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pH-responsive drug release from dependal-M loaded polyacrylamide hydrogels
Accepted Manuscript pH- responsive drug release from dependal-M loaded polyacrylamide hydrogels Raman Dwivedi, Alok Kumar Singh, Anju Dhillon
PII:
S2468-2179(16)30165-4
DOI:
10.1016/j.jsamd.2017.02.003
Reference:
JSAMD 82
To appear in:
Journal of Science: Advanced Materials and Devices
Received Date: 20 September 2016 Accepted Date: 9 February 2017
Please cite this article as: R. Dwivedi, A.K. Singh, A. Dhillon, pH- responsive drug release from dependal-M loaded polyacrylamide hydrogels, Journal of Science: Advanced Materials and Devices (2017), doi: 10.1016/j.jsamd.2017.02.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
pH- responsive drug release from dependal-M loaded polyacrylamide hydrogels Raman Dwivedi1, Alok Kumar Singh1, Anju Dhillon2* 1
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* Author to whom correspondence should be addressed: Email: [email protected], [email protected]
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HMR Institute of Technology and Management, Hamidpur, affiliated to Guru Gobind Singh Inderprastha University, New Delhi, India 2 Maharaja Surajmal Institute of Technology, C-4, Janakpuri, affiliated to Guru Gobind Singh Inderprastha University, New Delhi, India
Abstract
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Abstract
A preliminary study of dependal-M drug loaded polyacrylamide (PAM) hydrogel recognized persistent pH dependent release of drug from hydrogel matrix has been presented. PAM hydrogels with lesser crosslinker amount has been found to have higher drug loading capacity. Initial burst of drug release observed at pH 5.8 buffer solution and further release of to the hydrogel superficial surface is evident by UV-visible absorbance
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drug adhered
measurements. Drug release mechanism is based on diffusion. The associative interaction of drug in the polymer network complicates the release pattern of drug and release kinetics shows dependence on the cross linker and its ratio. The drug release kinetics in hydrogel with higher
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cross linker (H1) and less crosslinked hydrogel (H2) are followed by Higuchi’s model and Korsmeyer-Peppas model respectively. The calculated diffusion coefficient (D) is 2.57 for H1
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and 1.799 for H2.
Keywords: pH, drug release, kinetics, hydrogel, diffusion.
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pH- responsive drug release from dependal-M loaded polyacrylamide hydrogels Abstract A preliminary study of drug release from dependal-M drug loaded polyacrylamide
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(PAM) hydrogel recognized persistent pH dependent release of drug from hydrogel matrix. PAM hydrogels with lesser crosslinker amount was found to have higher drug loading capacity. Initial heavy pour of drug release observed in a pH 5.8 buffer solution was thought as a release of drug adhered at the hydrogels superficial surface, following which a slow drug release was evident by UV-visible absorbance measurements. Drug release mechanism was
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found to be based on diffusion. Associative interaction of drug in the polymer network complicated the release pattern of drug and release kinetics showed a great dependence on the
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cross linker and its ratio. Drug release kinetics in hydrogel with higher cross linker (H1) followed Higuchi’s model and less crosslinked hydrogel (H2) followed Korsmeyer-Peppas model. The diffusion coefficient (D) is of the order of 2.57 for H1 and 1.799 for H2.
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Keywords: pH; drug release; kinetics; hydrogels; diffusion.
ACCEPTED MANUSCRIPT 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
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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
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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,
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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
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humans and mammals, as their 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 increase
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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
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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 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 networks 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 performance in DDS [6]. Neutral hydrogels such as polyacrylamide (PAM) are more suitable for DDS as they are biocompatible and not very reactive. 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.
ACCEPTED MANUSCRIPT 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 anti protozoal and anti bacterial agent hostile to genre of escheriachia colli, salmonella etc [11]. It is also used for treating beaver fever, a common cause of
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gastroenteritis. In typhoid fever, furazolidone and metronidazole 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
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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 site of the ailment.
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the release of water/electrolyte along with sustained release of antibacterial drug directly to
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.
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Materials and methods
Dependal-M the model drug in the tablet form was procured from local medical representative. Acrylamide (AM) and N,N’-methylenebisacrylamide (MBA) were procured from sisco research laboratory (SRL) and were used as monomer and crosslinker for forming
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the hydrogel matrix. Potassium peroxo disulphate (KPS) (AR grade, central drug house, CDH) was used as initiator for polymerisation.
