pH responsive drug release from dependal M loaded polyacrylamide hydrogels 2017 Journal of Science Advanced Materials and Devices

Journal of Science: Advanced Materials and Devices 2 (2017) 45e50

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Journal of Science: Advanced Materials and Devices
journal homepage: www.elsevier.com/locate/jsamd

Original Article

pH-responsive drug release from dependal-M loaded polyacrylamide
hydrogels
Raman Dwivedi a, Alok Kumar Singh b, Anju Dhillon a, *
a
b

Maharaja Surajmal Institute of Technology, C-4, Janakpuri, Affiliated to Guru Gobind Singh Inderprastha University, New Delhi, India
HMR Institute of Technology and Management, Hamidpur, Affiliated to Guru Gobind Singh Inderprastha University, New Delhi, India

a r t i c l e i n f o

a b s t r a c t

Article history:
Received 20 September 2016
Received in revised form
12 January 2017
Accepted 9 February 2017
Available online 20 February 2017

A study of pH responsive drug release from dependal-M drug loaded polyacrylamide (PAM) hydrogel
matrix is reported. PAM hydrogel with different crosslinker concentrations has been taken for the

different drug loading capacities. The associative interaction of drug in the polymer network complicates
the release pattern of drug, and the release kinetics show a dependence on the cross linker and its ratio.
The drug release kinetics in hydrogel with higher cross linker (H1) and less crosslinked hydrogel (H2) are
followed by the Higuchi's model and the KorsmeyerePeppas model, respectively. Drug release mechanism is based on diffusion. Initial burst of drug release was observed at pH 5.8. The calculated diffusion
coefficient (D) is 2.57 for H1 and 1.799 for H2.
© 2017 The Authors. Publishing services by Elsevier B.V. on behalf of Vietnam National University, Hanoi.
This is an open access article under the CC BY license ( />
Keywords:
pH
Drug release
Kinetics
Hydrogel
Diffusion

1. Introduction
Numerous devices have come up for drug delivering application, in convoy to everlastingly advancing development in the field
of biomedical applications. However, logical system is the one
wherein the system itself is capable of sensing the varying exterior
surrounding conditions to deliver the necessary amount of drug at
the desired site [1]. Polymeric hydrogels are the best fit in the drug
delivery systems (DDS) as they present pulsated release of the
desired drug to the affected site in response to the changing
temperature, electric field strength and pH. These drug carrier
polymeric hydrogels are basically hydrophilic polymer structures
wherein, the three dimensionally (3-D) cross linked polymer chain
networks are reliable of swelling to the highest possible degree in
liquid media [2]. These water swollen polymer network matrices
can be made available in variety of forms such as nanoparticles,
micro particles and films for use in various medicinal applications
such as tissue engineering, as three dimensional scaffolds in drug

delivery system.
Hydrogel based DDS have gained a lot of curiosity among the
researchers, as the loaded drug in the porous structure of hydrogel
can be released at a controllable rate depending on the changing
* Corresponding author.
E-mail addresses: , (A. Dhillon).
Peer review under responsibility of Vietnam National University, Hanoi.

structure and physical property of hydrogel in different conditions
of pH [3] and temperature [4]. pH responsive 3-D polymer network
can be most effective as DDS in humans and mammals, as there
occurs pH variations at many particular body sites and thus this
criterion can be used to deliver the drug at a particular preconceived rate on a particular body site. There occurs a prompt
change in intraluminal (among tubes of stomach) pH from highly
acidic in the stomach to about pH 6 in the duodenum, again pH
gradually increases from 6.0 in the small intestine to about pH 7.4 in
the terminal ileum [5]. The physiological situation of these pH
changes can form the basis for pH sensitive drug release. Again the
performance of hydrogels such as its overall swelling or water
intake, drug carrying capacity, uncoiling and drug delivering capabilities are known to be affected by the character of the constituent polymer chains as well as by the extent of polymerization/
crosslinking grade. The greater monomer and cross-linker concentration in the reactant solution results in an increased association linking the macromolecules, resulting in a tighter gel
network with less porous fragments between cross-linkage. The
firmness of network also gets improved with the increasing crosslinking between polymer networks and this can affect its performance in DDS [6]. Neutral hydrogels such as polyacrylamide (PAM)
are more suitable for DDS as they are biocompatible and not very
reactive (Fig. 1). PAM based hydrogels have already been used in
several in vitro and in vivo studies to deliver various drugs such as
ibuprofen [7], cytarabine [8], famotidine [9], citric acid [10], etc.

