The aim of this study was to develop an extended-release tablet formulation using a new in
situ cross-linking method. The effects of polyvalent cations on theophylline release from tablets
made with the polyanionic polymers sodium alginate and sodium carboxymethylcellulose, were
investigated. Different miliequivalents of the di and tri-valent cation, Ca2+ and Al3+, were added
to tablet formulations. The results of the dissolution study showed that incorporation of cations
sustained the drug release. This is due to an in situ cross-linking between the polyanionic
polymers and the added cation in tablet formulation. The drug release prolongation and the
release kinetics were dependent on the nature of the polymers and the cations’ concentrations
and valences. The drug release rate decreased by an increase in cation concentration. The
combination of the two investigated polymers decreased the drug release rate to a higher extent
in comparison with formulations containing each polymer alone. A zero-order drug release
kinetic was observed in formulations containing 1:1:1 ratio of drug: Na alginate: NaCMC,
and the investigated cations. These results showed that the in situ cross-linking by polyanionic
polymers can be used for controlling the drug release rate.
Acute and Subchronic Toxicity?of Teucrium polium Total Extract in Rats
Iranian Journal of Pharmaceutical Research
(2009), 8 (4): 241-249
Received: October 2008
Accepted: May 2009
Copyright ? 2009 by School of Pharmacy Shaheed Beheshti University of Medical Sciences and Health Services
In Situ Cross-Linking of Polyanionic Polymers to
Sustain the Drug Release from Theophylline Tablets
Majid Saeedia,b*, Jafar Akbaria, Reza Enayatifarda, Katayoun Morteza-Semnanib,
Masoumeh Taherniaa and Hadi Valizadehd
aDepartment of Pharmaceutics, Faculty of Pharmacy, Mazandaran University of
Medical Sciences, Sari, Iran. bPharmaceutical Sciences Research Center,
Mazandaran University of Medical Sciences, 20th km. of Khazar road, Sari, Iran.
cDepartment of Medicinal Chemistry, Faculty of Pharmacy, Mazandaran University
of Medical Sciences, Sari, Iran. dDepartment of Pharmaceutics, Faculty of
Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
The aim of this study was to develop an extended-release tablet formulation
using a new in situ cross-linking method. The effects of polyvalent cations on
theophylline release from tablets made with the polyanionic polymers sodium
alginate and sodium carboxymethylcellulose, were investigated. Different
miliequivalents of the di and tri-valent cation, Ca2+ and Al3+, were added to
tablet formulations. The results of the dissolution study showed that
incorporation of cations sustained the drug release. This is due to an in situ
cross-linking between the polyanionic polymers and the added cation in tablet
formulation. The drug release prolongation and the release kinetics were
dependent on the nature of the polymers and the cations? concentrations and
valences. The drug release rate decreased by an increase in cation
concentration. The combination of the two investigated polymers decreased the
drug release rate to a higher extent in comparison with formulations containing
each polymer alone. A zero-order drug release kinetic was observed in
formulations containing 1:1:1 ratio of drug: Na alginate: NaCMC, and the
investigated cations. These results showed that the in situ cross-linking by
polyanionic polymers can be used for controlling the drug release rate.
Keywords: In situ cross-linking; Theophylline; Sodium alginate; NaCMC; Release;
Theophylline, an alkaloid found in the leaves of the
Cameliaisinesis is used
clinically as a bronchodilator in management of Chronic Obstructive Pulmonary
Disease (1). Conventional dosage forms of theophylline are administered 3-4
times a day to avoid large fluctuations in plasma concentration (2).
Sustained-release dosage forms, on the other hand, provide desirable serum
concentrations for prolonged period, thereby providing better patient
Hydrophilic gel-forming matrix tablets are widely used for oral
controlled-release dosage forms, owing to the ease of manufacturing and their
cost effectiveness. Numerous polymer, such as polysaccharides, have been used in
the tablets. They relax in the presence of water to form a gel layer around the
tablet (3). In these formulations, factors affecting the in vitro drug release
such as drug/polymer ratio, polymer viscosity, and the amount of additives have
been studied from the view point of formulation design (4).
