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Arab Journal of Nuclear Science and Applications, 47(1), (28-40) 2014
28
In-Vitro Release of Ketoprofen Behavior Loaded in Polyvinyl Alcohol /
Acrylamide Hydrogels Prepared by Gamma Irradiation
Ghada A. Mahmoud , Dalia E. Hegazy and H. Kamal National Center for Radiation Research and Technology (NCRRT), P.O. Box 29, Nasr City, Cairo,
Egypt. Received: 25/12/2013 Accepted: 15/1/2014
ABSTRACT
Hydrogels based on various ratios of polyvinyl alcohol (PVA) and acrylamide
(AAm) were prepared by gamma radiation. The formed hydrogels were
characterized by spectroscopic analysis (FTIR), differential scanning calorimetry
(DSC), thermogravimetric analysis (TGA) and swelling studied. It was found that
the thermal stability of the hydrogel decreases as the AAm content increases in the
hydrogel. The higher the AAm content in the hydrogel, the lower the values of Tm
and ΔHm. Ketoprofen was adopted as a model drug to study the adsorption and
release behavior of (PVA/AAm) hydrogel. The drug adsorption was decreased by
increasing AAm ratio in the hydrogel. From the in vitro drug release study in pH
progressive media, the basic medium was showed comparatively the highest release
and the (PVA/AAm) hydrogel of composition (70/30) was found to be the highest
release one. The mechanism of Ketoprofen release from the (PVA/AAm) matrix was
found to be non-Fickian mechanism for all investigated hydrogels at pH 7.
KEY WORDS: hydrogel; Radiation; Ketoprofen; Drug release
INTRODUCTION
Hydrogels are a network of polymer chains that are water-insoluble. Over the decades,
hydrogels have been invented for numerous pharmaceutical and biomedical applications (1.2).
Hydrogels are inherently soft, hydrophilic, porous, and elastic polymeric systems. The use of polymer
hydrogels as biopotential sorbent or carriers for the removal of the model molecules from aqueous
solutions or controlled release studies of them has been continued to attract con-siderable attention in
recent years (3-5).
PVA is an important water soluble polymer (1), it is biocompatible and non-toxic. It absorbs
water, swells easily and it has extensively been used in controlled release applications(6). Therefore, a
number of methods have been reported for preparation of PVA hydrogels, including chemical methods
using a covalent cross-linking agent (7,8), physical methods (9,10) and radiation methods using γ-
radiation(11,12) electron beams (13), or ultraviolet light (14). Radiation polymerization is a useful method
for producing hydrogels(15–17). It provides a very clean process, because no initiator and crosslinker
need to be added to reaction media(18). Moreover, since the hydrogels are not contaminated with
foreign additives, the pore size of hydrogels can be controlled by environmental conditions. AAm
based hydrogels are widely used in the drug release systems (19,20). PVA/AAm hydrogels have good
physical and mechanical properties in addition to their swelling and drug release capabilities (21).
Ketoprofen, 2-(3-benzoylphenyl)-propionic acid, is an analgesic, antipyretic and a non-steroidal
anti-inflammatory drug used for the treatment of rheumatoid arthritis, osteoarthritis and other chronic
musculoskeletal conditions(22,23). Conventional dosage forms of this drug, administered orally, three or
Corresponding author, Email: ghadancrrt@ yahoo.com
Arab Journal of Nuclear Science and Applications, 47(1), (28-40) 2014
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four doses per day, have side effects such as peptic ulceration or bleeding and anorexia, and some
additional side effects (24) that limit its use. Controlled release of the drug is expected to significantly
mitigate these side effects by targeting only the specific organs in the body. Diffusion in polymers is
an important mechanism in pharmacy for the controlled release of drugs. Diffusion in polymeric
systems is passive, if the driving force is purely a Brownian molecular motion, but diffusion can also
be activated by external effects, either by the influence of the release medium by swelling or by the
effects of physical forces as electrical, osmotic or convective forces (25).
In this study, PVA and AAm were chosen to make the hydrogel by gamma irradiation. The
structural properties of the (PVA/AAM) hydrogels were characterized by different techniques such as
FTIR spectroscopy, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC).
The swelling properties of the hydrogel were investigated. PVA based hydrogel was used as a drug
delivery carriers. The drug delivery will be estimated using Ketoprofen as a model of drug. For this
purpose, the effects of AAm content in the hydrogel, initial feed concentrations of drug and pH of
medium on the release of Ketoprofen were studied.
