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FARMACIA, 2008, Vol.LVI, 3
THE INFLUENCE OF SOME HYDROPHILLIC
POLYMERS UPON DILTIAZEM
HYDROCHLORIDE DISSOLUTION FROM
MATRIX DOSAGE FORMS FORMULATION
CAMELIA BALAZS1*, SORIN E. LEUCUTA2
Europharm S.A. Braşov
University of Medicine and Pharmacy "Iuliu Hatieganu" Cluj-Napoca,
13, Emil Isac Str., Cluj-Napoca, Romania, Department of
Pharmaceutical Technology and Biopharmaceutics
*corresponding author: balazs_camelia2006@yahoo.com
1
2
Abstract
Matrix tablets containing diltiazem hydrochloride were prepared by the direct
compression method, using hydrophilic polymers, hydroxypropyl methylcellulose (HPMC, type
Methocel K15M), hydroxypropyl cellulose (HPC, type Klucel HXF) and polyethylene oxide
(PEO, type Polyox 1105). Diltiazem hydrochloride dissolution from matrix tablets was in
accordance with the hydrophilic polymer type and level. Hence, it was obtained a slow release
for diltiazem. The in vitro release of diltiazem was determined using UV spectrophotometry at
237 nm. Results, in conformity with the requirements of one dissolution test for diltiazem, from
U.S.P., can be obtained with formulations based on PEO. The diltiazem release mechanism
from hydrophilic matrices was observed by correlation with kinetic models.
Rezumat
Comprimate matriceale conţinând clorhidrat de diltiazem au fost preparate prin
metoda comprimării directe, utilizând polimeri hidrofili, hidroxipropilmetilceluloza
(HPMC, tip Methocel K15M), hidroxipropilceluloza (HPC, tip Klucel HXF) şi
polietilenoxid (PEO, tip Polyox 1105). Dizolvarea clorhidratului de diltiazem din
comprimatele tip matriţă a fost în funcţie de tipul şi nivelul polimerului hidrofil în
formulare, obţinând viteză redusă de dizolvare. Cedarea in vitro a diltiazemului a fost
determinată spectrofotometric UV la lungimea de undă de 237 nm. Rezultate, în
conformitate cu prevederile unui test de dizolvare pentru diltiazem din farmacopeea S.U.A.,
se pot obţine cu formulări pe baza de PEO. Mecanismul de cedare al diltiazemului din
matriţele hidrofile realizate a fost urmărit prin corelarea cu modele cinetice.



Diltiazem hydrochloride
Polyethylene oxide
Hydrophilic matrix tablets
INTRODUCTION
Hypromellose (HPMC), hydroxypropylcellulose (HPC) and poly(ethylene oxide) (PEO) are water soluble polymers, available in a variety of
FARMACIA, 2008, Vol.LVI, 3
245
molecular weights and the corresponding viscosity types. Some sorts,
showing high viscosities in aqueous solution, are used in extended release
applications of hydrophilic matrices due to their hydration and swelling
capacities. This behaviour is not affected by the gastrointestinal pH, due to
their polymeric non ionic structures.
Swellable matrix tablets are activated by water, and drug release
control depends on the interaction among water, polymer and drug. The
mechanisms of drug release are diffusion of drug through the gel layer
produced and drug transport due to the relaxation of the polymer. The rate
of diffusion through the gel layer depends on drug dissolution and matrix
erosion [6].
HPMC matrices present a continuous swelling, while PEO matrices
have a quick hydration and gelation of the matrix, but generate a worse gel,
for polymer types with comparable viscosity. In this way, the PEO matrix
system is more susceptible of erosion process and the erosion speed is
greater than HPMC matrix system [3].
Different types of swellable matrix tablets can be prepared by using
hydrophilic polymers. The most common are the free swellable matrix
tablets (polymer and solid drug mixed and compressed) in which swelling is
unhindered. In order to introduce additional elements for the drug release
control, the swelling of these matrix tablets can be affected by matrix
surface modification [6]. In this way, diltiazem formulation with HPMC
and PEO in Geomatrix technology leaded to a constant release. This system
is based on three layer geometry, these layers delayed the initial hydration
of matrix core, limited the diffusion only in the lateral side of the tablet and
eroded gradually. In this way, it was obtained zero order release [5].
