Journal of Inorganic and Organometallic Polymers and Materials

https://doi.org/10.1007/s10904-019-01301-1

Synthesis and Characterization of Carboxymethyl Cellulose/

β‑Cyclodextrin/Chitosan Hydrogels and Investigating the Effect
of Magnetic Nanoparticles ­(Fe3O4) on a Novel Carrier for a Controlled
Release of Methotrexate as Drug Delivery
Zahra Naderi1 · Javad Azizian1 · Elham Moniri2 · Nazanin Farhadyar2

Received: 29 May 2019 / Accepted: 26 August 2019

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Abstract
In this paper, pH-sensitive magnetic hydrogels were prepared from carboxymethyl cellulose (CMC), β-cyclodextrin (β-CD)
and chitosan (CS) without a toxic agent by a simple method as a new carrier for a controlled drug release. Magnetic ­(Fe3O4)
nanoparticles were synthesized by chemical co-precipitation via in situ method under the presence of N ­ 2 gas. The effect of
magnetic ­(Fe3O4) nanoparticles amounts on CMC, β-CD and CS hydrogel for drug delivery of Methotrexate (MTX) was
investigated. The stability of hydrogel was evaluated using TGA, XRD, VSM, FT-IR, and FE-SEM measurements. The
SEM images demonstrated the ­Fe3O4 distribution in the hydrogel, while XRD patterns confirmed the cubic crystalline
phase of ­Fe3O4 nanoparticles. The hysteresis loop of low magnetic CMC/β-CD/CS hydrogel and high magnetic CMC/β-CD/
CS hydrogel is 6.32 and 11.6 emug−1, respectively. The swelling manner of the CMC/β-CD/CS hydrogels was studied at
a varied pH range 2–11. CMC/β-CD/CS hydrogel demonstrated slightly higher swelling amount as compared to magnetic
CMC/β-CD/CS hydrogel. The prepared hydrogel showed a pH-sensitive swelling manner with great water-absorbing at pH
9. The maximum capacity of swelling in CMC/β-CD/CS hydrogel, low and high magnetic CMC/β-CD/CS hydrogels were
obtained 8.8, 6.7 and 4.6 g g−1 respectively. In vitro, MTX release experiment was performed to attain the success of this
new method of magnetic CMC/β-CD/CS hydrogel for drug delivery progress. The results showed that the release percent of
CMC/β-CD/CS hydrogel was more significant than the other prepared hydrogel. The maximum drug release in CMC/β-CD/
CS hydrogel, low and high magnetic CMC/β-CD/CS hydrogels were obtained 92.7, 80.4 and 58.3% at pH 7.4, respectively.
Also, the MTX release investigated under an external alternating magnetic field (AMF). The studies illustrated that the
response of hydrogel nanocomposite to external stimulants could be used for novel drug delivery systems.

Keywords  Carboxymethyl cellulose · Fe3O4 nanoparticle · Drug delivery · β-Cyclodextrin · Chitosan · Hydrogel

1 Introduction properties, as non-toxicity, biocompatibility and eco-

Biopolymers contain monomeric biomolecules count that
is covalently bonded to form macromolecules. Improve
bio macromolecular polymers are applied in a broad field
such as water treatment, sensor, catalyst, drug delivery
[1–3]. Therefore, these polymers due to their exceptional
* Javad Azizian
Azizian@srbiau.ac.ir
1
Department of Chemistry, Science and Research Branch,
Islamic Azad University, Tehran, Iran
2
Department of Chemistry, Varamin‑Pishva Branch, Islamic
Azad University, Tehran, Iran
friendly have extensive usage in protein and drug delivery
[4–6]. Cyclodextrin (CDs) hydrogels are an excellent mate-
rial for the enhanced swelling ability and completed load-
ing drug progress [7, 8]. Carboxymethyl cellulose (CMC)
is abiotic cellulose ether with water-solubility produced
from the reaction of ­ClCH2COOH with anhydroglucose as
a sugar polymer of cellulose. Because of its high physico-
chemical properties and low immunogenicity, CMC was
used in the drug delivery procedures [9, 10]. Chitosan,
as biological macromolecules, has excellent features for
different applications in pharmaceutical and  biomedi-
cal fields such as drug delivery, tissue engineering, and
gene delivery [11–13]. Hydrogels are polymeric material

