1
Synthesis, Characterization and Swelling
Kinetics of Co-polymeric Hydrogels
A thesis submitted in partial fulfillment of the requirement
For the degree of
DOCTOR OF PHILOSOPHY
in the subject of
Chemistry
by
Rubab Zohra
Roll No. PHD-C-08-01
Registration No. 94-gwk-46
Institute of Chemical Sciences
Bahauddin Zakariya University,
Multan Pakistan
June 2013
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3
DEDICATION
Dedicated to
All those
who are blessed with
intellect and wisdom
but
never get a chance
to
hunt out their hidden talent.
4
ACKNOWLEDGEMENT
In the name of Allah, the most merciful, the most beneficent; all praise to He, Who
made me able to carry out my research work. I present my gratitude whole heartedly
to the Holy Prophet, Hazrat Muhammad (peace be upon him), who paved way for the
peace and prosperity of mankind and guided us from the inferno of bitterness and
ignorance to the heaven of love and knowledge.
There is always a room present empty for the teacher. Lucky are those who are
blessed with outstanding and competent leaders to lead them to their destiny. I am one
of those lucky persons who are selected to be blessed with such a highly qualified,
kind, sincere and hardworking teacher, Prof. Dr. Muhammad Aslam Malana.
I offer the bundle of thanks, from the depth of my heart, to Prof. Dr. Muhammad
Aslam Malana, Institute of Chemical Sciences, Bahauddin Zakariya University,
Multan, for his consistent encouragement, guidance, exclusive attitude and kind
cooperation throughout the course of study. I can never pay for his affectionate
behavior, full attention, impressive concentration and astonishing guideline due to
which, today I am able to continue my studies with my tough schedule of life.
I would like to express my special thanks to Prof. Dr. Muhammad Arif, Director,
Institute of Chemical Sciences, Bahauddin Zakariya University Multan, to provide
facilities to complete the research work.
I am thankful to Dr. Zafar Iqbal Zafar Professor, Institute of Chemistry, Bahauddin
Zakariya University Multan, for providing the technical help concerning the graphical
analysis of data.
I also acknowledge the appreciable efforts of Mr. M. Ashraf and Mr. M. Yousaf, the
Lab. Staff, of Physical Chemistry Laboratory, Bahauddin Zakariya University Multan
for their cooperation during my research work.
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I pay my special thanks to Forman Prof. Dr. Christy Munir, the Principle, and Prof.
Dr. Dildar, the Chairman, Chemistry Department, Forman Christian College (a
Chartered University) Lahore, for providing me the instrumental facilities. I am
also thankful to PCSIR (Pakistan Council of Scientific and Industrial Research)
Lahore for helping me in sample characterization. I am grateful to Dr. Muhammad
Saleem Khan, Prof. Centre of Excellence in Physical Chemistry, University of
Peshawer, Pakistan for providing me the facility of rheological characterization.
I would like pay my especial compliments to my husband Syed Suqlain Raza Rizvi,
who always encourages me and cooperates with me at the time of any problem; I have
to face during my studies. I am also thankful to my parents as well as my parents-in-
law; without their kind cooperation, it was quite impossible for me to continue my
studies. May they live long to see all my dreams being fulfilled. (Aamin)
It will be quite unfair, if I forget my little children, Maryam, Fatima, Zaineb, Irtaza
and Farwa, to say especial thanks to them. They missed their mother at the most of
their apparently little but, in fact, very huge problems of innocent childhood. I feel,
really, guilty to make my studies upgraded at the cost of the cute smile; they lose
when they do not find their mother to take care of them. May they live long & may be
blessed with uncountable happiness. (Aamin)
At the end, I would like to say special thanks to my very devoted friends Nazia
Manzoor, Sana, Qudsia, Baila, Rahila, and Sara who helped me at every moment and
encouraged me at each and every achievement regarding my research work.
Rubab Zohra
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DECLARATION
I hereby declare that the work described in this thesis was carried out by me under the
supervision of Prof. Dr. Muhammad Aslam Malana at Institute of Chemical Sciences,
Bahauddin Zakariya University Multan, Pakistan, for the degree of Doctor of
Philosophy in Chemistry.
I also hereby declare that the substance of this thesis has neither been submitted
elsewhere nor is being concurrently submitted for any other degree.
I further declare that the work embodied in this thesis is the result of my own research
and work of any other investigator if reported has been fully and properly
acknowledged.
Rubab Zohra
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Abstract
Copolymers of methacrylate (MA), vinyl acetate (VA), acrylic acid (AA) and N-
isopropylacrylamide (NiPAAm) were synthesized in various combinations through
free radical polymerization method. The co-polymers were characterized using
different techniques including FTIR, DSC/TGA and rheology. Swelling parameters
i.e. dynamic and equilibrium media sorption, media penetration velocity, swelling
mechanism and diffusion exponent (n) were investigated with respect to the nature of
cross-linker (EGDMA or DEGDMA), concentration of the cross-linking agent and
acrylic acid. Stimuli-responsiveness of these hydrogels was determined analyzing the
effect of change in media pH on swelling behavior. Based on preliminary swelling
studies, Tramadol HCl, the model drug was loaded in selected batches of co-
polymeric hydrogels under optimized conditions of pH (8.0) and temperature (37oC).
The drug release studies of these hydrogels were carried out in phosphate buffer
solution of pH 8.0 and at 37oC, using a UV/Visible spectrophotometer. Various
models were applied to interpret the drug release kinetics of the co-polymeric
hydrogels. Using equilibrium swelling data, network parameters i.e. Vs, Mc, q etc.
were calculated applying Flory-Rehner equation. Rheological characterization was
carried out to explore flow behavior of Poly (MA-co-VA-co-AA) physically cross-
linked hydrogels, at a temperature range of 10-37oC. The data obtained were
modulated using different models. It was found that the rate of media sorption and
equilibrium media sorbed through these hydrogels could be fairly controlled changing
the composition of co-polymers and swelling conditions say pH and temperature.
Most of synthesized hydrogels had a good correlation coefficient with the second
order kinetic model in acidic medium and first order kinetics in basic pH except
NiPAAm gels which mostly followed Schott’s model in preference to Maxwell-
9
Peppas approach. The hydrogels Poly (MA-co-VA-co-AA) showed Fickian swelling
mechanism (n<0.5) in pH below pKa of AA (4.75) and non-Fickian behavior
(0.5<n<1) above pKa of AA, whereas NiPAAm gels underwent non-Fickian
mechanism at all media pH values. Media penetration velocity and equilibrium media
content seemed to have a good correlation coefficient with each other in all
synthesized hydrogels. These co-polymeric systems had an excellent capacity to
absorb and retain the model drug within their network. It was found that the drug
loading and unloading capacity of the systems decreased with the concentration of the
cross-linker and improved with higher initial drug concentration. The gels followed
predominantly the first order drug release kinetics. The chemically cross-linked Poly
(MA-co-VA-co-AA) presented non-Fickian drug release mechanism, but in the
NiPAAm co-polymeric hydrogels, Fickian behavior was dominant. It was observed
that less concentration of the cross-linking agent, higher amount of AA and the basic
medium improved the molecular weight between the cross-links, Mc and reduced the
volume fraction of the polymer, Vs. Rheological studies revealed that Poly (MA-co-
VA-co-AA) had a threshold concentration of AA after that the gels violated the
general trends of yield stress (γ), fluidity index (n) and consistency coefficients (k).
These gels showed pseudo-plastic behavior (n<1). Good mechanical strength and
promising ability of drug loading and the release in the chemically cross-linked Poly
(MA-co-VA-co-AA) in basic medium indicate that these drug carriers are capable to
resist peristaltic pressure of gastrointestinal tract (GIT) and the acidic medium of
stomach thus may be used as colon-specific drug delivery systems. The rheological
analysis of physically cross-linked Poly (MA-co-VA-co-AA) favors these systems to
be used as topogels. Moreover, shift of lower critical temperature from 32oC to 33.6oC
by the incorporation of a good balance of hydrophobic and hydrophilic components
10
with N-isopropylacrylamide in co-polymeric hydrogels made them suitable to be
loaded with the drug at room temperature and release the drug at 37oC, human body
temperature.
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List of contents
1. INTRODUCTION 1
1.1.Hydrogels 1
1.2.Synthesis & Characterization 3
1.3.Stimuli-responsiveness of Hydrogels 6
1.4.Hydrogels in Drug Delivery 12
1.5.Tramadol HCl 16
1.6.Literature Review 18
1.7.Aims & Objectives 30
2. EXPERIMENTAL 33
2.1.Chemicals 33
2.2.Solution Preparation 33
2.3.Synthesis of Hydrogels 34
2.4.Characterization of Hydrogels 36
2.4.1. Fourier Transform Infra Red Spectroscopy (FTIR) 36
2.4.2. Scanning Electron Microscopy (SEM) 36
2.4.3. Differential Scanning Calorimetry /Thermogravimetric
Analysis, (DSC/TGA) 37
2.4.4. Mechanical Analysis 37
2.4.5. Rheological Measurements 38
2.5.Swelling Kinetics 38
2.6.Drug loading 40
2.7.In vitro Drug Release Studies 42
3. RESULTS & DISCUSSION 46
3.1.Synthesis of Hydrogels 46
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3.2.Characterization of Hydrogels 52
3.2.1. Fourier Transform Infra Red Spectroscopy (FTIR) 52
3.2.2. Scanning Electron Microscopy (SEM) 55
3.2.3. Differential Scanning Calorimetry/Thermogravimetric
Analysis (DSC/TGA) 59
3.2.4. Mechanical Analysis 68
3.3.Swelling Kinetics 69
3.3.1. Dynamic & Equilibrium Swelling 69
3.3.2. Media Penetration Velocity 84
3.3.3. Swelling Mechanism 93
3.4.Loading of Tramadol HCl 119
3.5.Drug Release Kinetics 124
3.5.1. Drug Release Profiles 124
3.5.2. Kinetic Order of Drug Release 129
3.5.3. Drug Release Models 145
3.6.Network Parameters 158
3.7.Rheological Studies 167
3.7.1. Flow Curves 168
3.7.2. Yield Stress 173
3.7.3. Temperature Dependence of Viscosity 175
3.7.4. Flow Curve Modeling 180
CONCLUSION 192
REFERENCES 195
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List of Tables
Table 1.1: pH Values from Several Tissues and Cells Compartments. 8
Table 1.2: Probability of Occurrence of Various Adverse Effects. 17
Table 2.1: Details of Chemicals Used in Investigation. 33
Table2.2: Various Compositions of Physically and Chemically Cross-linked Co-
polymeric Hydrogels. 34
Table 2.3: Compositions of Samples for Drug Loading and Drug Release Studies. 41
Table 3.1: Volume ratio of AA to EGDMA in Poly (MA-co-VA-co-AA)
Hydrogels. 48
Table 3.2: Summary of media penetration velocities, equilibrium media contents,
Schott,s model and power law parameters for the poly (MA-co-VA-co-AA) for
varying concentration of EGDMA. 74
Table 3.3: Summary of media penetration velocities, equilibrium media contents,
Schott,s model and power law parameters for the poly (MA-co-VA-co-AA) for
varying concentration of AA, cross-linked with EGDMA. 75
Table 3.4: Summary of media penetration velocities, equilibrium media contents,
Schott,s model and power law parameters for the poly (MA-co-VA-co-AA) for
varying concentration of DEGDMA. 76
Table 3.5: Summary of media penetration velocities, equilibrium media contents,
Schott,s model and power law parameters for the the poly (MA-co-VA-co-AA) for
varying concentration of AA, cross-linked with DEGDMA. 77
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Table 3.6: Summary of media penetration velocities, equilibrium media contents,
Schott,s model and power law parameters for the poly (MA-co-NiPAAm-co-AA)
hydrogels. 78
Table 3.7: Kinetic parameters of Tramadol HCl release from the matrix tablets of the
poly (MA-co-VA-co-AA) for varying concentration of EGDMA. 132
Table 3.8: Kinetic parameters of Tramadol HCl release from the matrix tablets of the
poly (MA-co-VA-co-AA) for varying concentration of DEGDMA. 132
Table 3.9: Kinetic parameters of Tramadol HCl release from the matrix tablets of
NiPAAm gels. 133
Table 3.10: Net work parameters determined from equilibrium swelling studies for the
poly (MA-co-VA-co-AA) for varying concentration of EGDMA in various pH media
at 37oC. 162
Table 3.11: Net work parameters determined from equilibrium swelling studies of for
the poly (MA-co-VA-co-AA) for varying concentration of AA, cross-linked with
EGDMA in various pH media at 37oC. 163
Table 3.12: Net work parameters determined from equilibrium swelling studies for the
poly (MA-co-VA-co-AA) for varying concentration of DEGDMA in various pH
media at 37oC. 164
Table 3.13: Net work parameters determined from equilibrium swelling studies of for
