Journal of Biomaterials and Nanobiotechnology, 2012, 3, 469-479 Published Online October 2012 (
Release of Anticancer Drug 5-Fluorouracil from Different
Ionically Crosslinked Alginate Beads
Merve Olukman1, Oya Şanlı1*, Ebru Kondolot Solak2
1 Department of Chemistry, Faculty of Science, Gazi University, Ankara, Turkey; 2 Department of Chemistry and Chemical Process-
ing Technology, Atatürk Vocational High School, Gazi University, Ankara, Turkey.
Email: *
Received June 5th, 2012; revised July 11th, 2012; accepted August 19th, 2012
In this research, the release of 5-Fluorouracil (5-FU) from different ionically crosslinked alginate (Alg) beads was in-
vestigated by using Fe3+, Al3+, Zn2+ and Ca2+ ions as crosslinking agent. The prepared beads were characterized by Fou-
rier Transform Infrared Spectroscopy (FTIR) Differential Scanning Calorimetry (DSC) and Scanning Electron Micros-
copy (SEM). The drug release studies were carried out at three pH values 1.2, 6.8 and 7.4 respectively each for two
hours. The effects of the preparation conditions as crosslinker type, drug/polymer (w/w) ratio, crosslinker concentration
and time of exposure to crosslinker on the release of 5-FU were investigated for 6 hours at 37˚C. It was observed that
5-FU release from the beads followed the order of Fe > Zn > Al > Ca-Alg and increased with increasing drug/polymer
ratio. At the end of 6 hours, the highest 5-FU release was found to be 90% (w/w) for Fe-Alg beads at the drug/polymer
ratio of 1/8 (w/w), crosslinker concentration of 0.05 M, exposure time of 10 minutes respectively. The swelling meas-
urements of the beads supported the release results. Release kinetics was described by Fickian and non-Fickian ap-
Keywords: Anticancer Drug; pH Responsive Release; Alginate; Ionically Crosslinking; Controlled Release;
1. Introduction
5-Fluorouracil (5-FU) is one of the most widely used
agents in cancer theraphy. Since its active form inhibits
DNA synthesis by inhibiting the normal production of
thymidine. It has a relatively high response in colon, rec-
tal, breast, gastrointestinal tract pancreas, head, ovarion
cancers [1-4]. The common method of administration of
5-FU is in the form of injections into vein [1,5,6] (intra-
venous) or as an infusion. However, such an administra-
tion causes severe gastrointestinal (vomiting, nausea,
poor appetite) neural, hematological, cardiac, dermatolo-
gical toxic effects. Since the drug is rapidly adsorbed
through blood capillaries into systematic circulation, re-
sults in relatively low levels of the drug near the side
action with subsequent loss of efficiency and increased
risk of toxicity. By using oral rate controlled formula-
tions, the incidence of side effects may be reduced since
the drug has short biological half-life due to fast metabo-
lism incomplete and non uniform oral absorption [6].
There are many studies in the literature for encapsulation
of 5-FU in polymeric materials. In those studies [1,2,4,
6-13]. Generally natural polymers were preffered to syn-
thetic polymers for the encapsulation because of their
free aviability, nontoxicity and biodegrability character-
istics. These polymers eventually undergo hydrolytic scis-
sion, producing by products that can be metabolized in
the body. Polymers like gelation [14]. Chi-tosan [15], co-
poly(D,L-lactic/glycolic acid [16], poly(D-L-Lactide-co-
glycolide) [1] have been used in the controlled delivery
of 5-FU.
