a s i a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 1 0 ( 2 0 1 5 ) 3 1 4 e3 2 1

H O S T E D BY Available online at www.sciencedirect.com

ScienceDirect

journal homepage: http://ees.elsevier.com/ajps/default.asp

Original Research Paper

Effect of formulation variables on in vitro release of

a water-soluble drug from chitosanesodium
alginate matrix tablets

Liang Li a, Jinfeng Li a, Shanshan Si a,b, Linlin Wang a, Chenjun Shi a,

Yujiao Sun a, Zhenglin Liang a, Shirui Mao a,*
a
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China
b
Jiangsu Hengrui Medicine Co., Ltd., Lianyungang 222047, China

article info abstract

Article history: The objective of this study is to investigate the feasibility of using chitosanesodium algi-
Received 20 July 2014 nate (CSeSA) based matrix tablets for extended-release of highly water-soluble drugs by
Received in revised form changing formulation variables. Using trimetazidine hydrochloride (TH) as a water-soluble
9 September 2014 model drug, influence of dissolution medium, the amount of CSeSA, the CS:SA ratio, the
Accepted 11 September 2014 type of SA, the type and amount of diluents, on in vitro drug release from CSeSA based
Available online 22 September 2014 matrix tablets were studied. Drug release kinetics and release mechanisms were eluci-
dated. In vitro release experiments were conducted in simulated gastric fluid (SGF) followed
Keywords: by simulated intestinal fluid (SIF). Drug release rate decreased with the increase of CSeSA
Chitosan amount. CS:SA ratio had only slight effect on drug release and no influence of SA type on
Sodium alginate drug release was found. On the other hand, a large amount of water-soluble diluents could
Matrix tablets modify drug release profiles. It was found that drug release kinetics showed the best fit to
Hydrophilic matrices Higuchi equation with Fickian diffusion as the main release mechanism. In conclusion,
Trimetazidine hydrochloride this study demonstrated that it is possible to design extended-release tablets of water-
Extended-release soluble drugs using CSeSA as the matrix by optimizing formulation components, and
provide better understanding about drug release from CSeSA matrix tablets.
© 2015 Shenyang Pharmaceutical University. Production and hosting by Elsevier B.V. All
rights reserved.

forms because of the economic benefits, the relative simplicity

1. Introduction of process development and scale-up procedures. For decades,
hydrophilic matrices have been widely utilized to prepare
Polymer-based monolithic matrix tablets are the most matrix tablets. In general, drugs are dispersed or dissolved in
commonly used to fabricate oral extended-release dosage