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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 monomer-crosslinker solution with stirring. This concoction was then emptied in to 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 hrs 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.
ACCEPTED MANUSCRIPT PAM hydrogel was then loaded with the model drug dependal-M via 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 it for period of 2 days for maximum swelling in
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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
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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.
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Results and discussion
Fourier Transform Infrared Spectroscopy (FTIR)
FTIR spectra of the samples were recorded in transmission mode with KBr pressed pellets. Spectra’s were recorded over the wave number ranging from 4,000–500 cm−1 using thermo Nicolet 380 infrared spectrophotometer.
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FTIR spectrum of dependal-M drug (D), PAM hydrogels (H1 & H2) (where 1 & 2 distinguishes the 2 hydrogels with different cross linker concentration i.e. 0.030 g and 0.010 g respectively), and of drug-loaded-PAM (DH2) were analysed (Figure 1) to find the variation in peak or peak shifting that could give an indication of bonding or association among the
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polymer molecules. The strong intensity bands appearing around 3430 cm-1 in H2 and 3405.5 cm-1 in H1 are undoubtedly associated with the N-H stretching vibrations. This
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difference may be related to the extent of cross linking interaction between the polymer chains wherein, this N-H group must be involved. These interactions may thereby be affecting the strength of intermolecular N-H hydrogen bond and hence their stretching frequency. The bands at 2939.2 and 2915 cm−1 in the spectra of H1 and at 2930 and 2773 cm-1 in H2 due to –C–H stretching of –CH2 (methylene) group is informative regarding the extent of polymerisation in PAM. These C-H vibration frequencies and band shifts are suggestive of greater extent of polymerisation and hence tighter gel network in H1. The characteristic band at 1648.9 cm−1 in H1 and at 1635 cm−1 in H2 is due to amide group (– CONH2) 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 are due to the difference in the strengths of
ACCEPTED MANUSCRIPT intermolecular and intramolecular hydrogen bonds. In case of DH2 (drug loaded H2) characteristic band of N-H stretching is shifted to 3435.6 cm-1 from 3430 cm-1 in the virgin H2 whereas, C-H vibration frequency appears at 2941 cm-1. In DH2 characteristic band of >C=O stretching of amide group appears at 1647.2 cm-1. These shifts in the bands of drug laden hydrogel suggest an association of drug within the polymer gel network. Drug occupies
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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.
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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
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H1 and H2 which were attained with regard to different crosslinker amount. The crosslinker plays 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 (Figure 2A& 2B), because with an increased crosslinker amount more and more polymerisation occurred which strengthened the network of hydrogel forming a more
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compact structure [13]. While, lesser amount of crosslinker resulted in a more porous surface (Figure 2C& 2D). 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 and drug
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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
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network via UV-visible studies. UV-vis 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 units and the solution was scanned in the UV region from 200-500 nm and from the spectra (Figure 3A) obtained we could work out the value of λmax 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 UV region to obtain the absorbance value at the λmax (322 nm) point. A
ACCEPTED MANUSCRIPT calibration curve was plotted of the absorbance values against known concentration values (Figure 3B) Drug Release from Dependal-M Laden PAM Hydrogel Drug release from 2 batches of hydrogels differing in the monomer: crosslinker ratios were comprehended in a buffer solution of pH 5.8. Buffer of pH 5.8 was deliberately chosen to
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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 5.8-6.0. Furazolidone and metronidazole combination works by penetrating into the protozoan and bacterial cell,
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excluding the mammalian cell and proceed directly to reduce cyto-toxic 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 =5.8) and 10 ml of the aliquot was
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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 Figure 4A.