Recently, the use of natural polymers in designing the drug delivery systems has
received much attention due to their excellent biocompatibility and
biodegradability (5). Sodium alginate is a biopolymer that is widely used as an
encapsulation matrix due to its ability to form hydrogel upon cross-linking. Its
ability of gel forming under mild conditions makes alginate the
polymer-of-choice in food, pharmaceutical and biotechnological applications.
Alginates are linear unbranched copolymers of β-D-manuronic acid (M) and α-L-guluronic
acid (G) units. The M and G monomers are 1→4 linked by glycosidic bonds, forming
homopolymeric M- or G-blocks and heteropolymeric MG blocks. In the presence of
polyvalent cations such as Ca2+ or Al3+, cross-linking occurs to form gels. The cations act as bridges between the anionic polymer chains, constituting junction
zones, forming a hydrogel network (6). Ca2+, a commonly used cross-linker,
preferentially interacts with G-blocks due to structurally favorable chelation
sites formed by the corrugated chains (7). Hence, selective ion binding is
formed with the of G-blocks (8). Due to the selective ion binding, cross-linking
of alginates of different chemical compositions results in gels with different
Sodium carboxymethylcellulose (NaCMC), another polyanionic polymer, is widely
used in oral controlled-release matrices (10-14). Its good compression
properties, nontoxic nature, and the ability to accommodate a large percentage
of drugs are some of the reasons for its popularity (15).
Researchers have used cross-linking as a means to retard the drug release from
alginate matrix tablets. Azarmi et al. (16) have reported a reduced drug release
rate at pH 7.4 with increasing calcium chloride dihydrate concentration
(0.75-19% w/w) incorporated into alginate matrices of Acetazolamide. Nokhodchi
and Tailor (5) observed slower theophylline release only at high (21% w/w)
calcium salt content. At intermediate calcium salt contents (11.8 and 16.7%
w/w), initial burst release was observed followed by a slower drug release. Drug
release was rapid at low calcium salt concentration (3.8% w/w) and this was
attributed to insufficient cross-linking to produce an insoluble barrier.
The objective of the present work was to demonstrate the ability of Ca2+ and
Al3+ to induce an in situ inter- and intra-cross-linking of polyanionic polymers
in tablet formulations. We investigated the effects of the in situ cross linking
on the release rate of theophylline.
The tablets were prepared using the following ingredients: theophylline (Daru-pakhsh
Co., Tehran, Iran), sodium alginate (Fluka, Switzerland), sodium
carboxymethylcellulose (NaCMC) (viscosity of the 1% solution at 25?C is 1240
cps) (Daicel Chemical, Osaka, Japan), calcium chloride di-hydrate (CaCl2.2H2O)
and aluminium chloride hexa-hydrate (AlCl3.6H2O) (Riedel-de Haen, Seelze,
Germany), NaOH, KCl, HCl, magnesium stearate (Merck, Germany) and potassium di-hydrogen
phosphate (Fluka, Switzerland).
Preparation of matrix tablets
A series of formulations containing a fixed amount of theophylline (100 mg),
different amounts of sodium alginate (50-100 mg) and/or NaCMC (50-100 mg), and
increasing amounts of CaCl2.2H2O or AlCl3.6H2O were sufficiently blended for 10
min. Magnesium stearate (1% w/w) was then added, followed by further mixing for
2 min. The resultant powder mixture was then compressed into tablets using a
single punch machine (Korsch, Germany), with 10-mm diameter flat punch. All
matrices were stored in a desiccator for at least 3 days to allow for tablet
relaxation before use.
The United State Pharmacopoeia (USP) basket method was used for all the in vitro
dissolution studies. In this method, a solution of HCl in distilled water
(pH=1.2), and phosphate buffer (pH 6.8) both without enzymes, were used as
dissolution media. The dissolution profile of theophylline was studied according
to the USP basket method at 100 rpm, in 900 ml of medium maintained at 37.0 ?