* Corresponding author. School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenhe District, Shenyang
110016, China. Tel./fax: þ86 24 23986358.
E-mail addresses: maoshirui@syphu.edu.cn, maoshirui@vip.sina.com (S. Mao).
Peer review under responsibility of Shenyang Pharmaceutical University.
http://dx.doi.org/10.1016/j.ajps.2014.09.002
1818-0876/© 2015 Shenyang Pharmaceutical University. Production and hosting by Elsevier B.V. All rights reserved.
 a s i a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 1 0 ( 2 0 1 5 ) 3 1 4 e3 2 1
hydrophilic matrix and they are available for release as the
matrix hydrates, swells (forms a gel), and dissolves [1]. Hy-
drophilic matrices have the capability to provide desired
release profiles for a wide range of drugs using established and
well-characterized excipients. So far, most commercially
available controlled-release products are fabricated using
nonionic polymers such as hydroxypropyl methylcellulose,
hydroxypropyl cellulose and polyethylene oxide [1e3]. At
present, a few anionic polymers, such as sodium carbox-
ymethyl cellulose, carbomer, xanthan gum and sodium algi-
nate (SA), also showed great potential for controlling drug
release [2,4].
Among the anionic polymers, SA, a water-soluble salt of
alginic acid, is a natural linear unbranched polysaccharide
extracted from marine brown algae. It consists of different
proportions of b-D-mannuronic acid (M) and a-L-guluronic
acid (G) units and can be prepared with a wide range of mo-
lecular weight (MW 50e100,000 kDa) [5,6]. Due to its biocom-
patibility and ease of gelation, SA hydrogels are particularly
attractive in oral drug delivery [5]. For example, verapamil
hydrochloride extended-release matrices (Calan®SR, Pfizer)
containing a combination of hydroxypropyl methylcellulose
and SA produce desired drug release profile in vivo [1]. The
presence of carboxylate groups that can accept or release
protons in response to pH change makes SA pH sensitive. At
pH values below the pKa of the M (3.38) and G (3.65) monomers,
the soluble sodium salt is converted to insoluble alginic acid.
In the matrix tablets, pH sensitivity of SA could affect char-
acteristics of the diffusion barrier and as a consequence drug
release [1]. Cryogenic electron microscopy reveals the hy-
drated surface layer formed by SA matrices in simulated
gastric fluid (SGF) was particulate and porous, which induced
crack formation or lamination of SA matrix tablet, leading to
burst release of drug in gastric environment. This compro-
mised the integrity of drug diffusion barrier and resulted in
loss of controlling release [7,8]. In contrast, a highly hydrated
continuous swollen layer was formed in simulated intestinal
fluid (SIF) [7]. However, SA-based matrix tablets usually could
not extend drug release for more than 12 h due to its swelling
and erosion in SIF [9,10]. To overcome this shortcoming, some
innovative approaches have been attempted to modify SA
matrices for better control of drug release, such as inclusion of
pH-modifiers [8], incorporation of crosslinking agents [5,11]
and combination with other hydrophilic matrices [12].
Among them, SA in combination with chitosan (CS) played a
key role in controlling drug release.
CS, obtained by deacetylation of chitin from crustacean
shells, is a cationic polysaccharide consisting of repeating D-
glucosamine and N-acetyl-D-glucosamine units linked via
(1e4) glycosidic bonds [13]. It was reported that CSeSA poly-
electrolyte complexes could be used as the oral controlled-
release matrix. Consequently, the integrity of SA matrices
could be improved by the interaction with CS and the drugs
entrapped were retained for a longer time. Meanwhile, CS also
showed drug release controlling capacity due to gelling [14]. In
previous reports, in situ polyelectrolyte complexes formation
based on the physical mixtures of SA and CS were found,
avoiding the complex process of preparing polyelectrolyte
complexes [15]. The new mechanism updated CSeSA based
drug delivery systems. SA has been attempted to control the
315
release of highly water-soluble drugs such as chlorphenir-
amine maleate [8], diltiazem hydrochloride [11], and verap-
amil hydrochloride [12], but with some limitations. Thus,
CSeSA matrix tablets loading a highly water-soluble drug
draw more attention as they are easy and economical to
prepare by using the common tableting procedures.
Therefore, in the present study, by using trimetazidine
hydrochloride as the model drug, which has high aqueous
solubility in both acidic and neutral media (both more than
1 g/ml at pH 1.2 and 6.8, respectively, at 20  C) [16], influence of
formulation variables on drug release from CSeSA matrix
tables were investigated systemically, and drug release ki-
netics and transport mechanisms were elucidated using
different mathematical models.
2. Materials and methods
2.1. Materials
Trimetazidine hydrochloride was purchased from Hubei-
Sihuan Pharmaceutical Co., Ltd. (Wuhan, Hubei, China). Chi-
tosan was purchased from Weifang Kehai Chitin Co., Ltd.
(Weifang, Shandong, China) with a molecular weight of about
400 kDa and a degree of deacetylation of 86.5%. Sodium algi-
nate (Table 1) [17] and microcrystalline cellulose (MCC, Avicel
PH-200) were kindly provided as a gift by FMC Biopolymer
(Philadelphia, Pennsylvania, USA). Lactose monohydrate
(FlowLac® 100) was kindly provided by Meggle Excipients &
Technology (Wasserburg, Germany). Pregelatinized starch
and magnesium stearate were kindly provided by Anhui
Shanhe Pharmaceutical Excipients Co., Ltd. (Huainan, Anhui,
China). Aerosil was purchased from Huzhou Zhanwang
Pharmaceutical Company, Ltd. (Huzhou, Zhejiang, China). All
other chemicals were of analytical grade.
2.2. Preparation of matrix tablets
The formulations studied are shown in Table 2. Tablets con-
taining CSeSA as polymeric carriers, microcrystalline cellu-
lose, pregelatinized starch and lactose monohydrate as fillers,
and magnesium stearate and aerosil as lubricants were pre-
pared by direct compression method. The model drug and the
excipients used were all passed through 80-mesh sieve. The
model drug and excipients except for magnesium stearate
were firstly blended for at least 10 min. Thereafter, magne-
sium stearate was added and mixed for another 2 min. Tablets
were prepared using a single punch tableting machine (DP30A;
Beijing Gylongli Company, Ltd., Beijing, China) equipped with
Table 1 e FMC biopolymer commercially available
alginate products for controlled-release.
Trade name Viscosity (mPa.s, 1% w/v M/G (%)
SA sol., 20  C)
Protanal LF200M 200e400 55e65/35e45
Protanal LF120M 70e150 55e65/35e45
Protanal LF240D 70e150 65e70/30e35
M/G: manuronate/guluronate [17].
316 a s i a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 1 0 ( 2 0 1 5 ) 3 1 4 e3 2 1