the poly (MA-co-VA-co-AA) for varying concentration of AA, cross-linked with
DEGDMA in various pH media at 37oC. 165
Table 3.14: Net work parameters determined from equilibrium swelling studies for the
NiPAAm hydrogels in various pH media at 37oC. 166
Table 3.15: Rheological Properties of Hydrogels: Theremorheological Propeties. 174
15
Table 3.16: Rheological Properties of Hydrogels: Application of different models to
calculate the yield stress values at low shear rate ( up to 14.7 s-1). 182
List of Figures
Fig. 1.1: A swellable matrix showing three regions during swelling 2
Fig. 1.2: Response of a smart polymer to different stimuli that triggers the drug
delivery. 7
Fig. 1.3: Illustration of the poly (acrylic acid) polymer carrying a specific drug. (A) In
the stomach the drug is present in the interior of the gel disk because the carboxylic
groups are not ionized ye. (B) The polymer has swollen due to the ionized groups'
electrostatic repulsions, releasing the drug molecules to the environment. 9
Fig. 1.4: Illustration of the polymer poly (vinyl amine) with a specific drug. (A) In a
neutral or alkaline environment, the drug molecules are retained in the interior of the
gel. (B) However, the polymeric net swells delivering the drug molecules in the
environment. 10
Fig. 1.5: The effect of phase transition temperature on the polymers volume and drug
delivery. 11
Fig. 1.6: a schematic drawing illustrating the controlled drug release. 15
Fig. 2.1: Calibration curve for Tramadol HCl in buffer solution of pH 8.0. 43
Fig 3.1: Hydrogel cylinders showing the effect of composition on visual aspects of
synthesized co-polymeric hydrogels. 50
Fig 3.2: Hydrogel without any cross-linker. 50
Fig.3.3 (a): The gel disc before washing in distilled water. 51
Fig. 3.3 (b): The gel disc after washing in distilled water. 51
16
Fig. 3.3 (c): The gel discs after drying at 40oC showing persistent milkiness owing to
the presence of higher amount of the cross-linking agent. 51
Fig 3.4: IR spectrum of optimized batch of poly (MA-co-VA-co-AA) hydrogel cross-
linked with EGDMA. 52
Fig 3.5: IR spectrum of optimized batch of poly (MA-co-VA-co-AA) hydrogel cross-
linked with DEGDMA. 53
Fig 3.6: IR spectrum of optimized batch of NiPAAm-2 hydrogel cross-linked with
DEGDMA. 54
Fig 3.7 (a): SEM structures of the optimized batch [E2] inner surface in dry state at
high magnification power. 56
Fig 3.7 (b): SEM structures of the optimized batch [E2] inner surface in equilibrium
state at pH 8.0. 56
Fig 3.8 (a): SEM structures of the optimized batch [D2] inner surface in dry state at
high magnification power. 57
Fig 3.8 (b): SEM structures of the optimized batch [D2] inner surface in equilibrium
state at pH 8.0. 57
Fig 3.9(a): SEM structures of the optimized batch [NiPAAm-1] inner surface in dry
state. 58
Fig 3.9 (b): SEM structures of the optimized batch [NiPAAm-2] inner surface in
equilibrium state at pH 8.0. 58
Fig 3.10 (a): DSC curves for poly (MA-co-VA-co-AA) having a range of AA, cross-
linked with EGDMA used as xerogels. 60
Fig 3.10 (b): TGA curves for poly (MA-co-VA-co-AA) having a range of AA, cross-
linked with EGDMA used as xerogels. 60
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Fig. 3.11(a): DSC /TGA curves for optimized batch of poly (MA-co-VA-co-AA)
cross-linked with EGDMA in dry state. 64
Fig. 3.11 (b): DSC /TGA curves for optimized batch of poly (MA-co-VA-co-AA)
cross-linked with EGDMA in equilibrium state at pH 8.0. 64
Fig. 3.12 (a): DSC /TGA curves for optimized batch of poly (MA-co-VA-co-AA)
cross-linked with DEGDMA in dry state. 65
Fig. 3.12 (b): DSC /TGA curves for optimized batch of poly (MA-co-VA-co-AA)
cross-linked with DEGDMA in equilibrium state at pH 8.0. 65
Fig. 3.13: DSC /TGA curves for optimized batch of poly (MA-co-AA-co-NiPAAm)
cross-linked with DEGDMA in dry state. 66
Fig 3.14(a): DSC /TGA curves for optimized batch of poly (MA-co-AA-co-
NiPAAm) cross-linked with EGDMA in equilibrium state at pH 8.0. 66
Fig 3.14(b): DSC /TGA curves for poly (MA-co-AA-co-NiPAAm) cross-linked with
DEGDMA in equilibrium state at pH 8.0. 67
Fig. 3.15 (a): Xerogel before applying stress. 68
Fig. 3.15 (b): Xerogel after applying maximum stress. 69
Fig. 3.15 (c): Xerogel regained the original shape and size after the stress is
removed. 69
Fig. 3.15: Xerogel showing the effect of applied stress. 69
Fig. 3.16: Different stages of swelling of co-polymeric hydrogel disk. 79
Fig. 3.17: Effect of concentration of EGDMA on dynamic and equilibrium swelling
of poly (MA-co-VA-co-AA) co-polymeric hydrogels at pH 8.0. 80
Fig. 3.18: Effect of concentration of AA on dynamic and equilibrium swelling of poly
(MA-co-VA-co-AA) co-polymeric hydrogels cross-linked with EGDMA at pH
18
8.0. 80
Fig. 3.19: Effect of pH on optimized batch of poly (MA-co-VA-co-AA) co-polymeric
hydrogels cross-linked with EGDMA. 81
Fig. 3.20: Effect of concentration of DEGDMA on dynamic and equilibrium swelling
of poly (MA-co-VA-co-AA) co-polymeric hydrogels at pH 8.0. 81
Fig. 3.21: Effect of concentration of AA on dynamic and equilibrium swelling of poly
(MA-co-VA-co-AA) co-polymeric hydrogels cross-linked with DEGDMA at pH
8.0. 82
Fig. 3.22: Effect of pH on optimized batch of poly (MA-co-VA-co-AA) co-polymeric
hydrogels cross-linked with DEGDMA. 82
Fig. 3.23: Effect of nature of the cross-linker on dynamic and equilibrium swelling of
poly (MA-co-AA-co-NiPAAm) co-polymeric hydrogels at pH 8.0. 83
Fig. 3.24: Effect of pH on NiPAAm-2 co-polymeric hydrogel sample. 83
Fig. 3.25: Effect of AA: EGDMA volume ration on equilibrium media sorbed at pH
8.0, at 37oC, in poly (MA-co-VA-co-AA) co-polymeric hydrogels. 84
Fig. 3.26: Media penetration velocity at pH 1-8 in polymers comprised of 1-10 mol %
EGDMA in poly (MA-co-VA-co-AA). 87
Fig. 3.27: Equilibrium media content at pH 1-8 as a function of media penetration
velocity in polymers comprised of 1-10 mol % EGDMA in
poly (MA-co-VA-co-AA). 88
Fig. 3.28: Media penetration velocity at pH 1-8 in polymers comprised of 6-40 mol %
AA in poly (MA-co-VA-co-AA) cross-linked with EGDMA. 88
Fig. 3.29: Equilibrium media content at pH 1-8 as a function of media penetration
velocity in polymers comprised of 6-40 mol % AA in poly (MA-co-VA-co-AA)
cross-linked with EGDMA. 89
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Fig. 3.30: Media penetration velocity at pH 1-8 in polymers comprised of 0.6-11 mol
% DEGDMA in poly (MA-co-VA-co-AA). 89
Fig. 3.31: Equilibrium media content at pH 1-8 as a function of media penetration
velocity in polymers comprised of 0.6-11 mol % DEGDMA in poly (MA-co-VA-co-
AA). 90
Fig. 3.32: Media penetration velocity at pH 1.0-8.0 in polymers comprised of 6-38.7
mol % AA in poly (MA-co-VA-co-AA) cross-linked with DEGDMA. 90
Fig. 3.33: Equilibrium media content at pH 1.0-8.0 as a function of media penetration
velocity in polymers comprised of 6-38.7 mol % AA in poly (MA-co-VA-co-AA)
cross-linked with DEGDMA. 91
Fig. 3.34: Media penetration velocity at pH 1.0-8.0 in NiPAAm hydrogels. 91
Fig. 3.35: Equilibrium media content at pH 1.0-8.0 as a function of media penetration
velocity in NiPAAm-2 hydrogel. 92
Fig. 3.36: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample
E1. 95
Fig. 3.37: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample
E2. 95
Fig. 3.38: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample
E3. 96
Fig. 3.39: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample
E4. 96
Fig. 3.40: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample
EA1. 97
Fig. 3.41: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample
EA2. 97
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Fig. 3.42: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample
EA3. 98
Fig. 3.43: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample
EA4. 98
Fig. 3.44: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample
D1. 99
Fig. 3.45: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample
D2. 99
Fig. 3.46 : raphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample
D3. 100
Fig. 3.47: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample
D4. 100
Fig. 3.48: G raphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample
DA1. 101
Fig. 3.49: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample
DA2. 101
Fig. 3.50 : Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample
DA3. 102
Fig. 3.51: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample
DA4. 102
Fig.3.52: Graphic of Maxwell-Peppas Model at pH 5.5 for the hydrogel sample
NiPAAm-1 103
Fig. 3.53: Graphic of Maxwell-Peppas Model at pH 7.4 for the hydrogel sample
NiPAAm-1. 103
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Fig. 3.54: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample
NiPAAm-1. 104
Fig. 3.55: Graphic of Maxwell-Peppas Model at pH 1.0 for the hydrogel sample
NiPAAm-2. 104
Fig. 3.56: Graphic of Maxwell-Peppas Model at pH 4.0 for the hydrogel sample
NiPAAm-2. 105
Fig. 3.57: Graphic of Maxwell-Peppas Model at pH 5.5 for the hydrogel sample
NiPAAm-2. 105
Fig. 3.58: Graphic of Maxwell-Peppas Model at pH 7.4 for the hydrogel sample
NiPAAm-2. 106
Fig. 3.59: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample
NiPAAm-2. 106
Fig. 3.60: Graphic of Schott’s model at pH 1.0 for the hydrogel sample E1. 107
Fig. 3.61: Graphic of Schott’s model at pH 1.0 for the hydrogel sample E2. 107
Fig. 3.62: Graphic of Schott’s model at pH 1.0 for the hydrogel sample E3. 108
Fig. 3.63: Graphic of Schott’s model at pH 1.0 for the hydrogel sample E4. 108
Fig. 3.64: Graphic of Schott’s model at pH 1.0for the hydrogel sample EA1. 109
Fig. 3.65: Graphic of Schott’s model at pH 1.0for the hydrogel sample EA2. 109
Fig. 3.66: Graphic of Schott’s model at pH 1.0 for the hydrogel sample EA3. 110
Fig. 3.67: Graphic of Schott’s model at pH 1.0 for the hydrogel sample EA4. 110
Fig. 3.68: Graphic of Schott’s model at pH 1.0 for the hydrogel sample D1. 111
Fig. 3.69: Graphic of Schott’s model at pH 1.0 for the hydrogel sample D2. 111
Fig. 3.70: Graphic of Schott’s model at pH 1.0 for the hydrogel sample D3. 112
Fig. 3.71: Graphic of Schott’s model at pH 1.0 for the hydrogel sample D4. 112
Fig. 3.72: Graphic of Schott’s model at pH 1.0 for the hydrogel sample DA1. 113
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Fig. 3.73: Graphic of Schott’s model at pH 1.0 for the hydrogel sample DA2. 113
Fig. 3.74: Graphic of Schott’s model at pH 1.0 for the hydrogel sample DA3. 114
Fig. 3.75: Graphic of Schott’s model at pH 1.0 for the hydrogel sample DA4. 114
Fig. 3.76: Graphic of Schott’s model at pH 5.5for the hydrogel sample
NiPAAm-1. 115
Fig. 3.77:Graphic of Schott’s model at pH 7.4for the hydrogel sample
NiPAAm-1. 115
Fig. 3.78: Graphic of Schott’s model at pH 8.0 for the hydrogel sample
NiPAAm-1. 116
Fig. 3.79: Graphic of Schott’s model at pH 1.0 for the hydrogel sample
NiPAAm-2. 116
Fig. 3.80 : Graphic of Schott’s model at pH 4.0 for the hydrogel sample
NiPAAm-2. 117
Fig. 3.81 : Graphic of Schott’s model at pH 5.5 for the hydrogel sample
NiPAAm-2. 117
Fig. 3.82 : Graphic of Schott’s model at pH 7.4 for the hydrogel sample
NiPAAm-2. 118
Fig. 3.83: Graphic of Schott’s model at pH 8.0 for the hydrogel sample
NiPAAm-2. 118
Fig. 3.84: Effect of the cross-linker concentration on absorbency of Tramadol
HCl. 120
Fig. 3.85: Absorbency of Tramadol HCl by poly (MA-co-VA-co-AA) cross-linked
with EGDMA provided with various initial concentrations of the drug. 120
Fig. 3.86: Absorbency of Tramadol HCl by poly (MA-co-VA-co-AA) cross-linked
with DEGDMA provided with various initial concentrations of the drug. 121
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Fig. 3.87: Absorbency of Tramadol HCl by NiPAAm-1 cross-linked with EGDMA
provided with various initial concentrations of the drug. 121
Fig. 3.88: Absorbency of Tramadol HCl by NiPAAM-2 cross-linked with DEGDMA
provided with various initial concentrations of the drug. 122
Fig. 3.89: Effect of nature of the cross-linker on absorbency of Tramadol HCl in poly
(MA-co-VA-co-AA) hydrogels. 122
Fig. 3.90: Effect of nature of the cross-linker on absorbency of Tramadol HCl in
NiPAAm gels. 123
Fig. 3.91: Influence of concentration of the cross linking agent on release rate of
Tramadol HCl. 125
Fig. 3.92: Influence of amount of Tramadol HCl in the matrix on the release rate for
the hydrogel E2 at pH 8.0. 126
Fig. 3.93: Influence of amount of Tramadol HCl in the matrix on the release rate for
the hydrogel D2 at pH 8.0. 126
Fig. 3.94: Influence of amount of Tramadol HCl in the matrix on the release rate for
the sample NiPAAm-1 at pH 8.0. 127
Fig. 3.95: Influence of amount of Tramadol HCl in the matrix on the release rate for
the sample NiPAAm-2 at pH 8.0. 127
Fig. 3.96: Effect of nature of the cross-linker on release rate of Tramadol HCl in poly
(MA-co-VA-co-AA) hydrogels 1.6 mg/ml initial drug concentration. 128
Fig. 3.97: Effect of nature of the cross-linker on release rate of Tramadol HCl in
NiPAAm gels having higher drug concentration. 128
Fig. 3.98: Zero order release kinetics of Tramadol HCl from the sample E1 at pH
8.0. 134
Fig. 3.99: Zero order release kinetics of Tramadol HCl from the sample E3 at pH
24
8.0. 134