In the specialty literature, diltiazem with HPC formulations were
found in the pulsatile drug release dosage forms, alongside with other
polymers, prepared by multilayer compression techniques [2].
The objective of this study was diltiazem hydrochloride
formulation with some hydrophilic polymers, with viscosity types usually
used in extended release, as HPMC type Methocel K15M, HPC type Klucel
HXF and PEO type Polyox 1105. There were prepared tablets by direct
compression. It was studied the diltiazem hydrochloride dissolution from
hydrophilic matrices resulted and the mechanism of active released.
MATERIALS AND METHODS
Materials
The diltiazem hydrochloride powder used was from Dr. Reddy’s
(India) producer.
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The hydrophilic polymers used were: Methocel K15MCR produced
by Dow Chemicals distributed by Colorcon; Klucel HXF, Hercules
producer and Polyox 1105 Union Carbide producer.
Other excipients used were: mycrocrystalline cellulose Vivapur
102 type, J. Rettenmaier&Sohne producer; colloidal silicium dioxide aerosil
200 type, Degussa producer; magnesium stearate, Magnesia producer.
The molecular weights for hydrophilic agents used and the
viscosity values (in cP) for aqueous solution of polymers are mentioned in
table I.
Polymer
Methocel K15MCR
Klucel HXF
Polyox 1105
Table I
Viscosity values for aqueous solution of polymers [3]
Molecular weight
Viscosity (cP)
Type 2208
15,000 (2% sol)
1,150,000
2,500 (1% sol)
900,000
8,800-17,600 (5% sol)
Methods
1. Hydrophilic matrices preparation
There were prepared tablets with 10 mm diameter by direct
compression method. The batch size was laboratory scale, 500 tablets. The
diltiazem hydrochloride, polymers and excipients powders were weighed,
sifted by 0.6 mm opening sieves. The powders were homogenized in a cube
with 1 liter volume, at 15 rpm rotation speed for 10 minutes, in a blender
type Pharmatech MB025. The compression was made using a tabletting
machine with one punch, using a medium tabletting force.
Three ratios diltiazem hydrochloride: polymer, 2:1, 1:1 and 1:2,
were established for each of the three polymers used for producing
hydrophilic matrices by direct compression. The formulation quantities for
active, polymer and excipients are mentioned in table II.
Table II
Formulation quantities
Diltiazem:
polymer
ratio
2:1
1:1
1:2
Diltiazem
hydrochloride
[mg]
120
120
120
Polymer
[mg]
Vivapur
102 [mg]
Magnesium
stearate [mg]
Aerosil
200 [mg]
Sum
[mg]
60
120
240
239
179
59
4
4
4
2
2
2
425
425
425
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FARMACIA, 2008, Vol.LVI, 3
2. In vitro dissolution study
In vitro dissolution tests were made according to “Diltiazem
Hydrochloride Extended-Release Capsules” monograph, USP 27 [1]. The
conditions for the 8th test were: apparatus 2 (paddles) at 100 rpm rotation
speed and 900 ml purified water at 370C as dissolution medium. The limits
for diltiazem hydrochloride dissolved percentages are mentioned in table III.
Table III
Limits for diltiazem hydrochloride dissolved percents [1]
Time (hours)
0
1
4
10
15
% dissolved
5-20%
30-50%
60-90%
min 80%
The prelevation times were 0.5, 1, 2, 3, 4, 6, 8 and 12 hours.
Dissolution tester was Sotax AT 7 Smart. The quantity of diltiazem
hydrochloride dissolved was measured by UV spectrophotometry at 237
nm. There were made three dissolution determinations for each formulation
and a mean value was calculated for each dissolution result [8].
3. Kinetics dissolution study
There were used mathematic models from literature to describe the
diltiazem hydrochloride release kinetics from the resulted hydrophilic
matrices.
