Journal of Biomaterials and Nanobiotechnology, 2011, 2, 445-453
doi:10.4236/jbnb.2011.24054 Published Online October 2011 (
Copyright © 2011 SciRes. JBNB
Preparation and Characterization of IPN
Microspheres for Controlled Delivery of Naproxen
Ebru Kondolot Solak
Department of Chemistry and Chemical Processing Technology, Atatürk Vocational High School, Gazi University, Ankara, Turkey.
Received July 14th, 2011; revised August 22nd, 2011; accepted September 8th, 2011.
Interpenetrating network (IPN) microspheres of sodium alginate (NaAlg) and poly (vinyl alcohol) (PVA) were prepared and
crosslinked with glutaraldehyde (GA) by using the water in oil (W/O) emulsification method to deliver naproxen sodium
(NS). NS was successfully encapsulated into IPN microspheres in different ratios of NaAlg and PVA (w/w), drug loading
percentage (w/w) and crosslinking time. Crosslink density of the matrices was affected by the time of crosslinker. The pre-
pared microspheres were characterized by Fourier transform infrared spectroscopy (FTIR). Pictures of selected micro-
spheres were determined using optic microscope. Results confirmed the dispersion of NS in the microspheres. Release of NS
from the microspheres was investigated in pH 1.2, 6.8 and 7.4 media for two hours respectively. The highest NS release was
obtained as 92% (w/w) by using UV spectroscopy. Equilibrium swelling was performed in pH 7.4 buffer solution at 37˚C.
Keywords: Controlled Release, Microspheres, Alginate
1. Introduction
IPN is a polymer comprising two or more networks
which are at least partially interlaced on a polymer scale
but not covalently bonded to each other. The network
cannot be separated unless chemical bonds are broken.
The two or more networks can be envisioned to be en-
tangled in such a way that they are concatenated and
cannot be pulled apart, but not bonded to each other by
any chemical bond [1,2].
Controlled release technology has important potential
in the fields of medicine, pharmacy and agriculture. In
these areas natural polymeric materials have been pre-
ferred over synthe tic poly mers du e to th eir lo w cost, non-
toxicity, easy availability an d biodegradability properties
[3-5]. Biodegradable polymers derived from NaAlg and
PVA have shown to be useful in pharmaceutical indus-
tries due to their ability for drug release [6-8]. Sodium
Alginate (NaAlg) is a biodegradable polymer that has
been widely used in controlled release applications of
pesticides [9-1 2] and dr u gs [13,14].
Poly(vinyl alcohol) (PVA) is also a suitable polymer
for drug release because of its desirable properties such
as nontoxicity and noncarcinogenicity and has been used
in many studies due to its biocompatibilit y. However it is
difficult to prepare beads from this polymer due to its
poor stability. A blending techniqu e can be considered as
a useful tool for the preparation of new alginate beads
with PVA to increase the bead forming ability in aqueou s
medium. PVA can strongly interact with NaAlg through
hydrogen bonding on a molecular level. For this reason
in several studies, NaAlg and PVA were chosen for the
microsphere formation and successfully crosslinked with
glutaraldehyde [15,16].
Naproxen Sodium (NS) is a non-steroidal and anti-in-
flammatory drug with analgesic properties however gas-
trointestinal side effects such as bleeding, ulceration or
perforation were commonly seen when this drug was
used. For this reason it is important to obtain prolonged
or controlled drug delivery to improve bioavailability or
stability and to target the drug to a specific site.
According to our literature survey there is no report
available about the formation of IPN structure of PVA
with NaAlg for the controlled release of NS in pH 1.2,
6.8 and 7.4 medium. The present investigation is related
to the in vitro release studies on IPN microspheres for-
mulations loaded with different amounts of NS. Release
characteristics of the formulations were studied for their
exposure time to cross-linking agent, at different amounts
of NS and polymers.
2. Materials and Methods
2.1. Materials
NaAlg (medium viscosity) was purchased from Sigma
Preparation and Characterization of IPN Microspheres for Controlled Delivery of Naproxen
Chemical Co. (St. Louis, MO). PVA was procured by
Merck (Darmstadt, Germany). The molecular weight and
degree of sapon ification of PVA wer e 72000 and greater
than 98%, respectively. Span-85, GA (25% w/w), hy-
drochloric acid, light liquid paraffin, hexane, Na2HPO4
and NaH2PO4 used in this study were all supplied by
Merck. A gift sample of NS was obtained from Novartis
(Summit, NJ).