Fig. 3.100: Zero order release kinetics of Tramadol HCl from the sample TE4 at pH
8.0. 135
Fig. 3.101: Zero order release kinetics of Tramadol HCl from the sample TE5 at pH
8.0. 135
Fig. 3.102: Zero order release kinetics of Tramadol HCl from the sample TE6 at pH
8.0. 136
Fig. 3.103: Zero order release kinetics of Tramadol HCl from the sample TD5 at pH
8.0. 136
Fig. 3.104: Zero order release kinetics of Tramadol HCl from the sample TNE5 at pH
8.0. 137
Fig. 3.105: Zero order release kinetics of Tramadol HCl from the sample TND4 at pH
8.0. 137
Fig. 3.106: 1st order release kinetics of Tramadol HCl from the sample E1 at pH
8.0. 138
Fig. 3.107: 1st order release kinetics of Tramadol HCl from the sample E3 at pH
8.0. 138
Fig. 3.108: 1st order release kinetics of Tramadol HCl from the sample TE1 at pH
8.0. 139
Fig. 3.109: 1st order release kinetics of Tramadol HCl from the sample TE2 at pH
8.0. 139
Fig. 3.110: 1st order release kinetics of Tramadol HCl from the sample TE3 at pH
8.0. 140
Fig. 3.111: 1st order release kinetics of Tramadol HCl from the sample TD1 at pH
8.0. 140
25
Fig. 3.112: 1st order release kinetics of Tramadol HCl from the sample TD2 at pH
8.0. 141
Fig. 3.113: 1st order release kinetics of Tramadol HCl from the sample TD3 at pH
8.0. 141
Fig. 3.114:1st order release kinetics of Tramadol HCl from the sample TNE1 at pH
8.0. 142
Fig.3.115:1storder release kinetics of Tramadol HCl from the sample TNE2 at pH
8.0. 142
Fig.3.116:1st order release kinetics of Tramadol HCl from the sample TNE3 at pH
8.0. 143
Fig.3.117:1st order release kinetics of Tramadol HCl from the sample TND1 at pH
8.0. 143
Fig.3.118:1st order release kinetics of Tramadol HCl from the sample TND2 at pH
8.0. 144
Fig.3.119:1st order release kinetics of Tramadol HCl from the sample TND3 at pH
8.0. 144
Fig.3.120: Hixson-Crowell kinetics of Tramadol HCl from the sample E1 at pH
8.0. 145
Fig.3.121: Hixson-Crowell kinetics of Tramadol HCl from the sample E3 at pH
8.0. 145
Fig.3.122: Hixson-Crowell kinetics of Tramadol HCl from the sample TE5 at pH
8.0. 146
Fig.3.123: Hixson-Crowell kinetics of Tramadol HCl from the sample TE6 at pH
8.0. 146
Fig.3.124: Hixson-Crowell kinetics of Tramadol HCl from the sample TD5 at pH
26
8.0. 147
Fig.3.125: Hixson-Crowell kinetics of Tramadol HCl from the sample TNE5 at pH
8.0. 147
Fig.3.126: Hixson-Crowell kinetics of Tramadol HCl from the sample TND4 at pH
8.0. 148
Fig.3.127: Higuchi kinetics of Tramadol HCl from the sample E1 at pH 8.0. 148
Fig.3.128: Higuchi kinetics of Tramadol HCl from the sample E3 at pH 8.0. 149
Fig.3.129: Higuchi kinetics of Tramadol HCl from the sample TE1 at pH 8.0. 149
Fig.3.130: Higuchi kinetics of Tramadol HCl from the sample TE2 at pH 8.0. 150
Fig.3.131: Higuchi kinetics of Tramadol HCl from the sample TE3 at pH 8.0. 150
Fig.3.132: Higuchi kinetics of Tramadol HCl from the sample TD1 at pH 8.0. 151
Fig.3.133: Higuchi kinetics of Tramadol HCl from the sample TD2 at pH 8.0. 151
Fig.3.134: Higuchi kinetics of Tramadol HCl from the sample TD3 at pH 8.0. 152
Fig.3.135: Higuchi kinetics of Tramadol HCl from the sample TNE1 at pH 8.0. 152
Fig.3.136: Higuchi kinetics of Tramadol HCl from the sample TNE2 at pH 8.0. 153
Fig.3.137: Higuchi kinetics of Tramadol HCl from the sample TNE3 at pH 8.0. 153
Fig.3.138: Higuchi kinetics of Tramadol HCl from the sample TND1 at pH 8.0. 154
Fig.3.139: Higuchi kinetics of Tramadol HCl from the sample TND2 at pH 8.0. 154
Fig.3.140: Higuchi kinetics of Tramadol HCl from the sample TND3 at pH 8.0. 155
Fig.3.141: Korsemeyer-Peppas kinetics of Tramadol HCl from the sample TE5 at pH
8.0. 155
Fig.3.142: Korsemeyer-Peppas kinetics of Tramadol HCl from the sample TD5 at pH
8.0. 156
Fig.3.143: Korsemeyer-Peppas kinetics of Tramadol HCl from the sample TNE5 at pH
8.0. 156
27
Fig.3.144: Korsemeyer-Peppas kinetics of Tramadol HCl from the sample TND4 at pH
8.0. 157
Fig. 3.145: Shear stress vs shear rate at 10oC. 168
Fig. 3.146: Shear stress vs shear rate at 20oC. 169
Fig. 3.147: Shear stress vs shear rate at 30oC. 169
Fig. 3.148: Shear stress vs shear rate at 37oC. 170
Fig. 3.149: Frequency- dependent property of ter-polymeric hydrogels at 10oC. 170
Fig. 3.150: Frequency- dependent property of ter-polymeric hydrogels at 20oC. 171
Fig. 3.151: Frequency- dependent property of ter-polymeric hydrogels at 30oC. 171
Fig. 3.152: Frequency- dependent property of ter-polymeric hydrogels at 37oC. 172
Fig. 3.153: Steady state viscosity of A1 as a function of shear rate at different
temperatures. 177
Fig. 3.154: Steady state viscosity of A2 as a function of shear rate at different
temperatures. 177
Fig. 3.155: Steady state viscosity of A3 as a function of shear rate at different
temperatures. 178
Fig. 3.156: Steady state viscosity of A4 as a function of shear rate at different
temperatures. 178
Fig. 3.157: Modeling of viscosities of hydrogels samples at shear rate of 10 s-1 using
Arrhenius equation. 179
Fig. 3.158: Ostwald’s model fit at 10oC. 183
Fig. 3.159: Ostwald’s model fit at 20oC. 183
Fig. 3.160: Ostwald’s model fit at 30oC. 184
Fig. 3.161: Ostwald’s model fit at 37oC. 184
Fig. 3.162: Ostwald de-Waele model fit at 10oC. 185
28
Fig. 3.163: Ostwald de-Waele model fit at 20oC. 185
Fig. 3.164: Ostwald de-Waele model fit at 30oC. 186
Fig. 3.165: Ostwald de-Waele model fit at 37oC. 186
Fig. 3.166: Bingham model fit at 10oC. 187
Fig. 3.167: Bingham model fit at 20oC. 187
Fig. 3.168: Bingham model fit at 30oC. 188
Fig. 3.169: Bingham model fit at 37oC. 188
Fig. 3.170: Modified Bingham model fit at 10oC. 189
Fig. 3.171: Modified Bingham model fit at 20oC. 189
Fig. 3.172: Modified Bingham model fit at 30oC. 190
Fig. 3.173: Modified Bingham model fit at 37oC. 190
Fig. 3.174: Application of Modified Bingham Model describing the overall flow
behavior of the acrylic acid ter-polymeric hydrogels at 37oC. All the sample hydrogels
are exhibiting excellent correlation factor values. 191
29
1. INTRODUCTION
1.1. Hydrogels
With ongoing research in devising advanced drug delivery formulations to offer
reliable and systematically controlled drug delivery carriers, the highly focused are
hydrogels. These structures imbibe water or biological fluids at least 10-20 times their
molecular weight (Kim et al., 1992). Hydrogels have a unique property to maintain
original shape during and after swelling (Omidian and Park, 2008) which is isotropic
in nature and the only change observed is increase in the size of the gel. Moreover,
low interfacial tension and low frictional surface by the presence of water on the
surface of hydrogels make them important to be used widely in the development of
biocompatible materials (Yaszemski et al., 2004; Slaughter, 2009). These materials
are familiar for their ability to overcome the problems of conventional dosage forms
and sustained drug release at specific site. These orient the drug exposure to diseased
cells keeping the normal cells protected (Stastny et al., 2002; Lowman and Peppas,
1991). Furthermore, high water content, soft and rubbery consistency and low
interfacial tension with water or biological fluids render hydrogels, a promisingly,
similar physical properties as those of living tissues (Rosiak & Yoshii, 1999; Rogero
et al., 2003). The groups such as hydroxyl (–OH), primary amide (–CONH),
carboxylic (–COOH) and sulphonic (–SOH3) etc are responsible for hydrophilic
nature for hydrogels. Capillary effect and osmotic pressure are other parameters that
also affect the equilibrium media sorbed of hydrogels (Dergunov & Mun, 2009). On
exposure to the aqueous medium, water will be absorbed by the hydrogel. At any
specific time after exposure to water, three regions are generally shown within the
hydrogel matrix. The first region is mechanically weak just like a ‘soft rubber’ and
highly swollen acting as a diffusional barrier for the remaining water. As such, the
30
second region is relatively strong, may be called ‘tough rubber’ and will be
characterized as moderately swollen. The third non-swollen region will remain almost
in this glassy state for a longer period of time (fig. 1.1).
Fig. 1.1: A swellable matrix showing three regions during swelling (Omidian and
Park, 2008).
Various factors affecting the equilibrium swelling, dimensional change and the drug
release mechanisms of these carriers, are the hydrophobic/hydrophilic balance of the
hydrogels, the crosslink density, the degree of ionization and their interaction with
counter ions are important ones (Yin et al., 2002). The cross-linking is responsible for
insolubility of these materials in water due to anionic interaction and hydrogen
bonding (Peppas et al., 2000). Hydrogels may be either cross-linked chemically or
physically. The linear polymer chains are covalently bonded with each other in
chemically cross-linked hydrogels. The interest for physically cross-linked hydrogel is
obvious since they are beneficial for post-process bulk modification and ease of
fabrication (Hennink & van Nostrum 2002; Li et al., 2002; Adams et al., 2003; Kubo
et al., 2005; Liu et al., 2009). The network structure of hydrogels can be tuned to be
macro-porous, micro-porous or non-porous. Macro-porous hydrogels have pores of
dimensions 0.1 to 1µm. The mechanism of drug release from these macro-porous
polymeric materials depends upon drug diffusion coefficient, porosity and tortuosity
31
of the gel network (Liu et al., 2000). These hydrogels are used as super-sorbents in
baby diapers (Ganji et al., 2101). Micro-porous hydrogels have small pore size
ranging from 100 to 1000Å and the drug release is accompanied by diffusion and
convection. Micro-porous hydrogels are used in biomedical applications and
controlled release technology (Ganji et al., 2101). Non-porous hydrogels formed due
to cross-linking of monomer chains, are the mesh like structures of macro molecular
dimensions (10-100Å) and have various uses i.e. as contact lenses and artificial
muscles (Ganji et al., 2010). Diffusion mechanism is the only one which facilitates the
drug release from non-porous hydrogel structures (Mc-Neill and Graham, 1993). In
the presence of chemical cross linking, the hydrogel is one molecule regardless of its
size. That is the reason the hydrogels are some time called infinitely large molecules
or super macromolecules. Again, due to the same perception, there is no concept of
molecular weight of hydrogels. The xerogels (dried gels) are usually clear and require
a long time to attain equilibrium swelling. Slow diffusion of water through the
compact polymer chain results in slow swelling property that has been useful in
controlled drug dug delivery (Kim et al. 1992). Different properties of hydrogels like
mechanical strength, surface properties, permeability, biocompatibility, rheological
outcomes and thermo-gravimetric behavior are highly affected by the water content in
the polymer networks.
1.2. Synthesis and Characterization
A number of methods have been reported for the synthesis of hydrogels. Since
hydrogels entrap drug within their pores by swelling in water, so the first approach
involves network fabrication using multi-functional co-monomers, which act as cross-
linking agents like glutarldehyde, ethylene glycol dimethacrylate and diethylene
32
glycol dimethacrylate etc. Various initiators are applied to initiate the
copolymerization reaction. The polymerization reaction can be performed in bulk, in
solution or in suspension. In the second method, linear polymers are cross-linked
either by irradiation or by chemical compounds. In ionic polymer network the
monomers used contain an ionizable group, which may be weakly acidic one like
carboxylic acid or a weakly basic group like substituted amines or strongly acidic and
basic group like sulfonic acid and quaternary ammonium compounds. In solution
polymerization, the multifunctional cross linking agent is mixed with ionic or neutral
monomers. UV light or redox initiator system is introduced to initiate the
polymerization reaction. The temperature control problems are minimized by the
presence of solvent serves as a heat sink to remove un-reacted monomers, the cross
linking agent and the initiator. The hydrogels can be made pH-sensitive or
temperature-sensitive by adding different monomers like itaconic acid, acrylic acid,
methacrylic acid (Ende & Peppas 1996; Ying etal., 1998; Jabbari & Nozari 1999;
Jianqi & Lixia 2002; Wang et al. 2006) or N-isopropylacrylamide as monomers
(Stringer and Peppas, 1996; Jhan and Andrade, 1973). Suspension polymerization is
employed to synthesize spherical polymer particles having a size of 1µm to 1mm. In
this method, the dispersion of monomers solution in the non-solvent forms fine
droplets which are stabilized by the addition of stabilizer
For preparation of hydrogels of unsaturated compounds, high energy radiations like
gamma and electron beam have been used. The irradiation of aqueous polymer
solution results in the formation of macro-radicals by forming radicals on the polymer
chains. Afterwards, the macro-radicals on various chains recombine with each other
and the covalent bonds result in synthesis of cross-linked structure (Tanaka, 1978;
Das et al., 2006).