13
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with hydrophilicity properties is suitable for use in human
tissues due to physicochemical characteristics [14, 15].
Intelligent hydrogels or stimuli-responsive hydrogels are a
group of polymers that change by ambient conditions such
as temperature, pH, light, ionic strength, magnetic field,
and electrical signal. Hydrogels usually respond to changes
in the external environment by increasing or decreasing
swelling [16–19]. The use of hydrogels is limited due to
poor mechanical properties. The mechanical and physical
properties of hydrogels have been improved by the addi-
tion of filler nano-structures (such as carbon, silica, inor-
ganic, semiconductors, metal and metal oxide) into the
hydrogels and production of nanocomposite hydrogels.
Nano-composite hydrogels are widely used in tissue engi-
neering, gene therapy, drug delivery, chemical and bio-
logical sensing [20–24]. However, some disadvantages are
still related to hydrogels, when applied for drug delivery
progress, such as reduced drug compound loading strength
for hydrophobic drugs [25]. Therefore, to resolve all these
disadvantages, β-cyclodextrin, carboxymethyl cellulose,
chitosan hydrogels have been produced. Hanna and Saad
[26] studied the synthesis of xanthan gum- chitosan-based
hydrogel was employing to the drug delivery of ciprofloxa-
cin. Craciun et al. [27] synthesized Nitrosalicyl-imine-chi-
tosan hydrogels based and studied its drug delivery activ-
ity using Diclofenac sodium as the model drug. Zhang
et al. [28] prepared supramolecular hydrogel formation
between chitosan and hydroxypropyl β-cyclodextrin and
studied the drug delivery. Javanbakht et al. [29] synthe-
sized Carboxymethyl cellulose-Cu-organic compound for
ibuprofen oral delivery application. Carvalho et al. [30]
synthesized cellulose hydrogel for the drug delivery of
doxorubicin. Ghorpade et al. [31] prepared Citric acid-
β-cyclodextrin/carboxymethyl cellulose hydrogel that
exhibited enhanced drug delivery activities of ketocon-
azole. Jeong et al. [32] reported that the preparation of
Carboxymethyl cellulose-containing β-cyclodextrin leads
to excellent drug delivery efficiency. Nakagawa et al. [33]
produced hydrogels to control curcumin using the triple
system of chitosan, kappa carrageenan and carboxymethyl
cellulose. Machín et al. [34] synthesized β-Cyclodextrin
hydrogels and studied the drug delivery process using
naproxen, nabumetone, naftifine, and terbinafine as the
model drugs. In this project, we prepared a pH-sensitive
hydrogel from carboxymethyl cellulose, β-cyclodextrin,
and chitosan and F ­ e3O4 nanoparticles as a novel carrier
and applied in the Controlled release of MTX. Therefore,
the behaviour of MTX release from hydrogel at the various
pHs (1.2, 5.3 and 7.4) was investigated. This work focuses
on the effect of a different amount of F­ e3O4 nanoparticles
in hydrogel for evaluation of the swelling and MTX release
properties. The structural features and morphological of
the synthesized hydrogels were evaluated.
13
Journal of Inorganic and Organometallic Polymers and Materials
2 Materials and Methods
All the chemical compounds were procured from sigma
Aldrich Ltd, USA.