0.5?C in a dissolution tester (Caleva 8ST). The amount of theophylline was 100
mg in all formulations. The matrices were placed in 900 ml of the HCl solution
(pH=1.2) for 2 h. Samples were withdrawn at predetermined time intervals (0.5,
1, 1.5, and 2 h), filtered and assayed specterophotometerically at 271.5 nm by
using UV/Visible spectrophotometer (Varian, Australia). After 2 h, the
dissolution medium was changed to phosphate buffer (pH=6.8). Samples were
withdrawn at predetermined time intervals (3, 4, 5, 6, 7, and 8 h), and analyzed
according to the perviously mentioned method. The mean of four determinations
was used to calculate the drug release from each formulation.
Various mathematical equations have been proposed for kinetic analysis of drug
release from the formulations. The zero order Eq. 1 describes the systems where
the drug release rate is independent of the drug concentration (17). The first
order Eq. 2 describes the release from systems where the release rate is
concentration dependent (18). According to Higuchi model Eq. 3, the drug release
from insoluble matrix is directly proportional to the square root of time and is
based on Fickian diffusion (19).
In these equations, Qt is the amount of drug released in time t, Q0 is the
initial amount of drug in tablet and k0, k1 and kH are the release rate
constants for zero order, first order and Higuchi models, respectively.
In order to define a model which representing the best, dissolution data can be
further analyzed by Ritger and Peppas and Korsemayer equation (20, 21).
Where Mt corresponds to the amount of drug released in time
t, M∞ is the total
amount of drug that must be released at infinite time, Kp is a constant and
is the release exponent indicating the type of drug release mechanism. In
cylindrical shape matrices, a release exponent of 0.45 can serve as an
indication for Fickian diffusion. If 0.45< n <0.89 anomalous transport could be
concluded, and if ?n? approaches to 0.89 the release mechanism can be described
as polymer swelling. Criteria for selecting the most appropriate model based on
best goodness of fit and smallest sum of squared residuals (22).
ANOVA followed by Tukey test was used to determine significant differences
between groups and ?P < 0.05? was considered as significant.
Results and Discussion
Table 1 shows the composition of the individual formulations. Figure 1 shows the
drug release from sodium alginate formulations. As seen in Figure 1, Al3+ and
Ca2+ caused a prolonged drug release in these formulations till 3 hours (P <
0.0001), but after 4 h this effect was not significant. Increasing the amount of cations in formulations did not show any decrease in theophylline release rate
after 3 h (P = 0.825 for formulations containing Al3+ and P = 0.517 for
formulations containing Ca2+). In these formulations, comparison of the tablets
containing similar miliequivalents of the two cations showed that Al3+ decreased
the drug release rate to a higher extent compared to Ca2+ before 3 h (P = 0.003
and P = 0.001 for comparing F5 to F7 and F6 to F8, respectively).
The dissolution rate data were analyzed based on Eqs. 1-4 and their results were
listed in Table 2. The results showed that in formulations containing sodium
alginate in a sodium alginate: drug ratio of 1:1 (F1 and F5-F8), the addition of
Al3+ and Ca2+ had no effect on the release kinetic of theophylline, and the
highest correlation coefficients were achieved with the first-order model. By
increasing the amounts of the cations, the release exponent (n) increased
compared to F1. The lowest value (n = 0.503) was obtained for formulation F1
containing no cation, and adding the amount of the cation increased this value.
The values of n showed that in F1, the release of theophylline was only
controlled by diffusion, whereas in the presence of cations, the mechanism of
release was slightly complex.
The presence of cations was able to extend the drug release process. This
phenomenon is related to an in situ gel formation between the cations and the
anionic polymer. The occurrence of in situ gel formation depends on
concentrations of the cations (23). In optimum concentration, the calcium
chloride is able to cross-link more efficiently with the sodium alginate because
a greater quantity of calcium ions is available to bind. As there is more
calcium ions to bind, a better and stronger gel is formed around the matrix and
this strong gel does not allow the dissolution medium to penetrate into the
matrix at a high speed, resulting in a reduction in release rate (5).
Figure 2 shows the drug release from NaCMC formulations. As seen in Figure 2,
Al3+ and Ca2+ caused a prolonged drug release from these formulations
(P<0.0001). The formulation series F9-F10 and F11-F12 contain equal miliequivalents of Al3+ and Ca2+. In these formulations, Al3+ decreased the drug
release to a higher extent compared to formulations containing Ca2+.