The selection criterion for the suited model was the correlation of
active dissolved percents with the time in a mathematic model linear
equation. The correlation coefficient R value needs to be approximately 1 [6].
RESULTS AND DISCUSSION
Diltiazem hydrochloride dissolution from hydrophilic matrices
results
The dissolution results are presented in table IV. These are values
obtained at diltiazem hydrochloride dissolution from hydrophilic matrices
prepared by direct compression.
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Table IV
Percentages of diltiazem released in different periods of time
Polyox 1105
Klucel HXF
Methocel 15M
Diltiazem :
0.5
1
2
3
4
6
8
12
polymer
hours
hour
hours hours hours hours hours hours
2:1
21.73
23.4
34.05
44.10
51.53
77.75
84.45
88.15
Dev std
0.147
0.326
0.488
0.652
0.817
0.637
0.731
0.147
1:1
12.82
18.14
25.67
33.26
38.19
47.2
55.42
63.20
Dev std
0.181
0.263
0.383
0.512
0.607
0.773
0.552
0.668
1:2
13.05
17.90
23.26
29.90
33.16
41.85
48.55
54.14
Dev std
0.174
0.245
0.328
0.435
0.504
0.648
0.413
0.387
2:1
19.12
21.75
30.61
39.44
43.96
93.95
94.80
95.01
Dev std
0.129
0.303
0.439
0.583
0.697
0.762
0.263
0.220
1:1
10.99
18.00
24.72
30.79
35.50
43.23
50.10
56.20
Dev std
0.155
0.261
0.369
0.360
0.564
0.708
0.362
0.289
1:2
11.47
16.14
20.50
26.72
29.95
38.22
45.68
52.30
Dev std
0.153
0.221
0.289
0.389
0.449
0.592
0.442
0.631
2:1
15.91
19.41
31.64
39.73
43.09
56.01
66.64
73.40
Dev std
0.220
0.276
0.463
0.599
0.669
0.802
0.246
0.411
1:1
9.94
17.83
26.14
34.26
40.94
51.67
61.44
70.22
Dev std
0.140
0.258
0.390
0.533
0.651
0.846
0.521
0.613
1:2
11.61
16.41
24.14
32.75
37.73
47.45
57.32
65.20
Dev std
0.155
0.225
0.341
0.476
0.566
0.735
0.413
0.512
Note: There are mean values for percents dissolved; dev std means standard deviation
Diltiazem hydrochloride dissolution determined by polymer type in
formulation is presented in fig. 1.
The diltiazem percents dissolved are lower in the case of Polyox
1105 matrix than in Methocel K15M and Klucel HXF matrices, at the 2:1
diltiazem: polymer ratio. This is due to the gel barrier generation speed at
the tablets matrices contact with the dissolution medium. The PEO matrix
rapidly swells, the hydration speed is high and the gel barrier is well defined
until the diltiazem diffusion starts, in comparison with HPMC and HPC
matrices. The HPMC and HPC matrices present a continuous swelling in
aqueous medium and the gel barrier are incompletely created at this ratio
active: polymer.
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FARMACIA, 2008, Vol.LVI, 3
100
100
Diltiazem : Polymer 2 : 1
80
70
70
60
50
40
Methocel K15M
30
20
Polyox 1105
10
hours
0
1
2
3
4
5
6
7
8
60
50
40
Methocel K15M
30
Klucel HXF
0
Diltiazem : polymer 1:1
90
80
% dissolved
% dissolved
90
9
10
11
20
Klucel HXF
10
Polyox 1105
hours
0
12
0
1
2
3
4
5
6
7
8
9
10
11
12
100
Diltiazem : polymer 1:2
90
80
% dissolved
70
60
50
40
30
Methocel K15M
20
Klucel HXF
10
hours
Polyox 1105
0
0
1
2
3
4
5
6
7
8
9
10
11
12
Figure 1
Diltiazem hydrochloride dissolution: polymer type influence
The diltiazem percents dissolved are lower in the case of
hydrophilic matrices generated by Methocel K15M and Klucel HXF than
the matrix generated by Polyox 1105, at the 1:1 and 1:2 diltiazem: polymer
ratios. The dissolution results for 1:1 and 1:2 ratios are conform to literature
notes. Diltiazem release from PEO matrices is more rapid and complete than
diltiazem release from HPMC and HPC matrices, polymer types with
comparable viscosities [7]. The reason is Polyox 1105 forms a weak gel, in
comparison with Methocel K15M and Klucel HXF. This Polyox barrier is
easily removed by dissolution medium and matrix system is more sensitive
to the erosion phenomenon. There is a decrease, emphasized in Diltiazem
tablet volume, and the erosion speed for PEO matrices at the mentioned
ratios is greater than HPMC and HPC matrices.
