Colloids and Surfaces A: Physicochemical and Engineering Aspects 673 (2023) 131815

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Colloids and Surfaces A: Physicochemical and

Engineering Aspects
journal homepage: www.elsevier.com/locate/colsurfa

Synthesis and characterization of biodegradable gum ghatti-cl-poly

(AA-co-NIPAm)/GO based hydrogel for metformin and sodium diclofenac
combined drug delivery system
Pragnesh N. Dave a, *, Pradip M. Macwan b, Bhagvan Kamaliya a
a
Department of Chemistry, Sardar Patel University, Vallabh Vidyangar 388 120, Gujarat, India
b
B. N. Patel Institute of Paramedical & Science (Science Division), Sardar Patel Education Trust, Bhalej Road, Anand 388001, Gujarat, India

H I G H L I G H T S G R A P H I C A L A B S T R A C T

• The synthesized nanocomposites based

hydrogel for Metformin and Sodium
Diclofenac combined Drug Delivery
System.
• Optimized pH (7.4) for maximum
controlled metformin release using
nanocomposites hydrogel.
• The zero order, first order kinetic
models, the Korsemeyar-Peppas model,
the Higuchi model, and the Hixson-
Crowell model have all been used to
study the drug release kinetics and
mechanism.
• Both metformin and sodium diclofenac
medication showed a Fickian mecha­
nism at pH 7.4
• Gum ghatti-cl-poly(Acrylic acid-co-N-
isopropylacrylamide)/GO based hydro­
gel for combined Drug Delivery System.

A R T I C L E I N F O A B S T R A C T

Keywords: In the current study, we investigated whether combining metformin with diclofenac, a non-steroidal anti-in­
Drug release flammatory medicine (NSAID), would be effective in examining the complex formation and analyzing the types
Gum ghatti and intensities of complexes that may occur from interactions between metformin and diclofenac. At varied pH
Graphene oxide
levels and at body temperature, the interaction of metformin with diclofenac was examined in-vitro. FTIR
Metformin hydrochloride
spectra, FE-SEM analysis, DSC analysis, DLS analysis, and drug loading studies were used to characterize the
Sodium diclofenac
Anti-inflammatory structure, morphology, thermal analysis, and average size values of the generated hydrogel. Hydrogel was loaded
with metformin hydrochloride and sodium diclofenac (DS) as a model drug, and the drugs were released in a pH-
dependent manner. The zero-order, and first-order kinetic models, the Korsemeyar-Peppas model, the Higuchi
model, and the Hixson-Crowell model have all been used to study the drug release kinetics and mechanism.
Studies on drug release showed noteworthy behaviors in relation to physiologically modeled pH’s, with a high
release rate at pH = 7.4. However, both metformin and sodium diclofenac medication showed a Fickian

* Corresponding author.
E-mail address: pragnesh7@yahoo.com (P.N. Dave).