2.1 Preparation of Carboxymethyl Cellulose/
β‑Cyclodextrin (CMC/β‑CD)
Carboxymethyl cellulose (­ Mw = 250,000) (1 g) was added
in 1 wt% NaOH solution and stirred. The epichlorohydrin
(300 µL) was added slowly to the mixture. β-Cyclodextrin
(0.5 g) was dispersed in deionized water and was added to
the above mixture and stirred for 1 h. The reaction solution
was finalized with the methanol solution. Then, the CMC/
β-CD was washed with methanol three times and dried in
vacuum at 40 °C.
2.2 Preparation of Magnetic Carboxymethyl
Cellulose/β‑Cyclodextrin/Chitosan (CMC/β‑CD/
CS)
The magnetic CMC/β-CD/CS was prepared by using the
precipitation chemical method of F ­ e3+/Fe2+. CMC/β-CD
(1  g) was dispersed in deionized water (100  mL) and
stirred until to homogenous solution. Then, the 10 mL of
­FeCl3/FeSO4 ­(Fe3+/Fe2+) solution (Table 1) was appended
to the above solution and stirred for 20 min at 40 °C and
vigorously stirred for 30 min under the presence of ­N 2
gas. The ammonia (3 M) was added as dropwise in the
mixture to pH reach 11 and stirred for 60 min at 60 °C.
The product was washed to pH reach 7. The magnetic
CMC/β-CD was appended in 50 mL of deionized water
under ultrasonic irradiation (SJIA-2000 W) for 10 min
and stirred at 60 °C. Then, the Chitosan (0.5 g) appended
in 50 mL of acetic acid (1 wt%), and the NaOH (0.1 M)
added to pH reaches 5.7. The magnetic CMC/β-CD sus-
pension was added slowly to chitosan solution under
vigorous stirring for 20  min at 60  °C. The product
was washed to pH reach 7. The magnetic CMC/β-CD/
CS was washed and dried overnight at 40 °C. Also, the
Table 1  The required amount of starting materials for the preparation
of magnetic CMC/β-CD/CS hydrogel
High magnetic Low magnetic CMC/β-CD/
CMC/β-CD/CS CMC/β-CD/CS CS hydrogel
hydrogel hydrogel
CMC–CD(g) 1 1 1
CS(g) 0.5 0.5 0.5
FeCl3(g) 2.35 1.17 0
FeSO4(g) 1.2 0.6 0
Journal of Inorganic and Organometallic Polymers and Materials
CMC/β-CD/CS (non-magnetic) hydrogel sample prepared
without the presence of iron ions and ammonia solution
with the same method.
2.3 Swelling Test
To evaluate the swelling manner of prepared hydrogels, we
applied the previous studies [9]. Regularly, 0.1 g of mag-
netic CMC/β-CD/CS hydrogel or CMC/β-CD/CS hydrogel
was appended in various pH buffer solutions (20 mL) at
25 °C for 24 h. The swelling measurement determined via
Eq. (1). The test was carried out in triplicate [35].
( ) ( )
g W2 − W1
Swelling = (1)
g W1
where ­W1 and ­W2 are the initial hydrogel weight and hydro-
gel weight of after swelling test, respectively.
2.4 MTX Loading and Release Tests
Regularly, 0.1  g magnetic CMC/β-CD/CS hydrogel or
CMC/β-CD/CS hydrogel was equilibrated in 100 mL aque-
ous MTX solution containing (100 ppm) for 24 h to MTX
loading in the hydrogel (27 °C). The content of Metho-
trexate solution was filtered and measured using UV–Vis
spectroscopy (λm = 305 nm) [35] by using the Eq. (2).
( )
C0 − Ct
Drug loading (%) = × 100
C0
where ­C0 is the initial concentration of MTX in the solution
and ­Ct is the concentration of MTX remained in the media.
The 0.1 g of MTX loaded hydrogel was appended into
20 ml buffer solution (pH 1.2, pH 5.3, and pH 7.4) while
shaking on a rotary at 37 °C (90 rpm). Regularly, removed