Diltiazem hydrochloride dissolution determined by polymer level
in hydrophilic matrices is presented in fig. 2.
The dissolution speed decreases with the increase in polymer level
in formulation, for the polymers used in formulation.
The diltiazem release depends on hydrophilic matrices specific
factors: drug level and polymer nominal viscosity and level in formulation [6].
For a small amount of polymer, simultaneously high proportion of
active in formulation, the diltiazem release is governed by matrix porosity
done by diltiazem dissolution and diffusion. The polymer level increase
brings to gel viscosity increasing and the active diffusion is decreased, with
dissolution speed decreasing.
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FARMACIA, 2008, Vol.LVI, 3
100
100
90
Methocel K15M
80
80
70
70
% dissolved
% dissolved
90
60
50
40
Klucel HXF
60
50
40
30
2:1
30
2:1
20
1:1
20
1:1
10
10
hours
1:2
0
hours
1:2
0
0
1
2
3
4
5
6
7
8
9
10
11
12
0
1
2
3
4
5
6
7
8
9
10
11
100
90
Polyox 1105
80
% dissolved
70
60
50
40
2:1
30
1:1
20
1:2
10
hours
0
0
1
2
3
4
5
6
7
8
9
10
11
12
Figure 2
Diltiazem hydrochloride dissolution: polymer level influence
Dissolution results in comparison with USP limits
The study purpose was USP limits proximity for diltiazem
dissolution from hydrophilic matrices prepared in this work. The limits for
the 8th test are mentioned in table III. The dissolved percents value needs to
be 20% maximum after the first hour, 30-50% after 4 hours, around 60%
after 8 hours and 70% minimum after 12 hours.
Diltiazem matrices formulation with Polyox 1105, 2:1 and 1:1
ratios diltiazem: polyox, are nearby with USP limits, 8th test, for diltiazem in
vitro dissolution.
Kinetics dissolution study
Hydrophilic matrix performance, as prolonged release system, is
dependent to: matrix water penetration, polymer swelling, substance
dissolution and diffusion and matrix erosion [7].
The kinetics study was used to elucidate the physical mechanisms
of drug transport by simply comparing the release data to mathematical
models.
Higuchi equation predicts a linear relation if Q is graphically
represented in function of the square root of time, t1/2, equation (1):
12
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FARMACIA, 2008, Vol.LVI, 3
Q  ( K H .t 1 / 2 )  c,
(1)
where Q is the cumulative percent of drug release in time (t), KH is
the Higuchi release constant (slope), c is the y axis intercept [6].
The values for correlation coefficient, R, between diltiazem
dissolved percents and square root of time, were approximately 1, for each
type of studied matrix, values presented in table V.
Table V
Correlation between diltiazem dissolved percents and time, in conformity
to kinetics models, Higuchi (H) and Korsmeyer-Peppas (K-P)
diltiazem :
H
Higuchi
K-P
Polymer
polimer
Correlation Constant
Correlation
n
ratio
coefficient Release KH
coefficient
Methocel
2:1
0.985
30.247
0.975
0.530
K15M
1:1
0.998
18.945
0.999
0.517
1:2
0.997
16.024
0.998
0.462
Klucel
2:1
0.911
32.449
0.928
0.578
HXF
1:1
0.997
16.916
0.996
0.512
1:2
0.998
15.391
0.997
0.488
Polyox
2:1
0.996
22.276
0.994
0.516
1105
1:1
0.996
21.659
0.996
0.617
1:2
0.997
19.852
0.998
0.566
The release mechanism described on this kinetics is by matrix
pores diffusion of drug dissolved.