Table 2 e Composition of the investigated tablet formulations containing 35 mg of trimetazidine hydrochloride (mg).
Batch CS SA LF200M SA SA Microcrystalline Pregelatinized Lactose Magnesium Aerosil
code LF120M LF240D cellulose starch monohydrate stearate
F1 17.50 17.50 e e 178.25 e e 1.25 0.50
F2 52.50 52.50 e e 108.25 e e 1.25 0.50
F3 70.00 70.00 e e 73.25 e e 1.25 0.50
F4 87.50 87.50 e e 38.25 e e 1.25 0.50
F5 105.00 105.00 e e 3.25 e e 1.25 0.50
F6 e 175.00 e e 38.25 e e 1.25 0.50
F7 25.00 150.00 e e 38.25 e e 1.25 0.50
F8 35.00 140.00 e e 38.25 e e 1.25 0.50
F9 43.75 131.25 e e 38.25 e e 1.25 0.50
F10 58.30 116.70 e e 38.25 e e 1.25 0.50
F11 116.70 58.30 e e 38.25 e e 1.25 0.50
F12 140.00 35.00 e e 38.25 e e 1.25 0.50
F13 175.00 e e e 38.25 e e 1.25 0.50
F14 87.50 e 87.5 e 38.25 e e 1.25 0.50
F15 87.50 e e 87.50 38.25 e e 1.25 0.50
F16 87.50 e e 87.50 138.25 e e 1.25 0.50
F17 87.50 e e 87.50 e 138.25 e 1.25 0.50
F18 87.50 e e 87.50 e e 38.25 1.25 0.50
F19 87.50 e e 87.50 e e 138.25 1.25 0.50

an 8 mm (F1eF15, F18) or 10 mm (F16, F17, F19) diameter
punch with beveled edges. Hardness of all the tablets was
adjusted to 40e80 N. Total tablet mass was around 250 mg
(F1eF15, F18) or 350 mg (F16, F17, F19).
2.3. In vitro release studies
where n is the number of time points, Rt is the dissolution
value of the reference at time t, and Tt is the dissolution value
of the test at time t. The release profiles were significantly
different if f2 < 50. Only one measurement should be consid-
ered after 85% dissolution of both the two contrastive for-
mulations [19].