33
The general use of a hydrogel is determined by its swelling degree and mechanical
properties, that is, its deformation and fracture under stress. Depending on some
specific factors like the degree of crystallinity, degree of cross-linking, and the values
of glass transition Tg and crystalline melting temperature Tm, hydrogels vary widely in
their mechanical behavior. Crystalline melting temperature is the melting point of the
crystalline domains of a co-polymeric hydrogel sample while glass transition
temperature is the point at which amorphous domains of a polymer takes on
characteristic properties of a glassy state. The polymer sample loses its strength at or
near Tg for an amorphous polymer and at or near Tm for a crystalline polymer. High
Tg characterizes high degrees of crystallinity and cross-linking, thus results in a
network of high strength and low extensibility and vice versa (Odian, 2004).
Mechanical behavior of a hydrogel is usually characterized by its stress-strain
properties (Allcock et al., 2003).This often involves monitoring the response of a
polymer as one applies tensile stress to it in order to elongate (strain) it until it
ruptures. Moreover, hydrogels are also characterized morphologically by using
different equipments like stereomicroscope and scanning electron microscope etc.
Rheological Characterization
The science of the deformation and flow of matter is called rheology (Scott-Blair,
1969; Steffe, 1992; Rao, 1999). Rheological properties analyze the flow behavior and
textural characteristics of materials. Specific flow requirements are fulfilled for the
success of a wide range of commercial products and industrial processes. Generally,
two steps are identified while discussing rheological behavior (Lee et al., 2009):
elastic behavior (if the material restores its original shape when the external force is
removed) and viscous or plastic behavior (where deformation ceases and material
does not regain its original shape when the applied force is removed) as exhibited in
34
ideal Newtonian liquids. Using rheological measurements the micro-structural
environment or mobility responsible for drug diffusion and compatibility can be
directly probed. Especially in topical drug delivery, from dermatological
formulations, an extensive study may lead to the possible employment of rheological
parameters and models to optimize the efficiency of these systems. Before the gels are
applied for drug delivery at specific sites, it is necessary to ensure adequate
characteristics for topical drug formulations, in order to obtain the desired therapeutic
effect. All these properties of drug formulations such as application easiness of
hydrogels, prolonged skin contact, appearance and sensation after gel application etc,
strongly depend on the rheological behavior and plasticity of the formulation.
Optimization and standardization of the rheological parameters face a major
technological problem because they are the direct factors affecting the therapeutic
activity of the active substances. However, rheological determinations are very
important in pharmaceutical point of view because of their contribution to the
characterization of manufacturing operations, of changes that may occur during
storage or transport, or of the behavior during administration of pharmaceuticals
(Tamburic and Craig, 1996; Owen et al., 2001).
1.3. Stimuli-responsiveness of Hydrogels
The ideal drug delivery system relies on the fact that the drug release profile is able to
respond to metabolic states and/or physiological variation (Bawa et al., 2009).
Stimuli-responsive polymers are in the vanguard of drug delivery technology because
they have exhibited highly sensitive to small signs and changes in the environment,
which introduce reasonable changes in their network structures and in the
physiological and chemical properties as required (Grainger, El-Sayed, 2010;
35
Kuckling, Urban, 2011 ). Conclusively, it can be said that stimuli-responsive
hydrogels are capable to respond to a stimulus by demonstrating physical or chemical
changes in its behavior, as for example, the delivery of the drug carried by it (Gupta et
al., 2002). An important feature of these smart polymers is that these are able to
recover their initial state, when the sign or stimulus ends thus undergoing reversible
macroscopical changes (Stuart et al., 2010). Stimuli-responsive hydrogels are
biocompatible, non-thrombogenic, strong, flexible and easy to shape. They are not
only easy to manufacture but also are capable to retain the drug’s stability and it is
possible to inject them in vitro to form a gel with the body temperature (Mahajan,
Aggarwarl, 2011). The stimuli that trigger the behavioral changes in these hydrogels
can be classified into three main groups: physical stimuli (temperature, ultrasounds,
light, mechanical stress), chemical stimuli (pH and ionic strength) and biological
stimuli (enzymes and bio-molecules) (fig 1.2) (Jeong, Gutowska, 2002; Kumar et al.,
2007).
Fig. 1.2: Response of a smart polymer to different stimuli that triggers the drug
delivery (Gupta et al., 2002).
36
These signs or stimuli can be either controlled artificially or may be promoted
naturally or by the physiological condition (Kopecek, 2007; Kim et al., 2009).
Presence of a sign or a stimulus can introduce changes on the surface and solubility of
the polymer as well as on sol-gel transition (Fogueri, Singh, 2009; Shaikh et al.,
2010).
pH-responsive Hydrogels
Remarkable changes of pH can be noticed in the human body and may be helpful to
orient therapeutic agents to a specific body area, tissue or cell compartment (table
1.1).
Table. 1.1: pH Values from Several Tissues and Cell Compartments
(Adapted from Bawa et al., 2009).
Tissue / Cell compartment pH
Blood 7.4-7.5
Stomach 1.0-3.0
Duodenum 4.8-8.2
Colon 7.0-7.5
Lysosome 4.5-5.0
Golgi complex 6.4
Tumor – Extracellular medium 6.2-7.2
The main property of these pH-sensitive hydrogels is that they are capable to accept
or release protons in response to pH changes (Grainger, El-Sayed, 2010). In their
network structures, there are present acid groups (carboxylic or sulfonic) or basic
groups (ammonium salts) (You et al., 2010). They change their solubility by changing
37
the electrical charge of the molecules (Shaikh et al., 2010). Thus, the decease of
electrical charge on the polymer molecules leads to the transition from a soluble state
to an insoluble form. The anionic pH-sensitive hydrogels e.g. poly (acrylic acid)
(PAA) or poly (methacrylic acid) (PMAA) have a great number of ionizable groups in
their structure (Grainger, El-Sayed, 2010). The carboxylic groups accept protons in
acidic pH and donate proton in the basic pH media (Gil, Hudson, 2004). At what pH
the polymer acidic groups will be ionized, depends on the pKa value of the acidic
monomer (the polymer composition and the molecular weight). So, in an oral drug
delivery system, the poly (acrylic acid) hydrogels deliver the drug in alkaline pH
(small intestine) and retains the drug in acidic pH (stomach) (fig. 1.3).
Fig. 1.3: Illustration of the poly (acrylic acid) polymer carrying a specific drug. (A) In
the stomach the drug is present in the interior of the gel disk because the carboxylic
groups are not ionized ye. (B) The polymer has swollen due to the ionized groups'
electrostatic repulsions, releasing the drug molecules to the environment (Grainger, El
-Sayed, 2010).
38
On the other hand, cationic polymers e.g. poly (4-vinylpyridine), poly (2-
vinylpyridine) (PVP) and poly (vinylamine) (PVAm), get protonated at higher pH
values and ionized positively at neutral or low pH values, undergoing a phase
transition at pH 5 due to the deprotonation of the pyridine groups (Gil, Hudson,
2004). Other poly bases are poly (N, N-dimethylaminoethyl methacrylate
(PDMEMA) and poly (2-diethylaminoethyl methacrylate) (PDEAEMA) gain protons
in acidic environment and release protons in basic medium due to having amino
group in them (fig. 1.4)
Fig. 1.4: Illustration of the polymer poly (vinyl amine) with a specific drug. (A) In a
neutral or alkaline environment, the drug molecules are retained in the interior of the
gel. (B) However, the polymeric net swells delivering the drug molecules in the
environment (Grainger, El-Sayed, 2010).
Thermo-responsive Polymers
Other important stimuli-responsive polymers are those ones which respond to external
temperature. Thermo-responsive polymers adopt in their network structure, a very
sensitive balance between the hydrophilic and hydrophobic groups and new
39
adjustment may be introduced even by a very small change in their temperature
(Bajpai et al., 2008). An important characteristic parameter of such polymers is the
critical solution temperature. If the polymer solution has a phase below the critical
solution temperature, it will be said to have lower critical solution temperature
(LCST) and it will become insoluble after heating. Hydrogen linkages between the
water molecules and the polymer tend to be unfavorable above the critical solution
temperature (LCST), so it dehydrates; the hydrophobic interaction predominates,
causing the polymer swelling (MacEwan et al., 2010). The LCST is the critical
temperature where the polymeric solution shows a phase transition from isotropic
state to anisotropic state. However, the incorporation of the hydrophobic or
hydrophilic groups in the polymeric network results in the change of the LCST. The
figure 1.5 illustrates the transition to the hydrogel phases.
Fig. 1.5: The effect of phase transition temperature on the polymers volume and drug
delivery (Almeida, 2012).
40
Poly (N-isopropylacrylamide) (PNiPAAm) belongs to the family of poly (N-
substituted acrylamide) gels. As pure (PNiPAAm) gels are soluble in water at room
temperature due to the hydrophilic interaction, i.e. the predominant hydrogen
bonding, so these are widely studied and used in drug delivery systems and
biomaterials. The solutions become opaque above the LCST (≈32oC) and turns into a
gel with a transition temperature approximately equal to body temperature and thus
the hydrophobic interactions predominate (Kulkarni, Aloorkar, 2010). Thus, it can be
briefed that the hydrogen bonds predominate between the polymer amide groups and
water molecules below LCST. Whereas, the hydrogen bonds get departed above the
lower critical solution temperature and the polymer dehydrates expelling water
molecules. The most favoring fact for PNiPAAm gels to be used for controlled drug
delivery is that the lower critical solution temperature can be adjusted through the
copolymerization of the hydrophobic or hydrophilic molecules or through controlling
the polymer molecular weight (Reul-Gariépy, Leroux, 2004). For example, adding a
hydrophobic monomer (butyl methacrylate etc) or on the molecular weight, result in
the decrease of LCST (Jeong, Gutowska, 2002). On the other hand, the introduction
of hydrophilic monomers (acrylic acid or hydroxyethyl methacrylate etc) fosters the
production of hydrogen bonds with thermo-sensitive monomers causing an increase in
LCST.
Dual Stimuli-responsive Polymers
By combining thermo-sensitive monomer (as, for example, N-isopropylacrylamide)
with pH-sensitive monomer (as, for example, AA or MAA), dual stimuli-sensitive
polymers can be obtained (You et al., 2010). Using same theory, nano-particles
containing vitamin B12, were prepared combining PNiPAAm and MAA with different
41
ratios. When the temperature increased from 37-40oC, and the pH was decreased from
6 to 4, the permeability increased causing the release of vitamin B12.
1.4. Hydrogels in Drug Delivery
Hydrogels have become important to be used for the development of controlled
delivery systems for a long time. When the drug containing hydrogel is introduced in
aqueous medium water, penetrating into the system, dissolves the drug. Diffusion is
the principal phenomenon, causing the release of the dissolved drug out into the
aqueous medium. The properties like pH sensitivity, thermal responsiveness, light
sensitivity and pressure sensitivity etc, may affect the diffusion of the drug through
the hydrogels depending upon their composition. The delivery systems constructed
from hydrogels for controlled release can be categorized into reservoir and matrix
devices.
Reservoir system: - In this type of delivery system, a reservoir (a drug-
enriched core) is enveloped within a uniform polymeric layer of hydrogel
which is capable to allow the diffusion of drug through it (Chasin and Langer,
1990; Chein, 1982). On contact with water, the system absorbs water by
diffusion and dissolves the drug up to the saturation solubility of the drug (Cs).
Now, the drug diffuses out through the membrane to the external environment,
thus decreasing the concentration of the drug below Cs. In the early stages, the
drug release follows zero order kinetics but later on, the release becomes
concentration dependent following first order kinetics. Such type of drug
delivery systems, are generally applied to deliver the active agent by oral,
ocular, uterine or trans-dermal routes.
42
Matrix system: - In such type of delivery system, the drug is homogeneously
dispersed as a solid into hydrogel matrix. The properties of matrix highly
affect the release of the active agent from the matrix. When the matrix is
placed into the aqueous medium, the diffusion of water and hydration of
matrix takes place at the same time. The hydration of the matrix occurs from
surface towards the centre of the core. The release of the drug acquires three
steps i.e. diffusion of water into the matrix, dissolution of the drug and
ultimately the diffusion of the dissolved drug from the matrix. In such
systems, the role of polymer-drug interaction is noticeable. Hence, the release
profile of the drug can be modulated trying the polymers interacting with
drugs.
As hydrogels have capability to orient their equilibrium water uptake due to the
change in environment, viz. temperature, pH and ionic strength of the release media
(Kim, 1996), these types of hydrogels can be used to develop controlled drug delivery
systems. Research is continued on new strategies to develop efficient delivery
systems, exhibiting controlled release fashion. For this purpose, a wide variety of
properties of hydrogels can be tuned and molded. Already, hydrogles have been
successfully applied to develop oral, ocular, trans-dermal and implantable drug
delivery. As oral delivery of drug is cheap and offers maximum patient compliance,
one can target mouth, stomach, small intestine and colon (Peppas et al., 2000) through
oral delivery system. The bio-adhesive property of the hydrogels helps to deliver
drugs at the specific sites of gastro-intestinal tract (GIT). Such systems may be used
to locally cure periodontal diseases, fungal and viral infection, post-operational pains
and oral cavity cancers. However, concerning the targeted and sustained drug delivery
43
in GIT, especially post-intestinal colon part, different challenges have to be overcome
i.e.
The system should offer improved patient compliance.
The reduction of administration frequency is also requires.
The delivery system should be made capable to remain at the specific site for a
long period of time.
To increase the resistance time in stomach and proximal portion of small
intestine.
To allow little or negligible swelling on non-targeted sites e.g. in acidic
medium of stomach in case of colon-targeted drug release systems.
To accommodate the pressure produced due to peristaltic movement of GIT
etc.