The results of kinetic analysis showed that in formulations containing NaCMC in
1:1 ratio of NaCMC: drug in 1:1 ratio (F2 and F9-F12), the addition of Al3+
changed the release kinetic of theophylline. In F2, which contained none of the
cations, the highest correlation coefficient was achieved with the first-order
model. Al3+ did not change the drug release kinetic in F9, but by increasing the
amount of this cation in F10, the best fitting was observed in Higuchi model and
based on n value (n = 0.4304) the mechanism of drug release was based on Fickian
diffusion. Ca2+ caused no change in the release kinetic of theophylline in
comparison with F2.
In formulation series F13-F16, both polymers (sodium alginate and NaCMC) were
used in a ratio of 1:1:2 to the drug. The effect of cations on the release
profile of Theophylline is shown in Figure 3. These profiles show that the
mixture of the two investigated polymers decreased the drug release rate more
than the F1 and F2 (each containing only one polymer). Also, Al+3 decreased the
drug release rate more prominently than Ca2+. This decrease in release rate was
more than those in F5-F8 which contained sodium alginate, and less than those in
F9-F12 which contained NaCMC.
The kinetic analysis showed that in formulations containing sodium alginate:
NaCMC: drug in 1:1:2 ratio (F3 and F13-F16), the presence of Al3+ changed the
release kinetic of theophylline. In F3, which contained none of the investigated
cations, the highest correlation coefficient was achieved with the Higuchi model
and based on the n value (n = 0.461), the drug release can be expressed as Fickian mechanism. Al3+ did not change the drug release kinetic in F13 (n =
0.428), but by increasing the amount of this cation in F14, the anomalous
transport was observed (n = 0.497). Ca2+ caused no change in the release kinetic
of theophylline in comparison with F3.
The next formulations (F4 and F17-F24) were designed with equal amounts of the
two polymers and the drug (1:1:1, sodium alginate: NaCMC: drug). Figures 4 and 5
show the drug release from these formulations. The decreasing effect of the
investigated cations on drug release rate was proved to be significant in these
formulations (P < 0.001). Al3+ decreased the drug release rate to a higher
extent compared to Ca2+ (P = 0.002 for comparison of F20 and F24).
The kinetic analysis showed that in these formulations, adding of Al3+ changed
the release kinetic of theophylline. In F4, which contained none of the
investigated cations, the highest correlation coefficient was achieved with the
Higuchi square root of time model. By increasing the amount of Al3+ (F17-F20),
the fitted model was the in zero-order. In the presence of Ca2+ the anomalous
mechanism was observed in drug release kinetic in F21 (n = 0.692). However, by
increasing the amount of this cation in F22-F24, the best fittings were observed
in zero-order model.
The release exponents (n) were increased in comparison with F4 by an increase in
the amounts of the cations. The lowest value (n = 0.522) was obtained for
formulation F4 containing no cation, and the presence of the cations increased
this value. The values of n showed that in F4, the release of drug was only
controlled by diffusion, whereas in the presence of cations, the mechanism of
release was slightly complex.
The interaction between polyvalent cations like Al3+ and Ca2+ and negatively
charged polymers like NaCMC or sodium alginate has been used in the past to
prepare drug loaded microspheres (24, 25). We investigated the effects of the
inclusion of low amounts of cations into Theophylline tablet formulations
containing polyanionic polymers individually and in combination. The addition of
Al3+ and Ca2+ extended the drug release process. This phenomenon is related to
an in situ gel formation between the cations and the anionic polymers. The
occurrence of in situ gel formation depends on concentrations of the cations
(24-29). The mechanism of gelation of sodium alginate with calcium was studied
by Vauthier et al. using rheological measurements (26). They reported that
alginate solution with a concentration just below the gel point formed swollen
aggregates of alginate molecules in the continuous phase in presence of calcium
ion. The gelation progress seemed to pass through a pre-gel state corresponding
to clusters of alginate molecules before a continuous and infinite gel was
formed. Remunan-Lopez and coworkers showed that the drug permeability from
sodium alginate films varied with the calcium chloride concentration used (27).