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The amount of drug absorbed in each of the hydrogel was worked out by back calculating the amount of drug left behind in the solution after the 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
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which predicted a more porous structure for H2 (it should be H1) and hence greater drug and water absorption capacity to the free spaces in its interpenetrating network structure. These
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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, 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 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
ACCEPTED MANUSCRIPT summarised for 2 different hydrogels (HI & 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 cross-linking ratio. The slower and lower amount of dependal M drug released from H1 with higher cross-linker amount is
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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 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
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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
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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. Drug Release Kinetics
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For studying the drug release kinetics and mechanism involved in detail, the drug release data was fitted in to various kinetic models such as zero order, first order, Higuchi’s model, Korsmeyer-peppas model using the equations given underneath [17,18]. Zero order: Qt/Q0=K0t
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First order: ln Qt/Q0= K1t
Haguchi’s model: Q/Q0= 2 (Dt / π) . = KHt 1/2
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Korsmeyer-Peppas model: Qt/Q0 = Ktn 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 of different kinetic models and is summarised in Table 2 along with the rate constant predicted of 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 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 Korsmeyer-Peppas kinetics 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
ACCEPTED MANUSCRIPT H1 & H2 is because of the different release kinetics followed i.e. H1 follows release according to 3rd equation while the release in H2 is according to 4 th equation of KorsmeyerPeppas. Plot of released drug amount records versus square root of time engaged (Figure 4B) 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 (D) was found out to be 2.57 for H1 and 1.799 for H2.
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coefficient can clearly verify the different release kinetics of the 2 hydrogels. The diffusion
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
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the Korsmeyer-Peppas equation and plot of log Qt/Q0 versus log t shown in Fig 4B. 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].
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Conclusion
This study highlighted the potential of dependal-M loaded hydrogel to be used in the rehydration therapy for relief from bacillary dysentery originating of 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
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ailment in the prevailing near neutral pH (5.8-6.0) condition. The drug release experiments conducted using two hydrogels with varying crosslinker ratio revealed that hydrogel with lesser crosslinker amount have a higher drug loading capacity. The release mechanism was found to be diffusion controlled and not accompanied by dissolution of matrix. Drug release
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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
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(lesser crosslinker) followed Korsmeyer-Peppas 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. Acknowledgement
Authors are thankful to the management Surajmal Memorial Education Society, Janakpuri and Management HMRITM, Hamidpur for providing the healthy and supportive environment for research work.
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ACCEPTED MANUSCRIPT Figure Captions: Figure 1 Comparative FTIR spectra of dependal M drug, hydrogel 1, hydrogel 2 and drug laden hydrogel 2. Figure 2 SEM micrographs of (A & B) hydrogel 1 and (C & D) are of hydrogel 2. Figure 3 A.UV-visible absorption spectra of dependal M drug in the range of 200-500 nm
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and B. Calibration curve for different standard solutions of dependal M drug. Figure 4 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 logarithimic plot of
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cumulative drug release as a function of log of engaged time.
ACCEPTED MANUSCRIPT Table Captions: Table 1 Summarised report of amount of drug released from both the hydrogels H1 & H2 with time.
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Table 2 Drug release kinetics and correlation coefficient values from different kinetic models
ACCEPTED MANUSCRIPT TABLE 1 Hydrogel 1
Hydrogel 2 Concentration
Absorbance (ppm)
Concentration Time (min)
Absorbance (ppm)
1.4185
24
15
30
1.7678
27
30
45
2.0544
30
45
60
2.2695
32
60
75
2.4472
34
90
2.5677
35
34
2.7137
37
2.8750
38
2.9824
39
75
3.1126
40
90
3.1814
41
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2.4746
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15
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Time (min)
ACCEPTED MANUSCRIPT TABLE 2 Correlation Coefficient (r2) Hydrogel identification
Higuchi ’s model
Korsmeyer - Peppas model
Release exponent 'n' From Korsmeyer - Peppas model fit
Rate constant KH Higuchi’s model
Rate constant KK from Korsmeyer model
First order
Hydrogel 1(H1)
0.9728
0.9753
0.9958
0.9950
0.217
7.4716
1.1834
Hydrogel 2(H2)
0.9382
0.9407
0.9779
0.9966
0.099
3.6539
1.1955
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Zero order
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Fig. 1
O
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H N H2N
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O (a) Polyacrylamide (PAM)
O
+ N
N N
O
O
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_
O
O
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(b) Furazodilone (dependal-M)
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Tran nsmittance (%)
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Fig 2 Fig.