2.2. Preparation of the IPN Microspheres and
Drug Loading
IPN microspheres of PVA and NaAlg were prepared by
emulsion-crosslinking method and GA was used as a
cross linking agent. NaAlg was dissolved separately in
distilled water at different concentrations by stirring.
After PVA was dispersed in NaAlg solution and stirred
overnight to obtain a homogeneous solution, required
amount of drug was dispersed in the polymer solution.
The drug loaded polymer solution was emulsified into
light liquid paraffin to form water-in-oil (W/O) emulsion
using a high speed stirrer in a beaker containing light
liquid paraffin oil, Span-85 (2% (w/v)), 0.1 M HCl and
the required amount of GA. The microspheres formed
were filtered, washed repeatedly with n-hexane and wa-
ter to remove the oil as well as excess amount of surfac-
tant and unreac t ed GA. T he se m i cr os p he re s w er e d ri ed in
oven at 40˚C and stored for further analysis.
The microspheres were prepared with different formu-
lations which were presen ted at Table 1. A schematic rep-
resentation of the structure of IPN is given i n Figure 1.
2.3. Fourier Transforms Infrared Spectroscopy
FTIR spectral measurements were performed with a
Mattson 1000 FTIR spectrometer (Welwyn Garden, Eng-
land) to confirm the presence of crosslinking and drug in
2.4. Optical Microscopy Study
Optical microscope imaging was performed using Leica
L2 optic microscope (California, United States).
2.5. Swelling Studies
The equilibrium swelling degree of the crosslinked
empty IPN microspheres was determined by measuring
gravimetrically the extent of their swelling in pH 7.4
buffer solution at 37˚C. To ensure complete equilibration
the samples were allowed to swell for 48 h. The excess
surface-adhered liquid drops were removed by blotting.
The swollen microspheres were weighed using electronic
balance (Precisa XB 220 A, USA). The microspheres
were then dried in an oven at 40˚C, until there was no
Table 1. Results of percent entrapment efficiency and yield at various crosslinker times.
Formulation Code Polymers % Naproxen sodium
loaded (w/w) Time of exposure
to GA (min) Entrapment
efficiency (%) Yield (%)
A1 NaAlg 50 5 61 78
A2 NaAlg 33 5 63 81
A3 NaAlg 20 5 68 77
A4 NaAlg 33 10 58 76
A5 NaAlg 33 15 56 80
B1 PVA 66 % (w/w)
NaAlg 33 % (w/w) 50 5 66 89
B2 PVA 66 % (w/w)
NaAlg 33 % (w/w) 33 5 60 85
B3 PVA 66 % (w/w)
NaAlg 33 % (w/w) 20 5 54 79
C1 PVA 50 % (w/w)
NaAlg 50 % (w/w) 50 5 69 86
C2 PVA 50 % (w/w)
NaAlg 50 % (w/w) 33 5 64 88
C3 PVA 50 % (w/w)
NaAlg 50 % (w/w) 20 5 63 85
D1 P VA 33 % (w/w)
NaAlg 66 % (w/w) 50 5 72 83
D2 P VA 33 % (w/w)
NaAlg 66 % (w/w) 33 5 67 78
D3 P VA 33 % (w/w)
NaAlg 66 % (w/w) 20 5 65 75
opyright © 2011 SciRes. JBNB
Preparation and Characterization of IPN Microspheres for Controlled Delivery of Naproxen447
Figure 1. Schematic representation of structure of IPN.
Copyright © 2011 SciRes. JBNB
Preparation and Characterization of IPN Microspheres for Controlled Delivery of Naproxen
Copyright © 2011 SciRes. JBNB
change in the dried mass of samples. The percent equili-
brium swelling degree was calculated as follows:
Equilibrium swelling degree (%) = 100
where Ms and Md are the mass of the swollen and dry
microspheres, respectively.