The slope, KH, was calculated in conformity with the model
equation. The KH represents drug release rate constant and is declared as
dissolved percents / hours1/2 or hours-1/2. The KH values were 22.3 and 21.6
hours-1/2 for the formulations with Polyox, 2:1 and 1:1 ratios, according to
USP limits, 8th test, for diltiazem dissolution (table V).
A common procedure for analyzing experimental data of drug
release from swelling hydrophilic systems is fitting them to the exponential
equation (2) from Korsmeyer-Peppas model, and determining the exponent n.
Mt
 K K  P .t n ,
M
( 2)
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FARMACIA, 2008, Vol.LVI, 3
Where Mt is the drug release quantity at time t (hours), M∞ is the
total drug release quantity after a long time, Mt/M∞ is the release fraction at
time t. KK-P is the release constant and n is a dimensionless number,
indication exponent for the release kinetics. The n index is the right slope of
graphic representation of log (normalized drug release, Mt/M∞) as a function
of log (release time, t) [4, 6]
The diffusion mechanism was confirmed by exponential equation
from Korsmeyer-Peppas model, the correlation coefficient values were
mentioned in table VI. The n index had 0.46 to 0.62 values (table VI).
This model describes drug release kinetics from swellingcontrolled drug delivery systems, dependent on matrix geometry. For a
cylinder matrix, 0.45 n value indicates t1/2 dependent kinetics, in accordance
with Fickian diffusion, 0.45<n<0.89 values show anomalous transport, nonFickian diffusion, sum of the two mechanisms, release controlled by
diffusion with relaxation / erosion of polymer [6].
Thus, the diltiazem hydrochloride release mechanism from the
realized hydrophilic matrix tablets, was performed by drug diffusion on the
gel layer generated by the polymer hydration and swelling. This stage was
followed by the gel layer erosion. Erosion phenomenon was more visible at
PEO matrices than HPMC and HPC matrices, at 1:1 and 1:2 diltiazem:
polymer ratios.
CONCLUSIONS
Hydrophilic matrix tablets were prepared by diltiazem
hydrochloride tablets formulation with different levels of water soluble and
swellable polymers, hypromellose, hydroxypropylcellulose and poly(ethylene oxide), using polymer and drug powders mixing and direct
compression technologies.
Diltiazem release from the produced swellable matrix tablets was
determined by the polymer type and the level in formulation.
At the smallest level of matrix agent in formulation, 2:1 ratio
diltiazem: polymer, the drug release was governed by the rapid hidration
and matrix generation for PEO. At this level the diltiazem release rate for
PEO matrix was lower than the rates for HPMC and HPC matrices.
At higher levels of matrix agent in formulation, 1:1 and 1:2 ratios
diltiazem: polymer, the drug release was determined by the higher vicosity
of the gel barrier in case of HPMC and HPC, and weakly, erodible gel layer
in case of PEO. At this levels, the diltiazem release rates for HPMC and
HPC matrices were lower than the rate for PEO matrix.
FARMACIA, 2008, Vol.LVI, 3
253
The diltiazem release rate was decreased while the polymer level
increased, for all three matrix agents used in diltiazem formulation in this
issue.
The drug dissolved results, close to U.S.P. in vitro dissolution test
limits, were the 2:1 and 1:1 diltiazem : polyox 1105 formulations.
The diltiazem hydrochloride release mechanism was done by drug
diffusion on the gel layer generated by the polymer hydration and swelling,
followed by the gel layer erosion. Erosion phenomenon was more visible at
PEO matrices than HPMC and HPC matrices, at 1:1 and 1:2 diltiazem:
polymer ratios.
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3. Maggi L., Bruni R., Conte U. “High molecular weight polyethylene
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