https://doi.org/10.1016/j.colsurfa.2023.131815
Received 24 March 2023; Received in revised form 24 May 2023; Accepted 4 June 2023
Available online 7 June 2023
0927-7757/© 2023 Elsevier B.V. All rights reserved.
P.N. Dave et al.
mechanism at pH 7.4. Combination therapy may lower the single agent’s effective dosage and inhibit metabolic
rescue mechanisms. To identify potential adverse effects on people, more research is required.
1. Introduction
The technique or process used to provide pharmaceutical substances
to achieve a therapeutic effect in people or animals is known as drug
delivery [1]. The creation of new materials or carrier systems for effi­
cient therapeutic drug delivery is a large area of study in the field of drug
delivery [2]. These systems are crucial in the treatment of many dis­
eases. A novel drug’s molecule requires expensive and time-consuming
development. The adoption of diverse methods, including dosage titra­
tion, individualized drug therapy, and therapeutic drug monitoring,
improve the safety efficacy ratios of older drugs [3]. Drug distribution
may be regulated, targeted, or constant. Understanding drug in­
teractions may help in early detection and avoidance of negative effects.
The capacity of stimuli-responsive hydrogels made of natural polymers
to drastically alter their volume and other characteristics in response to
minute changes in stimuli like temperature, pH, and specific chemicals
has recently gained a lot of interest [4]. Due to their exceptional qual­
ities, including hydrophilicity, biocompatibility, biodegradability, and
good water absorption capacity, they have been extensively employed in
biomedical domains [5,6].
The capacity of natural polysaccharides to be fermented in the large
intestine by microbial enzymes, which produce physical and diffusion
barriers and result in prolonged release, has led to their consideration as
prospective candidates for colon-specific drug delivery in recent years
[7]. Hovgaard and Brondsted evaluated the most recent uses of poly­
saccharides for the administration of colon-specific medications [8].
Many polysaccharides, including sodium alginate, chitosan, guar gum,
xanthan gum, pectin, and gellan gum, have been employed in the cre­
ation of tissue engineering techniques, biomedical implants, and drug
delivery systems up to this point. pH-sensitive hydrogels have been
employed often to create drug delivery systems among these hydrogels.
Because it affects how the human gastrointestinal (GI) tract works, the
pH plays a significant role in physiological media. Starting with the
stomach’s acidic pH (pH 2–3), it gradually increases in the small intes­
tine (pH 6.5–7) and colon (pH 6.5–7) (pH > 7). An efficient method is to
graft synthetic polymers onto the backbones of natural polymers to
create interpenetrating network architectures. According to a report,
cross-linked hydrogels feature multiple ionizing groups that are sensi­
tive to a variety of bodily stimuli, including pH, ionic strength, tem­
perature, etc [8].
Numerous biodegradable hydrogels have been employed for the
regulated distribution of proteins to skin wounds and bone deformities
so far [9–11]. The main benefit of using biodegradable polymers as drug
delivery vehicles is that they may be employed in controlled release
systems and can remain inside the patient because of their biocompat­
ibility. Gg is a naturally occurring polymer that has generated a lot of
research interest in the pharmaceutical and other sectors because of its
low cost, nontoxicity, biodegradability, biocompatibility, and high vis­
cosity [12]. The atomic structure of Gg consists of chains of 1 → 6
connected β-D-galactopyranose links, which are often single L-arabino­
furanose residues, as well as 4-O- and 2-O-substituted α-D-mannopyr­
anose units. Gg has just received GRAS (generally recognized as safe)
material approval in the United States. It has replaced synthetic food
additives consequently, improving the quality of numerous food items.
The mechanical and drug release characteristics of several
polysaccharide-based hydrogels have been enhanced by adding GO.
These GO-based polymer composites do in fact combine GO and
hydrogel characteristics. The regulated drug release profile of the drugs
has also been enhanced using GO-based composite hydrogels [13]. The
oxygen-containing groups of GO form strong connections with the
polymers, resulting in composites that are simple to mix and are
2
Colloids and Surfaces A: Physicochemical and Engineering Aspects 673 (2023) 131815
homogeneous [14]. In response to these problems, an effort was made to
create hydrogel composites based on gum ghatti with an inter­
penetrating network utilizing free radical copolymerization and a cross
linker-initiator system comprising N, N′ -methylene-bis-acrylamide
(MBA) and ammonium peroxydisulfate (APS) and Tetramethylethyle­
nediamine (TEMED) as an initiator.
The most often recommended drug for the treatment of type-2 dia­
betes (T2DM) is metformin (Fig. S1) (1,1-dimethyl biguanide hydro­
chloride)[15]. Metformin hydrochloride is an oral biguanide medication
that is extremely water-soluble (>300 mg/ml at 25 C; pKa = 2.8 and
11.5) and belongs to BCS class III (high solubility and low permeability)
[16]. It was discovered that the biguanide drug has antineoplastic
properties in addition to its anti-diabetic and indirect hypoglycemic
actions and may lower the incidence of numerous cancer forms in dia­
betic individuals [17]. Human glioblastoma (GBM) lines [18] and
glioma-initiating cells both showed anti-proliferative and anti-migratory
effects in in vitro experiments [19,20]. The respiratory chain’s
complex-I is inhibited by metformin to cause its effects [21]. According
to a recent study by Seliger et al. [22], using metformin to treat T2DM is
not substantially related to a lower incidence of glioma. Therapeutic
effects, such as those that have anti-proliferative and anti-migratory
effects on tumor cells, may have distinct modes of action and must be
separated from those that may have a dubious preventive impact on the
incidence of gliomas.
Diclofenac (Fig. S2), a non-steroidal anti-inflammatory drug pri­
marily used for its analgesic properties, may prevent tumor cells from
undergoing glycolysis [16]. It belongs to the Biopharmaceutics Classi­
fication System (BCS) class II (low solubility and high permeability) and
is only marginally water-soluble (pKa = 4). Menstrual discomfort, mild
to severe post-operative or post-traumatic pain, endometritis, and other
conditions are frequently treated with it. For the treatment of chronic
illnesses such as rheumatoid arthritis, osteoarthritis, chronic pain,
ankylosing spondylitis, and actinic keratosis, extended-release diclofe­
nac formulations are necessary [16]. According to epidemiological
research, COX-2 inhibitors may somewhat lower the risk of certain
cancer types linked to chronic inflammatory processes [23]. Diclofenac
is investigated as a potential inhibitor of the outward transport of lactate
in addition to other COX-dependent and independent modes of action
[24]. As a result, mitochondrial and glycolytic ATP synthesis is sup­
pressed, and glucose absorption is decreased [25].
Combining knowledge of the mechanism of drug interaction with the
identification of high-risk patients and drugs with a limited therapeutic
index will result in the most thorough understanding of clinically
important drug interactions. Drug interaction issues can be resolved
partially by altering the chemical pattern, blocking the molecule’s
reactive site, altering the dosing schedule, or by avoiding the simulta­
neous application of interacting drugs [26]. However, it is important to
understand the nature of interaction before taking any action to handle
the interaction difficulties. Before a new medicine is used in a thera­
peutic setting, we should be aware of potential interactions. Interaction
studies are crucial for medications that are now prescribed traditionally
to identify any potential issues. Gerthofer et al. investigated whether
treating BTICs (BTIC-8, − 11, − 13, and − 18) and tumor cell lines with
metformin and diclofenac simultaneously might have additive or even
synergistic effects (TCs, U87, and HTZ349). So, they looked at the
metabolic impacts, such as oxygen consumption and extracellular
lactate levels, the functional effects, such as proliferation and migration,
and the effects on the protein level, such as signaling cascades [25].
The main goal of the current study was to investigate complex for­
mation and analyze the kind and intensity of complexes that can result
from metformin and diclofenac interactions.
P.N. Dave et al. Colloids and Surfaces A: Physicochemical and Engineering Aspects 673 (2023) 131815