There are also some studies concerning the encapsula-
tion of 5-FU into alginate matrix [12,17,18] but they are
in a limited number. Alginate is a lineer copolymer of
D-Mannuric acid (M) and Gluronic acid (G) units which
is found in brown seaweeds and is commercially avail-
able as sodium salt. It is a cellulose based biodegredable
type polymer and is widely used in pharmaceutical ap-
plicatinos [18-29]. Gel formation of alginate matrix is ge-
nerally achieved by using divalent Ca2+ ions [19,21,22,
24-29]. However calcium-alginate beads or microparti-
cles when exposed to highly acidic (pH: 1.2) environment
of stomach may result in insoluble alginic acid form caus-
ing reduction in their degree of crosslinking hence the
beads degrades in a very short time after arriving to colon
(pH: 6.8, 7.4). For this reason Arıca et al. [27] and Sure-
*Corresponding author.
Copyright © 2012 SciRes. JBNB
Release of Anticancer Drug 5-Fluorouracil from Different Ionically Crosslinked Alginate Beads
kha et al. [28] studied the release of 5-FU only at pH con-
ditions of 7.4, Chui-Yu et al. Reinforced alginate micro-
particles by chitosan during gelation [13]. Dodova et al.
[12] prepared lectin-conjugated chitosan-Caalginate mi-
croparticles and loaded with 5-FU for the same purpose.
In the present study we have aimed to increase the
strength of alginate beads so that after passing through
stomach they can stand for a longer time period in intes-
tinal medium conditions. For this reason we have tried
different metal ions as Fe3+, Al3+, Zn2+, Ca2+ for the
crosslinking of alginate matrix, tried to find most suitable
cation for the crosslinking and evaluated the physico-
chemical properties of the beads prepared. Attention has
been paid for the effects of various factors on the release
such as drug/polymer ratio, pH of the dissolution me-
dium, crosslinking time and concentration. Although Fe3+
ions were previously used for the preparation of cross-
linked alginate-carboxymethyl cellulose beads for protein
theraupeutics [30] and carboxymethyl chitin nanoparti-
cles for 5-FU delivery [31]. There is no study concerning
the use of these ions in the delivery of 5-FU from the
alginate matrix.
2. Experimental
2.1. Materials
NaAlg (medium viscosity) was purchased from Sigma
Chemical Co (Louis, USA). 5-FU was provided by Sigma-
Aldrich (Steinem, Germany). Na2HPO4 and NaH2PO4
were all supplied from Merck (Darmstadt, Germany) and
were used as received. Iron (III) chloride, Aluminum
chloride, zinc chloride and calcium chloride were pro-
vided by Merck (Darmstadt, Germany).
2.2. Preparation of the 5-FU Loaded Beads
NaAlg was dissolved in distilled water to prepare 2%
(w/v) NaAlg solution. Different amounts of 5-FU were
added and mixed using a magnetic stirrer. The polymer
solution containing 5-FU was added drop wise into
crosslinking solution using a peristaltic pump (Masterflex,
L/S Digital Economy Drive, USA). The formed beads
were then removed from the crosslinker solution. To re-
move the adhered crosslinker, beads were washed with
water repeatedly then dried completely in an oven at
40˚C. Preparation conditions were displayed in Table 1.
In order to estimate the size of beads completely dry
beads from the different formulations were selected and
their sizes were measured by using a micrometer screw
gauge (Aldrich, Germany) and given in Table 1.
2.3. Equilibrium Swelling Study of the Beads
Equilibrium swelling degree of the crosslinked empty
beads was determined by measuring gravimetrically the
extent of their swelling in solutions at pH 1.2, 6.8 and 7.4
at 37˚C. To ensure complete equilibration, the samples
were allowed to swell for 24 h. The excess surface-ad-
hered liquid drops were removed by blotting. The swol-
len beads were weighed using electronic balance (Precise
XB 220 A, USA). The beads 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 (%) = sd
where Ms and Md were the mass of the swollen beads and
dry beads, respectively.
Table 1. Preparation conditions of the 5-Fluorouracil loaded NaAlg beads.