Following is the figure (fig. 1.6) illustrating a drug release profile considered to be the
most suitable, concerning above mentioned problems:
Fig. 1.6: a schematic drawing illustrating the controlled drug release (Bajpai et al.,
2008)
44
One of the popular routes for drug delivery is to apply the drug topically, thus
providing more patient compliance and preventing the side effects offered by using
injections or tablets and capsules through various administration routes. Instead of
conventional creams, the hydrogels have been designed for more patient convenience.
A number of reasons are there to seek attraction for drug delivery across the skin. To
deliver drug topically through different polymeric systems offers a number of
advantages e.g. ease of access, application and cessation delivery, sustained and
steady drug release, decreased side effects ,prevention of drug degradation in the GI
tract and absence of pain.
1.5. Tramadol HCl
Tramadol is a centrally-acting analgesic and is used to treat moderate to moderately
severe pain. The drug has a wide range of applications e.g. for treating restless-leg
syndrome, acid reflux and fibromyalgia. Tramadol was formulated by the
pharmaceutical company Grunenthal GmbH in the late1970s. It is usually marketed as
its hydrochloride salt (Tramadol hydrochloride) and as tartarate on rare occasions.
Tramadol is rare (at least in US) available for both injection (intra-venous and/or
intra-muscular) and as tablets for oral administration. Several manufacturers have
made generic tablets with well known dosing unit of 40 mg. It is also commonly
available in conjunction with Paracetamol and Acetaminophen etc. Tramadol comes
in many forms, including capsule, tablets, suppositories, effervescent tablets and
powders, ampoules of sterile solution for SC, IM and IV injections, powders for
compounding etc.
Experimentally, Tramadol has been applied in the form of an ingredient in topical
gels, creams and solutions for nerve pain and trans-dermal patch etc. It has a
45
characteristic mildly bitter taste, much better than morphine and codeine. Oral and
sublingual drops and liquid preparations are available with or without added
flavoring. The maximum dosage in any form of Tramadol is 400 mg per day. This is
also being used for treatment of post-operative, injury-related and chronic (e.g.
cancer-related) pain in pets like dogs, cats and rabbits etc. Experimentally, Tramadol
has been used in many small mammals including rats, flying squirrels, guinea pigs,
ferrets and raccoons etc. Tramadol is a very reliable and useful active principle
available to veterinarians to treat animals in pain especially cats and dogs because the
use of some non-steroidal anti-inflammatory substances in these animals may be
dangerous. In spite of being very useful, Tramadol may cause some serious side
effects.
Table 1.2: Probability of Occurrence of Various Adverse Effects
(Mullican and Hacy, 2001):
Effect Probability (%)
Any adverse effect 71
Drowsiness 17
Nausea 17
Dizziness 15
Constipation 11
Headache 11
Vomiting 7
Diarrhea 6
Dry mouth 5
Fatigue 5
Indigestion 5
Seizure (Gardner et al., 2000) <1
46
Structurally, Tramadol closely resembles with codeine. Both Tramadol and Codeine
are metabolized along the same hepatic path way and both compounds share the 3-
methyl ether group.
1.6. Literature Review
Over the past a few decades, the development of advanced pharmaceutical technology
and the astonishing rise of the biotechnology industry has revolutionized the approach
to design more and more efficient drug delivery systems. The main focus is on
hydrogels that are capable to reduce the problems of not only conventional dosage
forms but also prove themselves the most effective targeted drug delivery systems. A
myriad of novel drug delivery systems are under research and significant advances are
being made in nearly all aspects of drug delivery. This section briefly reviews the
main developments in this field, taken place in recent years.
pH-responsive hydrogels are proved to be efficient for controlled drug delivery. The
preliminary studies of swelling behavior are of great interest for researchers in
hydrogels.
One of pH-sensitive hydrogels is copolymer of polymethylmethacrylate (PMMA) and
polyhydroxy ethyl methylacrylate (PHEMA) which are anionic copolymers, swell
reasonably in neutral or basic pH but do not swell in acidic medium (Peppas and
Peppas, 1990).
Patel and Murthy synthesized copolymeric hydrogel beads of 2-hydroxy ethyl
methacrylate (HEMA) and methyl methacrylic acid (MMA) polymers using four
different crosslinking agents like EGDMA, DEGDMA, TriEGDMA and TEGDMA
and characterized by FTIR and DSC. The dynamic swelling of hydrogel beads was
47
carried out in water, methanol and water-methanol mixture (1:1). It was found that the
type of cross-linking agents used have very high effect on permeation of solvent
(Patel and Murthy, 2001).
Morishta et al. (2002) prepared micro-particles with poly (methacrylic acid-g-ethylene
glycol) PMAA-g-EG) that delayed the insulin delivery through the gel in an acidic
environment whereas, in neutral or alkaline pH, a faster drug delivery was observed
(Morishta et al., 2002).
Kim et al. (2003) investigated the dynamic swelling behavior of poly (methacrylic
acid-co-methacryloxyethyl glucoside) and poly (methacrylic acid- co-ethylene glycol)
hydrogels and determined the water transport mechanism through these anionic
hydrogels. The pH of swelling medium affected the swelling mechanism significantly
and appeared to be more relaxation controlled in a swelling medium of pH 7.0 (Kim
et al., 2003)
Bussemer et al. (2003) studied the swelling behavior of polymers for targeted drug
delivery systems. They observed that different swellable excipients have various
swelling energy or force. The order of swelling was found to be croscarmellose
sodium (Ac-Di-Sol) ˃ low-substituted hydroxypropyl cellulose (L-HPC) ˃ sodium
starch glycolate (Explotab) ˃ crospovidon (Kollidon-CL) ˃ hydroxypropyl methyl
cellulose (Methocel k100 M). Analysis of time-dependant swelling force indicated a
diffusion-controlled swelling mechanism, predominantly controlled by the penetration
rate of swelling medium. (Bussemer etal. 2003).
Vlachou et al. (2004) prepared hydrogel tablets comprising hydroxypropyl methyl
cellose (HPMC), HPMC with sodium dichlofenac and HPMC with furosemide. They
discussed the fronts created by the swelling process and their movement. They
48
concluded that various factors i.e. the dissolution, the diffusion of the drug, the
translocation of un-dissolved drug particles in the gel layer and the solubility of the
drug used affect the rate and mechanism of drug release from swellable matrices
(Vlachou et al., 2004).
Foss et al. (2004) synthesized nano-particles of P (AA-g-PEG) to administrate insulin
orally. They also reported that AA with pKa value of 4.5 became hydrophilic in basic
medium due to ionization (Foss et al., 2004). It is also noticed that swelling kinetics of
PHEMA and guar gum was determined by pH and ionic strength of outer medium
(Das et al., 2006).
Kumar et al. (2006) prepared insulin loaded hydrogles of cross-linked copolymers of
polyethylene glycol and methacrylic acid, by partitioning the insulin concentration the
highest release was observed at pH 7.4 while no leakage from the micro-particles of
hydrogels was noticed under acidic conditions (Kumar et al., 2006).
The synthesis and swelling behavior of pH-sensitive poly (2-
hydroxyethymethacrylate-co-acrylic acid-co-ammonium acrylate) hydrogels were
reported by Yarimkaya and Basan (2007). A sharp change in the water absorbency
and mesh size of networks with a change in pH of swelling solutions was observed.
They suggested these hydrogel systems as strong candidates for being used as oral
drug delivery systems and ion-exchanger for removal of metal ions from aqueous
media (Yarimkaya and Basan, 2007).
Xinming and Yingde reported the synthesis of poly (2-hydroxyethymethacrylate-co-
acrylamide) hydrogels for soft contact lens (SCL)-based ophthalmic drug delivery
system. They claimed that poly (2-hydroxyethymethacrylate-co-acrylamide)
hydrogels were transparent and useful SCL biomaterial. It was also noticed that the
49
water content increased with increase in acrylamide content and decreased with pH of
the medium (Xinming and Xingde, 2008).
A controlled release system comprising of N-succinyl chitosan/alginate synthesized
by ionic gelation was reported by Dai and coworkers (Dai et al., 2008). These gel
systems indicated a pH-dependent release profile of nifedipine.
Microspheres of interpenetrating networks of poly (methacrylic acid) and poly (vinyl
alcohol) cross-linked with glutaraldehyde were studied and found to able deliver
ibuprofen into the intestine (Mundargi et al., 2008).
Recently, Wallmersperger and his co-workers studied the swelling behavior of poly-
electrolyte gels under electrochemical stimulation by applying various models
(Wallmersperger et al., 2008). They investigated the hydrogel network by using the
porous media and the discrete element theory models. They reported that during all
the time steps of the discrete element stimulation, the direct physical access to the
system is possible.
Hybrid polymeric networks composed of polyacrylamide and chitosan were reported
by Martenez-Ruvalcaba et al. (2009). Swelling and ascorbic acid delivery kinetics
were determined for various chitosan concentrations. It was noticed that the swelling
was highly affected by pH of swelling solution as well as concentration of chitosan.
Young’s modulus was found to be increased with the amount of chitosan (Martenez-
Ruvalcaba et al., 2009).
Another pH-responsive system was designed by Fogueri and Singh (2009). They
studied poly (2-diethylaminoethyl methacrylate) (PDEAEMA) based hydrogels.
These hydrogels experience an increase in their membrane’s permeability in
50
decreased pH, due to the ionization of the polymer in an environment (Fogueri and
Singh, 2009).
pH-responsive hydrogels have been applied in number of ways including oral peptide
delivery (Kim and Peppas, 2002; Robinson and Peppas, 2002; Kim and Peppas,
2003), valves for microfluidic devices (Beebe et al., 2000), artificial muscles
(Schreyer et al, 2000; Shahinpoor and Kim, 2002; Shahinpoor and Kim, 2004 ).
Mullarney et al. (2006) reported hydrophobically modified copolymers of N, N-
dimethyl acrylamide and 2-CN-ethy-perflouroatanesulfonamide) ethyl acrylate
(FOSA) as controlled ocular drug delivery devices. It was found that the diffusion of
the model drug was less sensitive to pH of the buffered media over the range of pH 4-
8, however, increasing the media pH, slowed down the permeability slightly
(Mullarney et al., 2006).
Colon specific hydrogels of polysaccharides have been formulated because high
concentration of poly-saccharidase enzymes is found in the colon region of GI
(gastrointestinal tract). Drugs loaded in such hydrogels are found to be tissue specific
and sensitive to pH change or enzymatic actions that cause liberation of drug (Singh
et al., 2007).
The anionic hydrogels comprising of poly (vinyl alcohol) and poly (gamma-glutamic
acid) cross-linked thermally, were found to be pH-sensitive in nature and compatible
with the 3T3 fibroblast cell line. It was concluded that the drug diffusion in the
hydrogel suggested its probable use for the oral delivery of the bioactive agent (Lee et
al., 2008).
51
Kulkarni and Aloork (2010), recently, developed pharmaceutical systems comprised
of pH responsive hydrogels which were covalently bound to the enzyme glucose
oxidase (Kulkarni and Aloork, 2010). In this case, the changes in the pH of
environment are introduced due to oxidation of glucose in the blood, by glucose
oxidase. Being pH-responsive, the hydrogel gets swelled and release insulin.
Povea et al. (2011) reported the synthesis and characterization of interpenetrated
polymer networks of chitosan (CHI), polyacrylic acid (PAA) and polyacrylamide
(PAM). They also studied the release of bovine serum albumin (BSA) at different
pHs. It was found that the compression modulus of swelled hydrolyzed hydrogels
decreased with increasing equilibrium water content. Moreover, due to the higher
water content and porosity, higher BSA loading were achieved on hydrolyzed
hydrogels. A sustained protein release was observed at pH 6.8 and 7.4. it was also
determined that the hydrogels exhibited no cytotoxic effects on Haman skin dermal
fibroblasts as determined by MTT assay except for two specific compositions which
after seven days presented a viability lower than 80% respect to the control (Povea et
al., 2011).
In addition to pH-sensitive drug delivery systems, research is also carried out to
fabricate thermo-responsive hydrogels and explore their usage as drug delivery
carriers.
The swelling behavior of p (N-isopropylacrylamide-co-itaconic acid) (PNiPAAm/Ia)
hydrogels was studied by Krusic and his coworkers (Krusic et al., 2006). It was found
that the equilibrium degree of swelling was greater at lower temperature. They also
studied a swelling-deswelling behavior and it was found that deswelling rate of
52
hydrogel was faster than the swelling process. They also found that both the diffusion
exponent and diffusion coefficient increased with the acid content.
Lee et al. (2006) prepared porous thermo-responsive hydrogels from N-
isopropylacrylamide and poly (ethylene glycol) methylether acrylate. The physical
properties, swelling kinetics and solute permeation from these porous gels were
investigated to study the impact of pore volume in the gel on them. It was found that
by increasing MW of PEG, the surface area, pore volumes and equilibrium swelling
degree of these gels increased. However, MW of PEG influenced the shear modulus
and the effective cross-linking density, inversely (Lee et al., 2006).
Thermo-responsive monolithic hydrogels may be applied to tune drug delivery
profiles called “ON-OFF”. Bawa and his coworkers (2009) synthesized hydrogels
comprised of poly (N-isopropylacrylamide) cross-linked to butylmethacrylate (BMA)
which could deliver indomethacin in the presence of low temperature (ON) and stop
releasing the drug on higher temperature (OFF) (Bawa et al., 2009).
More recently, efforts have been done to design and characterize hydrogels with dual-
sensitive hydrogels co-polymerizing thermo-responsive and pH-sensitive polymers in
a specific balance to get the desired therapeutic results. For example Stayton’s group
has formulated a series of co-polymeric hydrogels having poly acrylic acid (PAA) and
N-isopropylacrylamide pendant chains as pH and thermo-responsive moieties
respectively (Yin et al., 2006).
On the other hand, nano-particles comprised of a polymeric network of poly (N-
isopropylacrylamide-co-methacrylic acid) [P (NiPAAm-co-MAA)] were synthesized.