MATERIALS AND METHODS
1. Materials
Poly(vinyl alcohol) (PVA; Mw 15,000) was purchased from Aldrich Co. and acrylamide
(AAm), obtained from (Merck, Germany)were used as received. Ketoprofen (Sigma chemical Co.,
USA), structure of the drug is shown below. The other chemicals were reagent grade and used without
further purification. The components of the citrate and phosphate buffers were reagent grade and
purchased from El-Nasr Co. for Chemical Industries (Egypt) and used as purchased without further
purification. Distilled water was used in all experiments.
Chemical structure of ketoprofen
2. Preparation of PVA/AAm Hydrogel
The PVA/AAm hydrogels were synthesized by the free radical polymerization. An aqueous
solution of 10% PVA (w/v) was dissolved at 80 oC in water bath with constant stirring for 6 h. After
cooling down to room temperature, various compositions of AAm were added to the solution, where,
the total concentration was of 20% .The resulting solutions were transferred into the glass tube to
irradiate by 60Co gamma source at room temperature with radiation dose 20 kGy. The dose rate of
irradiation was 3.065 kGy h-1 after copolymerization, the vials were broken, the formed polymeric
cylinder were removed and cut into discs of 2 mm thickness and 5 mm diameter. All samples were
washed in excess water to remove the unreacted component then air dried at room temperature.
3. Swelling Measurements
The clean, dried, sample of preweight was soaked in bidistilled water at room temperature for
different intervals time durations. The sample was removed and the excess water on the surface was
removed by blotting quickly with filter paper and weighed. The swelling ratio was calculated as
follows:-
Where Wd and Ws are the masses of dry and wet hydrogel, respectively.
Arab Journal of Nuclear Science and Applications, 47(1), (28-40) 2014
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4. Fourier Transform Infrared Spectroscopy (FTIR)
IR spectra of the investigated films were recorded over the range 400–4000 cm-1, using a
Mattson 1000, Unicom infrared spectrophotometer (Cambridge, England).
5. Thermogravemetric Analysis (TGA)
Thermogravimetric analysis (TGA) was conducted on a Shimadzu TGA system, Type TGA-50,
under nitrogen flow atmosphere of 20 ml/min to prevent thermal oxidation processes of polymer
samples. The heating rate was 10C/ min from ambient up to 500C.
6. Differential Scanning Calorimetry (DSC)
DSC measurements were performed using a Shimadzu DSC calorimeter (Kyoto, Japan)
equipped with data station. A heating rate of 10 C/min was utilized and the scans were carried out
under a flowing nitrogen gas at a rate of 20 mL/min.
7. Drug Loading to the Hydrogl
The loading of Ketoprofen drug onto PVA/AAm hydrogels were carried out by swelling
equilibrium method. The hydrogels were allowed to swell in the drug solution of known concentration
for 24 h at 37C and then dried at room temperature. The concentration of rejected solution was
measured to calculate the percent entrapment of the drug in the polymer matrix using a Unicam, UV–
Vis Spectrometer, Model 1000 at the wavelength 262 nm. The amount of adsorbate per unit mass of
adsorbent (qe) was calculated as follows:
Where Ci and Ce are the initial and equilibrium concentrations of adsorbate solution in mg/ml.
8. In-Vitro Release Studies
In vitro release studies of the drug were performed by placing the pre-weighed hydrogels loaded
with Ketoprofen drug in definite volume of releasing medium of buffer at pH 1.5 at 37C for 3 h and
subsequently in buffer of pH 7 at 37 C for 24 h. One milliliter sample was withdrawn on time
intervals to follow the release process. The concentration of Ketoprofen drugs was measured. After the
complete release; the hydrogels were immersed in pH 3.0 buffer solution and then, 0.1mol/L, HCl for
2 days to remove the remaining drug which may be loaded in the gel system. The total uncertainly for
all experiments ranged from 3to 5%.
RESULTS AND DISCUSSION
The prepared PVA/AAm hydrogels using γ-radiation copolymerization technique as mentioned in
the experimental part were then subjected to different characterization techniques; including FT-IR,
TGA, DSC and swelling behaviors.
