Original article

The effect of hydrophilic and lipophilic polymers and llers

on the release rate of atenolol from HPMC matrices
F. Lotpour
a
, A. Nokhodchi
a,b,
*, M. Saeedi
c
, S. Norouzi-Sani
a,d
,
J. Sharba
a
, M.R. Siahi-Shadbad
a
a
School of Pharmacy, Tabriz Medical Sciences University, Tabriz 51664, Iran
b
Department of Pharmacy, Kings College London, Franklin-Wilkins Building, 150 Stamford Street, SE1 9NN, London, UK
c
School of Pharmacy, Sari Medical Sciences University, Sari, Iran
d
School of Pharmacy, Department of Pharmaceutical Sciences, Idaho State University, Pocatello, 83209, USA
Received 10 February 2004; accepted 10 June 2004
Available online 23 August 2004
Abstract
The objective of this study is to investigate the effect of various polymers, and llers, and their concentrations on the release rate of atenolol
from polymeric matrices. Four polymers namely hydroxypropylmethylcellulose (HPMC), Eudragit RSPO, ethylcellulose (EC) and sodium
carboxymethylcellulose (NaCMC) were used. The dissolution proles showed that an increase in the concentration of HPMCand ECresulted
in a reduction in the release rate of atenolol. The results indicate that it is difcult to obtain a zero-order release from the matrices containing
either HPMC or EC. It is also observed that the amount of HPMC played a dominant role, affecting the drug release in binary mixtures of
EudragitHPMC. Generally, the presence of NaCMCcaused an increase in the release rate of atenolol fromHPMCmatrices. To determine the
effect of llers on the release rate of atenolol fromHPMCmatrices, lactose (a soluble ller) and dicalciumphosphate (an insoluble ller) were
used. The results showed that an increase in the concentration of llers resulted in an increase in the release rate of the drug from matrices and
hydrophilicity or hydrophobicity of llers had no signicant effect on the release prole. In order to determine the mode of release, the data
were analysed based on the equation Q = K (t l)
m
. Values of m were in the range of 0.320.99 indicating that release was controlled by both
diffusion and erosion, depending on the type of polymer and concentration.
2004 Elsevier SAS. All rights reserved.
Keywords: Atenolol; Release rate; Release kinetic; Polymers; Diffusion; Erosion
1. Introduction
One method of fabricating controlled-release dosage
forms is the incorporation of the drug in a matrix containing
a hydrophilic, rate-controlling polymer. Matrix systems are
popular in controlled-release formulation systems in terms of
economic, process development and scale-up procedures
[14]. Various cellulose derivatives are widely used in the
pharmaceutical eld as excipients for the preparation of
matrix systems used in sustained release formulations [4]. In
these swellable and erodable matrices, the release rate of
solute is controlled by one or more of the following process:
the transport of solute into the polymeric matrix, swelling of
the associated polymers, diffusion of the solute through the
swollen polymer, and erosion of the swollen polymer [5].
Several factors, such as the polymer type and concentration,
the drug particle size and the presence of additives and
excipients in the nal formulation can modify the drug re-
lease fromthe matrices [69]. The effect of polymeric excipi-
ents on drug release from matrices has been investigated by
Dabbagh et al. [10] and Baveja et al. [11]. They used blends
of hydroxypropylmethylcellulose (HPMC) and sodiumcar-
boxymethylcellulose (NaCMC) to achieve a zero-order re-
lease of propranolol hydrochloride [10,11]. Strubel et al. [12]
found that drug release from matrices made of hydroxypro-
pylmethylcellulose acetate succinate (HPMCAS, an enteric
* Corresponding author. Tel.: +44-20-7848-4787;
fax: +44-20-7848-4800.
E-mail address: Ali.nokhodchi@kcl.ac.uk (A. Nokhodchi).
IL FARMACO 59 (2004) 819825
www.elsevier.com/locate/farmac
0014-827X/$ - see front matter 2004 Elsevier SAS. All rights reserved.
doi:10.1016/j.farmac.2004.06.006
polymer) did not have pH-independent release. Prez-Marcos
et al. [13] used three varieties of carbomer and studied drug
properties and release as a function of technological variable,
type and proportion of polymer. They showed that in all
cases, drug release proles tted Higuchis model and
showed strong dependence on proportion of polymer [13].