/>2468-2179/© 2017 The Authors. Publishing services by Elsevier B.V. on behalf of Vietnam National University, Hanoi. This is an open access article under the CC BY license
( />

46

R. Dwivedi et al. / Journal of Science: Advanced Materials and Devices 2 (2017) 45e50

O
H
N
H2N
O
(a) Polyacrylamide (PAM)

_
O

+
N

N

N

O

O

O
O

(b) Furazodilone (Dependal-M)

Fig. 1. Chemical structure of (a) Polyacrylamide (PAM) (b) Furazodilone (Dependal-M).

Dependal-M drug is a combination of furazolidone and metronidazole, suggested in oral rehydration therapy for traveller's
bacillary dysentery from bacterial or mixed origin amoebiasis (intestinal or extra intestinal) ailments and also in warning-less cyst
passers. It is an effectual antiprotozoal and antibacterial agent
hostile to genre of Escherichia coli, Salmonella, etc. [11]. It is also
used for treating beaver fever, a common cause of gastroenteritis. In
typhoid fever, furazolidone and metronidazole combination is
given in a dose of 200 mg 4 times a day for 14 days. So, sustained
release of dependal-M can be a better alternative to encourage its
bio accessibility in amoebiasis and bacterial infections. Neutral PAM
hydrogel based drug delivery system can be supportive in such
situations. Dependal-M laden neutral PAM hydrogel can be a better
substitute for oral or intravenous (infusion) drug administration
therapy as the hydrogel can be a support for faster relief and
rehydration by the release of water/electrolyte along with sustained release of antibacterial drug directly to the site of the
ailment.
Our present work intended to study in detail the release
mechanism of drug from dependal-M embedded polyacrylamide
hydrogel and to test its potential as pH responsive polymeric carrier
device for rehydration and for controlled release of dependal-M to
intestinal protozoal or bacterial infected site.
2. Materials and methods
Dependal-M the model drug in the tablet form was procured
from local medical representative. Acrylamide (AM) and N,N0 methylenebisacrylamide (MBA) were procured from Sisco Research
Laboratory (SRL) and were used as monomer and crosslinker for
forming the hydrogel matrix. Potassium peroxo disulphate (KPS)

(AR grade, Central Drug House, CDH) was used as a initiator for
polymerisation.

For preparing PAM hydrogel network (H2), acrylamide monomer (0.8 g) was dissolved in 10 ml of distilled water and then
0.010 g of MBA crosslinker was added to the monomer solution
with stirring. Alternatively, 0.01 g of KPS was dissolved in another
10 ml of distilled water and was added dropwise to the above
prepared monomerecrosslinker solution with stirring. This
concoction was then emptied into a cylindrical vial of dimension
(1.2 cm diameter and 4.2 cm height) to form a hydrogel of the
similar dimension, after which the reaction was allowed to reach to
completion by leaving the mixture in the vial for 3 h at 500  C. The
vial was then broken to obtain the hydrogel which was then
washed several times with distilled water to remove any unreacted
species. Hydrogel 1 was also prepared adopting similar procedure
except for increasing the cross linker amount to 0.030 g.
PAM hydrogel was then loaded with the model drug dependalM via a method of soaking and saturation. Amount of water
required for equilibrium swelling of PAM hydrogel was determined
in advance and a known quantity of the model drug dependal-M
was dissolved in the water. The completely dried hydrogel sample
was dipped in the above mentioned drug solution (of known concentration) and left for a period of 2 days for maximum swelling in
the drug solution. Drug swollen hydrogel samples were taken out of
the solution after 2 days and washed many times with double
distilled water in order to wash away the drug held on to its superficial surface. The supernatant liquid after taking out hydrogel
was kept aside for absorption measurements so as to know the
amount of unabsorbed drug remaining back in the solution. Buffer
solution of pH 5.8 was prepared by making up the volume of the
solution of 7.5 ml glacial acetic acid and 75 g sodium acetate to
500 ml by distilled water. pH of the buffer solution was made sure
employing a pre calibrated pH meter.
3. Results and discussion
3.1. Fourier transform infrared spectroscopy (FTIR)
FTIR spectra of the samples were recorded in transmission mode