Code Drug/Polymer
ratio (w/w)
Concentration of
crosslinking agent (M)
Exposure time to
crosslinking agent (min)
efficiency (%)
Bead yield
Bead diameter
A1 1/8 FeCl3 0.1 10 12 96 1.25
B1 1/8 AlCl3 0.1 10 5 93 1.17
C1 1/8 CaCl2 0.1 10 4 84 1.11
D1 1/8 ZnCl2 0.1 10 7 89 1.13
A2 1/8 FeCl3 0.2 10 15 75 0.62
A3 1/8 FeCl3 0.05 10 10 82 1.00
A4 1/8 FeCl3 0.05 5 17 70 0.55
A5 1/8 FeCl3 0.05 15 7 78 1.10
A6 1/4 FeCl3 0.05 10 13 77 1.06
A7 1/2 FeCl3 0.05 10 14 62 1.10
A8 1/1 FeCl3 0.05 10 25 50 1.20
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Release of Anticancer Drug 5-Fluorouracil from Different Ionically Crosslinked Alginate Beads 471
2.4. Determination of 5-FU Content of the
The known mass of beads was crushed in an agate mortar
with a pestle, and then polymeric powder is 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
beads. At the end of the 1 h, precipitated NaAlg was fil-
tered and 5-FU was analyzed by using a UV spectropho-
tometer (Unico 4802 UV/VIS) at a wavelength of 266
nm using a calibration curve and water as the blank. Per-
centage of entrapment efficiency was then calculated as
Entrapment efficiency (%)
Practical 5-FU loading100
Theoretical 5-FU loading
2.5. Fourier Transforms Infrared Measurements
FTIR spectra of the 5-FU, NaAlg and 5-FU/NaAlg beads
crosslinked with Fe3+ were taken with a Mattson 1000
FTIR spectrometer and presented in Figure 1.
2.6. Differential Scanning Calorimetry (DSC)
The thermal analysis was carried out with differential
scanning calorimeter (DSC, Shimadzu, Japon). Measure
ments were performed over the temperature range of 0˚C -
300˚C at the heating rate of 10˚C/min. and displayed
Figure 2.
2.7. Scanning Electron Microscopy (SEM)
SEM micrographs were taken with QUANTA 400F Field
Figure 1. FTIR spectra of (a) 5-FU; (b) 5-FU loaded NaAlg (1/8 w/w) beads crosslinked with Fe3+; (c)NaAlg.
Copyright © 2012 SciRes. JBNB
Release of Anticancer Drug 5-Fluorouracil from Different Ionically Crosslinked Alginate Beads
Figure 2. DSC termograms of (a) Pure 5-FU; (b) NaAlg; (c) NaAlg beads crosslinked with FeCl3; (d) 5-FU loaded beads
crosslinked with FeCl3.
Emission SEM to examine the morphology and surface
structure of the beads at the required magnification at
room temperature and shown in Figure 3.
2.8. In Vitro Drug Release
In vitro drug release from the beads 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 me-
dium was changed to be pH: 1.2, 6.8 and 7.4, respec-
tively, to follow the gastrointestinal tract. At specific
time intervals, the 5-FU content was determined using
UV spectrophotometer at 266 nm. Equal volume of fresh
Copyright © 2012 SciRes. JBNB
Release of Anticancer Drug 5-Fluorouracil from Different Ionically Crosslinked Alginate Beads 473
HCl or phosphate buffer solution was added into the dis-
solution media to maintain a constant volume. From the
absorbance values the cumulative released amount per-
centage was determined. All experiments were performed
in triplicate to minimize the variational error. Standard
deviations from the average values were calculated.
3. Results and Discussion
3.1. Effect of Type of Crosslinker and
Crosslinker Concentration on the 5-FU
The release of 5-FU from the Fe-Alg, Al-Alg, Ca-Alg
and Zn-Alg beads were carried out for three pH values at
37˚C and the amount of drug release within a given time
was evaluated by UV spectroscopy. Effect of type and
valency of the ions in the crosslinking agents on the cu-
mulative release of 5-FU were shown in Figure 4. It was
reflected from the figure that cumulative drug release
from beads followed the order of Fe > Zn > Al > Ca-Alg
and the beads of Zn-Alg, Ca-Alg, Al-Alg eroded at the
pH values higher than 6.8 (Table 2).