DH1
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50µm
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(b)
(a)
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Fig. 3
( ) (c)
10µm
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(d)
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50µm
10µm
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Fig. 4
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EP
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(a)
AC C EP Sqrt (t)
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(b) Log (cumulative (%) drug release)
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Cumulative (%) drug release
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Fig. 5
(a)
(c)
log (time)
PII:
S2468-2179(16)30165-4
DOI:
10.1016/j.jsamd.2017.02.003
Reference:
JSAMD 82
To appear in:
Journal of Science: Advanced Materials and Devices
Received Date: 20 September 2016 Accepted Date: 9 February 2017
Please cite this article as: R. Dwivedi, A.K. Singh, A. Dhillon, pH- responsive drug release from dependal-M loaded polyacrylamide hydrogels, Journal of Science: Advanced Materials and Devices (2017), doi: 10.1016/j.jsamd.2017.02.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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pH- responsive drug release from dependal-M loaded polyacrylamide hydrogels Raman Dwivedi1, Alok Kumar Singh1, Anju Dhillon2* 1
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* Author to whom correspondence should be addressed: Email: [email protected], [email protected]
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HMR Institute of Technology and Management, Hamidpur, affiliated to Guru Gobind Singh Inderprastha University, New Delhi, India 2 Maharaja Surajmal Institute of Technology, C-4, Janakpuri, affiliated to Guru Gobind Singh Inderprastha University, New Delhi, India
Abstract
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Abstract
A preliminary study of dependal-M drug loaded polyacrylamide (PAM) hydrogel recognized persistent pH dependent release of drug from hydrogel matrix has been presented. PAM hydrogels with lesser crosslinker amount has been found to have higher drug loading capacity. Initial burst of drug release observed at pH 5.8 buffer solution and further release of to the hydrogel superficial surface is evident by UV-visible absorbance
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drug adhered
measurements. Drug release mechanism is based on diffusion. The associative interaction of drug in the polymer network complicates the release pattern of drug and release kinetics shows dependence on the cross linker and its ratio. The drug release kinetics in hydrogel with higher
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cross linker (H1) and less crosslinked hydrogel (H2) are followed by Higuchi’s model and Korsmeyer-Peppas model respectively. The calculated diffusion coefficient (D) is 2.57 for H1
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and 1.799 for H2.
Keywords: pH, drug release, kinetics, hydrogel, diffusion.
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pH- responsive drug release from dependal-M loaded polyacrylamide hydrogels Abstract A preliminary study of drug release from dependal-M drug loaded polyacrylamide
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(PAM) hydrogel recognized persistent pH dependent release of drug from hydrogel matrix. PAM hydrogels with lesser crosslinker amount was found to have higher drug loading capacity. Initial heavy pour of drug release observed in a pH 5.8 buffer solution was thought as a release of drug adhered at the hydrogels superficial surface, following which a slow drug release was evident by UV-visible absorbance measurements. Drug release mechanism was
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found to be based on diffusion. Associative interaction of drug in the polymer network complicated the release pattern of drug and release kinetics showed a great dependence on the
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cross linker and its ratio. Drug release kinetics in hydrogel with higher cross linker (H1) followed Higuchi’s model and less crosslinked hydrogel (H2) followed Korsmeyer-Peppas model. The diffusion coefficient (D) is of the order of 2.57 for H1 and 1.799 for H2.
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Keywords: pH; drug release; kinetics; hydrogels; diffusion.
ACCEPTED MANUSCRIPT 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
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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
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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,
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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
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humans and mammals, as their 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 increase
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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
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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 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 networks 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 performance in DDS [6]. Neutral hydrogels such as polyacrylamide (PAM) are more suitable for DDS as they are biocompatible and not very reactive. 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.
ACCEPTED MANUSCRIPT 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 anti protozoal and anti bacterial agent hostile to genre of escheriachia colli, salmonella etc [11]. It is also used for treating beaver fever, a common cause of
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gastroenteritis. In typhoid fever, furazolidone and metronidazole 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
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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 site of the ailment.
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the release of water/electrolyte along with sustained release of antibacterial drug directly to
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.
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Materials and methods
Dependal-M the model drug in the tablet form was procured from local medical representative. Acrylamide (AM) and N,N’-methylenebisacrylamide (MBA) were procured from sisco research laboratory (SRL) and were used as monomer and crosslinker for forming
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the hydrogel matrix. Potassium peroxo disulphate (KPS) (AR grade, central drug house, CDH) was used as initiator for polymerisation.