Some solutes (as, for example, peptide, leuprolide, vitamin B12 and insulin) increase
the permeability through the membrane at higher temperature and decrease when pH
53
increases (Sheikh et al., 2010). The co-polymemrs comprised by 2-
(dimethylaminoethyl) methacrylate (DMAEM) and acrylic acid or itaconic acid
synthesized by radiation copolymerization method can also respond to both impulses
i.e. pH and temperature. With the same objectives, an injectable hydrogel was
prepared by mixing different monomers i.e. NiPAAm, acrylamide (AAm) and
vinylpyrrolidone (VP) having naltrexone (opioid receptor antagonist) (You et al.,
2010). The hydrogel swells with simultaneous decrease in pH from 8.5 to 7.4 on one
hand, and increase in temperature from 25-37oC, on the other hand. In vitro studies
indicate that an extended drug delivery occurs within 28 days.
Other than pH- and thermo-responsiveness, some more factors also have significant
effects on drug release behavior of hydrogels like porosity of polymer network,
crosslink density, initial drug concentration etc. To estimate the applied capability of
hydrogels, these factors are also investigated by different researchers.
Pitarassi and co-workers studied the release behavior of amoxicillin in controlled
buccal and gastric conditions (Pitarassi et al, 2005). The gastric retention time of the
delivery system is increased in these gels thus ensuring the release of most of the drug
at the delivery site and increase in bioequivalence.
Mahkam et al (2006) synthesized and evaluated N-vinyl-2-pyrrolidinone (NVP) and
methacrylic acid hydrogels, as drug delivery systems. It was reported that the amount
of drug released depended on the degree of swelling. Moreover, the swelling was
modulated by the amount of cross linking of the polymer bonded drug (PBDs)
prepared (Mahkam et al., 2006).
Opera et al. (2009) reported cellulose/chondroitin sulphate hydrogels as sustained
release vehicles, followed by in-vitro swelling and drug release studies. They
54
determined the release profiles and release kinetics of codeine, as opiate used for its
analgesic, anti-tussive and anti-diarrheal properties (Oprea et al., 2009).
Super-porous hydrogels (SPHs) comprised of poly (2-hydroxyethylmethacrylate)
(PHEMA) were prepared and studied by Omidian and his co-workers (Omidian et al.,
2010). They physically treated different poly (HEMA-co-acrylic acid) hydrogels with
divalent calcium and trivalent aluminum cations to improve the swelling capacity of
the hydrogels. Moreover, it was found that the cells in the presence of hydrogel
showed high viability indicating the absence of cyto-toxicity and stimulatory effect.
Kumar et al. (2010) developed gastric retention devices; synthesizing fast swelling
highly porous acrylic acid based super-porous hydrogels (SPH). They studied the
effect of cross-linking agents, (BIS) and AcDiSol on physical properties of hydrogels
and release profile of SPH containing Metformin. It was found that the release
kinetics of SPH containing different cross-linker concentrations was found to be
consistent with the expected swelling behavior. AcDiSol was an important factor in
maintaining the two necessary properties of hydrogels for gastric retention i.e., fast
swelling and mechanical strength (Kumar et al., 2010).
Garala and Shah studied and reported the influence of cross-linking agent on the
release of drug from the matrix trans-dermal patches of HPMC/Eudragit RL 100
polymer blends (Garala and Shah, 2010)). They prepared the trans-dermal matrix
patches using the polymer blends of hydroxy propylmethyl cellulose (HPMC) and
Eudragit RL 100 (ERL) with triethyl citrate as a plasticizer and succinic acid as a
cross-linking agent. It was noticed that the trans-dermal drug delivery system (TDDS)
containing ERL in higher proportion gives sustained release of drug and the patches
55
containing cross-linking agent shows higher release than those without a cross-linking
agent.
Interleukins are conventionally applied as injection but now are given as hydrogels.
These hydrogels have offered better patient compliance. The hydrogels, forming in-
situ polymeric network, release proteins slowly. These are found to be biodegradable
and biocompatible too (Hiemstra et al., 2007; Klouda and Mikos, 2008; Sutter et al.,
2008). Hydrogels have also been applied in other forms of drug incorporation like
pulsatile drug delivery or oral drug delivery (Gazzaniga et al., 2008). For cancer drug
delivery, injectable hydrogels have also been investigated. In-situ gel-forming
hydrogels for prolonged duration have also been studied (Ta et al., 2008; Fang et al.,
2008).
Herandez et al. (2009) reported the preparation of chitosan ferrogels. The method of
the simultaneous co-precipitation of Fe ions in alkali media and chitosan, was
followed. As the presence of magnetic nano-particles increase the visco-elastic
modulus, so they reinforce the chitosan ferrogels (Herandez et al., 2009).
Hydrogels are, interestingly, considered the most suitable for topical application but
the type and concentration of the polymer content forming the gel system can affect
the stability and release rate of the applied drug (Dodov et al., 2003). Anionic
hydrogels have attained the paramount importance to be used as topical gels, because
they have better compatibility for patient, appropriate rheological characteristics, high
skin tolerance, easiness of application and removal from the skin. In this concern, the
physically cross linked derivatives of acrylic acid are very significant to be used as
topical gels (Hatefi and Amsden, 2002).
56
Bezerril et al (2006) characterized the rheological properties of Kaolin/chitosan
aqueous dispersions. It was found that the Kaokin/chitosan dispersions showed a
pseudo-plastic behavior which enhanced at lower shear rate. The increase in pseudo-
plasticity was supposed to be due to a higher occurrence of particle–polymer–particle
interaction stemming from the adsorption of chitosan macro-molecules on the surface
of Kaolin particles. A simple power law could describe the rheological behavior of
these dispersions (Bezerril et al., 2006).
Poly (acrylamide-co-acrylic acid) [P (AAM-co-AAC)] hydrogels were synthesized
and characterized with respect to the concentration of acrylic acid. The effect of AAc
concentration on the polymer–solvent interaction parameter (χ) and average molecular
mass between the cross-links (Mc) of the hydrogels was investigated. It was reported
that the swelling behavior of hydrogels at different pHs agreed with the modified
Flory-Rehner equation. It was also noticed that the hydrogels with higher AAc
exhibited a more rapid de-swelling rate than that of the hydrogels with less AAc
(Taran and Caykara, 2007).
The rheological properties of chitosam/xanthan hydrogels were reported by Martinez-
Ruvalcaba et al. (2007). They concluded that chitosan/xanthan hydrogels behave like
weak gels. The frequency in the range between 0.1-65 s-1 caused an almost linear
increase in the shear modulus. It was also found that the final structure and the final
properties of the hydrogels were affected significantly by hydrogel concentration and
nature of dispersion (Ruvalcaba et al., 2007).
Investigation of the visco-elastic properties of chitosan/PVA hydrogel was done by
Tang et al. (2007). Their results pointed out a reasonable mechanical strength of the
gel (Tang et al., 2007). Madrigal-Carballo et al. (2008) investigated the rheological
57
behavior of lecithin/chitosan vesicles. The results indicated that chitosan can facilitate
the transformation of planar sheets into closed structures such as vesicles. It was also
noticed that this system exhibits a thixotropic behavior (Madrigal-Carballo et al.,
2008).
Kempe et al. (2008) synthesized and analyzed chitosan solutions containing glycerol-
2-phospate. Using oscillating rheology for characterizing the micro-viscosity of the
sol and gel systems, the rheological properties of the gels were studied by them. It
was found that the necessary amount of glycerol-2-phospate induce gel formation is 6
%. It was noticed that neither the gelation process nor the chitosan/glycerol-2-
phosphate ratio has an effect on the pH to a significant extent (Kempe et al., 2008).
Dhawan et al. (2009) reported formulation and evaluation Diltiazem Hydrochloride
gels for the treatment of anal fissures. They prepared the gels using hydroxyl
propylmethyl cellulose (HPMC), methylcellulose (MC) and polyethylene oxide
(PEO) for topical application for the treatment for chronic anal fissure (CAF). It was
found that all the formulations exhibited pseudo-plastic behavior without any
indication of thixotropy. It was claimed that no adverse effects were reported by any
of the patients to whom the drug delivery devices were applied experimentally
(Dhawan et al., 2009).
The rheological properties of solutions of chitosan/agar blends with chitosan as the
major component were studied by Elhefian et al. (2010). A Newtonian behavior was
observed at all the temperatures (40 to 55oC) for the different blend proportions.
However, a few samples exhibited a shear thinning behavior which could be
attributed to the formation of a good interaction between chitosan and agar. All the
blend solutions were observed to follow the Arrhenius equation. When the period of
58
storage was extended to three weeks, different blend solutions behaved differently
(Elhefian et al., 2010).
Ortan et al. (2011) studied rheological properties of Loposomal hydrogels, comprised
of Carbopole as main component. They prepared Liposomes composed of
phospatidylcholine and cholesterol with incorporation of Anethi aetheroleum by thin
film hydration method. The rheological measurements were carried out two different
temperatures (23oC- storage temperature and 37oC- body temperature). The hydrogels
exhibited a thixotropic, non-Newtonian, pseudo-plastic behavior. They also reported
that rheological parameters depend on the polymer concentration and on the nature of
the incorporated form (Ortan et al., 2011).
1.6. Aims & Objectives
The formulation and synthesis of “smart” hydrophilic polymers and hydrogels have a
promising potential in future biomedical and biotechnology applications. The drug
delivery to specific site of action at required time and concentration is a basic need
and this offers a formidable challenge to be overcome if the potential benefits to
healthcare are to be achieved. Although, this problem remains for all types of
molecules yet it is especially dominated for biological and macromolecules.
This advancement will be achieved through preparation of new polymers or by
modification of natural polymers. Most expectedly, the development of smart and
stimuli-responsive drug delivery systems being sensitive to subtle changes in the local
cellular environment are likely to provide long-term solutions to many of the current
drug delivery problems. The applications of hydrogels may continue to flourish in
future, if efforts devoted to controlled molecule release are enhanced.
59
It is rightly said, advancing the knowledge and applications of hydrogels for
biotechnology especially sustained, targeted drug delivery is an important area with
significant potential that remains to be fully investigated. With the formulations of
novel materials and advanced methods of engineering chemical, mechanical and
biological functionality into hydrophilic polymer networks, we anticipate that in the
future, hydrogels will play and even more important role in biomedical applications
and nanotechnology.
Recent research has focused on synthesizing and characterizing hydrogels that exhibit
specific mechanical properties, thermal behavior, required pore size, environmental
responsiveness to different stimuli say temperature, pH or ionic strength and mass
transport control that can be tuned to gain very special pharmacological goals. It was
aimed to construct the hydrogel systems that can reduce “toxic” burst effects of a
drug, protect fragile drug in their dosing environment and allow site targeted drug
release.
The essential idea of this research work was to synthesize a variety of stimuli--
sensitive hydrogel systems comprising different monomers such that methacrylate
(MA), acrylic acid (AA), vinyl acetate (VA), N-isopropylacrylamide (NiPAAm), by
bulk free radical copolymerization. Keeping in view the challenges and respective
targets, it was planned to evaluate the co-polymeric drug devices as a multi-functional
biomaterial used as colon-specific drug delivery system on one hand and as a topogel
on the other hand. For this purpose, various combinations of monomers and the cross-
linking agents were planned to be copolymerized. Different experimental techniques
including Fourier Transform Infrared spectroscopy (FTIR), Scanning Electron
Microscopy (SEM), Differential Scanning Calorimetry (DSC), Thermo-gravimetric
60
Analysis (TGA), mechanical strength and rheology were applied to estimate the
feasibility of their used in their respective fields.
Various mathematical models were applied to interpret the swelling characteristics
and drug release mechanism of colon-specific drug devices and rheological properties
of topogels. The overall performance of these co-polymeric systems in controlling the
release of Tramadol HCl, the model drug, was analyzed using the selected batches of
different compositions under optimized conditions of pH, temperature and ionic
strength with various initial concentrations of the drug substance.
61
2. EXPERIMENTAL
2.1. Chemicals
The details of chemicals used in the research work are tabulated in the 2.1.
Table 2.1 Details of Chemicals Used in Investigation
Sr.
No.
Name of chemicals Chemical formula Mol.
Weight
%
purity
company
1 Methyl acrylate CH2CHCOOCH3 86.09 99 Merck
2 Vinyl acetate CH2CHOCOCH3 86.09 99 Fluka
3 Acrylic acid CH2CHCOOH 72.06 99 Fluka
4 Ethylene glycol
di methacrylate
CH2C(CH3)C(O)CH2----
CH2OC(O)C(CH3)CH2
198.22 100 Fluka
5 Benzoyl peroxide (C6H5CO)2O2 242.23 100 Merck
6 Sodium acetate CH3COONa.3H2O 136.08 99 KCCo.
7 Acetic acid CH3COOH 60 100 Merck
8 Disodium
H .Phosphate
Na2HPO 177.99 100 Riedal-
DeHaen
9 Citric acid C6H8O7 210.14 100 Merck
10 Hydrochloric Acid HCl 36.5 37 Merck
11 Diethylene glycol
dimethacryalte
CH2C(CH3)C(O)CH2
CH2CH2CH2OC(O)C(CH3)CH2
226 100 Aldrich
12 N-isopropyl acrylamide CH2CHCONHCH(CH3)2 113 97 Aldrich
13 Potassium dihydrogen
phosphate
KH2PO4 136 99 Aldrich
13 Potassium hydrogen
phthalate
C5H8KO4 204.22 99.95 Aldrich
14 Tramadol HCl C16H25NO2 263 98 Aldrich
2.2. Solution preparation
62
The deionized water was used for preparation of buffer solutions. To prepare buffer
solution of pH 1.0, 134.0 mL of 0.2 molar HCl solution was added into 50 mL of 0.2
molar solution of KCl. For preparation of buffer solution of pH 4.0, 100 mL of 0.1
molar solution of potassium hydrogen phthalate was prepared and mixed with 0.2 mL
of 0.1 molar HCl solutions. Using the same amount of potassium hydrogen phthalate
solution, buffer solution of pH 5.5 was prepared by adding 73.2 mL of 0.1 molar
solution of NaOH into it. Potassium dihydrogn phosphate was used to prepare the
buffer solution of pH 7.4. For this purpose, 100 mL of 0.1 molar potassium
dihydrogen phosphate solutions was prepared and 84 mL of 0.1 molar HCl solutions
was added to adjust the pH equal to 7.4. By dissolving 0.441 g of citric acid and
16.944 g of disodium hydrogen phosphate in 1000 mL of solution, the buffer solution
of pH 8.0 was prepared.