Drug release tests were carried out using a dissolution appa- 2.4. Mathematical analysis
ratus (ZRD6-B, Shanghai Huanghai Medicament Test Instru-
ment Factory, Shanghai, China) with the basket method (USP 2.4.1. Mathematical analysis of drug release kinetics
Apparatus I), rotating at 100 rpm at 37 ± 0.5  C. Unless specially Drug release kinetics from the prepared matrix tablets was
indicated, the tablets were submerged into 900 ml of simulated analyzed by fitting the dissolution data into Zero-order
gastric fluid (SGF: hydrochloric acid solution, pH 1.2, enzyme equation (Eq. (2)), First-order equation (Eq. (3)) and Higuchi
free) for 2 h, then the tablets were transferred to 900 ml of equation (Eq. (4)) [20]:
simulated intestinal fluid (SIF: phosphate buffer, pH 6.8,
enzyme free) for additional 10 h. This method was used to Mt
¼ k0 t (2)
M∞
simulate the situation of a tablet's transit through the gastro-
intestinal tract [18]. Aliquots of 10 ml were withdrawn at
Mt
different time intervals (1, 2, 4, 6, 8, 10 and 12 h) and were ¼ 1  ek1 t (3)
M∞
replaced with equal amounts of fresh release medium. The
sample solution of trimetazidine hydrochloride filtered through
Mt
a 0.45 mm membrane filter was determined by Agilent 1100 ¼ k2 t1=2 (4)
M∞
HPLC system (Agilent Technologies, Santa Clara, California,
USA). A 20 ml volume was injected into a Diamonsil® C18 column where Mt is the amount of drug dissolved at time t, M∞ is the
(200  4.6 mm, 5 mm; Dikma Technologies, Beijing, China) with amount of drug dissolved after infinite time (drug amount in
0.05 mol/l potassium dihydrogen phosphate (pH 3.0)/methanol the formulation), Mt/M∞ is the fractional release of the drug at
85/15 (v/v) as the mobile phase. Column temperature was kept time t, and k0, k1 and k2 are the release rate constants.
at a constant temperature of about 40  C; the flow rate was
1 ml/min and the detector's wavelength was set at 231 nm. 2.4.2. Mathematical analysis of the drug transport
Drug release studies were carried out in triplicate for each mechanism
formulation tested and standard deviations were calculated. The RitgerePeppas equation was applied (Eq. (5)) to char-
The difference in dissolution profiles was compared using acterize drug release mechanism from the polymeric sys-
similarity factor (f2). The similarity factor was calculated using tem [21]:
the Eq. (1):
Mt
¼ ktn (5)
(" #0:5 ) M∞
X
n
f2 ¼ 50  log 1 þ ð1=nÞ ðRt  Tt Þ2  100 (1) where the Mt/M∞  0.6 data are used for calculation, k is a
t¼1
constant incorporating structural and geometric
 a s i a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 1 0 ( 2 0 1 5 ) 3 1 4 e3 2 1
characteristics of the dosage form, n is the release (diffusion)
exponent, which depends on the release mechanism and
shape of the matrix tested and t is the release time. Exponent n
for polymeric controlled delivery systems of cylindrical ge-
ometry has values of n < 0.45 for Fickian diffusion,
0.45 < n < 0.89 for anomalous (non-Fickian) transport and
n > 0.89 for Case II (relaxation) transport.
The PeppaseSahlin equation (Eq. (6)) was further used to
account for the coupled effects of Fickian diffusion and Case II
(relaxation) transport [22,23]:
Mt
¼ kF tm þ kR t2m
M∞
where the first term of this equation represents Fickian
diffusion (F) contribution and the second term refers to the
macromolecular relaxation (R) contribution on the overall
release mechanism. kF and kR are the diffusion and relaxa-
tion rate constants, respectively; the coefficient m is the
purely Fickian diffusion exponent for a device of any
geometrical shape which exhibits controlled-release. The
ratio of Fickian contribution over relaxation contribution is
expressed as Eq. (7):
F kF 1
¼ *
R kR tm
3. Results and discussion
3.1. Preliminary evaluation of different pH media
This first experiment was used as a screening procedure to
investigate the influence of dissolution media on the in vitro
drug release. Fig. 1 illustrates drug release profiles from the
CSeSA matrix (F4, CS:SA:TH ¼ 2.5:2.5:1) in different pH media.
Although TH is a highly water-soluble drug (>1 g/ml) with
pH-independent solubility, the release profiles of TH from the
three studied media (i.e., SGF, SIF and SGF followed by SIF) are
still very different, indicating pH-dependent release charac-
teristics. The fastest drug release was found in SIF, and the
slowest release was in SGF followed by SIF, drug release in SGF
