2014

http://informahealthcare.com/drdISSN: 1071-7544 (print), 1521-0464 (electronic)

Drug Deliv, 2014; 21(3): 213–220! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10717544.2013.844743

ORIGINAL ARTICLE

Preparation of ferric ion crosslinked acrylamide grafted poly(vinyl alcohol)/sodium alginate microspheres and applicationin controlled release of anticancer drug 5-fluorouracil

Oya Sanlı and Merve Olukman

Department of Chemistry, Faculty of Science, Gazi University, Teknikokullar, Ankara, Turkey

Abstract

Ionically crosslinked microspheres of acrylamide (AAm) grafted poly (vinyl alcohol) (PVA)/sodium alginate (NaAlg) were prepared by crosslinking with FeCl3 and 5-fluorouracil (5-FU),which is an anticancer drug and was successfully encapsulated into the microspheres. The graftcopolymer (PVA-g-PAAm) was characterized by using Fourier transform infrared spectroscopy(FTIR) and elemental analysis. The prepared microspheres were characterized by FTIR andscanning electron microscopy (SEM). Microspheres were also characterized by particle diameter,equilibrium swelling values and release profiles. The release studies were carried out at threepH values 1.2, 6.8 and 7.4, respectively, each for 2 h. The effects of preparation conditions asPVA-g-PAAm/NaAlg ratio, drug/polymer ratio, crosslinker concentration and exposure time toFeCl3 on the release of 5-FU were investigated for 6 h at 37 �C. The highest 5-FU release wasfound to be as 99.57% (w/w) at the end of 6 h for PVA-g-PAAm/NaAlg ratio of 1:4 (w/w), drug/polymer ratio of 1:8 (w/w), crosslinker concentration of 0.05 M and exposure time of 10 min. Therelease results were also supported by the swelling measurements of the microspheres. Releasekinetics was described by Fickian and non-Fickian approaches.

Keywords

5-fluorouracil, anticancer drug, drug deliverysystems, graft copolymer, interpenetratingpolymer networks

History

Received 20 May 2013Revised 11 September 2013Accepted 11 September 2013

Introduction

Recently, polysaccharide microspheres have got much atten-

tion because of their low toxicity, good biocompatibility and

biodegradability, which are of interest for application in

biomedical and pharmaceutical industry (Dai et al., 2012).

Natural polymers like sodium alginate (NaAlg) (Sanlı &

Solak, 2009), chitosan (Al-Kahtani Ahmed et al., 2009) and

methyl cellulose (Rokhade et al., 2007) have been preferred

because of their biocompatibility and biodegradability.

However, there are some synthetic polymers that exhibit

biocompatibility under the physiological conditions used in

controlled release studies (Babu et al., 2008). For this

purpose, in this study, acrylamide was grafted onto poly

(vinyl alcohol) (PVA) and blended with NaAlg to prepare

semi-IPN microspheres.

5-Fluorouracil (5-FU) is one of the oldest chemotherapeu-

tic drugs in use. It is commonly used against many cancers

such as, colon, stomach, breast and pancreatic cancers.

It is a fluorinated analog of pyrmidine base uracil, which

is metabolized intracellulary to its active form, fluorodeox-

yuridine monophophate (FdUMP). The active form inhibits

DNA synthesis by inhibiting the normal production of

thymidine (Gupte & Ciftci, 2004).

The delivery of chemotherapeutic agents using polymeric

microspheres has become one of the most popular areas of

research because of the possibilities of reducing toxicities,

enhancing controlled release activity and also localizing the

drug delivery. For this purpose, attempts have been focused

on the development of drug delivery systems containing

antineoplastic drugs. Huang et al. (2009) studied in vitro

release of 5-FU from genipin-gelatin microcapsules. They

reported that uniform genipin-gelatin microcapsules would

provide many potential usages for pharmaceutical applica-

tions. Sastre et al. (2007) prepared microspheres of 5-FU-

loaded poly(D, L-lactide), poly(D, L-lactide-co-glycolide)

75:25 and poly(D, L-lactide-co-glycolide) 50:50 by the spray-

drying technique and subcutaneously injected in the back of

Wistar rats in order to evaluate the 5-FU release and

biodegradation characteristics. Huang et al. (2010) prepared

chitosan/chondroitin sulfate complex microcapsules to encap-

sulate the 5-FU by emulsion-chemical crosslinking method.

