ORI GIN AL PA PER

Chitosan/poly(vinyl alcohol) hydrogels for amoxicillinrelease

Aylin Altinisik • Kadir Yurdakoc

Received: 25 July 2013 / Revised: 13 October 2013 / Accepted: 15 December 2013 /

Published online: 25 December 2013

� Springer-Verlag Berlin Heidelberg 2013

Abstract Chitosan and poly(vinyl alcohol)-based hydrogel films were synthesized

using tartaric acid as a crosslinking agent. The films denoted as CVT were then

characterized using Fourier transform infrared, Nuclear magnetic resonance, X-ray

diffraction, and scanning electron microscopy analysis. TG/DTG and DSC analysis

were also carried out for the determination of thermal properties of hydrogel films.

Swelling properties of these hydrogel films were investigated at two different pHs

and temperatures. The swelling behaviors of all samples were increased in acidic

medium, while decreased in alkaline medium. The enzymatic degradation of the

hydrogels was studied using lysozyme, and degradation rates were found to be

parallel with the swelling ratio for CVT hydrogel. The hydrogels were also used for

the amoxicillin release in KCl/HCl and PBS buffer solutions. The release behaviors

of CVT hydrogel films were slower and can be controlled as compared with

commercial drug release systems. CVT hydrogel films may be more appropriate for

controlled release of amoxicillin.

Keywords Chitosan � Hydrogel � Biodegradation � Drug release �Amoxicillin

Introduction

In recent years, due to Helicobacter pylori infection, the number of patients from

peptic ulcer and gastric cancer has increased enormously. Helicobacter pylori are

spiral, gram-negative, microaerophilic rod-shaped bacteria with multiple flagella

[1]. Helicobacter pylori remains present on the luminal surface of the gastric

mucosa under mucous gel layer, is highly motile, and produces enzyme urease to

A. Altinisik � K. Yurdakoc (&)

Department of Chemistry, Faculty of Science, Dokuz Eylul University, Buca, 35160 Izmir, Turkey

e-mail: k.yurdakoc@deu.edu.tr

123

Polym. Bull. (2014) 71:759–774

DOI 10.1007/s00289-013-1090-1

change surrounding pH to protect itself from gastric acid [2]. Amoxicillin is an

efficient antibiotic drug for the treatment of Helicobacter pylori. The disadvantages

of conventional treatments could be due to poor permeability of the antibiotics

across the mucus layer or due to the availability of subtherapeutic antibiotic

concentrations at the site of infection after administration from conventional tablets

or capsules. Hydrogels found applications in formulating controlled and mucoad-

hesive drug delivery systems due to their hydrophilic and the network structure,

which helps to encapsulate and regulate the release of the drug. Polysaccharide

hydrogels have convenient feature such as biocompatibility, biodegradation,

mucoadhesivity, and ease of formulations mostly by ionotropic gelation method.

By controlling their degree of swelling and crosslinking, they can be useful as

potential carriers of drugs for controlled release applications [3]. Recently, several

authors have indicated that pH-sensitive swelling covalently and non-covalently

crosslinked hydrogels seem to be useful for localized antibiotic delivery in the

acidic environment of the gastric fluid. Amoxicillin mucoadhesive chitosan-based

microspheres [4] or carboxyl vinyl polymer [5, 6], and chitosan–poly(acrylic acid)

[7], poly(acrylic acid)–poly(vinyl pyrrolidone) complexes [8] have been synthe-

sized. Chitosan nanoparticles were recently obtained by crosslinking with polyeth-

ylene glycol dicarboxylic acid and tartaric acid by the water-in-oil microemulsion

method. The nanogels showed improved water solubility and pH-sensitive volume

transition [9]. Gels and film forms of chitosan were prepared with tartaric acid,

using crosslinkers 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, N-hydroxy-

succinimide as coupling agents, and release studies of vitamin B12 and blue

dextran were carried out [10]. One of the most important advantages of these

hydrogels is that they remain during more time than conventional ones on the

targeted area. The freeze-dried hydrogels for site-specific amoxicillin and metro-

nidazole delivery in the stomach were used [11, 12]. Several covalently crosslinked

chitosan-based hydrogels have been developed for site-specific therapy [13–16].