was in between. It was reported that release of a highly soluble
drug from SA matrix tablets was faster in SGF than in SIF,
Fig. 1 e Effect of different pH media on in vitro drug release.
317
especially in the first 2 h, due to the particulate and porous
formation in SGF [7,8]. However, as the CS was added into the
SA matrices, the opposite effect was observed in the present
study. Drug release in SGF and SIF was 35% and 45% after 2 h,
respectively. Moreover, drug release in SIF was complete
around 8 h. In contrast, drug release in SGF was extended for
more than 10 h. This phenomenon might be explained by the
physicochemical properties of CS and SA. Although SA could
form particulate and porous structure on the surface of SA
matrices in SGF, the gelling (swelling) of CS in SGF could
compensate for this structure defect, thereby improving the
(6) capacity of controlling release. On the other hand, due to
erosion of SA and slight disintegration of CS in SIF [9,24], drug
was released gradually with the increase of time. Theoreti-
cally, the rate of drug release in SGF followed by SIF should be
larger than that in SGF and smaller than that in SIF. However,
the abnormal results were obtained from the release profiles,
which might be associated with the new mechanism of
CSeSA based matrix tablets, namely a theory of self-
assembled film described in the previous report [15]. It was
disclosed that drugs were released from CSeSA matrix tablets
in SGF followed by SIF through CSeSA based hydrophilic
matrices and CSeSA polyelectrolyte complexes-based film.
(7) The film was only formed on the surface of tablets in gastro-
intestinal environment. The film could decrease the rate of
polymer swelling to a degree and also greatly limit the erosion
of tablets, therefore extending the release of TH significantly.
In order to mimick drug release environment in vivo and
combine with the new release mechanism, the release con-
dition, namely SGF followed by SIF, was chosen for the
investigation of formulation variables.
3.2. Effect of the amount of CSeSA on in vitro drug
release
With the objective of studying the effect of CSeSA amount on
TH release from matrices, tablets with various CSeSA to TH
ratios were prepared (F1eF5). Fig. 2 shows the release profiles
of TH from matrix tablets with varied amount of CSeSA (i.e.,
14%, 42%, 56%, 70% and 84% (w/w)) and the same CS:SA ratio
(CS:SA ¼ 1:1, w/w). The amount of CSeSA used had a
Fig. 2 e Effect of the amount of CSeSA on in vitro drug
release.
318 a s i a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 1 0 ( 2 0 1 5 ) 3 1 4 e3 2 1
significant effect on the drug release characteristics. As the
amount of CSeSA increased, drug release from matrices
slowed down. It was thought that increasing the concentra-
tion of hydrophilic polymer made the gel layer or swollen
layer become thicker and more tortuous, thereby decreasing
drug release [25,26].To understand drug release kinetics from
the polymeric matrices, release data were firstly analyzed
according to Zero-order, First-order and Higuchi models and
the main parameters are listed in Table 3. Due to obvious burst
release from F1 (14% CSeSA), data points with Mt/M∞  0.6
were just one, not suitable for fitting some models. Thus,
some results were absent in Table 3. Firstly, no formulations
fit the Zero-order kinetics model, meaning that it is very
difficult to get Zero-order release profile from highly water-
soluble drug loaded CSeSA matrix tablets. In contrast, the R2
values calculated from the Higuchi model (Mt/M∞  0.6) sug-
gested best fit. On the other hand, with the increase of CSeSA
amount, the R2 values calculated from the First-order model
increased. Drug release mechanism was also analyzed ac-
cording to RitgerePeppas and PeppaseSahlin models. For
PeppaseSahlin model, m ¼ 0.435 was determined because the
tablets present an aspect ratio (diameter/thickness) around
2.7 [23]. In general, the experimental data obtained from these
formulations showed a good fit for the two models with the
values of R2 more than 0.99. Using RitgerePeppas model, the
value of the exponent n was calculated. As shown in Table 3,
n ¼ 0.446 were obtained for tablets with 42% CSeSA. This
result was another indication that the dominant drug trans-
port mechanism appeared to be Fickian diffusion (n < 0.45). As
the amount of CSeSA increased to 56%, the drug transport
mechanism revealed anomalous transport with the value of n