Table 1
Optimized quantities used for the preparation of hydrogels.
Sample code Gum ghatti NIPAm AA APS MBA TEMED GO H2O
(gm) (gm) (ml) (mg) (mg) (ml) (mg) (ml)

GGNAGO-0 0.5 0.2 1.0 50 50 0.1 0 10

GGNAGO-1 0.5 0.2 1.0 50 50 0.1 1 10
GGNAGO-2 0.5 0.2 1.0 50 50 0.1 2 10
GGNAGO-3 0.5 0.2 1.0 50 50 0.1 3 10
GGNAGO-4 0.5 0.2 1.0 50 50 0.1 4 10
GGNAGO-5 0.5 0.2 1.0 50 50 0.1 5 10

2. Materials and methods
2.1. Materials
Gum ghatti (Gg), acrylic acid (AA), Ammonium persulfate (APS),
Tetramethyl ethylenediamine (TEMED) and N, N′ - Methyl­
enebisacrylamide (MBA) were purchased from LobaChemie (Mumbai,
India). N-isopropylacrylamide (NIPAm) was purchased from TCI. Gra­
phene oxide was purchased from Sigma Aldrich (Munich, Germany).
Metformin hydrochloride (CAS Number:1115–70–4) was purchased
from Himedia and Sodium diclofenac (SD) (CAS Number: 15307–79–6)
was purchased from Sigma Aldrich.
2.2. Synthesis of Gum ghatti-cl-poly(N-isopropylacrylamide-co-acrylic
acid)/GO
Gg-cl-Poly(NIPAm-co-AA)/GO hydrogels were synthesized according
to the reported method [27–30]. In the typical procedure, adding 0.5 g
Gg to 10 ml of distilled water in a 100 ml beaker and kept rest for 24 h
for better dissolution of the biopolymer in water. The composition was
sonicated for 40 min and after that GO (0–5 mg) to biopolymer solution
was added. The beaker was then filled with 0.2 gm of NIPAm and the
required amounts of APS, TEMED, and MBA were added as shown in
Table 1. In the final phase, 1 ml of AA was added with continuous
stirring. The beaker was left undisturbed at 50 ◦ C for 3hrs. After 3 hrs,
the beaker was allowed to cool at room temperature. The formed
homo-polymer was extracted using consecutive acetone extractions. The
hydrogel was allowed to dry gradually at 50 ◦ C for 48 h and ground into
a powder with a mortar and pestle.
2.3. Characterization of hydrogel
Fourier transform infrared (FT-IR) spectra of materials were recor­
ded on the Perkin Elmer instrument using the KBr plate method in the
range of 400–4000 cm− 1. X-ray diffraction (XRD) of materials was car­
ried out on Rigaku; miniflex 600, Japan with CuKα radiation (λ =
1.5418). The SEM images were taken on Philips, Netherland’s instru­
ment, and NT-MDT, Ntegra Aura respectively. DSC was performed to
characterize hydrogel for thermal stability. DSC was done in the DSC
unit (DSC model 7000x, HITACHI). The samples were heated at a tem­
perature of 10 ◦ C to 300 ◦ C in a close aluminum pan at the rate of 10 ◦ C/
min under nitrogen flow (10 ml/min). The particle size analyser of
samples was studied in a Dynamic Light Scattering (DLS) instrument,
Zetasizer, model: SZ100 nanopartica, supplied by Horiba Instruments
Ltd., Japan. In each case, 20 mg hydrogel as a dispersant was added to 2
ml of distilled water.
2.4. Drug loading study
2.4.1. Loading of metformin and sodium diclofenac onto the hydrogel
Model drugs sodium diclofenac and water-soluble metformin were
introduced into hydrogel using a swelling-diffusion method [12]. A 100
ml solution of metformin (1.0 mg/ml) and sodium diclofenac (1.0
mg/ml) was poured into the dried hydrogels (1.0 g), and they were then
incubated at 37 ◦ C for 24 h. After being taken out of the solutions, the
composite hydrogels were rinsed with deionized water and dried in an
oven at 50 ◦ C to a consistent weight. Using a UV-Visible spectropho­
tometer, the amounts of metformin and sodium diclofenac were deter­
mined (Shimadzu-1800). The drug entrapment efficiency (EE) of the
hydrogel was determined using Eq. 1 shown below [30].
( ) ( )
WD
DL % = × 100 (1)
W0
Where WD is the total amount of drug in solution after loading and W0 is
the total amount of drug in solution before loading.
2.4.2. In-vitro drug release study
The release profiles of model drugs from the drug-loaded hydrogel
(powder type) were studied in distilled water, at pH 1.2 buffer (simu­
lated gastric fluid), pH 7.4 buffer (simulated intestinal fluid), and pH 9.2
(borate). The calibration curves of the drugs were prepared in distilled
water, in pH 1.2 buffer, in pH 7.4 buffer, and in pH 9.2 buffer solutions
at 232 nm for metformin, at 276 nm for sodium diclofenac using UV-
Visible spectrophotometer (Shimadzu-1800). The release experiments
were performed by immersing drug-loaded hydrogels in 100 ml PBS
buffer (pH = 7.4), HCl (pH = 1.2), and Borax (pH = 9.2) solution. The
release studies were performed at a physiological temperature of 37 ◦ C
in an incubator at 100 rpm. A small volume of the release medium
(5.0 ml) was withdrawn at scheduled time intervals to determine the
drug concentration using a UV-Visible spectrophotometer and an iden­
tical volume of fresh medium was added.
2.4.3. Mechanism of drug release
The release data was fitted in the well-known Korsmeyer-Peppas
equation shown below to describe the drug release process [31,32].
Mt
= ktn (2)
M∞
where k is a release rate constant typical of the structure and geometry
of the drug delivery device, n is the diffusion exponent characteristic of
the release mechanism, and Mt/M∞ is the proportion of the drug
released at the time ’t’[33–35]. The values of n and k are obtained from
the slope and intercept of the log Mt/M∞ plot and the log t plot,
respectively. Depending on the relative rates of water diffusion into the
polymer matrix and the rate of polymer chain relaxation, there are three
different ways that drugs can be released from drug-loaded polymers.
For the sample, n = 0.89 relates to case II diffusion (the release mech­
anism is relaxation controlled), n = 0.45 relates to Fickian diffusion (the
release mechanism is diffusion controlled), and n between 0.45 and 0.89
relates to non-Fickian diffusion (a mixture of Fickian diffusion and
polymer chain relaxation) [36].
2.4.4. Kinetics of drug release
The best fit of the curves to several kinetic models, including the
zero-order model (Eq. 3), the first-order model (Eq. 4), the Higuchi
model (Eq. 5), the Korsmeyer-Peppas model (Eq. 6) and the Hixson-
Crowell model (Eq. 7) was used to determine the kinetics of drug
release from the hydrogel [34].

