Detection of magnetic nanoparticles using simple amr sensors in wheatstone bridge

Original ArticlepH-responsive drug release from dependal-M loaded polyacrylamide hydrogels Raman Dwivedia, Alok Kumar Singhb, Anju Dhillona,* a Maharaja Surajmal Institute of Technology,

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Original Article

pH-responsive drug release from dependal-M loaded polyacrylamide

hydrogels

Raman Dwivedia, Alok Kumar Singhb, Anju Dhillona,*

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

b 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

Article history:

Received 20 September 2016

Received in revised form

12 January 2017

Accepted 9 February 2017

Available online 20 February 2017

Keywords:

pH

Drug release

Kinetics

Hydrogel

Diffusion

a b s t r a c t

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 mecha-nism 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 (http://creativecommons.org/licenses/by/4.0/)

1 Introduction

Numerous devices have come up for drug delivering

applica-tion, in convoy to everlastingly advancing development in theﬁeld

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 bestﬁt 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 andﬁlms 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

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 pre-conceived 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 ca-pabilities are known to be affected by the character of the con-stituent polymer chains as well as by the extent of polymerization/ crosslinking grade The greater monomer and cross-linker con-centration in the reactant solution results in an increased associa-tion 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 cross-linking between polymer networks and this can affect its perfor-mance 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

* Corresponding author.

E-mail addresses: anju.dhillon@msit.in , anju.dhillon@gmail.com (A Dhillon).

Peer review under responsibility of Vietnam National University, Hanoi.

Contents lists available atScienceDirect Journal of Science: Advanced Materials and Devices

j o u r n a l h o m e p a g e : w w w e l s e v i e r c o m / l o c a t e / j s a m d

http://dx.doi.org/10.1016/j.jsamd.2017.02.003

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

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Dependal-M drug is a combination of furazolidone and

metro-nidazole, suggested in oral rehydration therapy for traveller's

bacillary dysentery from bacterial or mixed origin amoebiasis

(in-testinal or extra in(in-testinal) 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

sus-tained 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 mono-mer (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 500C 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

dependal-M 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 con-centration) 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 su-perﬁcial 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 cm1using 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) toﬁnd the varia-tion in peak or peak shifting that could give an indicavaria-tion of bonding

or association among the polymer molecules The strong intensity bands appearing around 3430 cm1in H2 and 3405.5 cm1in H1 are undoubtedly associated with the NeH stretching vibrations This difference may be related to the extent of cross linking inter-action 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 cm1 in the spectra of H1 and at 2930 and 2773 cm1 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 cm1in H1 and at 1635 cm1in 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

H 2 N

H N O

O

(a) Polyacrylamide (PAM)

N

O

_

+

O

N N

O O

(b) Furazodilone (Dependal-M)

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

R Dwivedi et al / Journal of Science: Advanced Materials and Devices 2 (2017) 45e50 46

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and intramolecular hydrogen bonds In case of DH2 (drug loaded

H2), characteristic band of NeH stretching is shifted to 3435.6 cm1

from 3430 cm1in the virgin H2, whereas CeH vibration frequency

appears at 2941 cm1 In DH2 characteristic band of >C]O

stretching of amide group appears at 1647.2 cm1 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

diffu-sion of water molecules and drug molecules Thus H2 hydrogel with

lesser crosslinker amount exhibits a higher water absorption

ca-pacity, 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

metroni-dazole) was prepared by dissolving 150 mg of drug via

ultra-sonication in 50 ml of distilled water as solvent to prepare a

solution of concentration 3000 ppm The stock solution was

suit-ably diluted to 100 times with distilled water so as to contain

300 ppm of dependal-M forﬁtting absorption limit to less than 3

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 thelmax(322 nm) point A calibration curve was plotted of the absorbance values against the known concen-tration values (Fig 4b)

3.4 Drug release from dependal-M laden PAM hydrogel Drug release from 2 batches of hydrogels differing in the mon-omer: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 pene-trating 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 (pH¼ 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 spectro-photometrically at 323 nm Calibration curve was used to deter-mine the released drug amount and cumulative percentage of drug release versus time is presented inFig 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 inter-penetrating 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) inTable 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 com-parison to a lesser initial release in hydrogel 1 with higher cross-linking 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

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

laden hydrogel 2.

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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, Kors-meyerePeppas model using the equations given underneath [17,18]

Zero order : Qt=Q0¼ K0t First order : In Qt=Q0¼ K1t Haguchi0s model : Q=Q0¼ 2ðDt=pÞ ¼ KHt1=2 KorsmeyerePeppas model : Qt=Q0¼ Ktn where Qtis the amount of drug released at time t, Q0is 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 ki-netic models and is summarized inTable 2 along with the rate constant predicted for these models Comparison of these r2values suggest diffusion as the preferred mechanism of release for dependal-M from H1 and H2 with r2value of 0.9958 for H1 and

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

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.

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0.9779 for H2 from bestﬁt Higuchi model So, Higuchi equation is

followed in preference to zero orﬁrst order release kinetics evident

from the r2value of H1 (signifying linearity in equation) While in

case of H2 release mechanism follows KorsmeyerePeppas kinetics

perceived by a higher r2value from dataﬁt to this model Contra-diction 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

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.

Time (min) Absorbance Concentration

(ppm)

Time (min) Absorbance Concentration

(ppm)

Table 2

Drug release kinetics and correlation coefﬁcient values from different kinetic models.

Hydrogel identiﬁcation Correlation coefﬁcient (r 2 ) Release exponent ‘n’

from KorsmeyerePeppas model ﬁt

Rate constant K H

Higuchi's model

Rate constant K K

from Korsmeyer model Zero order First order Higuchi's model KorsmeyerePeppas

model

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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

coefﬁ-cient 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 inFig 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

pre-sent 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

ki-netics in H1 (higher crosslinker) follow Higuchi's model and H2

(lesser crosslinker) followed KorsmeyerePeppas model

Unpre-dictably, 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

Techno-logical University, Delhi for providing the characterization facilities

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