with KBr pressed pellets. Spectra were recorded over the wave
number ranging from 4000 to 500 cmÀ1 using Thermo Nicolet 380
infrared spectrophotometer.
FTIR spectrum of dependal-M drug (D), PAM hydrogels (H1 and
H2) (where 1 and 2 distinguishes the 2 hydrogels with different
cross linker concentrations i.e. 0.030 g and 0.010 g, respectively) and
of drug-loaded-PAM (DH2) was analyzed (Fig. 2) to find the variation in peak or peak shifting that could give an indication of bonding
or association among the polymer molecules. The strong intensity
bands appearing around 3430 cmÀ1 in H2 and 3405.5 cmÀ1 in H1
are undoubtedly associated with the NeH stretching vibrations.
This difference may be related to the extent of cross linking interaction between the polymer chains wherein this NeH group must
be involved. These interactions may thereby be affecting the
strength of intermolecular NeH hydrogen bond and hence their
stretching frequency. The bands at 2939.2 and 2915 cmÀ1 in the
spectra of H1 and at 2930 and 2773 cmÀ1 in H2 due to eCH
stretching of CH2 (methylene) group is informative regarding the
extent of polymerisation in PAM. These CeH vibration frequencies
and band shifts are suggestive of a greater extent of polymerisation
and hence tighter gel network in H1. The characteristic band at
1648.9 cmÀ1 in H1 and at 1635 cmÀ1 in H2 is due to amide group
(eCONH2) of PAM (>C]O stretching) [12]. The vibrational modes of
amide groups are considerably affected by the involvement of these
groups in hydrogen bonding. The difference in the amide band in H1
and H2 is due to the difference in the strengths of intermolecular


R. Dwivedi et al. / Journal of Science: Advanced Materials and Devices 2 (2017) 45e50

47

units and the solution was scanned in the UV region from 200 to
500 nm and from the spectra (Fig. 4a) obtained we could work out
the value of lmax as 322 nm [16]. More standard solutions of
dependal-M were prepared with concentration ranging from
5200 ppm to 1000 ppm. These solutions were also suitably diluted
with distilled water and were scanned in the UV region to obtain
the absorbance value at the lmax (322 nm) point. A calibration curve
was plotted of the absorbance values against the known concentration values (Fig. 4b).
3.4. Drug release from dependal-M laden PAM hydrogel

Fig. 2. Comparative FTIR spectra of dependal-M drug, hydrogel 1, hydrogel 2 and drug
laden hydrogel 2.

and intramolecular hydrogen bonds. In case of DH2 (drug loaded
H2), characteristic band of NeH stretching is shifted to 3435.6 cmÀ1
from 3430 cmÀ1 in the virgin H2, whereas CeH vibration frequency
appears at 2941 cmÀ1. In DH2 characteristic band of >C]O
stretching of amide group appears at 1647.2 cmÀ1. These shifts in
the bands of drug laden hydrogel suggest an association of drug
within the polymer gel network. Drug occupies the pores formed
between the interconnected network structure and associative
interaction takes place. Drug is further released off from the
hydrogel network with the changing pH of the external medium in
conjunction with the changing physical and chemical structure of
hydrogel in the medium.
3.2. Scanning electron microscopy (SEM)
Morphological structure of hydrogel was examined using
scanning electron microscope (SEM, Hitachi). SEM images
demonstrated the dissimilarities in the surface morphology of H1
and H2 which were attained with regard to different crosslinker

amounts. The crosslinker plays a crucial role in the polymerization
reaction, bridging two or more polymer chains together. Higher
amount of crosslinker resulted in a smoother surface with lesser
pores (Fig. 3a and b), because with an increased crosslinker amount
more and more polymerisation occurred which strengthened the
network of hydrogel forming a more compact structure [13]. While
the lesser amount of crosslinker resulted in a more porous surface
(Fig. 3c and d). These pores, i.e. free space or region between the
interconnected networks, provide available regions for the diffusion of water molecules and drug molecules. Thus H2 hydrogel with
lesser crosslinker amount exhibits a higher water absorption capacity, drug holding and retention capacity as there are greater free
spaces between its networks [14,15]. This observation goes on well
with the calculated amount of drug ingrained into the hydrogel
network via UVevisible studies.
3.3. UVevis spectroscopy
Standard solution of dependal-M (furazolidone and metronidazole) was prepared by dissolving 150 mg of drug via ultrasonication in 50 ml of distilled water as solvent to prepare a
solution of concentration 3000 ppm. The stock solution was suitably diluted to 100 times with distilled water so as to contain
300 ppm of dependal-M for fitting absorption limit to less than 3