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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 monomer-crosslinker solution with stirring. This concoction was then emptied in to 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 hrs 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.
ACCEPTED MANUSCRIPT PAM hydrogel was then loaded with the model drug dependal-M via 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 it for period of 2 days for maximum swelling in
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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
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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.
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Results and discussion
Fourier Transform Infrared Spectroscopy (FTIR)
FTIR spectra of the samples were recorded in transmission mode with KBr pressed pellets. Spectra’s were recorded over the wave number ranging from 4,000–500 cm−1 using thermo Nicolet 380 infrared spectrophotometer.
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FTIR spectrum of dependal-M drug (D), PAM hydrogels (H1 & H2) (where 1 & 2 distinguishes the 2 hydrogels with different cross linker concentration i.e. 0.030 g and 0.010 g respectively), and of drug-loaded-PAM (DH2) were analysed (Figure 1) to find the variation in peak or peak shifting that could give an indication of bonding or association among the
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polymer molecules. The strong intensity bands appearing around 3430 cm-1 in H2 and 3405.5 cm-1 in H1 are undoubtedly associated with the N-H stretching vibrations. This
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difference may be related to the extent of cross linking interaction between the polymer chains wherein, this N-H group must be involved. These interactions may thereby be affecting the strength of intermolecular N-H hydrogen bond and hence their stretching frequency. The bands at 2939.2 and 2915 cm−1 in the spectra of H1 and at 2930 and 2773 cm-1 in H2 due to –C–H stretching of –CH2 (methylene) group is informative regarding the extent of polymerisation in PAM. These C-H vibration frequencies and band shifts are suggestive of greater extent of polymerisation and hence tighter gel network in H1. The characteristic band at 1648.9 cm−1 in H1 and at 1635 cm−1 in H2 is due to amide group (– CONH2) 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 are due to the difference in the strengths of
ACCEPTED MANUSCRIPT intermolecular and intramolecular hydrogen bonds. In case of DH2 (drug loaded H2) characteristic band of N-H stretching is shifted to 3435.6 cm-1 from 3430 cm-1 in the virgin H2 whereas, C-H vibration frequency appears at 2941 cm-1. In DH2 characteristic band of >C=O stretching of amide group appears at 1647.2 cm-1. These shifts in the bands of drug laden hydrogel suggest an association of drug within the polymer gel network. Drug occupies
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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.
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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
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H1 and H2 which were attained with regard to different crosslinker amount. The crosslinker plays 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 (Figure 2A& 2B), because with an increased crosslinker amount more and more polymerisation occurred which strengthened the network of hydrogel forming a more
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compact structure [13]. While, lesser amount of crosslinker resulted in a more porous surface (Figure 2C& 2D). 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 and drug
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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
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network via UV-visible studies. UV-vis 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 units and the solution was scanned in the UV region from 200-500 nm and from the spectra (Figure 3A) obtained we could work out the value of λmax 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 UV region to obtain the absorbance value at the λmax (322 nm) point. A
ACCEPTED MANUSCRIPT calibration curve was plotted of the absorbance values against known concentration values (Figure 3B) Drug Release from Dependal-M Laden PAM Hydrogel Drug release from 2 batches of hydrogels differing in the monomer: crosslinker ratios were comprehended in a buffer solution of pH 5.8. Buffer of pH 5.8 was deliberately chosen to
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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 5.8-6.0. Furazolidone and metronidazole combination works by penetrating into the protozoan and bacterial cell,
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excluding the mammalian cell and proceed directly to reduce cyto-toxic 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 =5.8) and 10 ml of the aliquot was
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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 Figure 4A.