2.3. Synthesis of Hydrogels
Four different chemicals i.e. Vinylacetate (VA), Methacrylate (MA), acrylic acid
(AA) and N-isopropylacarylamide (NiPAAm) were used as monomers. Various
details concerning the composition of hydrogels have been tabulated in the table 2.2.
Table 2.2 Various Compositions of Physically and Chemically Cross-linked Co-
polymeric Hydrogels
Sr.
No SET I P(MA-co-
VA-co-AA)
With EGDMA
(EGDMA,
mol %)
SET II P(MA-co-
VA-co-AA)
With EGDMA
(AA, mol %)
SET III P(MA-co-VA-
co-AA)
With DEGDMA
(DEGDMA,
mol %)
SET IV P(MA-co-VA-
co-AA)
With EGDMA (AA, mol %)
SET V P(MA-co-
VA-co-AA)
Physically cross-linked
(AA, mol %)
SET VI P (MA-co-AA-
co-NiPAAm)
gels
1
2
3
4
E1 (1 )
E2 (3.5)
E3 (6.5)
E4 (10)
EA1 (6)
EA2 (17.6)
EA3 (32)
EA4 (40)
D1 (0.6)
D2 (3)
D3 (5.8)
D4 (11)
DA1 (6)
DA2 (13.6)
DA3 (24)
DA4 (38.4)
A1 (6)
A2 (17.6)
A3 (32)
A4 (40)
NiPAAm-1
(cross-linked
with EGDMA)
& NiPAAm-2
(cross-linked
with EGDMA)
63
Afterwards, Benzoyl peroxide (BPO) was added as initiator, into all the solutions
separately, with concentration of 1 % (w/v), calculated on the basis of the mixture of
monomers used. Ethanol was used as solvent and its proportion was 100 (v/v) to the
total volume of the monomers used. The mixtures were stirred until dissolution and
nitrogen was bubbled through them for 10 minutes to remove dissolved oxygen that
otherwise act as an inhibitor for the reaction (Xinmig Li et al., 2008). The solutions
thus prepared were placed into the screw capped glass tubes of 1 cm internal
diameter. The ter-polymeric hydrogels were synthesized through radical
polymerization. The polymerization was carried out at slow heating rate to ensure the
uniform formation of polymer as the sudden increase in temperature may cause the
formation of bubbles inside the polymer network structure or polymeric cylinders
may be broken down. The heating process was started in a thermostat preset at 30oC.
After keeping the temperature of monomer mixtures at 30oC for 1 hour, the
temperature was increased by 5oC after every 1 hour regularly until the final
temperature of 68oC was attained. At 68oC, the polymeric column began to be milky
indicating the formation of hydrogels. The reaction mixture was kept at this
temperature for eight hours to allow completion of the polymerization reaction. The
polymeric columns were removed from test tubes and left over night for cooling and
settling. The dry cylinders were washed with de-ionized water to remove any un-
reacted materials that were not incorporated into the polymer network. These
hydrogel columns were air dried and cut into small disks of 3-5 mm thickness. These
disks were again washed thoroughly with de-ionized water to ensure complete
removal of the un-reacted material. The dried disks (xerogels) were preserved for
further evaluation.
64
The hydrogels without any cross-linking agent (A1, A2, A3, and A4) were in the form
of highly viscous liquids, so these were kept as such for rheological investigation.
2.4. Characterization of Hydrogls
Before performing the swelling experiments, the hydrogels were characterized using
various techniques so that the formation of hydrogels may be ensured and swelling
behavior may be well-predicted.
2.4.1. Fourier Transform Infra Red Spectroscopy (FTIR)
FTIR spectra of only a few samples were collected. The samples were selected on the
basis of their apparent hardness. For this purpose, a few hydrogel samples were
prepared with higher concentration of the cross-linker, EGDMA. The synthesized co-
polymeric hydrogels were characterized by FTIR. The spectrum of the gel was
recorded using a KBr pellet in an FTIR spectrometer (Shimdazu AGN-J 1KN) over
the range of 4000-400 cm-1. Since all of the samples from set 1 to set 4 have the same
functional groups, the FTIR spectrum of only selected one is given as the
representative one. Similarly, one spectrograph for the selected NiPAAm-2 sample is
presented here.
2.4.2. Scanning Electron Microscopy (SEM)
The SEM photographs were obtained both for xerogels and fully swollen hydrogel.
The xerogels were cut to expose their inner structure and used for SEM studies. For
swollen gel SEM studies, the hydrogels were first equilibrated in buffer solution of
pH 8 at 37oC, and then quickly frozen in liquid nitrogen and further freeze dried for at
least 24 hours until all solvent was frozen down. Then, the freeze dried hydrogels
were fractured and their interior morphologies were determined with SEM (Hitachi
3700 N) after being fixed on aluminum stubs. The SEM photographs were obtained at
65
different magnifications starting from ×200 to ×5000, in order to clearly specify the
pore size and shape.
2.4.3. Differential Scanning Calorimetry /Thermogravimetric Analysis,
(DSC/TGA)
The difference in heat between that which flows into the sample and that which flows
into the reference in monitored as a function of temperature or time, and the thermal
degradation of the samples were studied using a thermo-gravimetric analyzer [TA
instruments SDT Q.600 V20. 9 Build 20 simultaneous TGA-DSC]. In the first scan,
the samples were heated from room temperature to 250oC to evaporate the extra water
inside the gel structure. In the second scan, the hydrogel samples were heated from
room temperature to 600oC at a heating rate of 10oC/min under a nitrogen flow.
Before the thermo-gravimetric experiment, calibrations of the TA SDT Q.600, TGA
weight and temperature were carried out. Tin (m.p 419oC) was used to carry out the
temperature calibration.
2.4.4. Mechanical Strength
Mechanical strength of xerogels as well as fully swollen hydrogels at pH 8 was
determined applying the weight on them until the hydrogels were fractured (Chen et
al., 2000; Chen et al., 2000). Compression tests were performed on the hydrogel disks
both for xerogels and hydrogels swollen at pH 8 and 37oC. These tests were carried
out in a mechanical analyzer (Shimadzu AGN- 1kN for swollen gels, Shimadzu
AGN- 5kN for xerogels). The gel samples were selected so that the effect of the cross-
linker and acrylic acid on structural integrity and hardness of the material may be
determined.
66
2.4.5. Rheological Measurements
Before the rheological properties were measured, the macroscopic examination was
aimed at a series of olfactory (smell), visual (aspect, homogeneity, consistency and
color) and tactile features, according to F.R.X guidelines (Alina et al., 2011).
Rheological behavior was evaluated by using Anton Paar Rheometer, equipped with
MCR 301 SN 80199830; FW 3; ADj 1279d device. The measuring system was PP25-
SN 16290 having a diameter of 1 mm. The gels were characterized from flowing
point of view. Gel viscosity and shear stress were measured in ascending order of
shear rate. During the progress of the measurements, the experimental conditions
were kept constant. The experiments were conducted by changing the rotational speed
between 0.00764 and 76.5 rpm. As viscosity, shear stress and other rheological
parameters of semisolid pharmaceutical systems can be changed in a wide range with
temperature (Chang et al., 2002; Rudraraju and Wyandt, 2005), the temperature
selected for rheological tests is very important. In this work, the selected temperature
was 10oC, 20oC and 30oC to evaluate the temperature of the hydrogel storage and
37oC to study the rheological behavior at the human body temperature.
2.5. Swelling Kinetics
For the swelling characterization, five types of solutions (having pH 1.0, 4.0, 5.5 7.4
and 8.0) were used. The swelling tests were carried out at the body temperature of
man (37oC), using a heating bath with controlled temperature. This weight is
considered the initial weight or mo. Each disk of a hydrogel was inserted into a beaker
having a buffer of a certain pH value, inside a heating bath preset at 37oC. The initial
volume in every beaker was kept equal and enough to keep the expectedly fully
swollen gel disks, completely immersed in the solution. The mass of the swelling
samples was measured versus time after the excess surface water was removed by
67
gently tapping the surface with a dry piece of filter paper. The sample was weighed
every 15 minute for the first 2 hours, every 30 minute for 1.5 hours and subsequently
every 1 hour until the sample stopped absorbing; it was the point where either there is
desorption or swelling equilibrium is reached. At equilibrium, the quantity of water
retained inside the hydrogel can be expressed mathematically in various forms (Chen
et al., 2000; Chen and Park, 2000 and Dorkoosh 2002) and will be mentioned as
weight swelling index of hydration percentage (eq. 2.1):
S %=mt-mo/mo × 100 (2.1)
Where, S% is the weight swelling index, mt is the disk’s weight after swelling at time
‘t’ and mo is the weight of the dry sample.
The swelling degree Dh was calculated using the following equation:
Dh=wet weight/dry weight=Wt/mo (2.2)
The adequate pH over the maximum swelling degree is determined by the gravimetric
analysis in agreement with the maximum water retention and the determination of
water absorbed by the hydrogel. The calculation was carried out using the equation
2.1 and “swelling degree” was used as a technical term for S, for all the practical
intents and purposes.
The nature of water diffusion towards the inside of the gel was determined, using the
following equation: (below 0.6, fractional swelling values)
ln (Wt/We) = ln k +n ln t (2.3)
Where Wt and We stand for the quantities of water absorbed by the gel in time ‘t’ and
at equilibrium respectively; k is constant and is characteristic of the system under
consideration and n represents the diffusion exponent that throws light on the mode of
water transport into the gel. A value of n up to 0.5 expresses the Fickian diffusion
mechanism, and if lies between 0.5 and 1, it indicates that diffusion is of non-Fickian
68
or anomalous type (Ximming et al., 2008; Kumar et al., 2010). If n=1 , it is a special
case where the transport mechanism is known by the name of Type II indicating that
the migration of water into the disk occurs at constant speed and is purely controlled
by the relaxation of chains.
This equation is applied up to the fraction swelling values less than 0.6 (Kumar et al.,
2010); these are the initial swelling states (where the density of the device remains
almost constant), giving linearity when the ln (Wt/We) is related in function of the ln t.
Above 0.6 (the fractional swelling values) for the second kinetic order, the reciprocal
of the swelling average (t/Wt) is related to the treatment time‘t’ using the following
linear equation (Schott, 1992):
t/Wt =A+Bt (2.4)
In this equation, A and B are two coefficients having physical meanings which are
interpreted in the following manner (Jabbri and Nozari, 2010):
A= 1/ks We2 (2.5)
And
B= 1/We (2.6)
2.6. Drug Loading
The dried polymer disks were loaded with Tramadol HCl by soaking them in various
drug solutions, in 50 mL phosphate buffer solutions of pH 8.0 at 37oC till the
equilibrium swelling was attained. Five different sets were prepared as tabulated in
the table 2.3.
69
Table 2.3: Compositions of Samples for Drug Loading and Drug Release Studies
Sr. No. Set I
P(MA-co-VA-
co-AA)
With various
concentration
of EGDMA
Set II
P(MA-co-VA-
co-AA)
cross-linked
with
EGDMA
Set III
P(MA-co-VA-
co-AA)
cross-linked
with
DEGDMA
Set IV
P(MA-co-AA-
co-NiPAAm)
cross-linked
with
EGDMA
Set V
P(MA-co-AA-
co-NiPAAm)
cross-linked
with
DEGDMA
1
2
3
4
5
6
E1
E2
E3
E4
--
--
TE1
TE2
TE3
TE4
TE5
TE6
TD1
TD2
TD3
TD4
TD5
TD6
TNE1
TNE2
TNE3
TNE4
TNE5
TNE6
TND1
TND2
TND3
TND4
TND5
TND6
This method was preferred to in situ drug loading to avoid any probable degradation
of the drug substance or undesirable drug-polymer reaction when high temperature
was applied during the synthesis process. The wet drug loaded polymers were dried at
room temperature through simple evaporation. The drug loaded dried polymer disks
were cloudy when compared to similar disks without the drug, indicating the
significant proportion of the drug in the hydrogels (1-12% w/w dry) (Mullerney et al.,
2006). This degree of drug loading was necessary to ensure that enough drug
substance was available for spectrophotometric analysis. To calculate the partition co-
efficient, the equilibrium drug concentrations in the solution and in the hydrogel disk
were measured in duplicate. The loading solution was analyzed directly through UV-
visible spectrophotometer (Spectro UV-Vis double Beam PC 8 Scanning Autocell,
UVD-3200 LAMBOMED, INC.). The equilibrium drug concentration in each
polymer disk was calculated by subtracting the amount of the drug in the loading
solution from the initial concentration of drug in every buffer solution.
70
To measure the absorbency of Tramadol HCl by the hydrogels, the required solutions
of the drug were prepared in buffers of pH 8.0. Polymer-drug conjugate hydrogel
disks were prepared by immersing the xerogel to the solution of Tramadol HCl to
become fully swollen. Three xerogels of each composition were used to take an
average of the delivery results. The absorbency of Tramadol by the hydrogels was
calculated using the following equation (Xinming, 2008):
Absorbency (Q) = (C1V1-C2V2)/mo (2.7)
Where Q (mg/g) is the absorbency of Trammadol by the xerogel; C1 (mg/mL) is the
initial concentration of Tramadol solution; V1 (mL) represents the initial volume of
Tramadol solution; C2 (mg/mL) is the concentration of Tramdol after absorption by
the xerogel; V1 (mL) is the volume of Tramadol solution after absorption by the
polymer; and mo is the mass of the polymer in dry state.