between 0.45 and 0.89. And, the similar mechanism was also
found for formulations with 70% and 84% CSeSA. Release
mechanism was further elucidated by the PeppaseSahlin
model. As the amount of CSeSA increased, relaxation
contribution gradually played a role in drug delivery (Table 3).
However, Fickian diffusion still played a decisive role in drug
release with F/R > 1 (Eq. (7), data not shown), which was
consistent with the good fit to Higuchi model (Table 3). It
should be mentioned that Peppas equations were usually
utilized to analyze the early stage of drug release [27]. Ac-
cording to the previous studies [15], less erosion of CSeSA
based matrix tablets was observed in the late stage of release,
and therefore it could be deduced that the data with
Mt/M∞  0.6 might be mainly suitable for diffusion-based
release kinetics and the drug was released from the system
based on the mechanisms including swelling, diffusion and
erosion [2,26,28].
Table 3 e Estimated parameters obtained from fitting drug release data to Zero-order, First-order, Higuchi, RitgerePeppas
and PeppaseSahlin equations. The amount of CSeSA was in the range of 14%e84%.
Batch code Zero-order First-order Higuchi
2 2
k0 R k1 R k2
F1 (14%) e e 0.679 0.943 e e
F2 (42%) 0.092 0.543 0.243 0.947 0.322
F3 (56%) 0.083 0.704 0.172 0.950 0.259
F4 (70%) 0.077 0.814 0.140 0.966 0.223
F5 (84%) 0.076 0.849 0.135 0.975 0.215
3.3. Effect of CSeSA ratio on in vitro drug release
The physicochemical properties of CS and SA are
pH-dependent. Thus, the ratio of CS to SA might influence
drug release. Fig. 3 shows TH release characteristics from F4
and F6eF13 with different CSeSA ratios. As the SA was used
alone to control drug release, the release of TH could only be
extended for 8 h. This was explained by the swelling and
erosion of SA in SGF followed by SIF [9]. In contrast, once SA
was mixed with CS for controlling release, the drug release
rate decreased significantly. For example, when only 10% CS
(F7, CS:SA ¼ 1:6) was added into the formulation, drug release
in the first 2 h was 43% and was obviously lower compared to
that in the pure SA-based tablets with 52% TH released (F6,
CS:SA ¼ 0:1). More importantly, F7 (CS:SA ¼ 1:6) could extend
drug release for more than 12 h. Moreover, with the increase of
CS amount in the matrix, drug release decreased gradually. As
the CS:SA ratio changed from 1:6 to 1:1, the corresponding
release reduced from 43% to 34% in the first 2 h. After 12 h,
release also reduced from 88% (F7) to 79% (F4) (Fig. 3a). How-
ever, it seems that change of drug release mainly happened in
the first 4 h. Further analysis was conducted with the data
obtained in 4e12 h using the Zero-order equation. The release
rate constant (k0) was in the range of 4.4e4.7%/h. And, the
coefficient of correlation (R2) was in the range of 0.988e0.999.
The self-assembled film based matrix tablets, associated with
swelling, diffusion and erosion-based release mechanisms,
might result in the approximately Zero-order release charac-
teristics in SIF (4e12 h) [15,26,28]. As CS:SA ratio further
increased from 1:1 (F4) to 4:1 (F12), no significant change in
release profiles was found (Fig. 3b). When CS was used alone
as the matrix (F13), TH was released faster compared to F12
(CS:SA ¼ 4:1), probably due to the low capacity of CS for con-
trolling drug release in SIF [29]. However, no significant dif-
ference was found among these release profiles with f2 > 50.
3.4. Effect of SA type on in vitro drug release
It has been reported that the viscosity of SA and the ratio of
mannuronic acid (M) to guluronic acid (G) in the chemical
structure of SA could influence drug release from SA-based
matrix tablets [10]. Thus, it is essential to evaluate the effect
of SA type on drug release from CSeSA based matrix tablets.
Here, three types of SA were chosen for investigation (Table 1).
Fig. 4a showed the influence of the SA viscosity on the drug
release. No significant difference in drug release was found in
the two formulations (F4 vs. F14). Probably although SA LF200
has a higher viscosity than that of SA LF120, the slight
RitgerePeppas PeppaseSahlin
2 2
R k n R kF kR R2
e e e e e e
0.993 0.340 0.446 0.995 0.339 0.030 0.995
0.995 0.276 0.454 0.998 0.270 0.007 0.998
0.996 0.226 0.493 0.996 0.209 0.019 0.996
0.997 0.209 0.521 0.997 0.183 0.028 0.997
 a s i a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 1 0 ( 2 0 1 5 ) 3 1 4 e3 2 1 319