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The amount of drug absorbed in each of the hydrogel was worked out by back calculating the amount of drug left behind in the solution after the 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
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which predicted a more porous structure for H2 (it should be H1) and hence greater drug and water absorption capacity to the free spaces in its interpenetrating network structure. These
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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, 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 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
ACCEPTED MANUSCRIPT summarised for 2 different hydrogels (HI & 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 cross-linking ratio. The slower and lower amount of dependal M drug released from H1 with higher cross-linker amount is
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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 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
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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
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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. Drug Release Kinetics
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For studying the drug release kinetics and mechanism involved in detail, the drug release data was fitted in to various kinetic models such as zero order, first order, Higuchi’s model, Korsmeyer-peppas model using the equations given underneath [17,18]. Zero order: Qt/Q0=K0t
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First order: ln Qt/Q0= K1t
Haguchi’s model: Q/Q0= 2 (Dt / π) . = KHt 1/2
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Korsmeyer-Peppas model: Qt/Q0 = Ktn 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 of different kinetic models and is summarised in Table 2 along with the rate constant predicted of 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 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 Korsmeyer-Peppas kinetics 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
ACCEPTED MANUSCRIPT H1 & H2 is because of the different release kinetics followed i.e. H1 follows release according to 3rd equation while the release in H2 is according to 4 th equation of KorsmeyerPeppas. Plot of released drug amount records versus square root of time engaged (Figure 4B) 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 (D) was found out to be 2.57 for H1 and 1.799 for H2.
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coefficient can clearly verify the different release kinetics of the 2 hydrogels. The diffusion
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
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the Korsmeyer-Peppas equation and plot of log Qt/Q0 versus log t shown in Fig 4B. 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].
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Conclusion
This study highlighted the potential of dependal-M loaded hydrogel to be used in the rehydration therapy for relief from bacillary dysentery originating of 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
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ailment in the prevailing near neutral pH (5.8-6.0) condition. The drug release experiments conducted using two hydrogels with varying crosslinker ratio revealed that hydrogel with lesser crosslinker amount have a higher drug loading capacity. The release mechanism was found to be diffusion controlled and not accompanied by dissolution of matrix. Drug release
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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
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(lesser crosslinker) followed Korsmeyer-Peppas 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. Acknowledgement
Authors are thankful to the management Surajmal Memorial Education Society, Janakpuri and Management HMRITM, Hamidpur for providing the healthy and supportive environment for research work.
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ACCEPTED MANUSCRIPT Figure Captions: Figure 1 Comparative FTIR spectra of dependal M drug, hydrogel 1, hydrogel 2 and drug laden hydrogel 2. Figure 2 SEM micrographs of (A & B) hydrogel 1 and (C & D) are of hydrogel 2. Figure 3 A.UV-visible absorption spectra of dependal M drug in the range of 200-500 nm
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and B. Calibration curve for different standard solutions of dependal M drug. Figure 4 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 logarithimic plot of
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cumulative drug release as a function of log of engaged time.
ACCEPTED MANUSCRIPT Table Captions: Table 1 Summarised report of amount of drug released from both the hydrogels H1 & H2 with time.
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Table 2 Drug release kinetics and correlation coefficient values from different kinetic models
ACCEPTED MANUSCRIPT TABLE 1 Hydrogel 1
Hydrogel 2 Concentration
Absorbance (ppm)
Concentration Time (min)
Absorbance (ppm)
1.4185
24
15
30
1.7678
27
30
45
2.0544
30
45
60
2.2695
32
60
75
2.4472
34
90
2.5677
35
34
2.7137
37
2.8750
38
2.9824
39
75
3.1126
40
90
3.1814
41
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15
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Time (min)
ACCEPTED MANUSCRIPT TABLE 2 Correlation Coefficient (r2) Hydrogel identification
Higuchi ’s model
Korsmeyer - Peppas model
Release exponent 'n' From Korsmeyer - Peppas model fit
Rate constant KH Higuchi’s model
Rate constant KK from Korsmeyer model
First order
Hydrogel 1(H1)
0.9728
0.9753
0.9958
0.9950
0.217
7.4716
1.1834
Hydrogel 2(H2)
0.9382
0.9407
0.9779
0.9966
0.099
3.6539
1.1955
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Zero order
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Fig. 1
O
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H N H2N
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O (a) Polyacrylamide (PAM)
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+ N
N N
O
O
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_
O
O
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(b) Furazodilone (dependal-M)
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Tran nsmittance (%)
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Fig 2 Fig.
DH1
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50µm
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Fig. 3
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10µm
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10µm
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Fig. 4
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(b) Log (cumulative (%) drug release)
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Cumulative (%) drug release
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Fig. 5
(a)
(c)
log (time)