Chitosan possesses reactive functionalities represented by the amino groups, it is

easily degraded by enzymes, and the degradation products are not toxic. In our

previous work, synthesis, characterization, and enzymatic degradation of chitosan/

PEG hydrogel films were reported. It was found that the equilibrium, Seq and

maximum swelling, Smax at pH 7.4 for CP3T3 were 81 and 82 %, and 353 and

355 % at pH 1.2, respectively. The mass loss of CP3T3 reached at most 59 %, even

after 32 days in PBS without lysozyme; whereas in the presence of 1 mg/mL

lysozyme, the mass loss reached more than 73 % after 32 days. In the case of

CP10T3, the values were 10 and 81 % [17].

In this study, chitosan-based biodegradable, pH- and temperature-sensitive

hydrogel have been tried to synthesize using PVA instead of PEG and TA in the

similar way for using in drug release systems. The hydrogels were then

characterized by Fourier transform infrared analysis (FTIR), scanning electron

microscopy (SEM), X-ray diffraction (XRD) analysis, thermogravimetric analysis

(TGA), differential scanning calorimetry (DSC), and Nuclear magnetic resonance

(NMR). Swelling behaviors, pH and temperature sensitivities as well as biodegrad-

ability of hydrogels were also investigated.

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Experimental

Materials

Chitosan (highly viscous, viscosity; [400 mPa.s, 1 % in acetic acid at 20 �C,

degree of deacetylation 80 %, 48,165 Sigma) and poly(vinyl alcohol)

(Mn = 72,000, 97.5–99.5 mol% hydrolysis, 81,384 Sigma) were purchased from

Sigma-Aldrich. L(?) tartaric acid was obtained from Carlo Erba. All other

chemicals were analytical grade. Ultrapure water from Milli-Q water system was

used to prepare the aqueous solutions. Lysozyme from chicken egg white (50,000

U/mg) was purchased from Sigma-Aldrich and used without further purification.

Synthesis of CVT hydrogel films

1 g of chitosan flake was dissolved in 50 mL of 2 % (v/v) acetic acid in a beaker. It

was taken one night to dissolve completely, and the solution was filtered with

cheesecloth to remove undissolved chitosan. PVA was dissolved in 10 mL of

distilled water as 5 % w/v at 70 �C for 30 min.

Chitosan and PVA solutions were mixed together to prepare blend solution in a

beaker and stirred at room temperature for 30 min. Tartaric acid was dissolved in

distilled water, and the pH of the solution adjusted to 6.5 with 0.1-M NaOH solution

and then added to the reaction mixture. The mixture was stirred at room temperature

for 90 min and castled on Petri dish, which was dried at room temperature for

7 days. The amount of tartaric acid and chitosan remained constant, while the

amount of PVA was enlarged as 0.75, 1.25, and 2.50 g and the films named as

follows CV3T3, CV5T3 and CV10T3, respectively.

Characterization of hydrogel films

FTIR measurements

FTIR spectra of the films were recorded on the Perkin-Elmer FTIR spectropho-

tometer Spectrum BX-II recorded with ATR sampler with 25 scans at a resolution of

4 cm-1 in the range of 4,000–400 cm-1.

NMR analysis

13C and 1H NMR measurements were performed on Bruker DRX-300 and DRX-500

NMR spectrometers. Samples (5–20 mg) were dissolved in 1.5 mL of 20 % (w/w)

DCl/D2O at 80 �C.

SEM analysis

The surface morphologies of the films were studied at an accelerating voltage of

10 kV with dried and gold-coated samples. The SEM images were taken in the

range of 50–3,0009 magnifications using Jeol JSM 60 model SEM apparatus.

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123

XRD analysis

XRD patterns of the films were recorded with Philips X’Pert Pro X-Ray

diffractometer using Cu Ka radiation in the 2h range of 5�–60�.

Thermal analysis

TG/DTG was performed under nitrogen flow (2 cc/min) at a heating rate of 10 �C/

min from 30 to 500 �C with a Perkin-Elmer Diamond TG/DTA instrument. The

weights of the films varied from 2 to 3 mg.

Thermal properties of the hydrogel films were also characterized by a

differential scanning calorimeter (Perkin-Elmer Diamond DSC). The DSC

experiments were carried out according to the ASTM D3417. The outline of

measuring method, the sample is heated to a sufficient temperature (higher by

30 �C than the melting temperature) for depriving of heat history, in nitrogen

atmosphere as in TG/DTG. A specific temperature is held for 10 min. The sample

is then cooled to a temperature lowered by 50 �C than the crystallization peak at a

rate of 10 �C/min. As promptly as possible, the sample is heated to the same

temperature as determined in the first step. From the data in this process, the heat

of fusion is determined.