1  ml of the solution and replaced the same amount of
fresh buffer to keep the volume of the medium constant.
The percentage of MTX released was determined using
UV–vis spectroscopy analysis (UV240 Shimadzu UV–Vis
spectrophotometer) by Eq. (3).
∑ (step C). The dried hydrogels were immersed in various pHs
20Cn + Cn − 1
Percentage drug release % = × 100
m◦
(3)
where ­Cn and ­Cn−1 are concentrations of the MTX released
at times n and n−1, respectively. Also, n indicates the
time of withdrawing the solution, and ­m0 is the content of
MTX loaded on the hydrogels, mg [36, 37]. All tests were
performed in triplicate, and the mean of data is shown in
figures.
2.5 Characterization Devices
The morphology of the surface of the magnetic CMC/β-CD/
CS hydrogel or CMC/β-CD/CS hydrogel was performed by
the field emission scanning electron microscopy (FE-SEM;
MIRA3 TSCAN) equipped with EDS. The crystalline phase
of ­Fe3O4 nanoparticles was obtained using X-ray diffractom-
eter (XRD) Philips X’Pert at the wavelength of λ = 1.54 A°
with Cu-Kα radiation (30 kV, 30 mA) in the 2θ range from
5° to 80°. FT-IR spectroscopy analysis was distinguished
between 400–4000 cm−1 by a Perkin Elmer Spectrum 100.
Thermogravimetric Analysis (TGA) study was performed
using STA-1500 Scientific Rheometric Thermogravimetric
Analyzer at from 20 to 500 °C temperature range and with
a heating rate of 10 °C min−1 in an atmosphere of nitrogen.
Spectroscopy analysis of Ultraviolet–visible was determined
using (UV240 Shimadzu UV–Vis spectrophotometer) in the
wavelength of 200–800 nm. The magnetization of synthe-
sized hydrogels was performed with VSM (vibrating sample
magnetometer, 550) at room temperature.
3 Results and Discussion
3.1 Synthesis of Magnetic CMC/β‑CD/CS Hydrogel
or CMC/β‑CD/CS Hydrogel
This project was carried out for the synthesis of the novel
hydrogel as a carrier for controlled release of MTX. Figure 1
demonstrates a simple scheme of the preparation process
(2) of magnetic CMC/β-CD/CS hydrogel. The magnetic CMC/
β-CD/CS hydrogels prepared by a simple method without
a toxic agent. In the first step (A), the CMC/β-CD was pre-
pared from carboxymethyl cellulose and β-cyclodextrin by
using epichlorohydrin (ECH) as the cross-linker in a basic
media. Magnetic CMC/β-CD was produced from dissolv-
ing a mixture of F ­ eCl3 and F
­ eSO4 salts in CMC/β-CD solu-
tion and then, adding ammonia solution, by co-precipitation
method (step B). Chitosan contains cationic (­ NH3+) groups
in acidic media. Anionic groups ­(COO−) in CMC can have
electrostatic interactions with the cationic group (­ NH3+) in
the CS. These electrostatic interactions lead to gel formation
(2–11) for 24 h to confirm the stability and pH-sensitivity of
the hydrogels. The amount of swollen hydrogels at different
pH indicates that the hydrogels are pH-sensitive. To check
their stability, swollen hydrogels were dried and re-weighed.
Their weight was not significantly reduced (6  wt% decrease
of CMC/β-CD/CS hydrogel and fewer than 4 wt% decrease
of magnetic CMC/β-CD/CS hydrogels), which hints the high
stability of the hydrogels. The main scope is the evaluation
of ­Fe3O4 effect on loading and releases MTX drug.
13

