0.347492
0.294055
0.546258
0.698826
0.414059
0.367961
0.481638
0.981416
0.346829
0.592122
0.429197
0.503770
0.287284
0.562846
0.499501
0.422462
0.556996
0.402765
0.321811
0.821988
0.269578
1.166900
0.394624
The exponent (n), indicative of the mechanism of hydration from
pharmaceutical formulation, was calculated from the well-known Peppas
equation. The values of n were obtained by linear regression analysis. A
value of n=0.45 indicates Case I (Fickian) diffusion or square of time
kinetics, 0.45<n<0.89 indicates anomalous (non-Fickian) diffusion, n=0.89
indicates Case II transport and n> 0.89 indicates Super Case II transport. [9]
In the experimental formulations the exponent n is 0.45<n<0.89, indicating
anomalous (non-Fickian) diffusion.
FARMACIA, 2008, Vol.LVI, 4
379
CONCLUSIONS
21 hydrophilic matrixes of Hydroxypropyl methylcellulose and
Xanthan gum, diclofenacum sodium loaded were formulated and analyzed
as the degree of hydration. The hydration profiles of the examined matrix
were fitted with 4 kinetic models. The models which best described the
hydration kinetics of the matrix formulation was the Peppas model, for
which the characteristic parameters have been calculated.
In conclusion, Xanthan gum and Hydroxypropil Methylcellulose
demonstrated different abilities to hydrate with water. Xanthan Gum
displayed a high degree of swelling due to water uptake, in contrast,
Hydroxypropil Methylcellulose displayed a much lower hydration capacity.
In conclusion Xanthan gums is more hydrophilic than Hydroxypropil
Methylcellulose, therefore it hydrates more quickly forming immediately a
protective barrier layer.
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