3
P.N. Dave et al. Colloids and Surfaces A: Physicochemical and Engineering Aspects 673 (2023) 131815

Scheme 1. Possible mechanism for Gum ghatti-cl-poly (NIPAm-co-AA)/GO.

Mt 3. Results and discussion

= k0 t (3)
M∞
( ) 3.1. Synthesis mechanistic aspect
Mt
log = k1 t (4)
M∞ In the first step, the Gum ghatti and GO were mixed in water. In this
( ) mixture, the hydrophilic groups of Gg such as hydroxyls can interact
Mt 1
= k2 t2 (5) with hydrophilic groups (hydroxyl and carboxylic acid groups) on GO
M∞ via hydrogen bonding or electrostatic interactions to make a complex
( ) (GO-Gg-OH). Furthermore, this complex can form via a nucleophilic
Mt
= k3 tn (6) attack of hydroxyl groups of Gg polysaccharide on the epoxide ring of
M∞ GO via a ring-opening reaction. Crosslinking and graft copolymerization
√ ̅̅̅̅̅̅̅ √̅̅̅̅̅̅ of poly (acrylic acid and N-isopropyl acrylamide) onto the backbone of
3
M0 − 3 Mt = k4 t (7) Gg in the proximity of GO (GO-Gg-OH) was carried out in an aqueous
In the above-stated model Mt/M∞ is the cumulative fraction of drug medium using APS and TEMED as a radical initiator and MBA as a
release, ‘t′ is the release time, ‘n′ is the release exponent, M0 is the crosslinker. The persulfate decomposes on heating (at 50 ◦ C) and pro­
amount of drug loaded in the hydrogel, Mt is the amount of drug release duces sulfate radical anions, which abstract hydrogen from the Gg
at a time ‘t′ and k0, k1, k2, k3, and k4 are the release rate constants [35]. backbone (from OH or anomeric CH) to form corresponding radicals.
This persulfate saccharide radical system can radically initiate the
polymerization of AA and NIPAm monomers and lead to a graft copol­
ymer. Since the MBA is a crosslinking agent, and GO is accessible in the
system, the copolymer (GNAGO) comprises a cross-linked

4
P.N. Dave et al. Colloids and Surfaces A: Physicochemical and Engineering Aspects 673 (2023) 131815

Fig. 1. FT-IR spectra for (a) pure Gum ghatti (Gg), (b) pure graphene oxide
(GO), (c) GNAGO-0 hydrogel, (d) GNAGO-3 hydrogel, (e) GNAGO-0 drug-
loaded hydrogel and (f) GNAGO-3 drug-loaded hydrogel.

nanocomposite structure (Scheme 1) [37].