2.6. Entrapment Efficiency
Required amount of dry microspheres was crushed in an
agate mortar with a pestle, stirred with water and re-
fluxed at 25˚C for 1 h, to ensure the complete extraction
of NS from the beads. At the end of the 1 h, precipitated
microspheres were filtered and NS was analyzed by us-
ing a UV spectrophotometer (Unico 4802 UV/VIS) at a
wavelength of 271 nm. The percentage of entrapment
efficiency was then calculated as follows:
Practical loadi n g
Entrapment efficiency (%)100
Theoretical loading
2.7. In Vitro NS Release
In vitro drug release from the IPN microspheres was
studied at pH 1.2 HCl solution, pH 6.8 and pH 7.4 phos-
phate buffer solutions and incubated in a shaking water
bath (Medline BS-21, Korea) at 37˚C. At 2 h intervals
medium was changed to be pH: 1.2, 6.8 and 7.4, respec-
tively. At specific time intervals, the NS content was
determined using UV spectrophotometer at 271 nm.
Analyzed solution was added back to the dissolution
media to maintain a constant volume. From the absorb-
ance values the cumulative released amount percentage
was determined. All experiments were performed in trip-
licate to minimize the variation er ror. Th e averag e valu es
were used for further data treatment and pl ot t i ng.
3. Results and Discussion
3.1. Characterization of Microspheres
Results of FTIR spectra for powder NS, NaAlg, PVA,
empty IPN microspheres and NS loaded IPN micro-
spheres are shown in Figure 2.
The entire bead formulations showed a broad band
between th e 300 0 and 3500 cm–1, wh ich was attribu ted to
–OH stretching vibrations. The peak at 1618 cm-1 in the
spectrum of NaAlg is due to the stretching band of car-
bonyl stretching (C=O). A broad characteristic peak at
1625 cm–1 is due to the C=O of the NaAlg polymeric
chain and unhydrolyzed part in PVA in the IPN. In the
spectrums of NaAlg, PVA and IPN appear stretching
bands of C-H group at 2940 cm–1, 2986 cm–1 and 2920
cm–1, respectively. As it is seen from Figure 2 the inten-
sity of –OH peak corresponding to crosslinked IPN is
narrower than the uncrosslinked NaAlg and PVA as the
evidence of crosslinking.
Optic microscope images of dried NS loaded IPN mi-
crospheres were shown in Figure 3. As it was reflected
from the figure, microspheres almost maintain their
spherical form.
Swelling results were shown in Table 2. Swelling cha-
racteristics depends upon the amount of polymer. Equi-
librium swelling (%) increased with increasing amount
of PVA in the IPN matrix. Since PVA and NaAlg are
water soluble polymers, the swelling of IPN will increase
due to their higher water uptake.
3.2. In Vitro Release Study
% Cumulative release results were shown in Figure 4 for
50% (wt) NS loaded IPN microspheres. The formula-
tions of these microspheres were given in Table 1 as A1,
B1, C1 and D1. Similarly release results for 33% (wt)
and 20% (wt) NS loaded microspheres were shown in
Figure 5 and Figure 6, respectively. % 33 NS loaded
IPN microspheres were formulated as A2, B2, C2, D2
and % 20 NS loaded IPN microspheres were shown as
A3, B3, C3, D3.
Figure 2. FTIR spectra of (a) NS, (b) NS loaded IPN mi-
crospheres, (c) empty IPN microspheres, (d) powder NaAlg
(e) powder PVA.
Preparation and Characterization of IPN Microspheres for Controlled Delivery of Naproxen449
Figure 3. Optic microscope imaging of NS loaded IPN mi-
Figure 4. % Cumulative release of NS from different IPN
formulations loaded with 50 % of drug at concentration of
GA: 2.5% and exposure time to GA: 15 min. Symbols: A1
(), B1 (), C1 (), D1 ().
Figure 5. % Cumulative release of NS from different IPN
formulations loaded with 33 % of drug at concentration of
GA: 2.5% and exposure time to GA: 15 min. Symbols: A2
(), B2 (), C2 (), D2 ().
Figure 6. % Cumulative release of NS from different IPN
formulations loaded with 20% of drug at concentration of
GA: 2.5% and exposure time to GA: 15 min. Symbols: A3
(), B3 (), C3 (), D3 ().
Table 2. % Equilibrium swelling degree for the empty IPNs
at pH 7.4.