They reported that the release performance of the microcap-

sules could be controlled by the degree of crosslinking, drug

loading and pH of the release medium. Reddy et al. (2008)

synthesized semi-IPN microspheres of glutaraldehyde cross-

linked NaAlg and N-isopropylacrylamide, loaded with 5-FU.

Drug release from the microspheres at 25 and 37 �Cconfirmed the thermosensitive nature in vitro dissolution.

Address for correspondence: Oya Sanlı, Department of Chemistry,Faculty of Science, Gazi University, Teknikokullar 06500, Ankara,Turkey. Tel: +90 3122021107; Fax: +90 312 2122279. Email:osanli@gazi.edu.tr

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Ganguly et al. (2011) studied the release of 5-FU to the colon.

The coated microspheres were found to be more suitable for

colon targeting than the uncoated formulations. Blend

microspheres of poly(3-hydroxybutyrate) and cellulose acet-

ate phthalate was prepared by Chaturvedi et al. (2011) for the

colon delivery of 5-FU.

A few studies have examined drug release from Fe3þ

crosslinked beads, microspheres and nanospheres (Mi et al.,

1997; Sungur, 1999; Aiedeh & Taha, 2001). Mi et al. (1997)

Prepared iron (III)-carboxymethylchitin microspheres for

sustained release of 6-mercaptopurine, which is an anticancer

agent. They reported that carboxmethylchitin might prove

useful as a polymer carrier for the sustained release of

anticancer drugs in various dissolution media. Sungur (1999)

studied the crosslinking carboxymethylcellulose with ferric

ions for the controlled release of erythromycin. Aiedeh &

Taha (2001) prepared chitosan succinate and hydroxyamated

chitosan succinate, and used this semisynthetic polymer in the

preparation of theophylline iron (III) crosslinked polymeric

beads. They reported that the generated beads proved to be

successful in prolonging drug release. Kim et al. (2012)

prepared alginate-carboxymethylcellulose beads with Fe3þ

ions and studied controlled release of protein therapeutics.

In this study, we have first synthesized PVA-g-PAAm and

than blended with NaAlg to produce the semi-IPN micro-

spheres by crosslinking with FeCl3. The microspheres formed

have been characterized by variety of techniques to under-

stand their drug release and morphological characteristics as

well as chemical interactions. Particle size, microspheres’

yield, entrapment efficiency and equilibrium swelling degree

of the microspheres were determined and 5-FU release rates

were investigated at pH values of 1.2, 6.8 and 7.4. The effects

of PVA-g-PAAm/NaAlg ratio, exposure time, crosslinker

concentration, pH and drug/polymer ratio on 5-FU release

were researched and discussed to optimize the release of 5-FU

from the microspheres.

Experimental

Materials

NaAlg (medium viscosity) was purchased from Sigma

Chemical Co. (St. Louis, MO). 5-FU was provided by

Sigma-Aldrich (Steinem, Germany). Na2HPO4, NaH2PO4,

hydroquinone, DMSO, acetone, benzophenone, FeCl3, PVA

and AAm (microspheres of acrylamide) were all supplied

from Merck (Darmstadt, Germany) and used as received. The

molecular weight and degree of saponification of PVA were

72.000 and498%, respectively.

Synthesis of the graft copolymer of PVA with AAm

The graft copolymer of PVA and acrylamide was prepared by

using ultraviolet (UV) radiation. Briefly, 10 g of PVA was

dissolved in 100 mL of water at 60 �C and then AAm (6 M)

solution was added to this solution and mixed for 30 min.

