Research paper
The effect of polymer blends on release proﬁles of diclofenac sodium
from matrices
Soliman Mohammadi Samani*, Hashem Montaseri, Abdolghani Kazemi
Department of Pharmaceutics, Shiraz University of Medical Sciences, Shiraz, Iran
Received 4 November 2002; accepted in revised form 4 February 2003
Abstract
The purpose of this study was to evaluate the effect of polymer blends on the in vitro release proﬁle of diclofenac sodium. Several
controlled release matrices of diclofenac sodium with different proportions of hydroxypropyl methylcellulose (HPMC; viscosity grade 60
and 500 mPa.s), carbopol 940 and lactose as a water soluble ﬁller were prepared. The results showed that when HPMC (viscosity grade 60
mPa.s) alone was used as matrix former, diclofenac sodium was released fast but the release rate became slower with HPMC (viscosity grade
500 mPa.s) at higher polymer/drug ratios (more than 0.8:1). However in lower polymer/drug ratios (lower than 0.7:1) the release rate still was
fast. The results showed that carbopol can extend the release time appreciably but the release proﬁles had considerable ﬂuctuations, and drug
release in ﬁrst hours was slow but increased appreciably with time at the end of proﬁles. When an appropriate blend of HPMC (viscosity
grade 60 or 500 mPa.s) and carbopol 940 was used, the drug release became more uniform and its kinetic approached to zero order and
release ﬂuctuations were diminished. The results with these polymer blends showed that it is possible to reduce the total amounts of polymer
in each formulation. According to kinetic analysis data, drug release from these matrix tablets did not follow Fick’s law of diffusion and the
results were in agreement with the earlier reports.
q 2003 Elsevier Science B.V. All rights reserved.
Keywords: Diclofenac sodium; Matrices; Hydrophilic polymer; Carbopol; Hydroxylpropyl methylcellulose
1. Introduction
Diclofenac sodium is a potent nonsteroidal anti-inﬂammatory
drug which has anti-inﬂammatory, analgesic and
antipyretic properties. It is used for the treatment of
degenerative joint diseases such as rheumatoid arthritis,
osteoarteritis, and ankylosing spondilitis. Diclofenac
sodium is rapidly dissolved in intestinal ﬂuid and reaches
its maximum blood concentration (Cmax) within 30 min and
is metabolized mainly by hepatic hydroxylation and
subsequent conjugation [1]. In healthy human volunteers,
mean plasma clearance of diclofenac sodium was 16 l/h and
mean elimination half-life of the terminal phase was 1.2–
1.8 h [2]. In order to diminish diclofenac sodium
gastrointestinal irritation, which is a common problem
with all nonsteroidal anti-inﬂammatory agents, effective
enteric-coated dosage forms have been developed. However,
it was previously reported that food effectively delays
the absorption of the drug which causes a non-reproducible
pharmacokinetic proﬁle, and the drug has no immediate
therapeutic effect [3]. The beneﬁts of administering
diclofenac sodium in a controlled release dosage form
have been demonstrated by Fowler et al. [2]. In several
investigations the feasibility of development of a sustained
release form for diclofenac sodium was studied. The main
activities in this regard were preformed around the
designing of a matrix type formulation [4–8] which appear
to be a very attractive approach from process development
and scale up points of view. Different polymers such as
hydroxypropyl methylcellulose (HPMC), sodium carboxy
methylcellulose, and ethylcellulose were used in these
studies. HPMC is the most important hydrophilic polymer
used for the preparation of oral controlled release drug
delivery systems [9–11]. One of the most important
characteristics of HPMC is the high swellability, which
has a considerable effect on the release kinetics of the
incorporatrd drug [12–14]. In vitro drug release of watersoluble
drugs, such as diclofenac sodium, is controlled by
0939-6411/03/$ - see front matter q 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0939-6411(03)00030-4
European Journal of Pharmaceutics and Biopharmaceutics 55 (2003) 351–355
www.elsevier.com/locate/ejpb
* Corresponding author. P.O. Box 71345-1581, Department of
Pharmaceutics, Faculty of Pharmacy, Shiraz University of Medical
Sciences, Shiraz, Iran. Tel./fax: þ98-711-2290091.
E-mail address: smsamani@sums.ac.ir (S.M. Samani).
diffusing out of the gel layer, which is produced by
hydration of polymer in the presence of biological ﬂuids
[14,15]. For soluble drugs, the most important factor in the
selection of a polymer matrix is the medium inﬁltration rate.
With a constant drug load, the medium inﬁltration rate can
be controlled by changing the polymer content of matrix or
introducing various polymers [14].
The aim of this study was to evaluate the effects of
polymer blends in rate and kinetics of diclofenac release
from matrix tablets. In this regard, blends of HPMC (60
mPa.s)- carbopol 940 and HPMC (500 mPa.s)- carbopol 940
were used to adjust the medium inﬁltration rate through the
matrix tablets and controlled hydration, gelation or swelling
process of matrix. The effects of various ratios of these
polymers with lactose as a water-soluble excipent also were
studied.