Formulation Code Equilibrium swelling degree (%)
A 117.83 ± 4.78
B 1043.40 ± 3.45
C 376.54 ± 1.25
D 157.36 ± 1.43
It was seen from the figures that NaAlg microspheres
produced nearly 92% cumulative drug release in 10 h,
whereas IPN microspheres produced up to 80% cumula-
tive release at the end of the 10 h. Alginate is a natural
water-soluble polymer and contains hydroxyl and car-
boxyl groups, which impart hydrophilicity to the mole-
cule. On the other hand PVA is virtually a linear polymer
with a small hydrated volume compared to alginate and
thus PVA produces a compact network of macromolecu-
lar chains in the IPN. The release rates of NS to an ex-
ternal medium are more difficult compared to the NaAlg
microspheres. Similar results can be found from the pub-
lished reports [16,17]. In the study of Krishna Rao and
coworkers, controlled release of cefadroxil from IPN
microspheres based on chitosan, acrylamide-grafted-
poly(vinyl alcohol) and hydrolyzed acrylamide-grafted-
poly(vinyl alcohol) were investigated. They have re-
ported that the blend microgels have shown longer drug
release rates than the plain chitosan microgels.
Effect of 33 % (wt) NaAlg content in formulations B1,
B2 and B3 on the release rates were presented in Figure
7. Als o rel eas e studies were done for 50 % (wt ) a nd 6 6 %
(wt) NaAlg content and release results were shown in
Figure 8 and Figure 9, respectively. The microspheres
containing % 50 NaAlg has the formulations given in
Copyright © 2011 SciRes. JBNB
Preparation and Characterization of IPN Microspheres for Controlled Delivery of Naproxen
Figure 7. % Cumulative release of NS from IPN micro-
spheres containing 33% of NaAlg at concentration of GA:
2.5% and exposure time to GA: 15 min. Symbols: B1 (),
B2 (), B3 ().
Figure 8. % Cumulative release of NS from IPN micro-
spheres containing 50% of NaAlg at concentration of GA:
2.5% and exposure time to GA: 15 min. Symbols: C1 (),
C2 (), C3 ().
Table 1 as C1, C2, C3 and the microspheres containing
% 66 NaAlg has the formulations given in Table 1 as D1,
D2, D3.
Release results showed that formulations containing
the highest amount of NS (50 wt%) displayed higher re-
lease than those formulations containing low amount of
NS. As the amount of drug increased from 20% to 50%,
the % cumulative release rate increased from 26 to 84.
This is obvious that as the amount of NaAlg increases in
the matrix, diffusion of NS occur faster and higher from
the swollen IPN [17]. Ramesh Babu and coworkers pre-
pared IPN microgels of sodium alginate-acrylic acid for
the controlled release of ibuprofen. They reported that
Figure 9. % Cumulative release of NS from IPN micro-
spheres containing 66% of NaAlg at concentration of GA:
2.5% and exposure time to GA: 15 min. Symbols: D1 (),
D2 (), D3 ().
formulations containing the highest amount of drug (75%)
displayed faster and higher release rates than those for-
mulations containing a small amount of ibuprofen.
3.3. Effect of Crosslinking Agent on the NS
Varying exposure time of microspheres to GA at a fixed
amount of the NS/polymer ratio (20 wt%) are displayed
in Figure 10 which clearly indicates that with increasing
exposure time to GA (5 - 15 min), th e cumulative release
decreases. Increasing exposure time to GA results in an
increase in the crosslink density of the beads which gives
rise to a compact network of macromolecular chains. As
expected, the release of NS becomes slower at higher of
GA, but becomes faster at lower amount of GA. The
maximum NS release was obtained as 80% from the
microspheres prepared with an exposure time of 5 min-
To understand the extent of crosslinking of the poly-
mer, it is necessary to calculate the molar mass (MC)
between the crosslinks of the polymer. MC can be calcu-
lated from the equilibrium swelling volume of the poly-
mer in a solvent [13].
Degree of crosslinking of polymer beads was calcu-
lated using Flory-Rehner equation as given below:
13 2
ln 1
 
 
is the volume fraction of the polymer in the swollen
state and can be calculated as:
opyright © 2011 SciRes. JBNB
Preparation and Characterization of IPN Microspheres for Controlled Delivery of Naproxen
Copyright © 2011 SciRes. JBNB
 
.2d d
 
 
 
23 13
3232 3N
 
and tempera-
ture is taken as Kelvin.