1. FT-IR Analysis
FT-IR spectra of PVA and (PVA/ AAm) hydrogels are shown in Figure (1). A broad band
appeared around 3348 cm-1 in both cases is attributed to the O-H stretching vibration of the hydroxyl
group of PVA. A sharp band at 1094 cm-1 corresponds to the symmetrical stretching C-O-C (in acetyl
group) present in the PVA backbone due to the unhydrolyzed acetate groups of poly (vinyl acetate). The
asymmetric N-H stretching vibration of the primary amide overlaps with the stretching vibrations O-H.
Arab Journal of Nuclear Science and Applications, 47(1), (28-40) 2014
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The aliphatic C-H stretching vibrations appear at 2923cm-1. A strong band at 1659cm -1 was observed
and can be attributed to the stretching carbonyl (C=O) groups in the carboxamide functional groups of
the PVA/ AAm hydrogel. The presence of strong bands at 1616 cm-1 corresponding to the asymmetric
bending N-H groups (26, 27). From FT-IR results, it can be concluded that the formation of PVA/AAm
copolymer using ionizing radiation was occurred.
Figure (1): FT-IR spectra of PVA and PVA/AAm hydrogels.
2. Thermal Stability of the Prepared PVA/AAm Hydrogel
Thermogravimetric analysis (TGA) is considered as the most important method for studying
the thermal stability of polymeric materials. It monitors the weight changes in a sample as a function
of temperature. The relative thermal stability of the different hydrogels was assessed by comparing the
weight change in the temperature range 0 –600 C and TGA data is shown in Figure (2) and presented
in Table (1). Pure PVA hydrogel shows a stable thermogram up to temperature of 211oC, beyond
which a smooth decrease in weight is observed. Whereas PVA/AAm hydrogel shows its famous four
degradation steps which due to the loss of associated water, anhydride formation, decarboxylation and
backbone degradation, respectively (28, 29). It can also be noted that, the thermal stability of the prepared
PVA/AAm hydrogel decreases as the AAm content increases in the hydrogel. The weight loss for
PVA/AAm hydrogel is lower than that of pure PVA hydrogel as shown in Table (1). The copolymer
hydrogel (PVA/AAm) of composition (70/30) possesses the highest thermal stability, which is almost
similar to that of pure PVA. The analysis of the thermograms shows that the PVA/AAm hydrogels are
relatively stable in the temperature range of 100–200 C, and the degradation of hydrogel is controlled
mainly by the composition of the hydrogel.
Arab Journal of Nuclear Science and Applications, 47(1), (28-40) 2014
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Table (1): Thermal parameters for PVA/AAm hydrogels at various compositions.
PVA/AAm
(wt%)
Tonst
(oC)
Char residue
(%)
Tg
(oC)
Tm
(oC)
H
(J/g)
100/0 211 4.6 79 225 49
70:30 210 9.3 91 210 45
50:50 201 10.3 94 206 30
30/70 200 11,6 99 204 22
* Tm is the Melting temperature
* Tg is the glass transition temperature
* H is the melting enthalpyt
Figure (2): TGA thermal diagrams of PVA/AAm hydrogels of various compositions.
3. Thermal Parameters
DSC thermal d foagramsr various compositions of PVA/AAm hydrogels were made and
shown in Figure (3). The thermal parameters of PVA/AAm hydrogels ; Tm ,Tg and ΔHm, were
evaluated and shown in Table (1). Pure PVA hydrogel has been exhibit an endothermic peak that
corresponds to the Tm at 225 ◦C. Both Tm and ΔHm decrease as the percentage of AAm increases in the
gel. The higher the AAm content in the hydrogel, the lower the values of Tm and ΔHm. The decrease in
ΔHm values of PVA/AAm hydrogels compared with the pure PVA can be attributed to the increase in
Arab Journal of Nuclear Science and Applications, 47(1), (28-40) 2014
33
crosslinking network structure. In addition, the area under the melting peak decreases as the AAm
content increases. This indicates a smaller fraction of crystalline phase and a larger fraction of
amorphous phase, which may benefit anionic transition. The introducing of AAm into PVA caused
changes in the morphological structure in which the crystallinity domains in (PVA/AAm) decreases
due to the increase in crosslinking network formation that caused by radiation process. It is well
known that, below Tg, molecules do not have segmental motion, and some portions of the molecules
may not wiggle around, but may only be able to vibrate slightly. The Tg of pure PVA is about 79; by
the addition of AAm the Tg is slightly increased. This increase in Tg is due to the increase in
crosslinking network structure which decreases the segmental motion and the mobility of the chains.