Enzymatic degradation

The in vitro degradation of the CVT hydrogel films were investigated in phosphate

buffered solution (PBS, pH 7.4) at 37 �C containing 1 mg/mL lysozyme according

to the procedure carried out before [17].

Swelling measurements

The water content of the films sample was determined according to the following

Equation:

S% ¼ ms � md

md

� 100 ð1Þ

where ms and md represent the masses of swollen and dried state samples,

respectively.

Release study

Drug-loaded samples (25 mg amoxicillin g-1 hydrogel) were also prepared using a

similar method for release experiments. The in vitro release of the entrapped drug,

amoxicillin, was carried out by placing the hydrogel film samples loaded with the

drug into a 10 mL of solution with pH 1.2 and 7.4 at 37 �C in water bath. At

periodic intervals, 0.5 mL of solution containing drug was withdrawn and tested at

kmax = 395 nm using Shimadzu 160A model UV–Vis spectrophotometer by

oxidation process with N-bromosuccinimide (NBS) [18]. The amount of released

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amoxicillin was calculated from the calibration curve. The experiments were also

carried out for solution with pH 7.4 (in PBS) at 37 �C.

Result and discussion

Fourier transform infrared (FTIR) spectra of the CVT hydrogel films

The FTIR spectra relative to the chitosan (CS) and CVT hydrogel films are shown in

Fig. 1. Chitosan shows bands around 893 and 1,156 cm-1 corresponding to

saccharide structure [19]. In spite of the several bands clustering in the amide II

band range from 1,510 to 1,570 cm-1, there were still strong absorption bands at

1,637 and 1,547 cm-1, which are characteristic of chitosan and have been reported

as amide I and II bands, respectively.

The sharp bands at 1,383 and 1,424 cm-1 were assigned to the CH3 symmetrical

deformation mode. The broadband at 1,030 and 1,080 cm-1 indicates the C–O

stretching vibration in chitosan. Another broadband at 3,433 cm-1 is caused by

amine N–H symmetrical vibration, which is used with 1,637 cm-1 for quantitative

analysis of deacetylation of chitosan. The bands at 2,866 and 2,900 cm-1 are the

typical C–H stretch vibrations [19–25].

In the spectrum of CVT, the characteristic band of C=O vibrations of amide

groups is seen at about 1,660 cm-1 which is the presence of the crosslinked between

chitosan and tartaric acid. On the other hand, the characteristic band of carboxylic

acid was not appeared.

Fig. 1 FTIR spectra of chitosan and CVT hydrogel

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The broadband observed between 3,550 and 3,200 cm-1 is associated with the

stretching O–H from the intermolecular and intramolecular hydrogen bonds. The

vibration band between 2,840 and 3,000 cm-1 refers to the stretching C–H from

alkyl groups, and the bands between 1,750 and 1,735 cm-1 are due to the stretching

C=O and C–O from acetate group remaining from PVA [26–29].

The bands at 1,110, 1,430, 1,637, and 1,660 cm-1 are mainly associated with

PVA.

NMR analysis of CVT hydrogel film

In the NMR spectra of CVT, the peaks of the vinyl groups of PVA [30] at 5.8 and

6.3 ppm do not appear in CVT spectrum. Disappearances of these peaks showed the

interaction between amino groups of chitosan and vinyl groups of PVA. The new

peaks at 2 and 2.8 ppm indicated an interaction with TA and PVA. In the 13C NMR,

the peaks at 40, 70, and 170 ppm were observed which indicate the interaction with

PVA and TA.

SEM analysis of CVT hydrogel films

SEM images of the films are shown in Fig. 2. SEM images indicated that CVT

surface morphology was changed as CS [17]. There are very small spheres in CS

film surface, but after crosslinking reaction spheres had become thinner fibers. In

addition, these fibrous structures may be an indication of the interaction between

PVA and CS. On the other hand, crystal structure of CVT hydrogel increased with

crosslinking compared to CS hydrogel. This result was also supported by XRD

analysis.

XRD analysis of CVT hydrogel films

The XRD patterns of chitosan and CVT hydrogel film were shown in Figs. 3 and 4.