Drug release from 2 batches of hydrogels differing in the monomer:crosslinker ratios were comprehended in a buffer solution of
pH 5.8. The buffer of pH 5.8 was deliberately chosen to mimic the
conditions existing in the intestine right the way through the
suffering by protozoal or bacterial infection. PAM hydrogel can
present water/electrolyte for the rehydration and can release the
drug in the intestinal tract at near neutral pH of about 5.8e6.0.
Furazolidone and metronidazole combination works by penetrating into the protozoan and bacterial cell, excluding the
mammalian cell and proceed directly to reduce cytotoxic 5-nitro
group causing rupture of its DNA strand and eventually to the
collapse of bacterial or protozoan cell. Drug laden hydrogel was
immersed in the buffer solution (pH ¼ 5.8) and 10 ml of the aliquot
was withdrawn at regular intervals out of the drug laden hydrogel

dipped buffer solution. The solution after measurement was again
put back to the reserved hydrogel immersed solution for further
measurement. The withdrawn samples were evaluated spectrophotometrically at 323 nm. Calibration curve was used to determine the released drug amount and cumulative percentage of drug
release versus time is presented in Fig. 5a.
The amount of drug absorbed in each of the hydrogels was
worked out by back calculating the amount of drug left behind in
the solution after each of the hydrogel was swelled to equilibrium
in (3000 ppm) drug solution. The amount of drug absorbed was
found out be 210 ppm for H1 and 250 ppm for H2 which is well in
agreement of the SEM and FTIR results which predicted a more
porous structure for H2 (it should be H1) and hence a greater drug
and water absorption capacity to the free spaces in its interpenetrating network structure. These results specify that drug
loading will be on the same wavelength (proportional to) as the
porosity and swelling properties of the hydrogels.
Similarly, the release contour of the hydrogel entity above all is a
function of interactions of the drug within the polymeric network,
the solubility of the drug, and swelling profile of the hydrogel in the
suspension standard. The release pattern of all the hydrogels was
governed by a heavy pour in the beginning caused by the existence
of the drug on the shell of the hydrogels, followed by a prolonged
release of drug from the core of the hydrogel. Higher concentration
gradient through the bulk of the hydrogel may be a reason for the
opening heavy pour of the drug, followed by reduction in the
release rate, attributable to the diffusion difficulty meant for drug,
covering more distance within the thicker core of hydrogel for
simultaneous release. The amount of dependal-M released from the
hydrogel matrix in relation to time engaged is summarized for 2
different hydrogels (HI and H2) in Table 1. These 2 hydrogels differ
in the amount of crosslinker linking the macromolecular polymer
chains. The amount of dependal-M released from hydrogel 2 (with

lesser cross linker) is quite significant in the beginning in comparison to a lesser initial release in hydrogel 1 with higher crosslinking ratio. The slower and lower amount of dependal M drug
released from H1 with higher cross-linker amount is because of the
more rigid structure of this hydrogel formed due to the lessening of
the pores verified by SEM micrographs and also this initial release


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R. Dwivedi et al. / Journal of Science: Advanced Materials and Devices 2 (2017) 45e50

Fig. 3. SEM micrographs of (a and b) hydrogel 1 and (c and d) are of hydrogel 2.

of drug is because of the drug near the hydrogel surface (greater
loading of 250 ppm in H2 as compared to 210 ppm in H1) which can
easily diffuse out. However, later a greater slowdown in the release
rate was seen in case of H2 as compared to H1. This occurrence can
be attributed to a more attractive association between the drug and
polymer matrix in H2 and hence diminishing release rate of drug
thereafter from the matrix while such an effect can be neglected in
H1 which already must have balanced the charges on its groups by
more evident crosslinking interactions. So, the leftover reactive
groups in the weakly crosslinked polymer matrix (H2) can be a
driving force for greater association with drug forming some weak
bonds therein among themselves and hence slowing down the
release rate.
3.5. Drug release kinetics
For studying the drug release kinetics and mechanism involved
in detail, the drug release data was fitted into various kinetic
models such as zero order, first order, Higuchi's model, KorsmeyerePeppas model using the equations given underneath
[17,18].

Zero order : Q t =Q 0 ¼ K0 t
First order : In Q t =Q 0 ¼ K1 t
Haguchi0 s model : Q =Q 0 ¼ 2ðDt =pÞ ¼ KHt 1=2
KorsmeyerePeppas model : Q t =Q 0 ¼ Ktn

Fig. 4. a. UVevisible absorption spectra of dependal-M drug in the range of
200e500 nm. b. Calibration curve for different standard solutions of dependal-M drug.

where Qt is the amount of drug released at time t, Q0 is the original
drug concentration in the gel, D is the diffusion coefficient of a
diffusant, n is release exponent and K is the release rate constant.
Correlation coefficient values (r2) were calculated for different kinetic models and is summarized in Table 2 along with the rate
constant predicted for these models. Comparison of these r2 values
suggest diffusion as the preferred mechanism of release for
dependal-M from H1 and H2 with r2 value of 0.9958 for H1 and


R. Dwivedi et al. / Journal of Science: Advanced Materials and Devices 2 (2017) 45e50

49

Fig. 5. a. Drug release profile of two dependal-M laden hydrogel matrices. b. Plot of drug release amount versus square root of time engaged with inset showing logarithmic plot of
cumulative drug release as a function of log of engaged time.