Addition of surfactants is another approach to modify the
drug release from matrices [1421].
The objectives of the present study were: (a) to investigate
the in vitro characteristics of atenolol from various
controlled-release matrices; (b) to examine the effect of
soluble and insoluble llers on the release proles of atenolol
from HPMC matrices; (c) to investigate the effect of binary
polymer blends on the release behaviour; (d) to study the
effects of type of ller and polymer on the kinetic release of
atenolol from polymeric matrices.
2. Materials and methods
2.1. Materials
Atenolol (Darou Pakhsh, Iran), hydroxypropylmethylcel-
lulose K4M (Colorcon, UK), sodium carboxymethylcellu-
lose (Colorcon, UK), ethylcellulose (Colorcon, UK),
Eudragit RSPO (Rohm Pharma, Germany), lactose monohy-
drate (Merck, Germany), magnesium stearate (BDH Chemi-
cals Ltd, Poole, Dorest, UK), and dicalcium phosphate dihy-
drate (Merck Germany) were obtained.
2.2. Methods
2.2.1. Tablet preparation
Tablet preparation carried out by 15 min mixing of
atenolol with different polymers and surfactants. After the
addition of 1% w/w of magnesium stearate, the mixing pro-
cedure was continued for a further 2 min. The mixtures were
compressed on an 11-mm punch and die using a single
tableting machine (Korsch, Germany) at a compression
speed of 20 tablets/min. Sufcient compression force was
applied in order to produce tablets of 56 kg hardness, as
determined using a hardness tester (Erweka, TBH30MD,
Germany).
Different preparation methods were conducted for llers.
Dicalcium phosphate and lactose were mixed with drug,
granulated with distilled water (about 100 ml water was used
to granulate 50 g sample) using a pestle and mortar for a
period of 20 min and then passed through a N
o
. 18 sieve. The
granules were dried 4 h at 60 C, and then calibrated through
the same sieve. Magnesium stearate (1% w/w) was added to
the dry granules and was mixed for a period of 2 min. The
nal mixture was compressed on an 11-mm single-punch
machine (see Table 1 for the composition of matrices).
2.2.2. Dissolution studies
The United State Pharmacopoeia (USP) basket method
was used for all the in vitro dissolution studies. In this
method, distilled water containing HCl which simulated gas-
tric uid (pH 1.2), and intestinal uid (phosphate buffer pH
6.8) without enzyme, were used as dissolution media. The
dissolution prole of atenolol according to the USP basket
method at 100 rpm, in 900 ml maintained at 37 C. The
amount of atenolol was 100 mg in all formulations. The
matrices were placed in 900 ml of gastric uid for 2 h. The
samples were withdrawn at predetermined time intervals,
ltered and assayed spectrophotometrically at 274 nm. After
2 h the dissolution medium the dissolution medium pH was
changed from 1.2 to 6.8 using phosphate buffer. The mean of
Table 1
Different formulations of atenolol matrices and their composition (mg)
Code Atenolol HPMC EC Eudragit NaCMC Lactose DCP
F
1
100 75
F
2
100 100
F
3
100 125
F
4
100 100
F
5
100 150
F
6
100 200
F
7
100 75 25
F
8
100 50 50
F
9
100 25 75
F
10
100 100
F
11
100 75 25
F
12
100 50 50
F
13
100 25 75
F
14
100 100
F
15
100 75 25
F
16
100 50 50
F
17
100 25 75
F
18
100 75 25
F
19
100 50 50
F
20
100 25 75
820 F. Lotpour et al. / IL FARMACO 59 (2004) 819825
three determinations was used to calculate the drug release
from each of the formulations.
2.2.3. Kinetic models
To determine the drug release mechanism and to compare
the release prole differences among matrices, the drug re-
leased percentage versus time were used. The release data
were analysed with the following mathematical models.
(1)
Q= K
1
t
n
In Eq. (1), Qis the percent of drug released at time t and K
1
is a kinetic constant incorporating structural and geometric
characteristics of the tablets and n is the diffusional exponent
indicative of the release mechanism. The value of n for a
cylinder is <0.45 for Fickian release, >0.45 and <0.89 for
non-Fickian transport and n = 0.89 for the case II release
and >0.89 for super case II type release [22].