After that, benzophenone as a photoinitiator (0.1%, w/w) was

added to this solution and polymerization was carried out

under a slow stream of nitrogen gas for 6 h with constant

stirring. The polymerization was terminated by adding

saturated hydroquinone solution. Then, the resultant solution

was added into excess amount of acetone to precipitate the

polymer. The polymer was dried at 40 �C till constant weight.

The graft percentage was found as 18% by using elemental

analysis results which is presented in Table 1.

Preparation of the 5-FU-loaded microspheres

Briefly, NaAlg (2%, w/v) and PVA-g-PAAm (8%, w/v) were

dissolved in distilled water by heating. Polymer solution

containing 5-FU in various drug/polymer ratios was added

dropwise into FeCl3 solution (0.05, 0.1 and 0.2 M) with a

peristaltic pump (Masterflex, L/S Digital Economy Drive,

Canada and USA). The formed microspheres were removed

from crosslinking solution at 5, 10 and 15 min and washed

with water. The microspheres were then dried completely in

an oven at 40 �C. The microsphere preparation conditions are

presented in Table 2. A shematic presentation of synthesis of

semi-IPN is given Figure 1.

Swelling experiments

Equilibrium water uptake by the microspheres was deter-

mined by measuring the extent of the swelling of the matrix in

pH 1.2, 6.8 and 7.4. To ensure complete equilibration,

samples were allowed to swell for 24 h. Excess surface-

adhered liquid drops were removed by blotting. The swollen

microspheres were weighted using electronic balance (Precise

XB 220 A, USA). The microspheres were then dried in an

oven at 40 �C, until there was no change in the dried mass of

the samples. The percent equilibrium swelling degree was

calculated as follows:

Equilibrium swelling degree %ð ÞMs �Md

Md

� 100 ð1Þ

Where Ms and Md were the mass of the swollen

microspheres and dry microspheres, respectively.

Determination of 5-FU content of the microspheres

The known mass of microspheres was crushed in an agate

mortar with a pestle and then the polymeric powder was taken

in a flask. Water (50 mL) was added and refluxed at 25 �C for

1 h, to ensure the complete extraction of 5-FU from the

microspheres. At the end of 1 h, precipitated NaAlg was

filtered and 5-FU was analyzed by using a UV spectropho-

tometer (Unico 4802 UV/VIS, UK) at a wavelength of 266 nm

using a calibration curve and water as a blank. Percentage of

entrapment efficiency was then calculated as follows:

Entrapment efficiency ð%Þ¼ Actual 5� FU loading

Theoretical 5� FU loading

� 100

ð2Þ

Table 1. The elemental analysis results.

Polymer N (%) C (%) H (%) Grafting percentage

AAm-g-PVA 3 (52) 51 (15) 7 (94) 18

214 O. Sanlı & M. Olukman Drug Deliv, 2014; 21(3): 213–220

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Fourier transform infrared measurements

Infrared spectra of PVA and PVA-g-PAAm, 5-FU and 5-FU-

loaded microspheres were taken with Fourier transform

infrared (FTIR) spectrometer of Unicam co., Mattson 1000

(UK) and presented in Figures 2 and 3.

Scanning electron microscopy

Scanning electron microscopy (SEM) photographs were taken

with QUANTA 400 F Field Emission SEM (USA) and shown

in Figure 4.

In vitro drug release

In vitro drug release from the semi-IPN microspheres was

studied in 250 mL, pH 1.2 HCl solution, pH 6.8 and pH 7.4

phosphate buffer solutions and incubated in a shaking water

bath (Medline BS-21, Korea) at 37 �C. At 2-h intervals,

medium was changed to: 1.2, 6.8 and 7.4 pH, respectively. At

specific time intervals, the 5-FU content was determined

using UV spectrophotometer at 266 nm. Equal volume of

fresh HCl or phosphate buffer solution was added into the

dissolution media to maintain a constant volume. All

experiments were performed in triplicate to minimize the

variational error. Standard deviations from the average values

were calculated.