Fig. 3 e Effect of the ratio of CSeSA on in vitro drug release. Fig. 4 e Effect of the SA type on in vitro drug release.

variation could not induce significant change in diffusion ki-

amount and the solubility of diluents [2]. To get more knowl-
netics due to the very soluble property of TH [28]. Similarly,
edge about drug release characteristics from CSeSA based
the different ratios of MeG had no significant influence on
formulations, a large amount of diluents were added to the
drug release (Fig. 4b, F14 vs. F15). Theoretically, based on
matrix tablets (F16, F17 and F19). Fig. 5 shows the release
different gelling and swellingeerosion characteristics induced
behavior when microcrystalline cellulose (a diluent insoluble
by the amount of M and G [9], high M (SA LF240D) might be
in water), pregelatinized starch (a partly water-soluble
more advantageous than high G (SA LF120M) in sustaining the
diluent) and lactose monohydrate (a water-soluble diluent)
release of a water-soluble drug in SGF followed by SIF [10].
were added to formulations. Compared to 15.3% (w/w)
However, as mentioned in Section 3.1, CS could modify drug
microcrystalline cellulose formulation (F15), approximately
release from SA-based matrices in SGF followed by SIF me-
the same release profiles (F15, F16 and F17) were obtained,
dium, partly reducing the diversity of release profiles. More-
indicating that the diluents that have low solubility in water
over, CSeSA polyelectrolyte complexes could be formed on
had no significant effect on drug release. Similarly, when
the surface of tablets in SGF followed by SIF medium, which
15.3% (w/w) lactose monohydrate was added to matrix tablets,
also discounted the diversity in swelling and erosion arising
drug release had no significant change compared to F15
from different SA types [15], leading to similar release profiles
(f2 > 50). However, as the amount of lactose monohydrate
irrespective of SA type.
increased to 39.5%, drug release was obviously accelerated
with f2 ¼ 48.2 < 50, implying only a large amount of water-
3.5. Effect of diluents on in vitro drug release soluble diluents could modify the release behavior. This can
probably be explained by the mechanism that a large amount
Diluents are usually used to make the formulation more of water-soluble diluents could increase the porosity of
suitable for industrial scale production. However, it was re- swollen matrices and decrease gel strength, especially for the
ported that drug release was sometimes influenced by the CSeSA polyelectrolyte complexes film based tablets [2]. These
320 a s i a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 1 0 ( 2 0 1 5 ) 3 1 4 e3 2 1
Fig. 5 e Effect of diluents on in vitro drug release.
effects could increase drug diffusion coefficient and accelerate
the erosion of matrices through porous film [28]. Finally, drug
release rate was changed.
4. Conclusions
The present study demonstrated that some formulation var-
iables could indeed influence the release of a water-soluble
drug (TH from CSeSA matrix tablets). It was shown that CS
could compensate the loss of SA in SGF followed by SIF by the
synergistic reaction with SA, further extending drug release
for a longer time. The amount of CSeSA had the largest effect
on drug release kinetics. In contrast, CS:SA ratio had slight
effect on drug release and the type of SA had no significant
effect on the release of TH. Meanwhile, drug release rate was
changed as a large amount of water-soluble diluents were
added to CSeSA matrix tablets. Finally, deep understanding
drug release characteristics and release mechanisms from
CSeSA matrix tablets could facilitate product optimization
and avoid time-consuming and cost-intensive series of trial-
and -error experiments.
Acknowledgments
This project is financially supported by Liaoning Institutions
excellent talents support plan (No. LR2013047). The authors
wish to thank FMC Biopolymer for the supply of sodium
alginate and microcrystalline cellulose, Shanhe Pharmaceu-
tical Excipients Co., Ltd. for the supply of pregelatinized starch
and magnesium stearate, and Meggle Excipients & Technol-
ogy for the supply of lactose monohydrate.
references
[1] Tiwari SB, DiNunzio J, Rajabi-Siahboomi A. Drugepolymer
matrices for extended release. In: Wilson CG, Crowley PJ,
editors. Advances in delivery science and technology:
controlled release in oral drug delivery. New York: Springer;
2011. p. 131e160.
[2] Maderuelo C, Zarzuelo A, Lanao JM. Critical factors in the
release of drugs from sustained release hydrophilic matrices.
J Control Release 2011;154:2e19.
[3] Park JB, Lim J, Kang CY, et al. Drug release-modulating
mechanism of hydrophilic hydroxypropylmethylcellulose
matrix tablets: distribution of atoms and carrier and texture
analysis. Curr Drug Deliv 2013;10:732e741.
[4] Sokar MS, Hanafy AS, El-Kamel AH, et al. Pulsatile core-in-