However, Eq. (1) is based on the assumption that release
occurs as soon as the matrix is placed in contact with uid
thus predicts an intercept at the origin. Ford et al. [7,23]
introduced a similar equation with a correction for lag peri-
ods.
(2)
Q= K
2
(t 1)
m
The lag period is the time required for the matrix to
hydrate and reach equilibrium before erosion and the ad-
vance of the solvent front occurs through the matrix. These
authors [23] concluded that these lag periods in dissolution,
despite being relatively constant and small, cannot be ig-
nored when describing release using exponential functions as
they improve the t of the data. Furthermore, such lag peri-
ods can considerably alter the values of both derived kinetic
constant and diffusional exponents. For these reasons, in this
study the data between 5% and 60% release were tted with
a computer program[23] to Eq. (2). Values of mnear 0.5 indi-
cate predominantly diffusion control and of 1 correspond to
zero-order release [23].
For comparison purposes, the data between 5% and 60%
was also subjected to Eq. (3), which may be considered a
simple, Higuchi type equation.
(3)
Q= K
3
t
0.5
+ C
Eq. (3), for release data dependent on the square root of
time, would give a straight line release prole, with K
3
presented as a root time dissolution rate constant and C as a
constant.
3. Results and discussion
3.1. The inuence of polymer type and its concentration
The drug release results from different matrices contain-
ing various polymers are shown in Figs. 16. Fig. 1 shows the
dissolution characteristics of matrices prepared with differ-
ent amounts of HPMC. In vitro release proles of atenolol
showed that a reduction in the amount of HPMC resulted in
an increase in the release rate of atenolol (Fig. 1). For ex-
ample, the percentage of drug released from formulations
containing 75, 100 and 125 mg HPMCafter 2 h at pH1.2 was
45.74%, 42.2% and 35.2%, respectively, indicating a signi-
cant effect of HPMC concentration on a reduction in the
release rate of atenolol from HPMC matrices. This is due to
an increase in the viscosity of the gel as well as the formation
of a gel layer with a longer diffusional path with an increase
in the concentration of HPMC. This could cause a decrease in
the effective diffusion coefcient of the drug and therefore a
reduction in the drug release rate. This indicates that
drug/polymer ratio is an important factor affecting the rate of
release drugs from HPMC matrices [6,2426]. Fig. 1 also
shows that the release rate in acidic media is faster than at pH
Fig. 1. The release proles of atenolol from HPMC matrices.
Fig. 2. The release prole of atenolol from ethylcellulose matrices.
821 F. Lotpour et al. / IL FARMACO 59 (2004) 819825
6.8. This can be attributed to an increase in viscosity of gel
layer at pH 6.8 and indicates that obtaining of zero-order
kinetic with HPMC-matrices is difcult.
Table 2 gives the results after tting to Eqs. (1) and (2), of
the kinetic constant K
1
(% min
n
) and K
2
(% min
m
), release
exponents n and m and the lag time (min) of the different
batches. Table 2 also gives the root time release rates K
3
(%
min
0.5
) calculated according to Eq. (3).
Eq. (1) gives an estimate of n based on Eq. (1) without lag
time correction. The high values of the sum of squares (ss)
suggest that this empirical equation does not provide a good
t for the results (the mean of ss for 20 formulations is 11).
The addition of a lag period l to Eq. (1) to produce Eq. (2)
resulted in good ts for the data (the mean of ss for 20 for-
mulations according to Eq. (2) is 7). Such estimates of the lag
periods are considerably more accurate than those used by
Ford et al. [7] and Mitchell et al. [27] on the basis of root time
plots. The reductions in the values of the sum of squares
justify the inclusion of lag periods, despite their being rela-
tively constant, into calculations. The mean of ss based on
Eq. (3) is high (14.84) indicates that this equation also does
not provide a good t for the results. Therefore, in this study
only Eq. (2) will be discussed in order to nd out the mecha-
nism of release.
Table 2 shows that as the concentration of HPMC in-
creased, the release exponent (m) slightly increased. The
highest value (m = 0.54) was obtained for formulation F
3
containing 125 mg of HPMC and the lowest value (m = 0.45)
was obtained for formulation F
1
containing 75 mg of HPMC.