Figure (3): DSC thermal diagrams of (a) PVA, PVA/AAm hydrogels of compositions; (b) 70/30, (c)
50/50 and (d) 30/70.
4. Swelling Studies
In order to evaluate the effect of PVA/AAm hydrogel network structure, the swelling behavior of
various compositions of PVA/AAm hydrogel as a function of time were carried out and shown in Figure
(4). It was found that the swelling capacity of the hydrogels increased with the decrease in AAm content
in PVA/AAm hydrogel , i.e. increases PVA content in network structure. This may be due to the
increase in crosslinking network structure of PVA/AAm hydrogel with increasing AAm contents in the
polymer sturcure as explained by DSC. Actually the hydrogen bonding due –OH groups of PVA tends to
crystallize the PVA chains through physical cross-linking which due to steric hindrance of the bulky
amide groups restricts the chains and decreases the crystallinity of PVA segments (30).
The effect of swelling medium on the swelling percent of PVA/AAm hydrogel was investigated
and shown in Figure (5). The swelling of PVA/AAm hydrogel was carried out in distilled water, pH of 2
and pH of 7 buffers. It can be observed that nearly equal swelling has been observed in distilled water,
pH 2 and pH 7 buffers.
Arab Journal of Nuclear Science and Applications, 47(1), (28-40) 2014
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Time (min)
0 200 400 1000 1200 1400
Sw
elli
ng (
%)
0
200
400
600
800
1000
100/0
70/30
50/50
30/70
PVA/AAm
Figure (4): Effect of time on the swelling percent of PVA/AAm hydrogels prepared at irradiation
dose of 20 kGy at room temperature.
Time (min)
0 200 400 1000 1200 1400
sw
elli
ng (
%)
0
200
400
600
800
1000
distilled water
buffer 2
buffer 7
Figure (5): Effect of the swelling medium on the swelling percent of PVA/AAm hydrogels of
composition (70/30) that prepared at irradiation dose of 20 kGy at room temperature.
5. Ketoprofen Uptake
Before the investigation of release experiment, the adsorption behavior of various
compositions of the prepared PVA/AAm hydrogels towards ketoprofen was investigated. The
Arab Journal of Nuclear Science and Applications, 47(1), (28-40) 2014
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hydrogels were swollen in ketoprofen solution of concentration 100 mg/L at pH 7. The amount of
ketoprofen adsorbed into 0.1 gm of PVA/AAm hydrogel was measured and given in Figure (6). It can
be seen that the uptake was decreased with increasing the AAm content in the hdrogel. The increase of
AAm in the hydrogel results in increasing the crosslinking network structure as confirmed by DSC
data. The swelling was found to be decreased by increasing the AAm content in the hydrogel which
impedes the interior of ketoprofen drug into the gel.
Hydrogel composition (%)
90 80 70 60 50 40 30 20
0.45
0.50
0.55
0.60
0.65
0.70
Dru
g u
pta
ke (
mg/m
l)
PVA
10 20 30 40 50 60 70 80 AAm
Figure (6): Effect of hydrogel composition on the ketoprofen uptake of initial concentration 200 mg/L
hydrogels prepared at irradiation dose 20kGy.
6. Release of Ketoprofen
6.1. Effect of pH
The in vitro release of ketoprofen from PVA/AAm hydrogel was investigated at various pH's of
medium and shown in Figure (7). It can be seen that the drug release increases with the increase in pH
of medium. At low pH, the release of such hydrogel decreases because there is a high H+ concentration
then H-bond is formed and the migration of drug molecules becomes low. In this case the hydrogel
can keep the solute because the texture structure becomes strong. Whatever, the acidic medium is not
suitable for releasing process of the drug.
Arab Journal of Nuclear Science and Applications, 47(1), (28-40) 2014
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pH
0 2 4 6 8 10
0.0
0.2
0.4
0.6
0.8
1.0
1.2D
rug
re
lea
se
(m
g/m
l)
Figure (7): Effect of pH on the ketoprofen release from PVA/AAm (70/30) hydrogel at initial
concentration 100 mg/L hydrogel prepared at irradiation dose 20kGy.