3.2. Fourier transform infrared spectroscopy (FTIR Spectroscopy)

Gum ghatti showed a wide absorption band at 3340.70 cm− 1

(Fig. 1a) because of the presence of -OH in galactopyranose and gluco­
pyranose rings, a peak at 2910.58 cm− 1 arises because of the C-H
stretching mode of the -CH2 group, and peak at 1610.56 cm− 1 is because
of the C–– O stretching vibrations[38]. It was determined that the py­
ranose rings of polysaccharides’ C-O and C-C stretching vibrations were
responsible for the absorption peaks between 1026.13 cm− 1 and
1323 cm− 1. The peaks at 1310 cm− 1 and 1210 cm− 1 were caused by
stretching vibrations of the C-O-C [39]. The FTIR spectra of GO (Fig. 1b)
revealed a strong and wide O-H stretching vibration at 3410 cm− 1, ar­
omatic C– – C stretching at 1610 cm− 1, carbonyl/carboxyl C– – O stretch­
ing at 1724 cm− 1 [40], and alkoxy C-O stretching vibration at
1050 cm− 1 [41].
The O-H stretching from the carboxylic group is responsible for the
conspicuous peak at 3363 cm− 1. The peak at 3178 cm− 1 is caused by N-
H bending vibration from the NIPAm-CONH2 group. Furthermore, the
distinctive peak at 1735 cm− 1 is due to the C–– O stretching of the car­
boxylic acid group of PAA, and the peak at 1612 cm− 1 is due to NIPAm
C–– O stretching [42]. The aromatic C–– C stretching vibration causes the
peak at 1450 cm− 1, whereas the C-N stretching vibration causes the
peak at 1280 cm− 1. The results show that a Gum ghatti-cl-poly
(NIPAm-co-AA) hydrogel was formed. The small alterations in the FTIR
spectra with the addition of GO, the broad peak around
3400–3200 cm− 1 (Fig. 1c-d) indicates the establishment of a hydrogen
bonding between hydrogels and graphene oxide [43].
The spectrum of GNAGO-0 and GNAGO-3 hydrogel containing
metformin hydrochloride and Sodium diclofenac (Fig. 1e-f) shows the Fig. 2. FE-SEM images for (a) pure graphene oxide, (b) GNAGO-0 hydrogel and
characteristics peak of N-H stretching bands of metformin hydrochloride (c) GNAGO-3 hydrogel.
at 3348 cm− 1; additionally, the spectrum bands at 2923 cm− 1 and
942 cm− 1 cans be assigned to C-H stretching and C-O stretching vibra­ and MET. Thus, it demonstrates the drug loading in hydrogels [47].
tions, respectively. It can be observed that the vibration bands of Gum
ghatti overlap with other bands in the region 1689–1018 cm− 1 [44]. The
high vibration at 1735 cm− 1 corresponds to the C– – O stretch of GNAGO 3.3. Scanning electron microscopy (SEM)
and was transferred to the SD of GNAGO at 1689 cm− 1. After loading,
the band allocated to the C-O-C stretch was moved from 1164 cm− 1 to Fig. 2 displays SEM images of hydrogels made from gum ghatti-cl-
1157 cm− 1 [45] of Metformin and sodium diclofenac [46]. The devel­ poly(NIPAm-co-AA), graphene oxide (GO), and gum ghatti-cl-poly
opment of new bonds between polymer, SD, and MET might explain the (NIPAm-co-AA)/GO. Due to abrasion and disassembly, the GO has a
shifting of the absorption bands. Furthermore, the spectra revealed ab­ multi-layered, disordered structure, as shown in Fig. 2(a), as well as a
sorption bands at 3448 cm− 1 that were ascribed to the N-H group of DCF pleated sheet-like structure [48]. The surface morphology of the

5
P.N. Dave et al.
Fig. 3. DSC profile for (a) GNAGO-0 hydrogel, (b) GNAGO-3 hydrogel, (c)
GNAGO-0D drug loaded hydrogel and (d) GNAGO-3D drug loaded hydrogel.
hydrogel without graphene oxide seems rough, but it gets smooth with
graphene oxide. The graphene oxide particles may operate as a nucle­
ating center over which the polymer develops at a constant rate [43].
The agglomerated structures were formed because of the addition of GO.
Fig. 4. DLS plots for (a) pure gum ghatti (Gg), (b) pure graphene oxide (GO), (c) GNAGO-0 hydrogel and (d) GNAGO-3 hydrogel.
6
Colloids and Surfaces A: Physicochemical and Engineering Aspects 673 (2023) 131815
This suggested that GO was responsible for causing the scattered phase
to agglomerate.
3.4. Thermal analysis (DSC)
The thermogram of GNAGO-0 (Fig. 3a) indicated an initial endo­
thermic peak at 101.2 ◦ C (with an enthalpy of − 132.18 J/g) owing to
absorbed moisture and an endothermic peak due to decomposition at
245.2 ◦ C (with an enthalpy of − 195.62 J/g). The Thermogram of
GNAGO-3 (Fig. 3b) indicated an early endothermic peak at 102.3 ◦ C
(with an enthalpy of − 14.18 J/g) owing to moisture loss, as well as
endothermic peaks at 207.23 ◦ C (with an enthalpy of − 8.33 J/g) and
251.20 ◦ C (with an enthalpy of − 62.58 J/g). This effect might be
induced by the existence of free protonated amine groups in NIPAm for
interaction with carboxylic groups in AA. Fig. 3c and d reveal a strong
endothermic peak at 178.67 ◦ C (with an enthalpy of − 6.99 J/g and
− 6.08 J/g) and an endothermic peak at 260.12 ◦ C (with an enthalpy of
− 50.61 J/g and − 50.95 J/g), indicating drug breakdown. The existence
of a drug peak indicates that the drug is not interacting with the
hydrogel formulation’s polymers and is present in its intact form in the
hydrogel matrix [49].
3.5. Dynamic light scattering (DLS) investigations
According to Fig. 4, the GG and GO intensity-average size values
P.N. Dave et al. Colloids and Surfaces A: Physicochemical and Engineering Aspects 673 (2023) 131815

Table 2
Percentage drug loading of GNAGO-0 and GNAGO-3 hydrogels at fixed tem­
perature and fixed pH values.