These results indicated that the release of atenolol was only
controlled by diffusion mechanism for the matrices contain-
ing different concentrations of HPMC.
Similar results were obtained for the matrices containing
the different ratios of ethylcellulose (EC) (Fig. 2). It can be
observed that as the polymer fraction increased, the release
rate of the drug decreased (values of K
3
in Table 2). For
Fig. 3. The release prole of atenolol from EudragitHPMC matrices.
Fig. 4. Release prole of atenolol from NaCMCHPMC matrices.
Fig. 5. The effect of lactose on the release rate of atenolol from HPMC
matrices.
Fig. 6. The effect of dicalciumphosphate on the release rate of atenolol from
HPMC matrices.
822 F. Lotpour et al. / IL FARMACO 59 (2004) 819825
example, almost 100% of atenolol released after 3 h from
formulation containing 100 mg EC (F
4
), whereas the per-
centage of drug released after 3 h from matrices containing
200 mg EC was 44.98%. Table 2 shows that the release
exponent (m) remained around 0.5; this indicates diffusion
release mechanism[28]. It can be concluded that the polymer
content between 100 and 200 mg did not affect the release
mechanism. Fig. 2 also demonstrates the pH dependence
release for EC-matrices, as described for HPMC-matrices.
The release rate of atenolol from EC matrices at pH 1.2 was
faster than at pH 6.8. Negative values of C indicate a burst
release of drug and high positive values imply a delay to
release. The data in Table 2 indicate that matrices containing
100 mg had a burst release while matrices containing 200 mg
EC did not.
Fig. 3 shows the release prole of atenolol from matrices
containing HPMC, Eudragit RSPO and their combinations.
Atenolol release increased as the proportion of Eudragit
RSPO increased in the EudragitHPMC blend. It is observed
that the amount of HPMC played a dominant role, affecting
the drug release in these mixtures. According to Fig. 3, the
release percent of atenolol from matrices containing only
100 mg HPMC after 2 h is 42.2%, and it is 66.5% for
matrices containing only 100 mg Eudragit RSPO. In the case
of the blends of EudragitHPMC a signicant increase in the
release rate was observed, when the ratio of EudragitHPMC
increased (see K
3
values in Table 2).
The dissolution prole of atenolol from matrices contain-
ing the blends of HPMCand NaCMCin various weight ratios
is shown in Fig. 4. In the case of matrices containing 1:3 and
1:1 ratios of NaCMCHPMC, the drug release rate was not
affected by the concentration of NaCMC, and they produced
the same release proles as the formulations containing only
HPMC. However, when the concentration of NaCMC in-
creased to the ratio of 3:1 (NaCMC/HPMC) the release rate
of atenolol considerably increased (Fig. 4). The m value was
increased from 0.53 to 0.99 when the concentration of
NaCMC was increased from 25 to 75 mg (Table 2). The m
values in Table 2 for these formulations showed that the drug
release mechanismwas changed fromdiffusion (m= 0.53) to
erosion (m = 0.99) as more NaCMC was added to HPMC
matrices.
3.2. Inuence of llers and their concentration
In order to investigate the effects of llers on the release
rate of atenolol and also the release mechanism, HPMC
matrices as the inert matrix, lactose (a soluble ller) and
dicalcium phosphate (an insoluble ller) were chosen.
Figs. 5 and 6 show the effect of replacement of HPMC by
lactose or DCP on the release prole of atenolol, respec-
tively. In vitro release proles of atenolol showed that a
decrease in the ratio of HPMC/lactose or HPMC/DCP from
3:1 to 1:3 resulted in an increase in the release rate of
atenolol.