2. Materials and methods
2.1. Materials
Diclofenac sodium was obtained from Sobhan Pharm.
Co. (Iran). Two viscosity grades of HPMC (60, 500 mPa.s)
were supplied by Daroupakhsh Pharm. Co. (Iran). The
carbopol 940 was from BF Goodrich. All other chemical
and reagents were pharmaceutical grade.
2.2. Formulation of diclofenac sodium matrices using
HPMC 60 or 500 mPa.s or carbopol
Diclofenac sodium matrices were produced by mixing
diclofenac sodium with lactose, HPMC 60 or 500mPa.s or
carbopol 940 and magnesium stearate and then passing the
mixture through a No. 20 sieve. The granules were
compressed to tablets with a 10 mm punch and die using
a single punch Erweka machine (formulation A1–A11).
2.3. Formulation of diclofenac sodium matrices using
HPMC and carbopol
These matrices were produced by mixing diclofenac
sodium with lactose, HPMC (60 mPa.s) – carbopol 940 or
HPMC (500 mPa.s) – carbopol 940 and magnesium stearate
and then passing the mixture through a No. 20 sieve. Finally
the granules were compressed to tablets as mentioned above
(formulation A12–A19). The constituents of each formulation
are presented in Table 1. The hardness of tablets in all
formulations was adjusted in about 5–7 kgf.
2.4. Dissolution studies
Tablets of each formulation were subjected to dissolution
testing using a USP XXIII paddle- type dissolution
apparatus, in 900 ml buffer solution with pH of 1 and 6.8.
The rate of stirring was 50 ^ 1 rpm. The amount of
diclofenac sodium was 100 ^ 5 mg in all formulations.
The dissolution medium temperature was maintained at
37 ^ 1 8C. At each sampling interval, 5 ml of the
dissolution medium was withdrawn and an equal volume
of fresh buffer solution was replaced. Diclofenac sodium
was determined at 275 nm using a double beam UV/VIS
Spectrophotometer (Cecil CE). Experiments were performed
for six tablets in each formulation and mean values
were obtained.
2.5. Analysis of dissolution data
Numerous mathematical models describing drug release
from HPMC-based controlled release formulation has been
Table 1
The ingredients of various formulations of diclofenac sodium matrices, each of these formulations contains 100 mg diclofenac sodium
Code of formulation HPMC 60 mPa.s (mg) HPMC 500 mPa.s (mg) Carbopol 940 (mg) Lactose (mg) Magnesium stearate(mg)
A1 50 – – 50 2
A2 60 – – 50 2.1
A3 70 – – 50 2.2
A4 – 50 – 40 2.2
A5 – 60 – 30 2.2
A6 – 70 – 50 2
A7 – 80 – 50 2.1
A8 – 90 – 50 2.2
A9 – – 50 50 2
A10 – – 70 50 2.2
A11 – – 30 70 2
A12 – – 40 60 2
A13 50 – 20 50 2.2
A14 60 – 10 50 2.2
A15 55 – 15 50 2.2
A16 – 60 10 50 2.2
A17 – 55 15 50 2.2
A18 – 50 20 50 2.2
S.M. Samani et al. / European Journal of Pharmaceutics and Biopharmaceutics 55 (2003) 351–355352
developed. But probably the most important aspect when
developing new pharmaceutical products or evaluating drug
release mechanisms is suitable predictive ability and
accuracy of the model. In many cases, the use of simple
empirical or semi-empirical models such as classical
Higuchi equation and the so called power law is fully
sufﬁcient [9].
Dissolution data were analyzed using the equation
proposed by Ritger and Peppas [16] to describe the
mechanism of drug release from matrices.
Mt
M1
¼ Ktn
Where Mt corresponds to the amount of drug released in
time t, M1 is the total amount of drug that must be released
at inﬁnite time, K is a constant and ‘n’ is the release
exponent indicating the type of drug release mechanism. If n
approaches to 0.5 the release mechanism can be Fickean. If
n approaches to 1 the release mechanism can be zero order
and on the other hand if 0.5 , n , 1 non- Fickean transport
could be obtained [16].
The cumulative percentage of released drug versus time
data was assessed for zero order release kinetic. The
logarithm of the amounts of the remaining drug must be
released versus time data were assessed for ﬁrst order
kinetic and the data of cumulative percentage drug release
versus square root of time data were used to evaluate for
Higuchi model kinetic.
Fig. 1. The effect of various ratios of HPMC 60 mPa.s on the release proﬁle
of diclofenac sodium from matrices.
Fig. 2. The effect of various ratios of HPMC 500 mPa.s on the release
proﬁle of diclofenac sodium from matrices.