Results and discussion

Characterization of the graft copolymer ofPVA-g-PAAm

Grafting of AAm onto PVA was achieved in the presence of

UV irradiation. FTIR spectra of PVA and grafted PVA are

shown in Figure 2. In case of PVA, a broad band at 3368/cm

was seen due to O–H stretching vibrations. Aliphatic C–H

stretching vibration was indicated at 2921/cm. Similar C–H

stretching could be seen in the grafted copolymer spectra at

2895/cm. The peak due to asymmetric N–H stretching

vibration of primary amide overlapped with O–H stretching

vibrations. A band at 1632/cm confirms the presence of

C¼O stretching vibration, which was not observed in PVA.

Grafting was also confirmed by the presence of band at

1579/cm corresponding to asymmetric N–H bending. The

elemental analysis results and percentage grafting are given

in Table 1 for characterization purposes. Presence of nitrogen

in the results also confirms the grafting of AAm onto PVA.

Characterization of the microspheres

FTIR spectra of the 5-FU and 5-FU-loaded semi-IPN

microspheres are shown Figure 3. A broad band between

3000/cm and 3500/cm is attributed to –NH stretching

vibrations in the spectrum of 5-FU, aliphatic C–H stretching

band was observed at 2932/cm both in 5-FU and in the

microspheres. Bands at 1660/cm and 1654/cm showed C¼O

stretching vibrations, respectively, due to 5-FU and 5-FU-

loaded semi-IPN microspheres. The other peak observed at

3422/cm indicated O–H stretching vibration of the semi-IPN

microspheres. In addition, a peak at 1251/cm which repre-

sents C–F stretching vibrations was seen in both 5-FU and

5-FU-loaded semi-IPN microspheres, proving the presence of

5-FU in the microspheres.

Shapes of dried empty and 5-FU-loaded microspheres are

presented in Figure 4. As it is reflected from the figure, both

empty and 5-FU-loaded microspheres almost maintain spher-

ical form at empty and drug-loaded conditions.

The results of entrapment efficiency (%), microsphere

yield (%) and microsphere diameter are shown in Table 2.

Table 2. Preparation conditions of the 5-FU-loaded PVA-g-AAm/NaAlg semi-IPN microspheres.

Formulationcode

Drug/polymerratio (w/w)

PVA-g-AAm/NaAlgratio (w/w)

Concentration ofcrosslinkingagent (M)

Exposure time tocrosslinkingagent (Min)

Entrapmentefficiency (%)

Microsphereyield (%)

Microspherediameter (mm)

A1 1:8 1:4 0.05 10 20.17 71.2 0.75� 0.01A2 1:8 1:3 0.05 10 13.65 62.36 0.67� 0.003A3 1:8 1:2 0.05 10 39.6 61.91 1.08� 0.007A4 1:8 1:1 0.05 10 30.17 47.4 0.71� 0.002A1.1 1:8 1:4 0.2 10 17.56 80.69 0.79� 0.04A1.2 1:8 1:4 0.1 10 13.25 78.85 0.78� 0.005A1.3 1:8 1:4 0.05 15 28.63 77.04 1.17� 0.04A1.4 1:8 1:4 0.05 20 7.72 71.42 1.20� 0.04A1.5 1:4 1:4 0.05 10 32.2 60.69 1.12� 0.01A1.6 1:2 1:4 0.05 10 52.60 58.94 1.20� 0.02A1.7 1:1 1:4 0.05 10 53.68 55.15 1.28� 0.01A1.0 1:4 0.05 10A2.0 1:3 0.05 10A3.0 1:2 0.05 10A4.0 1:1 0.05 10

Figure 1. Schematic representation of synthesis of semi-IPN.