Fig. 1  A simple scheme showing the preparation of magnetic CMC/β-CD/CS hydrogel
Fig. 2  X-ray diffraction analysis of low magnetic CMC/β-CD/CS
hydrogel (a), and high magnetic CMC/β-CD/CS hydrogel (b)
13
Journal of Inorganic and Organometallic Polymers and Materials
3.2 X‑Ray Diffraction
Figure 2 demonstrates the XRD pattern of the magnetic
CMC/β-CD/CS hydrogel in the different 2θ range. The XRD
profile of ­Fe3O4 showed characteristic peaks related to the
planes (220), (311), (400), (422), (511), (440) and (533) at
2θ = 30.2°, 35.6°, 43.4°, 53.7°, 57.3°, and 62.9°, respectively
[38]. The peak plane of F ­ e3O4 showed the cubic phase crys-
tal structure. Clearly, by enhancing the ­Fe3O4 nanoparticles
to the amorphous phase of CMC/β-CD/CS hydrogel, the
crystallinity of magnetic CMC/β-CD/CS is enhanced. The
crystallite size was computed as Scherer formula [39–48]
value of magnetic CMC/β-CD/CS hydrogel was calculated
to be 10.4 nm.
3.3 FTIR‑Analysis
To band formation of CMC, β-CD, CS, magnetic CMC/
β-CD/CS, MTX and MTX loaded hydrogel was identified
with FTIR spectroscopy (Fig. 3). Figure 3a demonstrates
the FTIR spectrum of CMC, which shows the wideband at
3444 cm−1 that can be corresponded to the hydroxyl groups
and ­H+ interactions. The C–H stretching asymmetrical
Journal of Inorganic and Organometallic Polymers and Materials