cup valsartan tablet formulations: in vitro evaluation. Asian
J Pharm Sci 2013;8:234e243.
[5] Lee KY, Mooney DJ. Alginate: properties and biomedical
applications. Prog Polym Sci 2012;37:106e126.
[6] Augst AD, Kong HJ, Mooney DJ. Alginate hydrogels as
biomaterials. Macromol Biosci 2006;6:623e633.
[7] Hodsdon AC, Mitchell JR, Davies MC, et al. Structure and
behaviour in hydrophilic matrix sustained release dosage
forms: 3. The influence of pH on the sustained-release
performance and internal gel structure of sodium alginate
matrices. J Control Release 1995;33:143e152.
[8] Ching AL, Liew CV, Chan LW, et al. Modifying matrix micro-
environmental pH to achieve sustained drug release from
highly laminating alginate matrices. Eur J Pharm Sci
2008;33:361e370.
[9] Sriamornsak P, Thirawong N, Korkerd K. Swelling, erosion
and release behavior of alginate-based matrix tablets. Eur
J Pharm Biopharm 2007;66:435e450.
[10] Liew CV, Chan LW, Ching AL, et al. Evaluation of sodium
alginate as drug release modifier in matrix tablets. Int
J Pharm 2006;309:25e37.
[11] Mandal S, Basu SK, Sa B. Sustained release of a water-soluble
drug from alginate matrix tablets prepared by wet
granulation method. AAPS PharmSciTech
2009;10:1348e1356.
[12] Al-Zoubi NM, AlKhatib HS, Obeidat WM. Evaluation of
hydrophilic matrix tablets based on carbopol (R) 971P and
low-viscosity sodium alginate for pH-independent controlled
drug release. Drug Dev Ind Pharm 2011;37:798e808.
[13] Ding J, Na L, Mao S. Chitosan and its derivatives as the carrier
for intranasal drug delivery. Asian J Pharm Sci
2012;7:349e361.
[14] George M, Abraham TE. Polyionic hydrocolloids for the
intestinal delivery of protein drugs: alginate and chitosan e a
review. J Control Release 2006;114:1e14.
[15] Li L, Wang LL, Shao Y, et al. Drug release characteristics
from chitosanealginate matrix tablets based on the
theory of self-assembled film. Int J Pharm
2013;450:197e207.
[16] FPMAJ (Federation of Pharmaceutical Manufacturers
Association of Japan). The reevaluation collection:
physicochemical property of trimetazidine hydrochloride.
2014 [accessed 29.06.2014], http://www.fpmaj-saihyoka.com/
cgi-bin/pdfsearch/pdfsearch.cgi?
sub¼header&action¼listframe&key¼%83g%83%8A%83%81%
83%5E%83W%83W%83%93.
[17] Fu S, Thacker A, Sperger DM, et al. Rheological evaluation of
inter-grade and inter-batch variability of sodium alginate.
AAPS PharmSciTech 2010;11:1662e1674.
[18] Wang YJ, Assaad E, Ispas-Szabo P, et al. NMR imaging of
chitosan and carboxymethyl starch tablets: swelling and
hydration of the polyelectrolyte complex. Int J Pharm
2011;419:215e221.
[19] FDA (Food and Drug Administration, USA). SUPAC-MR:
modified release solid oral dosage forms. Scale-up and
postapproval changes: chemistry, manufacturing, and
controls; in vitro dissolution testing and in vivo
bioequivalence documentation. 1997.
 a s i a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 1 0 ( 2 0 1 5 ) 3 1 4 e3 2 1
[20] Oh TO, Kim JY, Ha JM, et al. Preparation of highly porous
gastroretentive metformin tablets using a sublimation
method. Eur J Pharm Biopharm 2013;83:460e467.
[21] Ritger PL, Peppas NA. A simple equation for description of
solute release II. Fickian and anomalous release from
swellable devices. J Control Release 1987;5:37e42.
[22] Serra L, Domenech J, Peppas NA. Drug transport mechanisms
and release kinetics from molecularly designed poly(acrylic
acid-g-ethylene glycol) hydrogels. Biomaterials
2006;27:5440e5451.
[23] Peppas NA, Sahlin JJ. A simple equation for the description of
solute release. III. Coupling of diffusion and relaxation. Int
J Pharm 1989;57:169e172.
[24] Rasool BKA, Fahmy SA, Galeel OWA. Impact of chitosan as a
disintegrant on the bioavailability of furosemide tablets:
in vitro evaluation and in vivo simulation of novel
formulations. Pak J Pharm Sci 2012;25:815e822.
[25] Franek F, Holm P, Larsen F, et al. Interaction between fed
gastric media (Ensure Plus®) and different hypromellose
321
based caffeine controlled release tablets: comparison and
mechanistic study of caffeine release in fed and fasted media
versus water using the USP dissolution apparatus 3. Int
J Pharm 2014;461:419e426.
[26] Ghori MU, Ginting G, Smith AM, et al. Simultaneous
quantification of drug release and erosion from
hypromellose hydrophilic matrices. Int J Pharm
2014;465:405e412.
[27] Rinaki E, Valsami G, Macheras P. The power law can describe
the 'entire' drug release curve from HPMC-based matrix
tablets: a hypothesis. Int J Pharm 2003;255:199e207.
[28] Siepmann J, Siepmann F. Modeling of diffusion controlled
drug delivery. J Control Release 2012;161:351e362.
[29] Huanbutta K, Cheewatanakornkool K, Terada K, et al. Impact
of salt form and molecular weight of chitosan on swelling
and drug release from chitosan matrix tablets. Carbohydr
Polym 2013;97:26e33.