DOI: 10.3109/10717544.2013.844743 AAm grafted PVA/sodium alginate microspheres 215

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As can be seen from the table, the microspheres formed have

particle sizes ranging from 0.67� 0.003 to 1.28� 0.01 mm in

diameter. The diameter of the microspheres increased as the

amount of NaAlg in the microspheres was increased, whereas

it did not change significantly with the increase in crosslinker

concentration. Entrapment efficiency percentage increased as

the drug content of the microspheres increased. Highest

entrapment efficiency obtained was 54% for the drug/polymer

ratio of 1:1, PVA-g-PAAm/NaAlg ratio of 1:4. Microsphere

yield increased as the crosslinker concentration was increased

and the highest microsphere yield obtained was �81%.

Effect of PVA-g-PAAm/NaAlg ratio on the 5-FU release

To understand the drug release from 5-FU-loaded semi-IPN

microspheres of NaAlg and PVA-g-PAAm, in vitro release

experiments were performed at pH values of 1.2, 6.8 and 7.4

each for 2 h. Effects of PVA-g-PAAm/NaAlg ratio in the

formulations A1, A2, A3 and A4 on the release rates are

presented in Figure 5. The percent cumulative release was

found to be higher in case of A1 than A2, A3 and A4. As the

NaAlg content of the microspheres increased, release became

more controlled at low pH values. Due to the high and more

controlled release of 5-FU from the microspheres with a PVA-

g-PAAm/NaAlg ratio of 1:4, this ratio was preferred in the

rest of the study.

Swelling results of the crosslinked microspheres shown in

Table 3 indicated that as the amount of grafted copolymer in

the microspheres decreased, the equilibrium water uptake

increased from 530.8% to 1093.2%.

Effect of concentration of FeCl3 on the 5-FU release

The percentage cumulative release versus time curves for

varying amounts of FeCl3 (0.05, 0.1 and 0.2 M) at fixed

amount of PVA-g-PAAm/NaAlg ratio are displayed in

Figure 6. The percentage cumulative release was quite fast

and high at low concentration of FeCl3 (i.e. 0.05 M),

whereas the release becomes quite slow on increasing the

concentration of FeCl3 (i.e. 0.2 M). At high concentrations

of FeCl3, polymeric chains become more rigid due to the

contraction of microvoids, thus decreasing the release of 5-

FU through polymeric matrices. Similar observations were

also found in the literature (Nokhodchi & Tailor, 2004; Sanlı

& Is� ıklan, 2006; Sanlı et al., 2007;). Sanlı et al. (2007) have

changed glutaraldehyde (GA) concentration from 1% to

2.5% during the bead preparation and reported that as the

GA concentration was increased from 1% to 2.5%,

diclofenac sodium release decreased from PVA/NaAlg

beads at pHs of 6.8 and 7.4. Nokhodchi & Tailor (2004)

have prepared theophylline-loaded NaAlg matrices.

Increasing the amount of AlCl3 from 1� 10�4 to

Figure 2. FTIR spectra of (a) PVA and (b) PVA-g-AAm.

216 O. Sanlı & M. Olukman Drug Deliv, 2014; 21(3): 213–220

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6.8� 10�4 moles, the release of theophylline decreased from

95.1% to 29.5%. As the high release was obtained at FeCl3concentration of 0.05 M, we have continued the studies with

this concentration.

Effect of the exposure time to crosslinker on the 5-FUrelease

5-FU release from the microspheres was subjected to a

number of physical and chemical parameters including those

Figure 3. FTIR spectra of (a) 5-FU and (b) 5-FU-loaded semi-IPN microspheres.

Figure 4. Microscopic pictures of (a) empty (b) 5-FU-loaded microspheres.