Fig. 3  FTIR spectra of CMC

(a), β-CD (b), CMC/β-CD (c),
CS (d)

13

bands observed at 2911 cm−1 [49]. The band at 1422 and
1609 cm−1 demonstrated the asymmetrical and symmetri-
cal of ­RCOO− groups stretching vibrations, respectively.
The peak bands found in the 1015 cm−1 were ascribed to
the C–O stretching of the polysaccharide structure [49,
50]. The FTIR of β-CD (Fig.  3b) showed the different
absorption peaks at 1030, 1429, 2922, and 3407 cm−1 due
to C–O stretching vibrations, –CH2 Bending vibrations,
CH– aliphatic and hydroxyl group. A peak band was found
at 937.04 cm−1 demonstrates the vibration of α-(1 → 4) glu-
copyranose ring of β-CD, which that shows the β-CD was
grafted onto CMC [51]. The FTIR spectrum of CS (Fig. 3d)
suggests that the bands at 1597, 1658 and 3453 cm−1 due to
the ­NH2 Bending vibrations, C=O and NH stretching vibra-
tions, respectively [38]. It can be observed from the FTIR
spectrum of CMC/β-CD/CS; the absorption peaks shift to
high wavelength and show the CMC modified with β-CD.
The FTIR spectrum of the magnetic CMC/β-CD/CS hydro-
gel indicates the peak bands Compared to the CMC/β-CD/
CS spectra can be found to shift to higher wavenumber,
which can be due to the low hydrogen bond’s number [38].
Moreover, the bands observed in the 578 and 621 cm−1 were
ascribed to the Fe–O stretching (Fig. 4a). The FTIR spectra
of MTX (Fig. 4b), the peaks at 3154 cm−1 and 3300 cm−1
demonstrated the OH and NH stretching vibrations [50].
The peaks at 1402 and 1605 cm−1 suggests C=C and C=N
aromatic. In the FTIR spectrum of MTX-loaded, magnetic
CMC/β-CD/CS hydrogel (Fig. 4c), the absorption peak at
1459 and 1544 cm−1 ascribed the NH and N ­ H3+ stretch-
ing vibration, respectively. The other characteristic peaks
were observed to shift higher wavenumber and demonstrated
loading process was carried out completely [50, 51].
3.4 Structural Morphology
The surface structural morphology of dried CMC/β-CD,
CMC/β-CD/CS hydrogel, low magnetic CMC/β-CD/CS
hydrogel and high magnetic CMC/β-CD/CS hydrogel were
evaluated by using FE-SEM technique (Fig. 5a–c). It can be
seen, the SEM image of CMC/β-CD/CS hydrogel indicates
the rough and rugged shape of particles (Fig. 5a). The SEM
images of magnetic CMC/β-CD/CS hydrogel demonstrated
that the dispersion of ­Fe3O4 on CMC/β-CD/CS hydrogel.
Figure 5b shows the low magnetic CMC/β-CD/CS hydrogel,
which the number of nanoparticles was relatively small. The
high magnetic CMC/β-CD/CS hydrogel indicates more num-
bers of nanoparticles and the F­ e3O4 agglomerated particles
due to magnetic bipolar interaction’s properties (Fig. 5c).
The elemental structure of the hydrogel samples was ana-
lyzed by EDS. The EDS of CMC/β-CD/CS hydrogel, low
and high magnetic CMC/β-CD/CS hydrogel is demon-
strated in Fig. 5a–c respectively. The particular peaks of Fe
illustrated in the EDS spectra of both magnetic hydrogels.
13
Journal of Inorganic and Organometallic Polymers and Materials
The amount of Fe in low and high magnetic CMC/β-CD/
CS hydrogel was 23.93 and 50.75 wt%, respectively. These
results were in agreement with original materials for the
preparation of magnetic CMC/β-CD/CS hydrogel applied
in the synthesis process.
3.5 Magnetic Measurements
The Magnetic properties of low magnetic CMC/β-CD/
CS hydrogel and high magnetic CMC/β-CD/CS hydrogel
were evaluated with an applied magnetic field at 25 °C.
The vibrating sample magnetometer was used for mag-
netic properties study. The hysteresis loop of low magnetic
CMC/β-CD/CS hydrogel and high magnetic CMC/β-CD/
CS hydrogel is 6.32 and 11.6 emug−1, respectively [52, 53].
Figure 6 suggests the magnetic properties are excellent for
the drug release process.
3.6 Thermal Manner Analysis
The thermal manner of the CMC/β-CD/CS hydrogel and
magnetic CMC/β-CD/CS hydrogel was studied using TGA
(Fig. 7). The CMC/β-CD/CS hydrogel displays two steps at
35–130 °C and 200–320 °C, which showed the removal of
adsorbed ­H2O molecules and decomposition of polysaccha-
ride, respectively. The second step of magnetic CMC/β-CD/
CS hydrogel was performed at 240–350 °C. The difference
in mass from CMC/β-CD/CS hydrogel and magnetic CMC/
β-CD/CS hydrogel at 500 °C is about 7 wt%. The results
suggested that the thermal stability of magnetic CMC/β-CD/
CS is higher than CMC/β-CD/CS hydrogel due to the pres-
ence of ­Fe3O4 nanoparticles [54, 55].
3.7 Swelling Test
The investigation of swelling ability for drug delivery system
of the hydrogel is a crucial factor. The swelling efficiency
regularly controls the MTX release from the CMC/β-CD/
CS hydrogel and magnetic CMC/β-CD/CS hydrogel. The
swelling test of the hydrogel was analyzed in the pH of
2–11 to evaluate the pH sensitivity of the hydrogel [48, 49].
It was found that the swelling percent of CMC/β-CD/CS
hydrogel and magnetic CMC/β-CD/CS hydrogel at pH 9
was more significant than another pH. It can be seen, the
prepared hydrogels were stable in different media due to
the weight of hydrogels changes about 10% after swelling
test [56]. In the high pH condition (6.8 and 7.4), COOH of
the CMC ­(pka = 4.7) and the amine group of CS ­(pka = 6.5)
dissociated and converted to negatively charged ions, which
making electrostatic repulsion and water penetrating in the
hydrogel [56]. In pH < 6.5, the amine group was protonated
and convert to N­ H3+, and in pH > 4.7, the acidic group was
ionized and caused the electrostatic interaction between the
Journal of Inorganic and Organometallic Polymers and Materials

Fig. 4  FTIR spectra of magnetic

CMC/β-CD/CS (a), MTX (b)
and MTX loaded magnetic
CMC/β-CD/CS (c)