Dave et al. showed that the release of indomethacin from sustained release
pellets of sodium alginate was dependent on the concentration of calcium
chloride: a slower drug release was obtained when the concentration of calcium
chloride increased (28). Bodmeier and coworkers showed that the disintegration
time of alginate beads was a function of the counter-ion concentration (29).In
another study, Hosny et al. showed that the release rates of diclofenac sodium
from sodium carboxymethylcellulose and sodium alginate beads were dependent on
concentrations of the calcium and aluminum ions in solution (25). Azarmi and
coworkers reported the same results in acetazolamide matrix tablets (16).
Our study showed that the NaCMC formulation (F2) had a burst drug release during
the first 60 min. The burst release was also observed in sodium alginate
formulation (F1). The occurrence of the burst release can be attributed to the
time needed for gel formation. This phenomenon was observed for other
formulations except for formulations F17-F24, presumably due to the higher
After the tablet is brought into contact with an aqueous medium, the calcium and
aluminum salts and the drug dissolve from the tablet surface and diffuse into
the bulk solution. Water penetrates through the pores left by the dissolved drug
molecules and calcium and aluminum salts. The anionic polymer chains of the
NaCMC and sodium alginate begin to swell. Molecules, which now dissolve from the
tablet body, have to diffuse through the swelled polymer chains. The polyvalent
cations can cross-link the anionic polymer chains:Ca2+can cross-link two and
Al3+ up to three strains of polymer chains. A viscous gel is formed on surface
of the tablets. In all the investigated formulations, Al3+ decreased the drug
release rate more than the same miliequivalents of Ca+2. This might be due to
the higher valence of Al3+. As shown in Figure 1 to 3 the cross-linking and gel
formation was faster in case of higher cation concentrations. Evaluation of the
effects of these cations on the both polymers showed that Al3+ and Ca2+ were
more effective on NaCMC. This is in accordance with the results reported by
Hosney et al. (24). The same results were also reported by Azarmi and coworkers.
Their results showed that aluminum and calcium ions caused a prolonged drug
release for acetazolamide matrices containing NaCMC. Increasing the amounts of
the cations in formulations decreased the release rate of acetazolamide. The
study showed that the formulations containing Al3+ decreased the drug release
rate to a higher extent compared to formulations containing Ca2+ (16).
Nokhodchi and Taylor showed that formulations of theophylline (with different
amounts of the drug and sodium alginate) containing equal moles of AlCl3 and
CaCl2, produced different release profiles. The formulation containing aluminum
chloride decreased the drug release rate to a higher extent compared to
formulations containing calcium chloride. Aluminum ions have an extra positive
charge compared to calcium ions thus each molecule of aluminum is able to bind
to one more alginate molecule. Because of this, the aluminum was capable of
forming a gel, which did not allow the dissolution medium to quickly enter the
tablet, more quickly. Thus, the dissolution rate was lower compared to the
formulation containing the same number of moles of calcium chloride (5). It
seems that Al3+ can produce cross-linking in three sites but Ca2+ produce it in
two sites. This difference in valence should affect the gel network, and the
drug release rate.
In our study, the combinations of the two polyanionic polymers were also
evaluated. The results showed that the decreasing effect on the release rate
from the combination formulations with the same ratio to drug (F13-F16) were
significantly higher (p < 0.01) in comparison with formulations containing only
sodium alginate (F5-F8). Increasing the polymer content in F17-F24 resulted in
the highest decrease in release rate (P < 0.0001). This also resulted in a
change in the release kinetic. Nokhodchi et al. showed that the addition of HPMC
can alter the drug release profile by an additional mechanism. They showed that
the presence of HPMC in alginate matrices containing various concentrations of
calcium chloride and aluminum chloride had a considerable effect on the release
profile of theophylline. Their results showed that in producing a sustained
release formulation by cross-linking, with the aid of HPMC a lower concentration
of cation can be used to get the same or better release profile (5). In our
study, it seems that combination of the two polyanionic polymers led to inter-
and intra-cross-linking between the polymeric chains. This explains the stronger
decrease in release rate and the kinetic behaviour of the related formulations.
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