Table 2
Correlation coefﬁcients for release data of diclofenac sodium from different formulations after ﬁtting to zero order, ﬁrst order, Higuchi and Peppas Models
Code of formulation Zero order model Higuchi model First order model Peppas model na
A1 0.9983 0.9682 0.9617 0.9990 0.9389
A2 0.9958 0.9749 0.9537 0.9984 0.8641
A3 0.9973 0.9736 0.9381 0.9970 0.8551
A4 0.9942 0.9827 0.9889 0.9980 0.7696
A5 0.9975 0.9799 0.9141 0.9979 0.7768
A6 0.9708 0.9793 0.9244 0.9873 0.7721
A7 0.9881 0.9756 0.9248 0.9969 0.8944
A8 0.9854 0.9695 0.9777 0.9309 0.8482
A9 0.9638 0.8800 0.8950 0.9601 1.0803
A10 0.9435 0.8632 0.9154 0.9541 0.9188
A11 0.9935 0.9251 0.7916 0.9901 1.1478
A12 0.9975 0.9799 0.9141 0.9979 0.7768
A13 0.9942 0.9449 0.9622 0.9911 0.9222
A14 0.9936 0.9488 0.8726 0.9939 0.8612
A15 0.9936 0.9548 0.9523 0.9957 0.8764
A16 0.9943 0.9460 0.9445 0.9831 0.8235
A17 0.9981 0.9776 0.9932 0.9964 0.7151
A18 0.9957 0.9607 0.9853 0.9907 0.7679
a
‘n’ is release exponent in Peppas equation [9]
S.M. Samani et al. / European Journal of Pharmaceutics and Biopharmaceutics 55 (2003) 351–355 353
3. Results and discussion
Early dissolution studies revealed that diclofenac sodium
did not have appreciable solubility at pH 1 dissolution
medium because of the weak acidic property of diclofenac
sodium even after 2 h. In this regard dissolution proﬁle of
diclofenac sodium at this pH was not shown.
Figs. 1 and 2 show the effect of various HPMC (60
mPa.s)/drug and HPMC (500 mPa.s)/drug ratios on
dissolution proﬁles respectively. With higher ratios, the
rate of drug release were decreased. Also an increase in
polymer viscosity grade had the same effect. From these
ﬁgures it is apparent that these polymers can not separately
produce an appropriate release rate. The results showed that
only HPMC (500 mPa.s) in high polymer/drug ratio can
extend the release time up to 10 h. In spite of prolonged
release time, the correlation coefﬁcient does not ﬁt to zero
order kinetic (Table 2).
Fig. 3 shows the effects of carbopol 940 alone on the
release pattern of diclofenac sodium. It is apparent that this
polymer in low polymer/drug ratio can sustain the drug
release, but the pattern of release is not suitable. From this
ﬁgure, it is obvious that the release of diclofenac sodium in
early hours is very slow and after approximately 4 h the rate
Fig. 3. The effect of various ratios of carbopol 940 on the release proﬁle of
diclofenac sodium from matrices.
Fig. 4. The effect of various proportions of carbopol 940–HPMC 60 mPa.s
on the release proﬁle of diclofenac sodium from matrices.
Fig. 5. The effect of various proportions of carbopol 940- HPMC 500 mPa.s on the release proﬁle of diclofenac sodium from matrices.
S.M. Samani et al. / European Journal of Pharmaceutics and Biopharmaceutics 55 (2003) 351–355354
of release appreciably increase. Therefore, these formulations
can not be practically useful. To correct the release
pattern of diclofenac sodium from matrices, blends of
HPMC and carbopol 940 were used as a matrix former. The
release proﬁle of drug from these formulations are shown in
Figs. 4 and 5. The release ﬂuctuations in these formulations
were decreased and the kinetic of diclofenac release
approached to zero order kinetic (A17). These ﬁgures
show that the blends of carbopol 940- HPMC (60 mPa.s) are
better than carbopol 940- HPMC (500 mPa.s) and in these
formulations the release ﬂuctuations are minimum. These
data showed that a combination of anionic polymer
(carbopol 940) with nonionic HPMC produce a synergetic
increase in viscosity. This is probably due to the stronger
hydrogen bonding between the carboxyl groups of carbopol
and hydroxy groups of HPMC, leading to stronger crosslinking
between two polymers and diminish the release
ﬂuctuations [17]. Although in this study the ratio of HPMC/
Carbopol 940 is higher than the ratios used by Rao et al.
[17]. The curve ﬁtting data for zero order, ﬁrst order,
Higuchi model and Peppas model are presented in Table 2.
According to Fig. 3 the release rate of diclofenac sodium
increase with an increase in lactose/ carbopol ratio.
4. Conclusion
The results obtained in this study conﬁrmed that carbopol
940 can be used as a matrix former, but according to Fig. 3
drug release from this matrices at the beginning is slow and
increase appreciably with time. Also when carbopol 940
was used alone the release ﬂuctuations were considerably
high and the kinetics of release did not ﬁt to zero order
model. When carbopol 940 was used with HPMC (60 or 500
mPa.s) the release data became uniform and release of
diclofenac sodium increased at the beginning (Figs. 4 and
5). This behavior of HPMC and carbopol blend has been
reported by Rao et al. [17]. With blend of HPMC and
carbopol, it is possible to reduce the total amount of
polymers in matrix tablets and minimize the size and weight
of these tablets (Table 1).
Acknowledgements
This project was ﬁnancially supported by Shiraz
University of Medical Sciences (Grant No 77- 554).
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