13
 Journal of Inorganic and Organometallic Polymers and Materials

13
 Journal of Inorganic and Organometallic Polymers and Materials
◂Fig. 5  SEM/EDS images of, CMC/β-CD/CS hydrogel (a1, a2), low
magnetic CMC/β-CD/CS hydrogel (b1, b2) and high magnetic CMC/
β-CD/CS hydrogel (c1, c2)
negative and positive charge ion and the swelling percentage
was decreased. The influence of the ­Fe3O4 nanoparticles on
swelling degree was also evaluated. It is obvious (Fig. 8),
the swelling degree of magnetic CMC/β-CD/CS hydrogel
was reduced as compared with CMC/β-CD/CS hydrogel.
This decrease in swelling capacity can be attributed to the
existence of F ­ e3O4. The presence of F ­ e3O4 nanoparticles
restricts the development of polymer chains. The interac-
tions between F ­ e3O4 and the biopolymer chains can increase
the points of connection and thus reduce the swelling capac-
ity [57, 58]. In addition, by increasing the amount of F
­ e 3O 4,
the swelling percentage of hydrogel gradually decreased
[59].
3.8 Drug Loading Study
The drug loading efficiency was studied to explore the
capacity of magnetic hydrogels as new carriers. The MTX
loaded hydrogels were prepared by a simple mixing method.
The content of MTX loading was evaluated using UV–Vis
spectra. The MTX loading percentage was determined for
three samples. The MTX loading amount of CMC/β-CD/CS
hydrogel, low magnetic CMC/β-CD/CS hydrogel and high
magnetic CMC/β-CD/CS hydrogel were 51, 74 and 85%,
respectively. The percentage of drug loading in the magnetic
hydrogel increased with increasing magnetite content. This
increase can be due to the high surface area of nanoparti-
cles. The interaction between the hydroxyl group of ­Fe3O4
in magnetic CMC/β-CD/CS hydrogel and MTX agent group
causes the significant MTX loading compared to pure CMC/
β-CD/CS hydrogel samples [60, 61].
3.9 Drug Release Studies
The cumulative release of MTX from hydrogels was per-
formed to evaluate the suitability of CMC/β-CD/CS hydro-
gel, low and high magnetic CMC/β-CD/CS hydrogel as drug
delivery. The dried hydrogels containing the MTX drug were
used to study the in vitro release of drugs. The drug will
be released by the swelling of the hydrogel in a solution
and until it reaches the equilibrium state. The release of
MTX from hydrogels is a pH-related behaviour; therefore
the release of MTX from hydrogels and magnetic hydrogels
was investigated at pH 1.2, 5.3 and 7.4 at 37 °C (Fig. 9).
The content of the drug released at pH 1.2 was low, and
this event could be assigned to the low swelling capacity of
the hydrogel. At higher pH (5.3, 7.4), the amount of drug
released was increased significantly for all hydrogels as
compared at pH 1.2, primarily due to the partial swelling
of hydrogel in an acidic environment. Additionally, the low
release of MTX under acidic media is arisen from the low
solubility of MTX. The low solubility of MTX at pH 1.2
is originated from the presence of weak carboxylic acid on
drug with ­pKa of about 4.8 [62]. The results obtained show
that the amount of MTX released for non-magnetic hydro-
gel is higher than the magnetic hydrogel. High swelling of
hydrogel leads to an increase in the pore size in the hydrogel
and thus makes the MTX release easier. The rapid release of
MTX in the first hours is due to the dissolution and release
of the drug absorbed on the surface of the hydrogel. The
release of MTX at pH 5.3 was slower than 7.4. The results
can be explained by the pKa amounts of functional groups in
the drug and biopolymer. At pH 7.4, the carboxylate groups
in the CMC with pKa 4.7 are negatively charged (­ COO−),
and the amine groups in the CS with pKa 6.5, are as amine
­(NH2) form (non-ionic). Due to different amounts of pKa,
hydrogels can exhibit amphoteric properties. The MTX con-
tains the two carboxylate groups (pKa 3.8 and 4.8) and the
amine group (pKa 5.6) [62]. Thus, MTX is dominated at pH
7.4 ­(NH2, ­CO2−), and at pH 5.3 ­(NH3+, ­CO2−). At pH 7.4,
electrostatic repulsion forces between the MTX and anionic
groups of carrier lead to a rapid release of methotrexate from
hydrogels. Whereas, at pH 5.3, the attractive electrostatic
force between the protonated amine groups of MTX and
the anionic carboxylate groups of the biopolymer and also,
­NH3+ groups of the biopolymer and COO– groups of MTX
­(NH3+…COO−), leads to the slow release of MTX from the
hydrogel. Finally, the effect of an external alternating mag-
netic field (AMF) was investigated on the behaviour of the
release from magnetic CMC/β-CD/CS hydrogel (Fig. 9d).
The results showed that, with the use of external AMF,
the amount of released drug was increased from magnetic
CMC/β-CD/CS hydrogel. The use of AMF may be assigned
to the alignment of magnetic nanoparticles ­(Fe3O4), which
leads to an increase in the release of the drug. Due to the
constant movement of magnetic nanoparticles, the oscilla-
tion of applied AMF can operate as an incentive to stimulate
magnetic nanoparticles. This motion of magnetic nanopar-
ticles can lead to the relaxation of polymer chains [63, 64].
Figure 9 showed the release of MTX from high magnetic
CMC/β-CD/CS hydrogels was more elevated than low mag-
netic CMC/β-CD/CS hydrogels under external AMF.
4 Conclusion
The new pH-sensitive CMC/β-CD/CS hydrogel and mag-
netic CMC/β-CD/CS hydrogel was successfully prepared
via a straightforward method. Structural data were evalu-
ated by TGA, FT-IR, SEM, XRD, and VSM studies. SEM
analysis indicated that the F
­ e3O4 nanoparticles had affected
the morphology structure of the CMC/β-CD/CS hydrogel.
13
 Journal of Inorganic and Organometallic Polymers and Materials