Table 1
Summarized report of amount of drug released from both the hydrogels H1 and H2 with time.
Hydrogel 1

Hydrogel 2

Time (min)

Absorbance

Concentration
(ppm)

Time (min)

Absorbance

Concentration
(ppm)

15
30
45
60
75
90

1.4185
1.7678
2.0544
2.2695
2.4472
2.5677

24

27
30
32
34
35

15
30
45
60
75
90

2.4746
2.7137
2.8750
2.9824
3.1126
3.1814

34
37
38
39
40
41

Table 2
Drug release kinetics and correlation coefficient values from different kinetic models.
Hydrogel identification

Hydrogel 1 (H1)
Hydrogel 2 (H2)

Correlation coefficient (r2)
Zero order

First order

Higuchi's model

KorsmeyerePeppas
model

0.9728
0.9382

0.9753
0.9407

0.9958
0.9779

0.9950
0.9966

0.9779 for H2 from best fit Higuchi model. So, Higuchi equation is
followed in preference to zero or first order release kinetics evident
from the r2 value of H1 (signifying linearity in equation). While in
case of H2 release mechanism follows KorsmeyerePeppas kinetics

Release exponent ‘n’
from KorsmeyerePeppas
model fit

Rate constant KH
Higuchi's model

Rate constant KK
from Korsmeyer model

0.217
0.099

7.4716
3.6539

1.1834
1.1955

perceived by a higher r2 value from data fit to this model. Contradiction in the values of rate constant predicted of the two methods
for H1 and H2 is because of the different release kinetics followed
i.e. H1 follows release according to 3rd equation while the release in


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R. Dwivedi et al. / Journal of Science: Advanced Materials and Devices 2 (2017) 45e50

H2 is according to 4th equation of KorsmeyerePeppas. The plot of

released drug amount records versus square root of time engaged
(Fig. 5b) was studied to calculate the diffusion coefficient D [19]. By
means of the slope of above plot, we could work out the diffusion
coefficient of both the hydrogels. The value of the diffusion coefficient can clearly verify the different release kinetics of the 2
hydrogels. The diffusion coefficient (D) was found out to be 2.57 for
H1 and 1.799 for H2.
To further make sure of the diffusion and not erosion or
dissolution as the prime and preferred mechanism of release,
release exponent value was calculated for H1 and H2 using the
KorsmeyerePeppas equation and plot of log Qt/Q0 versus log t
shown in Fig. 5b. For both H1 and H2 value of ‘n’ came out to be less
than 0.45 indicative of Fickian diffusion of drug from hydrogel
matrix [20].
4. Conclusion
This study highlighted the potential of dependal-M loaded
hydrogel to be used in the rehydration therapy for relief from
bacillary dysentery originating from protozoal or bacterial infection
in intestinal tract. Water and drug swollen PAM hydrogel can present faster relief for the rehydration by providing water/electrolyte
and release the drug at the intestinal tract ailment in the prevailing
near neutral pH (5.8e6.0) condition. The drug release experiments
conducted using two hydrogels with varying crosslinker ratios
revealed that hydrogel with lesser crosslinker amount has a higher
drug loading capacity. The release mechanism was found to be
diffusion controlled and not accompanied by dissolution of matrix.
Drug release pattern was complicated in view of the associative
interaction of drug within the polymeric network. The release kinetics in H1 (higher crosslinker) follow Higuchi's model and H2
(lesser crosslinker) followed KorsmeyerePeppas model. Unpredictably, the slow release of drug after the opening pour from
hydrogel with lesser crosslinker amount was attributed to some
associative interaction between the drug and matrix, slowing down
the release rate.

Acknowledgements
Authors are thankful to the Management of Surajmal Memorial
Education Society, Janakpuri and Management of HMRITM,
Hamidpur for providing the healthy and supportive environment
for research work. Authors extend their thanks to Delhi Technological University, Delhi for providing the characterization facilities.

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