The XRD patterns of all types of chitosan show crystalline peak approximately at

2h = 20� [31]. The results showed that chitosan, crosslinked chitosan films and

PVA were given similar XRD patterns with a characteristic broad peak at around

2h = 20.3�. However, the crosslinked chitosan showed higher and sharper

crystalline peaks as compared to those with non-crosslinked chitosan, which meant

that the crystalline structure of chitosan was changed after crosslinking. The

crystallinity of chitosan hydrogel film increased with crosslinking reaction in CVT

hydrogel film. As a consequence, there seems to be an obvious correlation between

the crosslinking and the rise in crystallinity due to recrystallization of CVT hydrogel

film. The crystallinity (CrI) was determined as in the method using the equation

CrI ¼ I110 � Iam=I110 where I110 is the maximum intensity (2h = 20�) of the (110)

lattice diffraction, and Iam is the intensity of amorphous diffraction at 2h = 16�[32]. According to the crystallinity results, the observed increase in CrI was in good

agreement with the fact that of crosslinking reaction. The CrI of CVT and chitosan

is as 62.5 and 45.4 %, respectively.

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Thermal analysis of CVT hydrogel films

TG/DTG results were given in Table 1. The temperature of degradation (Td) of

chitosan film was 249 �C. CVT films have two extra stages of mass losses, which

were due to the degradation of the samples. The second stage mass loss of CVT was

observed at the temperature range of 297 �C and third stage was completely

degraded at 426 �C, which might be attributed to the effect of PVA and TA onto

hydrogel.

It has been observed in the DSC profiles of chitosan that it did not melt or

degrade between 20 and 200 �C, as shown in the literature [33]. However, in this

study, as shown in Table 2, a broad endothermic peak centered at the temperatures

between 76 and 90 �C was observed for the DSC curves of the chitosan film and

Fig. 2 SEM images of CVT hydrogel

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CVT samples. These may be attributed to the melting of the CS and the CVT

hydrogel films, respectively. Enthalpy of fusion (DH) values was calculated from

the area under the endothermic peak caused by the melting of the CS and the CVT

hydrogel films.

Fig. 3 X-ray diffraction patterns of chitosan and CVT Hydrogel films

Fig. 4 Enzymatic degradation of CVT hydrogel films in 1 mg/mL lysozyme/PBS, and in PBS withoutlysozyme at 37 �C as a function of time

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Enzymatic degradation of CVT hydrogel films

The degradation reaction is catalyzed by lysozyme and its mechanism was

explained [34–36]. Lysozyme biodegrades the polysaccharide by hydrolyzing the

glycosidic bonds present in the chemical structure. The degradation behaviors of the

films in the presence and in the absence of lysozyme were investigated in PBS at

37 �C (Fig. 4). The mass loss of CVT reached at most 5 % even after 32 days in

PBS without lysozyme, while in the presence of 1 mg/mL lysozyme, the mass loss

reached more than 34 % after 32 days. Similarly, the mass loss of chitosan at most

7 % even after 32 days in PBS without lysozyme, while in the presence of 1 mg/mL

lysozyme, the mass loss was more than 68 % after 32 days and it was proportional

to the degradation time.

Swelling experiments

Dynamic swelling studies were performed to investigate the time-dependent

swelling behavior of CVT films in solutions with different pHs. The swelling S %

was calculated from Eq. 2.

The water absorbency of hydrogel films in solutions with pH 1.2 and pH 7.4 at

37 �C was shown in Table 3. The degree of equilibrium swelling of CVT hydrogels

was decreased with increasing PVA content due to the high hydrophobicity of PVA.

Swelling of hydrogels was dependent on the pH of medium because of –NH2 groups

in chitosan.

The swelling kinetics of hydrogels was determined by the following equation

[37].

t

S¼ Aþ Bt ð2Þ

where S is the degree of swelling at time t, B ¼ 1Smax

is the inverse of the maximum

swelling, A ¼ 1dS=dtð Þ0

¼ 1S2

maxksis the reciprocal of the initial swelling rate (ro) the gel.