The release results can be related to the mechanism of
the bonding of iron, aluminum, zinc and calcium ions
with NaAlg. Since calcium and zinc cations are divalent,
their bonding to alginate was expected to occur in a pla-
nar two-dimensional manner as represented in the
egg-box model [32] shown in Scheme 1. Trivalent alu-
minium and iron cations were expected to form a three
dimensional valent bonding structure with the alginate.
Possible scheme for the crosslinking of NaAlg with Fe3+
and Al3+ was given in Scheme 2. Reaction mechanism of
sodium alginate with Zn2+ and Ca2+ ions is similar to Fe3+
and Al3+. Dissimilarly two alginate chains were used in
the crosslinking with Zn2+ and Ca2+.
Figure 3. Microscopic pictures of (a) Empty Fe-Alg and (b) 5-FU loaded Fe-Alg beads.
Figure 4. Effect of type and valency of the ions in the crosslinking agents on the cumulative release of 5-FU (: FeCl3, :
nCl2, : AlCl3, : CaCl2). Z
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Release of Anticancer Drug 5-Fluorouracil from Different Ionically Crosslinked Alginate Beads
Table 2. Equilibrium swelling degree for empty beads.
Formulation Code pH = 1.2 pH = 6.8 pH = 7.4
A 51.19 ± 1.07 108.17 ± 1.58 188.65 ± 2.46
B 217.65 ± 2.56Beads eroded Beads eroded
C 135.58 ± 1.44Beads eroded Beads eroded
D 229.23 ± 1.73Beads eroded Beads eroded
Scheme 1. Egg-box model representing M2+ cations reacting
with alginates.
Three dimensional bonding model was expected to be
the reason for the extended crosslinking through the
whole body of matrix. On the other hand diffusion ability
of the NaAlg crosslinked matrix can be explained by the
ionic size of the crosslinker cations. The size of alumi-
num (0.50 Å) was smaller than the size of the iron (0.64
Å) cations. Iron ions were expected to fill larger space
between the alginate chains producing a loose arrange-
ment in the matrix leading to high release. Musa and
coworkers [29] have studied the parameters involved in
the preparation and release of metoclopramide hydro-
chloride and cisapride in calcium, barium, aluminum
crosslinked matrices of alginate and reported that the
crosslinker type was shown to have a pronounce influ-
ence on the drug release. In addition aluminum ion con-
stitute complex with 5-FU causes low drug release. In the
rest of the study due to the high release of 5-FU from
Fe-Alg beads we have continued with Fe3+ as the cross-
linker ion [32].
Figure 5 shows the effect of crosslinker concentration
on the 5-FU release. It was seen from the figure that the
cumulative release of 5-FU beads increased as the
crosslinker concentration decreased from 0.2 to 0.05 M.
Similar results were also observed in the literature [20,
30]. In the rest of the study crosslinker concentration was
selected as 0.05 M due to the high release at this con-
3.2. Effect of Exposure Time to Crosslinker on
the 5-FU Release
One of the ways of changing drug release from the beads
Scheme 2. Scheme for the crosslinking of NaAlg with [M3+: Fe3+, Al3+ cations].
Copyright © 2012 SciRes. JBNB
Release of Anticancer Drug 5-Fluorouracil from Different Ionically Crosslinked Alginate Beads 475
is to change the crosslinking density of the matrix by
employing various time of exposure to crosslinking agent.