± 0.0014

± 0.0021
0.02282

0.07144
Sample Temp. pH Metformin drug Sodium Diclofenac drug
code (◦ C) loaded (%) loaded (%)

n
GNAGO-0 30 6.8 46.53 93.33

GNAGO-3
(pH-9.2)

0.93543
0.93158
0.98609
0.96964

0.93288

0.84386
0.82395
0.94607
0.99311
GNAGO-3 30 6.8 46.34 99.16

0.8307
R2

± 0.00266

± 0.0031
0.04809

0.13819
n
GNAGO-3
(pH-7.4)

0.95717
0.94916
0.99749
0.97605

0.95191

0.93341
0.90049
0.99052

0.91219
0.996
R2

± 0.01484

± 0.03527
0.11501

0.38232
n
Metformin and Sodium diclofenac drug release kinetics of GNAGO-0 and GNAGO-3 at different pH values (pH = 1.2, pH = 7.4 and pH = 9.2).
GNAGO-3
(pH-1.2)

0.99373
0.99028
0.96442
0.88078

0.99179

0.96447
0.94337
0.94481
0.93574

0.95563
R2

± 8.19157E-4
Fig. 5. Cumulative drug release against time (hrs) plots for metformin loaded

± 0.00318
0.03639

0.05408
GNAGO-0 and GNAGO-3 hydrogels at pH = 1.2, pH = 7.4 and pH = 9.2 and
37 ◦ C temperature.
n
GNAGO-0

(sonicated under similar circumstances for the process of preparing

(pH-9.2)

0.98199
0.94194

0.94816

0.87262
0.85851
0.96393
0.99817

0.86328
0.9467
0.951

GNAGO) in pure water were about 1.87 nm (81.67 %) and 1.15 nm

R2

(3.68 %) and 72.87 nm (2.20 %). These values indicate the Gum ghatti
amorphous nature and for GO the particle gets distributed after soni­
cation in water [41]. After the polymerization of hydrogels GNAGO-0
and GNAGO-3 intensity-average sizes, nanocomposites were to be
± 0.00333

± 0.00394
0.06028

64.5 nm (4.92 %) and 93.2 nm (80.6 %) demonstrating a significant

0.1076
increase in the average particle size of GO upon complexation with
n

hydrogel.
GNAGO-0
(pH-7.4)

0.95736
0.94707
0.99653
0.97607

0.95063

0.91863
0.99357
0.98939

0.92586
0.9393

3.6. Drug loading efficiency

R2

The model drug of metformin and sodium diclofenac loaded onto

hydrogel (GNAGO-0 and GNAGO-3) is depicted in Table 2 below.
± 0.01416
± 0.0127

From the above table (Table 2) it can be seen that the drug loading
0.17871

0.35491
Sodium Diclofenac

efficiency of the synthesized GNAGO-0 and GNAGO-3 hydrogel is 46.53

% and 46.34 % for metformin while for sodium diclofenac drug for the
n

Metformin

same hydrogel is 93.33 and 99.16 % at a temperature at 30 ◦ C and pH of

GNAGO-0
(pH-1.2)

0.88898
0.86038
0.95735
0.96058

0.87033

0.93102
0.86463

0.98741

0.89035
0.9811

6.8.
R2

3.7. In-Vitro Drug release study

log(Mt/M∞) vs

log(Mt/M∞) vs
Mt/M∞ vs t1/2

Mt/M∞ vs t1/2
Mt vs t

Mt vs t
log Mt vs t

log Mt vs t

3.7.1. Effect of pH on Metformin drug release

The effect of pH on metformin and sodium diclofenac release
Mt vs t

Mt vs t
Linear

M0 −

M0 −
̅̅̅̅̅̅̅

̅̅̅̅̅̅̅
̅̅̅̅̅̅

̅̅̅̅̅̅
log t

log t

behavior through Gg-cl-poly(AA-co-NIPAm) and Gg-cl-poly(AA-co-

√

√
fit

√
3

3
3

NIPAm)/GO (3 mg) has been studied. From Fig. 5 it is evident that for
the hydrogels GNAGO-0 and GNAGO-3 the cumulative drug release was
Hixson-Crowell