Molar masses between crosslinking and polymer cal-
culated for the NS loaded beads are presented in Table 3.
As it is seen from Table 3 when the crosslinking of the
polymer increased Mc values decreased, since the net-
work becomes more intensive structure. Also, the Mc
values increased with an increase in NaAlg content of the
formulation, indicating an intensive structure.
3.4. Analysis of Kinetic Results
Solvent sorption by a microsphere depends mechanisti-
cally on the diffusion of water molecules into the gel
matrix and subsequent relaxation of macromolecular
chains of the microsphere [19]. The release data of all the
systems have been further substantiated by fitting the
fraction release data t
M to an empirical equation
proposed by Peppas [20].
Figure 10. % Cumulative release of NS from IPN micro-
spheres containing different time of crosslinking agent.
66% NaAlg, 20% NS, 25% of GA. Symbols: 5 min (), 10
min (), 15 min ().
Sb S
 
and S
are the densities of the polymer and
solvent, respectively. Ma and Mb are the mass of the
polymer before and after swelling, respectively. Vs is the
molar volume fraction of the polymer in the swollen
In the equation, t
is the amount of NS released at
time t and
is the drug released at equilibrium time;
k, a constant characteristic of the drug-polymer system;
and n, the diffusional exponent which suggests the nature
of the release mechanism. Fickian release is defined by
initial 12
t time dependence of the fractional release for
slabs, cylinders and spheres. Analogously Case-II trans-
Interaction parameter can be calculated from the
Flory-Rehner equation [18].
Table 3. Values of MC, k, n, r for NS containing IPNs.
Formulation Code k (min–n) × 102 n r MC Diffusion Mechanism
A1 0.0087 0.8765 0.9793 1492 Anomalous Transport
A2 0.0180 0.7475 0.9862 1597 Anomalous Transport
A3 0.0230 0.6983 0.9756 1671 Anomalous Transport
A4 0.0189 0.6538 0.9774 1748 Anomalous Transport
A5 0.0257 0.6578 0.9865 1886 Anomalous Transport
B1 0.0009 0.9064 0.9917 2596 Anomalous Transport
B2 0.0008 0.1013 0.9987 2547 Case II
B3 0.0031 0.8865 0.9946 2508 Anomalous Transport
C1 0.0008 1.0402 0.9980 1986 Case II
C2 0.0006 1.1657 0.9959 2067 Case II
C3 0.0042 0.7852 0.9947 2247 Anomalous Transport
D1 0.0005 1.2415 0.9967 1954 Case II
D2 0.0008 1.1357 0.9948 1941 Case II
D3 0.0004 1.3475 0.9972 1983 Case II
Preparation and Characterization of IPN Microspheres for Controlled Delivery of Naproxen
port is defined by an initial linear time dependence of the
fractional release for all geometries [21]. A value of n;
0.5 indicates the Fickian transport (mechanism), while n;
1 is of Case II or non-Fickian transport (swelling con-
trolled). The intermediary values ranging between 0.5
and 1.0 are indicative of the anomalous transport. The
least squares estimations of the fractional release data
along with the estimated correlation coefficient values, r,
are presented in Table 3. From these data, the n value
ranged between 0.6538 - 1.3475, indicating that, NS
from the microspheres slightly deviates from the Fickian
4. Conclusions
This work demonstrates the effective encapsulation of
NS into NaAlg and PVA to produce IPN microspheres
by emulsification crosslinking method. The IPN micro-
spheres demonstrated better controlled release results
than pure NaAlg, indicating the suitability of IPN for
microsphere preparation. The crosslink density was sig-
nicantly affected by the amount of GA and the polymers
in the formulations. The release of NS was found to be
dependent on the extent of crosslinking, the amount of
drug loading and the polymer content of the matrix. The
release mechanism showed a slight deviation from the
Fickian behavior. It can be concluded that microspheres
prepared in this study can be effectively used as a con-
trolled release device for the release of NS.
5. Acknowledgements
The author is grateful to the Gazi University Scientific
Research Foundation for support of this study and to
Novartis Company for the supply of the drug (Naproxen
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