The effect of the exposure time to FeCl3 on the release
rate of 5-FU has been investigated by varying the time of
exposure to FeCl3 as 5 - 15 min. The results were given
in Figure 6, which clearly indicated that increasing ex-
posure time to FeCl3 decreased the cumulative release of
5-FU. Similar results were given in the literature [4,
11,12,14]. Although the maximum 5-FU release from the
Fe-Alg beads was obtained with the exposure time of 5
min., since these beads did not stand to pH value of 7.4.
We have continued in the rest of the study with exposure
time of 10 min.
3.3. Effect of Drug/Polymer Ratio on the 5-FU
Effect of 5-FU/NaAlg ratio on 5-FU release from Fe-Alg
beads was shown in Figure 7. The figure showed that a
decrease in the 5-FU/polymer ratio from 1/1 to 1/8
causes an increase in the release of 5-FU from the beads.
The highest cumulative 5-FU release obtained at the end
of 6 hr is 90 % for the 1/8 drug/polymer ratio. As 5-FU
content of the bead decreases, a loose structure in the
polymeric bead forms and this loose structure causes the
liquid to easily penetrate into the bead and eases the dif-
fusion of the 5-FU. As the drug/polymer ratio decreased
from 1/1 to 1/8 particle size of the beads also decreased
(Table 1). Release from smaller size bead is faster than
those from the large size bead due to smaller diffusional
path length for the drug and the larger surface area of
contact of small particle with the dissolution media [33,
3.4. Characterization of the Beads
FTIR spectra of 5-FU, 5-FU/NaAlg (1/8 w/w) beads
crosslinked with Fe3+ and NaAlg were shown in Figure
1. A broad band between the 3000 and 3500 cm–1, is at-
tributed to—NH stretching vibrations in the spectrum of
5-FU. This band was seen approximately at 3500 cm–1 in
the spectrum of drug loaded NaAlg, because the over-
Figure 5. Effect of crosslinker concentration on the 5-FU release. Concentration of FeCl3: 0.05 M, exposure time to FeCl3 10
min. drug/polymer; 1/8 (: 0.2 M, : 0.1 M, : 0.05 M).
Figure 6. Effect of exposure time to crosslinker on the 5-FU release. Concentration of FeCl3: 0.05 M, drug/polymer: 1/8. (: 5
min., : 10 min., x: 15 min).
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Release of Anticancer Drug 5-Fluorouracil from Different Ionically Crosslinked Alginate Beads
Figure 7. Effect of drug/polymer ratio on 5-FU release. Concentration of FeCl3: 0.05 M, exposure time to FeCl3 10 min.
(drug/polymer ratio; 1/8 (), 1/4 (), 1/2 (), 1/1 ()).
overlapping of -OH band of NaAlg with -NH band of
5-fluorouracil. In the spectrum of NaAlg, drug loaded
NaAlg and 5-FU appeared band of carbonyl stretching
(C=O) at 1650 cm–1, 1625 cm–1 and 1638 cm–1, respect-
tively. C-H group stretching band of NaAlg and drug
loaded NaAlg appeared were seen at 2930 cm–1 2925
cm–1, respectively. The peak at 1275 cm–1 was belong to
C-F stretching band in the spectrum of 5-FU. This peak
was seen at 1280 cm–1 in the spectrum of drug loaded
NaAlg which can be taken as the evidence of encapsula-
DSC trackings of pure 5-FU, NaAlg, NaAlg beads
crosslinked with FeCl3, 5-FU loaded beads crosslinked
with FeCl3 were displayed in Figure 2 melting peak of
5-FU was observed at 282˚C. However no characteristic
peak of 5-FU was observed in DSC curves of the 5-FU
loaded beads suggesting that drug is molecularly dis-
persed in the polymer matrix.
Shape of dried empty NaAlg and 5-FU loaded NaAlg
beads were shown in Figure 3. As it was reflected from
the figure that, both empty and 5-FU loaded beads almost
maintain spherical form at empty and loaded conditions.