Hixson-Crowell

found to be about 40.87 % and 38.78 % at a pH of 1.2. While for the

Korsmeyer–

Korsmeyer–

same hydrogel samples, the drug release was found to be 90.58 % and
First-order

First-order
Zero-order

Zero-order
Peppa’s

Peppa’s
model

model

93.61 % in more basic media at pH = 7.4 while the release reached the
Higuchi

Higuchi
models
Kinetic
Table 3

value of 79.90 % and 82.36 % at pH = 9.2. The environment of the

gastrointestinal tract (GIT) was reproduced by employing the buffer

7
P.N. Dave et al. Colloids and Surfaces A: Physicochemical and Engineering Aspects 673 (2023) 131815

Fig. 6. Scattered plots of metformin drug release data in different models.

change approach to carry out the in vitro release of metformin HCl from
the optimized hydrogel. Only 40.87 % of the loaded drug was released at
the end of the first 24 h, as shown in Fig. 5, indicating low drug release
over the first 24 h in 0.1 N HCl solution (pH 1.2). Contrarily, the drug
was easily released at higher pH (pH 7.4), where up to 93.61 % and
82.36 % of the loaded drug were released after 24 h, respectively. The
carboxyl groups of the graft copolymer (GNAGO), used for the drug-
loaded hydrogel, remain united at acidic pH and favor the formation
of hydrogen bonding between carboxyl groups of GNAGO in an acidic
solution, which may account for the pH-dependent release of metformin