DOI: 10.3109/10717544.2013.844743 AAm grafted PVA/sodium alginate microspheres 217

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related directly to the release medium, the release conditions

(temperature, pH), preparation conditions and those resulting

from the change in the characteristics of the microspheres

(Sanlı et al., 2007). One of the ways of changing drug release

from the microspheres is to change the crosslinking density

of the matrix by employing various time of exposure

to crosslinking agent. The effect of exposure time on the

release rate of 5-FU has been investigated by varying

exposure time from 10 to 20 min. The maximum 5-FU

release was obtained as 99.57% for the microspheres prepared

with exposure time of 10 min. In the rest of study, exposure

time was selected as 10 min due to the high release at this

exposure time. Similar observations were found in some of

the studies in previous literature (Yuan et al., 2007; Sanlı &

Solak, 2009). Yuan and co-workers (Yuan et al., 2007)

prepared protein-loaded chitosan microspheres crosslinking

with genipin. They reported that under the same genipin

concentration (0.5 mM), the crosslinking degree increased

with increasing crosslinking time. The crosslinking degree

increased significantly as the crosslinking time changed from

4 to 16 h (Figure 7).

Effect of the drug/polymer ratio on the 5-FU release

Figure 8 shows the release profiles of the microspheres at

different amounts of drug loadings. Release data showed that

5-FU release from the microspheres with 1:8 drug:polymer

ratio was much higher than that of microspheres 1:4, 1:2 and

1:1 drug:polymer ratio. As the amount of drug increased from

1:8 to 1:1, 5-FU content of the microspheres increases. Low

drug content could lead to the easier penetration of solution

through microspheres and drug diffusion could be fast from

the microspheres. Similar results were obtained in the

literature (Zinutti et al., 1996; Nokhodchi & Tailor, 2004;

Yu et al., 2008). Zinutti et al. (1996) prepared ethylcellulose

microspheres containing 5-FU by an oil-in-oil evaporation/

extraction method. They have studied three drug/polymer

ratios (1:1, 1:2 and 1:3) and found that as the drug ratio

decreased from 1:1 to 1:3, 5-FU release increased.

Analysis of kinetic results

The event of solvent sorption by a bead depends mechanis-

tically on the diffusion of water molecules into the gel matrix

and subsequent relaxation of macromolecular chains of the

0

10

20

30

40

50

60

70

80

90

100

0 120 240 360

Cum

ulat

ive

Rel

ease

(%

)

Time (Minute)

pH=1,2 pH=6,8 pH=7,4

Figure 8. Effect of drug/polymer ratio on 5-FU release. PVA-g-AAm/NaAlg ratio: 1:4, concentration of FeCl3: 0.05 M, exposure time toFeCl3: 10 min. (circle, 1:8; triangle, 1:4; diamond, 1:2; square, 1:1).

0

10

20

30

40

50

60

70

80

90

100

0 120 240 360

Cum

ulat

ive

Rel

ease

(%

)

Time (Minute)

pH=1,2 pH=6,8 pH=7,4

Figure 5. Effect of PVA-g-AAm/NaAlg ratio on the 5-FU release.Concentration of FeCl3: 0.05 M, exposure time to FeCl3: 10 min, drug/polymer ratio: 1:8 (diamond indicates 1:1; square, 1:2; triangle, 1:3;circle, 1:4).

0102030405060708090

100

0 120 240 360

Cum

ulat

ive

Rel

ease

(%

)

Time (Minute)

pH=1,2 pH=6,8 pH=7,4

Figure 6. Effect of crosslinker concentration on the 5-FU release. PVA-g-AAm NaAlg ratio: 1:4, exposure time to FeCl3: 10 min; drug/polymerratio: 1:8 (diamond indicates 0.2 M, triangle: 0.1 M, circle: 0.05 M).

0102030405060708090

100

0 120 240 360

Cum

ulat

ive

Rel

ease

(%

)

Time (Minute)

pH=1,2 pH=6,8 pH=7,4

Figure 7. Effect of exposure time to crosslinker on the 5-FU release.PVA-g-AAm/NaAlg ratio: 1:4, concentration of FeCl3: 0.05 M, drug/polymer ratio: 1/8. (square: 5 min, circle: 10 min, multiplication symbol:15 min).

Table 3. Equilibrium swelling degree of microspheres.