6.2. Effect of Time
Figure (8) shows the drug release behavior of various compositions of PVA/AAm hydrogels as
a function of time at pH 7. It can be seen that the release from PVA/AAm hydrogel increases
substantially with time up to 500 min and then tends to level off. The amount released depends upon
the composition of the hydrogel in the polymer matrix. It was found that the release of ketoprofen
increases as the PAAm content decreases in the hydrogel. This is possibly due to the formation of
lightly cross-linked PVA/AAm hydrogel given that the cross-linking process in that case takes place
between acrylamide and PVA which was confirmed by DSC. Also, increase the AAm content in
PVA/AAm hydrogels decreased the swelling capacity; therefore, the diffusion and liberation rate of
ketoprofen throughout the polymer matrix was decreased.
The mechanism of transporting the ketoprofen from PVA/AAm hydrogels was analyzed by the
Fick’s law (31).
The Fick’s law model is expressed as:
where n is the swelling exponent; k is the swelling rate front factor; and Wt and W∞ are the drug
release by the hydrogel at time t and the equilibrium time, respectively. A double-log plot of the
swelling ratio versus the time provides the value of n, which determines the nature of the solvent
diffusion process, that is, Fickian , non-Fickian diffusion kinetics or Super Case II models. When n ≤
0.5, the mechanism is Fickian type in which the sorption is diffusion controlled. When n ═ 1,
relaxation control occurs, leading to zero-order release. When the value of n is between 0.5 and 1, the
release follows non-Fickian diffusion, where the system will be diffusion and relaxation controlled. ln
F vs. ln t graphs are plotted for ketoprofen release from various compositions and shown in Figure (9).
Arab Journal of Nuclear Science and Applications, 47(1), (28-40) 2014
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The diffusion exponents (n) and diffusion constants (k) are calculated from the slopes and intercepts of
the lines, respectively, and listed in Table 2. The release of Ketoprofen at pH 7 showed the non-
Fickian mechanism for all investigated hydrogels which means the rate of diffusion of drug from the
polymer is comparable to rate of polymer chain relaxation. It can be said that, for higher swelling
values of the hydrogels, the transport of drug into the hydrogel matrix where the lower polymer
relaxation rate resulted in higher diffusion rate (32).
Time (min)
0 100 200 300 400 500 600 700
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
30/70
50/50
70/30
PVA /AAm
Dru
g r
ele
ase
(m
g/m
l)
Figure (8): Effect of time on the ketoprofen release from various compositions of PVA/AAm
hydrogel at pH 7 and initial concentration 100 mg/L
Figure (9): Swelling kinetic curve of PVA/AAm hydrogels as ln F versus ln t.
Arab Journal of Nuclear Science and Applications, 47(1), (28-40) 2014
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Table 1: Kinetic parameters of ketoprofen release at various compositions of PVA/AAm hydrogels
at pH 7
PVA/AAm (%) n k R2
30/70 0.75 0.2853 0.9825
50/50 0.72 0.4210 0.9770
70/30 0.76 0.4291 0.9862
6.3. Effect of Feed Concentration
The effect of initial drug concentration on the drug release was investigated and shown in
Figure (10). The increase in the initial drug concentration from 50 to 200 mg/L in the swelling
medium leads to increase the amount of release of drug. The reason for such result was attributed to
the specific bonding of positively charged drug with partially ionized groups of the hydrogel, and the
higher free volume available for diffusion.
Drug concentration (mg/ml)
0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2
Dru
g r
ele
ase
(m
g/m
l)
0.0
0.2
0.4
0.6
0.8
1.0
Figure (10): Effect of ketoprofen concentration on the release from PVA/AAm (70/30) hydrogel at
pH 7.
CONCLUSION
In this study, various compositions of PVA/AAm hydrogel of total concentration 20% was
prepared by gamma radiation at irradiation dose of 20 kGy. The thermal stability and swelling percent
of the prepared hydrogel decreased as the AAm content increased in the hydrogel. Both Tm and ΔHm
decreased as the percentage of AAm increased in the gel and the PVA/AAm hydrogel of composition
(70/30) possesses the highest thermal stability. The release of ketoprofen drug from the PVA/AAm
hydrogel was studied and showed that the release of ketoprofen increased as the PAAm content
Arab Journal of Nuclear Science and Applications, 47(1), (28-40) 2014
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decreased in the hydrogel. The release of ketoprofen followed a non-Fickian type and the acidic
medium is not suitable for releasing process of the drug. The increase in the initial drug concentration
leads to increase the amount of ketoprofen releasing. It is suggested that such prepared hydrogel is of
practical interest in the field of drug delivery system under control release as it possessed that pH
stimuli- responsive character.
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