The results of bead diameter, entrapment efficiency (%)
and bead yield (%) were shown in Table 1. As can be
seen from the table the beads formed have particle sizes
ranging from 0.55 to 1.25 mm in diameter. The size of
the beads changed with drug/polymer (w/w) ratio, cross-
linker type and crosslinker concentration. Entrapment
efficiency percentage increased with the increase in
crosslinker concentration whereas decreased with the
exposure time to crosslinker. Similar results were ob-
served in the literature. Şanlı and coworkers [21] pre-
pared poly(vinyl alcohol)/sodium alginate and poly(vinyl
alcohol)-grafted-poly (acrylamide)/sodium alginate blend
beads for the delivery of diclofenac sodium and reported
that with increasing exposure time to crosslinking agent
(2.5 - 5 min.) the entrapment efficiency decreased.
3.5. Analysis of Kinetic Results
Solvent sorption by a bead depends mechanistically on
the diffusion of water molecules into the gel matrix and
subsequent relaxation of macromolecular chains of the
bead [35]. The release data of all the systems were fur-
ther substantiated by fitting the fraction release data
to an empirical equation proposed by Peppas
kt M
where t is the amount of 5-FU released at time t and M
is the drug released at equilibrium time; k, a con-
stant 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
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 frac-
tional release for all geometries [37]. A value of n; 0.5
indicates the Fickian transport (mechanism), while n; 1 is
of Case II or non-Fickian transport (swelling controlled)
[38]. 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 0.4486 - 1.1506, indicating 5-FU release from
the Fe-Alg beads deviates from the Fickian transport.
The values of diffusion coefficients, D, for the trans-
port of aqueous drug solution from the beads were cal-
culated using the sorption and desorption results as in
Equation (7).
where θ is the slope of the linear portion of the plot of
Copyright © 2012 SciRes. JBNB
Release of Anticancer Drug 5-Fluorouracil from Different Ionically Crosslinked Alginate Beads 477
Table 3. The results of k, n and r calculated from Equation (6).
Formulation Code k (min–n) n r D (cm2/s) × 10–13 Diffusion Mechanism
A1 0.0040 0.7832 0.965 50.7 Anomalous Transport
A2 0.0039 0.8926 0.976 8.72 Anomalous Transport
A3 0.0067 0.8659 0.981 55.1 Anomalous Transport
A4 0.0025 1.1506 0.972 31.9 Case II
A5 0.0017 0.9911 0.969 15.2 Anomalous Transport
A6 0.0065 0.7624 0.978 13.3 Anomalous Transport
A7 0.0119 0.5979 0.970 0.0078 Anomalous Transport
A8 0.0363 0.4486 0.966 8.27 Anomalous Transport
Mt/M vs t1/2, and r is the radius of the beads; M is equi-
librium sorption. To calculate D from desorption experi-
ments, θ was computed from the initial linear portion of
the desorption plot, i.e. ln(1 M
t/M) vs. time, t. The
calculated values of D from Equation (7) for sorption and
desorption runs are also presented in Table 3. The D
values for desorption were smaller than those observed
for sorption, and these ranged from 0.0078 × 10–13 to
55.1 × 10–13 cm2/s [38].
4. Conclusion
Studies on the release of 5-FU from sodium alginate
beads crosslinked with Fe(III), Al(III), Zn(II) and Ca(II)
ions indicated that the crosslinking with Fe(III) lead to
highest release of 5-FU from the beads. Release of 5-FU
from NaAlg beads crosslinked with FeCl3 increased with
the decrease in the drug content. It was also observed that
release of 5-FU was much higher at high pH values com-
pared to low pH values. Optimum conditions for 5-FU
release were determined as crosslinker concentration of
0.05M, exposure time to crosslinker of 10 min and drug/
polymer ratio of 1/8. The highest 5-FU release at these
conditions was found to be 90% (w/w).
5. Acknowledgements
The authors are grateful to the Gazi University Scientific
Research Foundation for support of this study.
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