Formulation Code pH¼ 1.2 pH¼ 6.8 pH¼ 7.4

A1.0 171.8� 3.4 720.3� 3.5 1093.2� 8.9A2.0 138.6� 2.9 677.1� 4.7 960.3� 4.7A3.0 134.6� 6.2 529.3� 3.2 844.5� 3.6A4.0 129.6� 1.1 480.4� 1.0 530.8� 1.2

218 O. Sanlı & M. Olukman Drug Deliv, 2014; 21(3): 213–220

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bead (Bajpai & Sharma, 2005). The release data of all the

systems were further substantiated by fitting the fraction

release data Mt=M1 to an empirical equation proposed by

Peppas (1985).

ktn ¼ Mt

M1ð3Þ

Where Mt is the amount of 5-FU released at time t and M1is 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 t1=2 time

dependence of the fractional release for slabs, cylinders and

spheres. Analogously, Case-II transport is defined by an

initial linear time dependence of the fractional release for all

geometries (Ritger & Peppas, 1987). A value of n¼ 0.5

indicates the Fickian transport (mechanism), while n¼ 1 is of

Case II or non-Fickian transport (swelling controlled)

(Yu et al., 2008). 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 4. From these data, the n value ranged

between 0.2361 and 0.9509, indicating 5-FU release from the

semi-IPN microspheres deviates from the Fickian transport.

The values of diffusion coefficients, D, for the transport

of aqueous drug solution from the microspheres were

calculated using the sorption and desorption results as in

Equation (4).

D ¼ r�

6M1

� �2

� ð4Þ

where � is the slope of the linear portion of the plot of Mt/M1versus t1/2, and r is the radius of the microspheres; M1 is

equilibrium sorption. To calculate D from desorption experi-

ments, � was computed from the initial linear portion of the

desorption plot, i.e. ln(1�Mt/M1) versus time, t. The

calculated values of D from Equation (4) for sorption and

desorption runs were also presented in Table 3. The D values

for the desorption were smaller than those observed for

sorption, and these ranged from 2.470� 10�13 to

10.930� 10�13 cm2/s (Babu et al., 2006).

Conclusions

PVA-g-PAAm/NaAlg was synthesized and semi-IPN micro-

spheres were prepared by crosslinking with Fe3þ ions for oral

treatment gastrointestinal tract of 5-FU. The release was

found to be pH sensitive and 5-FU release was higher at high

pH values than at low pH values. Release was found to be low

at high concentrations of crosslinker, whereas high at short

time of exposure to crosslinker. Decrease in drug content of

the microspheres enhanced the 5-FU release. PVA-g-PAAm/

NaAlg ratio affected the release. As the amount of NaAlg was

increased, release became more controlled. The highest 5-FU

release was found to be 99.57% for PVA-g-PAAm/NaAlg

ratio of 1:4 and drug/polymer ratio of 1:8, crosslinker

concentration of 0.05 M and exposure time of 10 min to

crosslinker.

Declaration of interest

The authors report no conflicts of interest. The authors alone

are responsible for the content and writing of this work.

The authors are grateful to the Gazi University Scientific

Research Foundation for support of this study.

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Formulationcode k (min�n) n r D (cm2/s)� 10�13

A1 0.0275 0.6641 0.904 7.877A2 0.0487 0.5533 0.935 5.770A3 0.1330 0.3719 0.904 8.760A4 0.1350 0.3477 0.873 2.470A1.1 0.0032 0.9482 0.951 4.330A1.2 0.0190 0.6844 0.864 4.225A1.3 0.0029 0.9509 0.939 7.700A1.4 0.0074 0.7469 0.977 6.400A1.5 0.2350 0.2361 0.930 4.028A1.6 0.1130 0.3695 0.927 8.464A1.7 0.0523 0.5016 0.909 10.930

DOI: 10.3109/10717544.2013.844743 AAm grafted PVA/sodium alginate microspheres 219

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