It can be seen fromFig. 6 that lowconcentration of DCP in
HPMC matrices had no considerable effect on the release
rate of atenolol. Although, DCP is hydrophobic ller, an
increase in concentration of DCP from 50 to 150 mg resulted
in an increase in the release rate from HPMC matrices. This
indicates that both lactose and DCP had similar effect on the
dissolution prole of atenolol from HPMC matrices. So it
Table 2
The kinetic of release of different formulations of atenolol
Formulation
code
Eq. (1) Eq. (2) Eq. (3)
K
1
(% min
n
) n ss K
2
(% min
m
) m l (min) ss K
3
(% min
0.5
) C (%) Ss
F
1
5.29 0.45 3.74 5.47 0.45 0.84 3.69 3.85 3.41 4.94
F
2
3.13 0.54 5.64 3.34 0.53 1.52 5.47 4.13 2.87 5.38
F
3
2.41 0.56 38.3 2.73 0.54 3 27.5 3.66 4.08 36.6
F
4
10.1 0.46 43 10.12 0.45 10.1 10.7 8.33 2.62 44.9
F
5
4.67 0.56 3.1 2.42 0.69 9.41 3 6.32 3.52 4
F
6
7.07 0.35 27.3 8.39 0.32 6.99 21.7 2.3 10.7 55.1
F
7
5.35 0.53 2.18 6.3 0.5 2.7 1.8 6.36 2.53 1.75
F
8
5.53 0.51 3.09 5.8 0.5 0.81 3.06 5.87 0.84 3.03
F
9
7.82 0.4 13.8 1.2 0.75 41.9 3.3 4.23 7.47 9.74
F
10
3.11 0.54 5.65 3.16 0.54 0.66 0.11 4.13 2.93 5.93
F
11
0.91 0.87 0.66 0.88 0.88 0.32 0.77 6.91 19.2 16.7
F
12
1.47 0.77 13.1 0.44 0.99 15.7 9.48 6.5 14.1 34.5
F
13
3.09 0.54 9.48 3.11 0.54 0.08 5.47 4.08 2.76 9.61
F
14
3.13 0.54 5.64 3.34 0.53 1.52 10.1 4.13 2.87 5.38
F
15
3.64 0.55 2.68 3.88 0.54 0.97 2.5 4.98 4.98 3.64
F
16
4.46 0.57 4.58 7.27 0.47 6.42 1.73 6.83 5.86 2.87
F
17
3.14 0.54 5.9 3.37 0.53 1.63 2.71 4.12 2.83 5.59
F
18
1.92 0.66 17.8 1.05 0.76 11.1 14.1 4.77 7.86 29.2
F
19
3.11 0.66 8.5 1.78 0.77 6.95 7.06 7.23 10.1 12.5
F
20
3.14 0.54 5.9 3.37 0.53 1.63 5.7 4.12 2.83 5.59
823 F. Lotpour et al. / IL FARMACO 59 (2004) 819825
can be concluded that hydrophilicity or hydrophobicity of
ller has a little effect on the release behaviour of atenolol
fromHPMCmatrices. The explanation for the effect of llers
on the release rate of atenolol was that llers reduced the
tortuosity of the diffusion path of the drug.
Changing the polymer/ller ratio increases the release rate
by altering the diffusivity of drug in gel layer. Water diffusiv-
ity depends only on the total concentration of viscosity-
inducing agents in the system irrespective of their nature or
polymerization degree [29]. Replacement of polymer by
lactose or DCP decreases the concentration of polymer in gel
layer and therefore diffusion of water into the tablet is facili-
tated. Lactose also decreases the tortuosity of the path of the
diffusion [30]. The results conrmed the nding of Lapidus
and Lordi [30] that replacement polymer by either a soluble
or insoluble diluents increased dissolution rate.
Table 2 shows that HPMC matrices containing lactose or
DCP produced negative values for C based on Eq. (3), indi-
cating burst release for the matrices containing these llers
(compare Cvalues for the matrices without the ller and with
ller). Comparing the n values (Table 2) for these formula-
tions showed that the presence of lactose had no signicant
effect on the release mechanism, whereas the n value was
increased as the ratio of HPMC/DCP decreased. The values
of exponent (m) indicated that both diffusion and erosion are
involved in the release of drug in formulation containing
DCP (the m value is 0.530.76).
4. Conclusion
In conclusion, the results of the present study conrm that
the drug release rate and mechanism of atenolol release from
hydrophilic and hydrophobic matrices is mainly controlled
by the drug: polymer ratio, although the ratio of binary
polymer blends may have to be considered. The results also
showed that an increase in the concentration of llers re-
sulted in an increase in the release rate of the drug from
matrices and hydrophilicity or hydrophobicity of llers had
no signicant effect on the release prole. Regarding the
mechanism of release, the results showed that in most cases
the drug release was controlled by both diffusion and ero-
sion, depending on the type of polymer and concentration.
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