15 12
A CMC/β-CD/CS hydrogel
B
Low magnecCMC/β-CD/CS hydrogel
10 10
High magnec CMC/β-CD/CS hydrogel

5
8
Magnezaon (emu/g)

Swelling (g/g)
6
0

4
-5

2
-10

0
-15 2 3 5 7 9 11
-20000 -15000 -10000 -5000 0 5000 10000 15000 20000 pH
Applied field (Oe)

Fig. 8  The swelling behaviors of hydrogel at different pH, results are

Fig. 6  Magnetization curve as a function of applied magnetic field for expressed as the three independent experiments
low magnetic CMC/β-CD/CS hydrogel (a), and high magnetic CMC/
β-CD/CS hydrogel (b)
Moreover, the ­Fe3O4 nanoparticles effect on the swelling
100
and MTX release manner of the CMC/β-CD/CS hydrogel
was evaluated. The swelling percent of the CMC/β-CD/CS
hydrogel was higher than of the magnetic CMC/β-CD/CS
80 hydrogel, which pertained on the pore size of the hydro-
gel. Enhancing the ­Fe3O4 nanoparticles on CMC/β-CD/CS
hydrogel led to a rise in thermal stability of the CMC/β-CD/
WT Loss (%)

60
CS hydrogel. Moreover, the swelling manner of CMC/β-CD/
CS hydrogel and magnetic CMC/β-CD/CS hydrogel was
40 evaluated in a different medium, and it was found that the
B
A swelling capacity of prepared hydrogels was enhanced at
high pH value. The MTX released study suggests that the
20 prepared magnetic CMC/β-CD/CS hydrogel not only was
affected by the pH of media but also a magnetic sensitivity to
an external AMF. The result showed the synthesized CMC/
0
0 100 200 300 400 500 β-CD/CS hydrogel and magnetic CMC/β-CD/CS hydrogel
Temperature (°C) could be used as an oral MTX delivery system.

Fig. 7  TGA thermograms of CMC/β-CD/CS hydrogel (a), low mag-

netic CMC/β-CD/CS hydrogel (b)

13
Journal of Inorganic and Organometallic Polymers and Materials

A 20
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