8
P.N. Dave et al.
Table 4
Korsmeyer-Peppas model drug release mechanism.
Exponent (n) Drug release mechanism
n ≤ 0.45 Fickian diffusion (Case I diffusional)
0.45 < n < 0.89 Anomalous (non-Fickian) diffusion
n = 0.89 Zero order release (Case II transport)
n > 0.89 Super case II transport
Fig. 7. Cumulative drug release against time (hrs) plots for sodium diclofenac
loaded GNAGO-0 and GNAGO-3 hydrogels at pH = 1.2, pH = 7.4, and pH = 9.2
and 37 ◦ C temperature.
HCl from GNAGO-3 based hydrogel. The hydrogel segments become stiff
as a result, which reduces swelling, makes it harder for drugs to release,
and limits water absorption. On the other hand, at an alkaline pH, the
GNAGO hydrogel’s carboxyl groups ionize and enhance the repulsion
between the resulting carboxylate ions (COO-), which causes the
copolymer chains to relax, resulting in swelling and a spectacular drug
release. For the carboxyl groups in the grafted copolymer, the pro­
portions of glucuronic acid, galacturonic acid, and uronic acid in pure
GG are responsible. However, at basic pH, the methyl ester of acrylic
acid (AA and graphene oxide) also ionizes to produce additional
carboxylate ions (COO-), increasing the grafted copolymer’s sensitivity
to pH [50].
3.7.2. Mathematical model for drug release study (Metformin)
Different kinetic models are fitted using the release data. These
models’ operational equations are listed in Table 3. The effectiveness of
these models in fitting the kinetic data is seen in Fig. 6. Table 3 presents
pertinent regression values and release exponents.
The findings are in line with the Korsmeyer-Peppas (K-P) model, as
evidenced by this with an R2 value of 0.970. This suggests that drug
release from hydrogel is mainly driven by Fickian diffusion and/or
polymeric matrix erosion. To find the best-fit model, release profiles of
the drug-loaded hydrogels produced by GNAGO were examined (Fig. 6).
The values of the release constant and the correlation coefficient (R2)
were discovered. The optimal R2 value for a best-fit model is one that is
closer to 1. First-order release kinetics’ R2 values, which ranged from
0.8604 to 0.9902 and 0.8889–0.9937, were found to be lower than those
for zero-order kinetics. R2 scores in the Higuchi model ranged from
0.9573 to 0.9974, revealing diffusion-controlled drug release. In
contrast, the diffusion exponent (n) value in the Korsemeyer-Peppas
model varied from 0.0228 to 0.1787, while the correlation coefficient
(R2) was between 0.8807 and 0.9760. The correlation coefficient (R2)
for the Hixson-Crowell model is in the range of 0.8703–0.9917 [49].
9
Colloids and Surfaces A: Physicochemical and Engineering Aspects 673 (2023) 131815
These outcomes supported the hydrogel compositions Fickian behavior
(n < 0.45, Table 4).
3.7.3. Effect of pH on sodium diclofenac drug release
Fig. 7 shows the drug release profile of GAGO-0 and GNAGO-3
hydrogels at pH 1.2, 7.4, and 9.2 buffer solutions at 37 ◦ C. Results
indicated that the rate and the percentage of drug release from the
GNAGO-0 and GNAGO-3 was higher at pH= 7.4 than that of pH= 1.2.
These results were consistent with the swelling rates of the hydrogel,
which was higher at basic pH than that of acidic medium. After 2 hr, the
cumulative release of DS at pH 1.2, 7.4 and 9.2 were obtained ca.3.79 %
and ca.90.35 % and 83.91 for GNAGO-0. While the cumulative release of
DS at pH 1.2, 7.4 and 9.2 were obtained ca.3.91 % and ca.94.46 % and
84.36 for GNAGO-3 after 2 hrs. The probable reason for the higher
release rate of the drug at the basic media might be due to the
neutralization of carboxylate groups in acrylic acid monomer and gra­
phene oxide filler. The repulsion forces between carboxylate groups
leads to increase the pore size and subsequently, the diffusion of drug
occurs easily. In contrast, the low release of drug from hydrogels are
arisen from referring to (a) low solubility of DS in acidic media [51] and
(b) probably protonation the carboxylate groups and decrease in pore
size due to the decreased swelling capacity. In fact, the drug release was
consistent with the swelling of beads in buffer solutions [52].
3.7.4. Mathematical model for drug release study (Sodium diclofenac)
Different kinetic models are fitted using the release data. These
models’ operational equations are listed in Table 3. The effectiveness of
these models in fitting the kinetic data is seen in Fig. 8. Table 3 presents
pertinent regression values and release exponents. The findings are in
line with the Korsmeyer-Peppas (K-P) model, as evidenced by this with
R2 value 0.9982. This suggests that drug release from hydrogel is mainly
driven by Fickian diffusion and/or polymeric matrix erosion. To find the
best fit model, release profiles of the drug-loaded hydrogels produced by
GNAGO were examined (Fig. 8). The values of the release constant and
the correlation coefficient (R2) were discovered. The optimal R2 value
for a best fit model is one that is closer to 1. First-order release kinetics’
R2 values, which ranged from 0.8585 to 0.9433 and 0.8438–0.9644,
were found to be lower than those for zero-order kinetics. R2 scores in
the Higuchi model ranged from 0.0.9448 to 0.9935, revealing diffusion-
controlled drug release. In contrast, the diffusion exponent (n) value in
the Korsemeyer-Peppas model varied from 0.0540 to 0.3549, while the
correlation coefficient (R2) was between 0.9357 and 0.9982. The cor­
relation coefficient (R2) for the Hixson-Crowell model is in the range of
0.8307–0.9556 [49]. These outcomes supported the hydrogel compo­
sitions’ Fickian behavior (n < 0.45, Table 4).
With the help of the release data, various kinetic models are fitted.
Table 3 lists the operating equations for these models. Fig. 8 illustrates
how well these models fitted the kinetic data. Relevant regression results
and release exponents are shown in Table 3. The results support the
Korsmeyer-Peppas (K-P) model, as shown by the R2 value of 0.9982. This
implies that Fickian diffusion and/or polymeric matrix degradation are
primarily responsible for the drug release from hydrogel. Release pro­
files of the medication-loaded hydrogels made by GNAGO were inves­
tigated to determine the model that suited the data the best (Fig. 8). The
correlation coefficient (R2) and release constant values were found. A
best fit model’s ideal R2 value is one that is closer to 1. R2 values for first-
order release kinetics were 0.8585–0.9433 and 0.8438–0.9644,
respectively, and were found to be less than for zero-order kinetics. The
Higuchi model’s R2 values, which indicated diffusion-controlled drug
release, varied from 0.0.9448 to 0.9935. In comparison, the Korsemeyer-
Peppas model’s diffusion exponent (n) ranged from 0.0540 to 0.3549,
while the correlation coefficient (R2) ranged from 0.9357 to 0.9982. The
Hixson-Crowell model’s correlation coefficient (R2) lies between 0.8307
and 0.9556 [12]. These results confirmed the Fickian behavior of the
hydrogel compositions (n < 0.45, Table 4).
P.N. Dave et al.
Fig. 8. Scattered plots of sodium diclofenac drug release data in different models.
4. Conclusion
• In the current study, GO was grafted onto Gg-cl-poly(AA-co-NIPAm)
chains and copolymerized using N, N′ -methylene-bis-acrylamide
(MBA), ammonium persulfate (APS) and TEMED as a crosslinker,
initiator system in an aqueous solution to create the hydrogel gum
ghatti-cl-poly(AA-co-NIPAm)/GO.
10
Colloids and Surfaces A: Physicochemical and Engineering Aspects 673 (2023) 131815
• Instrumental techniques like FTIR, FE-SEM, DSC and DLS were
employed for the analysis of the synthesized hydrogels.
• The drug release study was performed at different pH’s and these
revealed that the drug release was more favored at a pH value of 7.4
as the graft copolymer (hydrogel) employed to make the drug-loaded
hydrogel’s carboxyl groups maintain their homogeneity at acidic pH
and facilitate the formation of hydrogen bonds between them in
P.N. Dave et al.
acidic solution. Both metformin and sodium diclofenac drug-loaded
hydrogel followed Fickian diffusion.
CRediT authorship contribution statement
Pragnesh N Dave:Conceptualization; Project administration; Re­
sources; Software; Supervision; Validation; Visualization; Writing - re­
view & editing. Pradip M. Macwan: Visualization; Roles/Writing -
original draft. Bhagvan Kamaliya:Data curation; Formal analysis;
Investigation; Project.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Data availability
Data will be made available on request.
Acknowledgment
The authors are highly thankful to ScHeme Of Developing High
quality research-SHODH Scholarship Scheme (SHODH), Scholarship
Scheme funded by Education Department, Government of Gujarat, for
providing fellowship and contingency to one of the authors for carrying
out the research work. The authors are also thankful to the Department
of Chemistry, Sardar Patel University, Vallabh Vidyanagar for the lab­
oratory facility and the CISST Department for the characterization of the
samples.
Appendix A. Supporting information
Supplementary data associated with this article can be found in the
online version at doi:10.1016/j.colsurfa.2023.131815.
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