Table 1 Results of thermogravimetric analysis in nitrogen flow

Sample First stage Second stage Third stage

T (�C) Mass loss % T (�C) Mass loss % T (�C) Mass loss %

Chitosan 55 13 249 43 – –

CVT 34 11 297 47 426 15

Table 2 Melting point, enthalpy of fusion and decomposition temperature of CVT

Melting point T (�C) Enthalpy of fusion (J/g) Decomposition temperature (�C)

CS 76 22.5 211

CVT 90 25.9 259

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The values of the initial swelling rate, ro [g solution (g hydrogel)-1 s-1] and

maximum swelling, Smax [g solution (g hydrogel)-1] were calculated from the slope

and intersection of the lines and swelling rate constant, ks [g Hydrogel (g solution)-1

s-1] are presented in Table 3 for CVT hydrogels. According to the results, it may be

said that swelling process is conformed to the second-order kinetic model. As shown

in Table 3, increase of ro with the increase of PVA content is due to the decrease in

the swelling ratio.

pH sensitivity of hydrogels

Figure 5a represented the variation of the equilibrium-swelling ratio of hydrogel as

a function of the pH of the swelling medium (pH 2–8, I = 0.01) at 37 �C.

Maximum swelling was observed at pH 2. It can be seen that the hydrogels

swelled mostly in acidic medium compared to the neutral or basic medium and

explained on the basis of protonation of the amino groups of chitosan. In the case of

CVT, hydrogels exhibited a reversible pattern with a faster response in swelling

than in deswelling as shown in Fig. 5b. The response times were determined as 12

and 20 min in acidic and basic area, respectively.

Temperature sensitivity of hydrogels

Temperature-dependent reversible swelling behaviors of CVT were found, as shown

in Fig. 5c. At the first run, the equilibrium-swelling ratio was measured at 37 �C. Then,

the equilibrium-swelling experiment was done at 37 �C from 4 �C for the same film

sample. The equilibrium-swelling ratio increased with decreasing the temperature to

4 �C. When the temperature was raised to 37 �C again (3rd run), the equilibrium-

swelling ratio increased to the level of the first run at 37 �C. These heating/cooling runs

were repeated two times. The similar reversible and reproducible temperature

dependence of swelling–deswelling behavior was observed for all samples.

Thus, all hydrogel samples have almost the same temperature dependency, higher

swelling ratio was observed at higher temperature and lower swelling ratio was

observed at lower temperature.

Table 3 Swelling parameters of CVT at pH 1.2 and 7.4

Seq

(%)

Smax

(%)

ks 9 104 [g CVT

(g solution)-1 s-1]

ro [g solution

(g CVT)-1 s-1]

pH 7.4

CV3T3 250 277 2.8 0.046

CV5T3 230 258 2.6 0.057

CV10T3 149 177 2.5 0.130

pH 1.2

CV3T3 1,200 1,452 0.25 0.019

CV5T3 903 1,080 0.36 0.023

CV10T3 355 452 0.61 0.080

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As reported for chitosan–polyvinyl pyrrolidone hydrogels [38], the release was

around 80 % in 180 min. In our work, the release for CV10T3 hydrogel is 70 %. In

an another work [39], the release experiments were done at pH 2.1 for poly[N-

acryloylglycine-chitosan] interpolymeric pH and thermally responsive hydrogels

and release rate was found around 70 % in 180 min. It was also found that the

release was not as low as in the case of CV10T3, which was 7 %. The pH sensitivity

of our gel was greater than the works reported in the literature.

The sample with higher PVA content was more sensitive to the temperature

changes, showing more distinctive temperature-dependent swelling–deswelling

response. It would be a desirable character for controlled-drug release system with

swelling property controllable by pH and temperature.

Release studies

Amoxicillin was selected as our model drug; HCl/KCl solution and Na2HPO4–

KH2PO4 (pH 7.4) solution were used as modulated media. The percent cumulative

release of amoxicillin from hydrogels to solutions was calculated by:

Fig. 5 a pH-dependent swelling behavior of hydrogel (hydrogel sample equilibrated at pH 2.3, thenalternated between solutions at pH 8 and 2), b pH-dependent reversible swelling behavior of hydrogel(hydrogel sample equilibrated at pH 2.3, then alternated between solutions at pH 8 and 2), c swelling anddeswelling behavior of CVT hydrogel as a function of time at different temperatures in buffer at pH 7.4

Polym. Bull. (2014) 71:759–774 769

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%R ¼ Ct

Co

� 100 ð3Þ

where Ct and Co are the amount of drug released at time t and initial amount of

amoxicillin in the hydrogels, respectively. To investigate the parameters of release

kinetics, Eq. (4) was used and the plot of t/Ct versus t was presented in Table 4.

t

Ct

¼ aþ bt ð4Þ

Here, Ct is the amount of drug released at time t, b = 1/Cmax is the inverse of the

maximum amount of released drug, a = 1/Cmax2 krel = 1/ro is the inverse of the

initial release rate, and krel is the constant of the kinetic of release. Figure 6a and b

depicts the percent cumulative release of amoxicillin from CVT hydrogels at pH 1.2

and pH 7.4, respectively, at 37 �C.

Figure 6a and b shows that drug release is pH dependent. The percentage

cumulative release of amoxicillin from CVT hydrogels was higher in acidic medium

than in the basic medium. On the other hand, change in the amount of PVA was

affected on release rate. Amoxicillin release rate was decreased with increasing

amount of PVA. As shown in Table 4, it was observed that release results are very

similar to swelling results. This parallel behavior is reasonable, since drug release

from CVT hydrogels into solution is swelling controlled.

Diffusion study

The following equation is used to determine the nature of diffusion of buffer

solutions into hydrogels:

Ce

Co

¼ F ¼ ktn ð5Þ

where F is the fractional uptake at time t, k is a constant related with the macro-

molecular network system and the penetrant, and n is the diffusional exponent,

which is indicative of the transport mechanism.

For the CVT hydrogels, ln F versus ln t graphs were plotted, n exponents and

k parameters were calculated from the slopes and intercepts of the lines,

Table 4 Release kinetics parameters and diffusion parameters of CVT hydrogels in solutions with

different pH

Cmax (mg) k(rel) (s-n) ro (mg s-1) k (mg/min) n R2

pH 1.2

CV3T3 25 4 9 10-3 2.9 n.d. n.d. n.d.

CV5T3 25.5 2.4 9 10-3 1.5 n.d. n.d. n.d.

CV10T3 23.4 1.01 9 10-3 0.56 0.107 0.38 0.990

pH 7.4

CV3T3 13.9 1.96 9 10-3 0.30 2.9 9 10-3 1.25 0.997

CV5T3 13.8 1.36 9 10-3 0.26 0.9 9 10-3 1.50 0.993

CV10T3 5.5 1.18 9 10-3 0.04 0.12 9 10-3 1.62 0.981

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respectively, and were listed in Table 4 which showed that only CV10T3 hydrogel

presented a non-Fickian release with n values 0.38, but other release pattern was not

determined in acidic medium.

Conclusions

A novel biodegradable TA crosslinked PVA–chitosan hydrogel films were

synthesized and characterized in this study. As can be seen from the FTIR spectra

Fig. 6 Effect of different ratio of PVA on the in vitro release rate (%) of amoxicillin at a pH 1.2 andb pH 7.4

Polym. Bull. (2014) 71:759–774 771

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that the formation of the crosslinked structure was confirmed by comparing the

absorption bands of amide I and amide II for all samples. In the NMR spectra of

CVT, the -CHNH2 peak was disappeared, the peak of -NHCOR was formed. In

addition, the –R-NHR which was indicated that crosslinked TA. SEM analysis has

been seen that after the crosslinking reaction, sphere had become thinner fibers. The

crystallinity might be increased with crosslinking as chitosan hydrogel. XRD results

were showed an increase at crystalline structure, which were also supported in SEM

analysis. By measuring the melting point temperature by DSC, the internal three-

dimensional structure of crosslinked chitosan hydrogel film turned out to become

dense by the adding PVA. The thermal stabilities of the crosslinked chitosan

samples were higher than chitosan film sample. There were differences between

enzymatic degradation of CVT and CS hydrogels because of the different crystal

form. However, in that CVT hydrogel films were broken down more slowly

according to the chitosan film. Swelling properties of hydrogels were dependent on

pH and amount of crosslinker. The swelling ratio increased with the decrease of pH

value of the surrounding buffer solution. On the other hand, these values were tree-

fold higher than PEG-based films as compared with our previous work. All films

also showed similar reversible temperature-dependent swelling behavior and the

high swelling ratio at high temperatures. The swelling rate would be controllable by

changing the content of PVA. In addition, reversible swelling properties were

demonstrated that these hydrogels might be pH-sensitive system. The hydrogels of

lower content of crosslinker showed the highest degree of swelling and release rate.

The release behavior of amoxicillin from the hydrogel was very sensitive with the

pH of medium. It has been also determined that release of amoxicillin was very high

at pH 1.2.

Acknowledgments The authors thank Prof. Dr. Peter Claus and Dr. R. Meusinger, Darmstadt Technical

University, Germany for their help and NMR measurements.

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