2.7. In vitro drug release studies
In vitro drug release of Tramadol HCl from co-polymeric hydrogels was evaluated in
triplicate using a (Spectro UV-Vis double Beam PC 8 Scanning Autocell, UVD-3200
LAMBOMED, INC.). The dried drug loaded disks were transferred into 50 mL of
buffer solution of pH 8.0 at room temperature. At specified time intervals, 3.0 mL of
aliquots were removed from every buffer solution and the absorbance was determined
using UV-visible spectrophotometer at the maximum absorption wave length (240nm)
already measured using a stock solution of Tramadol HCl in phosphate buffer of pH
8.0. Three aliquots of various solutions were studied for any single point of release
curve. After absorbance measurements, aliquots were returned to the original solution,
so that the volume may be kept constant. To transform absorbance determinations into
concentrations, calibration curve was used (Gomez et al., 2012). The calibration curve
is shown in the fig 2.1.
71
Fig. 2.1: Calibration curve for Tramadol HCl in buffer solution of pH 8.0.
y = 0.3419x - 0.0658
R² = 0.9911
-0.5
0
0.5
1
1.5
2
2.5
0 2 4 6 8
Ab
sorb
ance
Concentration of Tramadol HCl (mg/mL)
72
Release kinetics
To study the release kinetics of Tramadol HCl from the matrix tablets, the release data
were fitted to the following equations:
Zero order equation (Najib and Suleiman, 1985):
Qt=ko.t (2.8)
Where Qt stands for the percentage of drug released at time t and ko is the release rate
constant;
First order equation (Desai et al., 1966):
ln (100- Qt) =ln100-k1t (2.9)
Where k1 stands for release rate constant for the first order kinetics;
Higuchi’s equation (Higuchi, 1963):
Qt=kH.t1/2 (2.10)
Where kH represents the Higuchi release rate constant;
Hixson-Crowell model (Hixson, 1931):
(100- Qt) 1/3=1001/3-kHC.t (2.11)
Where, kHC stands for Hixson-Crowell rate constant.
Moreover, for better characterization of the drug release mechanisms, the Korsmeyer-
Peppas (Korsmeyer et al., 1983) semi-empirical model was applied:
Qt/Qe=kKP.tn (2.12)
Where Qt/Qe is the fraction of the drug released at time t, kKP is a constant
corresponding to the structural and geometric characteristics of the device and n is the
73
release exponent which is indicative of the mechanism of the drug release. In case of
cylindrical geometries such as tablets, for fitting the data to the equations, only the
points within the interval 10-70% were used. In case of Hixson-Crowell and
korsmeyer-Peppas models, the data taken was within 10-60% drug release.
74
3. RESULTS & DISCUSSION
3.1. Synthesis of Hydrogels
As incorporation of a multitude of co-monomers with specific functional groups, into
hydrogel co-polymeric networks lead to a number of novel applications (Houwei et
al., 2010), so a variety of monomers (i.e. methacrylate, vinylacetate, acrylic acid and
N-isopropylacrylamide) was selected to design new hydrogel systems using different
combination schemes. Both physically and chemically cross-linked hydrogels were
formulated to apply for different purposes. During synthesis of hydrogels, different
changes were observed. Initially, the samples having either low concentration of the
cross-linkers or without any cross-linking agent, exhibited no considerable change in
appearance. The hydrogels with greater cross-linking agent content, started to be
cloudy from the bottom of tubes. Gradually, the milkiness extended in the whole tube.
The nature of the cross-linker also seemed to affect the temperature at which
opaqueness became visible. In monomeric mixtures having EGDMA as chemical
cross-linker, milkiness appeared at lower temperature (say ≥50oC) whereas the tubes
having DEGDMA started to be milky after 60oC. Examining the macroscopic
characteristics is the first approximation of the preparation because the changes
observed in the quality of visual, olfactory and tactile properties are indicators of the
gel preparation (Alina et al., 2011). Visually, the hydrogel having no cross-linker was
transparent and shining, seemed to be highly viscous semisolid material as shown in
the Fig. 3.2. No air bubbles or other foreign macroscopic particles were observed.
The general texture of hydrogels was found to be very smooth. There was no sign of
any characteristic smell. To examine the tactile characteristics, the hydrogel was
applied on the backhand; the semi solid material was converted into a gel after some
time of spreading it on the skin. A smooth and comfortable feeling appears when
75
applied on the skin of the back hand, indicating its biocompatibility to some extent.
The Fig. 3.1 clearly indicates the compositional effect on visual aspects of
synthesized co-polymeric hydrogels. From left to right, the milkiness is observed to
be decreasing gradually up to the middle of the row, and then approaching maximum
intensity in the extreme right hydrogel cylinder. The opaqueness vanished away in the
hydrogels with low concentration of cross-linker, after the washed disks were dried as
is shown in the Fig. 3.3. However, the milkiness was persistent in hydrogels with the
higher cross-linker to acrylic acid volume ratio. The milky appearance may be
attributed to different reasons. The temporary opaqueness renders to hydrogen
bonding between water molecules and hydrophilic parts of polymeric gels (Zafar et
al., 2008). This hydrogen bonding may have constructed a hydration shell around the
hydrophobic parts of the hydrogels (Krusik et al., 2006). It may also be assumed that
the milkiness was either due to the decreased solubility of polymer in comparison to
monomers, or the presence of un-reacted contents in the network which were removed
during washing with water. On the other hand, the gradual change in visual aspect of
the co-polymeric cylinders as exhibited in Fig. 3.1 can be explained if we consider the
initial composition of the hydrogels emphasizing on two important contents i.e. AA
and the cross-linker. The volume ratio between AA and the cross-linker changes
gradually from left to right, keeping the volume of all other components constant as
given below:
76
Table 3.1: Volume Vatio of AA to EGDMA in Poly (MA-co-VA-co-AA) Hydrogels.
Sample volume ratio
(AA: EGDMA)
1 0.2: 0.5
2 0.5: 0.5
3 1.0: 0.5
4 2 : 0.5
5 2 : 0
6 2 : 0.1
7 2 :0.5
8 2 : 1.5
9 2 : 2
It is observed that the co-polymeric cylinders with comparable volume ratio of AA to
EGDMA (0.5:0.5, 2:2), present more and persistent milkiness whereas when the ratio
is disturbed, no matter which component is more, milkiness disappears. As milkiness
is the evidence of gel formation, so it is concluded that there is lying some specific
coordination between EGDMA, the cross-linking agent and acrylic acid, the most
efficient monomer to facilitate swelling of the hydrogels (Sen and Yakar, 2005).
Moreover, this behavior may also be interpreted in another way. The permanent
milkiness in the tubes 9 and 10 may be attributed to the higher percentage of
EGDMA, which may facilitate the greater amount of the monomers in the gel system,
increasing the particle size of ternary copolymers. This larger particle size may be
responsible for greater light scattering and thus milkiness in the system. Furthermore,
the increase of percentage gelation and cross-linking density with increase in cross-
77
linking agent in these specific hydrogel systems can be explained by the chain transfer
agent properties of EGDMA and formation of intermolecular cross-links during cross-
linking of the system. On the other hand, in the sample 1 and 2, the same function
may be performed by higher concentration of AA which is responsible for physical
cross-links through permanent hydrogen bonding. To find the gelation content of the
ter-polymeric hydrogel the following relation was used:
Gelation content (%) = (Wd/Wi) ×100 (3.1)
Where Wd is the weight of the washed and dried hydrogel and Wi is the initial weight
of the hydrogel without washing with deionized water. The gelation contents were
found to vary from 74 to 83%. This indicates that the degree of gelation depends on
the process conditions as well as the amount of the cross-linking agent used. On the
other hand, it indicates that the un-reacted materials or non cross-linked parts of the
hydrogels were varied from 26 and 17% respectively. The variation in the gelation
contents of hydrogels may also be affected by the rate of change in temperature as
well as the time given to the polymerization process at specific temperatures (Dogu
and Okay, 2005). However, in the present case it is expected that the gelation contents
of the synthesized hydrogels are affected due to the change in the concentration of
the cross linking agent as the rate of change in temperature has been controlled by
equal intervals of time during the whole process of synthesis. The literature also
indicates that the addition of EGDMA content may increase the crosslink density in
hydrogels, which may result in higher polymerization and more stabilization of
hydrogel systems (Akkas, 2007; Sen and Yakar, 2005). It has been indicated by Chen
and Guan (Chen et al. 2001) that the degree of polymerization increases with the
increase in the concentration of cross-linkers. It is also indicated that multi-armed
cross-linkers may enhance the cross-linking density of the gel. Being a tetra-
78
functional cross-linking agent, EGDMA has been widely used as a cross-linking agent
due to its multiple functional tendencies (Sen and Yakar, 2005) and it may also
increase the percentage gelation of hydrogel systems (Chen et al. 2001). Literature
also indicates that the amount of EGDMA may affect the particle size of copolymers
and higher amount of EGDMA results in bigger particle size of copolymer hydrogel
systems (Hamadan et al., 2007).
Fig. 3.1: Hydrogel cylinders showing the effect of composition on visual aspects of
synthesized co-polymeric hydrogels.
Fig. 3.2: Hydrogel without any cross-linker.
79
Fig. 3.3 (a): The gel disc before washing in distilled water.
Fig. 3.3 (b): The gel disc after washing in distilled water.
gels with low
EGDMA content
gels with high
EGDMA content
Fig. 3.3 (c): The gel discs after drying at 40oC showing persistent milkiness owing to
the presence of higher amount of the cross-linking agent.
80
3.2. Characterization of Hydrogels
3.2.1. Fourier Transform Infra Red Spectroscopy (FTIR)
Fig. 3.4 presents the spectrum of Poly (MA-co-VA-co-AA) cross-linked with
EGDMA. Broad bands appearing at 3528-3459 cm-1 are indicative of the presence of
hydrogen bonded –OH groups in the polymer network. Formation of carboxylic acid
dimmers is confirmed by the peak appeared at 2955cm-1. The peak at 1736 cm-1
corresponds to C=O stretching vibration of the ester group. The peak at 1648 cm-1
indicates the formation of coil or helix which is due to the cross-linking inside the
hydrogel network (Yu and Xiao, 2008; Pal et al., 2008). Furthermore, the presence of
carboxylate anions is also confirmed by the peak appeared at 1448 cm-1 (symmetric
vibrations). As, both methacrylate and vinylacetate have ester bonds, so typical peaks
are shown at 1376-1165 cm-1.
Fig 3.4: IR spectrum of optimized batch of poly (MA-co-VA-co-AA) hydrogel cross-
linked with EGDMA.
81
The IR spectrograph of poly (MA-co-VA-co-AA) hydrogel cross-linked with
DEGDMA is shown in the figure 3.5. The presence of hydrogen bonded –OH is
indicated by a broad peak near 3600cm-1. The peak appeared at 2950 cm-1,
corresponds to the –OH stretching duo to acrylic acid dimmers. Again, the peak
shown at 1743 cm-1 (C=O stretching vibration) indicates the carboxylic group of ester
bond. The peak appeared at 1643 cm-1 ( very close to 1648 cm-1) confirms the
formation of coil or helix which is indication of cross-linking inside the polymer
network (Yu and Xiao, 2008; Pal et al., 2008). Moreover, the presence of carboxylate
anions is indicated by the peak appeared at 1448 cm-1 (symmetric vibrations). As ester
bonds are present in both methacrylate and vinylacetate, the peaks are appeared at
1376-1165 cm-1.
Fig. 3.5: IR spectrum of optimized batch of poly (MA-co-VA-co-AA) hydrogel cross-
linked with DEGDMA.
82
The IR spectrum of selected Poly NiPAAm hydrogel sample is represented in the Fig.
3.6. The peak appeared at 3550=3450cm-1typically indicates the presence of hydrogen
bonded –OH group vibration (Pal et al., 2008). The spectrograph exhibited the peak at
3000-2900 cm-1 corresponding to –OH, due to acrylic acid dimmer. Moreover, the
peak appeared at 1750-1700cm-1 (C=O stretching vibration) is due to the carboxyl
group of ester bond. The peak observed at 1650-1600 cm-1(C=O stretching vibration)
is due to acrylic acid. The specific peak appeared at 1700-1600 cm-1 also shows the
bond stretching of –(C=O)-NH-R, confirming the incorporation of N-
isopropylacrylamide in the polymer network (Pal et al., 2009). The peak appeared
near 1648 cm-1 confirms the formation of coil or helix which is indicative of cross-
linking inside the polymer network (yu and Xiao, 2008; Pal et al. 2008). Furthermore,
the peaks observed at 1500-1400 cm-1 (asymmetric and symmetric vibrations) indicate
the presence of carboxylate anions. As there are ester bonds in all the monomers
constituting the polymer network, a –(C=O)-O- asymmetric stretching vibration peak
is observed at 1200-1100 cm-1.
Wave number (1/cm)
Fig. 3.6: IR spectrum of optimized batch of NiPAAm-2 hydrogel cross-linked with
DEGDMA.
83
3.2.2. Scanning Electron Microscopy (SEM)
The morphology of the co-polymer hydrogel systems was studied by SEM as
shown in Figs. 3.7-3.9. By comparison with the morphologies of the dry gel and
swollen gel, the hydrogel system shows two different features regarding the
degree of porosity. Before swelling, it is observed that the dried gel shows some
sort of macro-pores indicating the surface morphology with higher swelling
capacity of the hydrogel systems as shown in Fig. 3.7(a), 3.8(a), 3.9(a) and 3.9(b).
The morphology of the gel swollen at equilibrium degree of swelling in the buffer
solution of pH 8.0 is shown in Fig. 3.7(b) and 3.8(b). At equilibrium degree of
swelling of the gel, lesser degree of porosity is seen and the macro-pores have
been changed into very thin micro-pores due to almost complete swelling of the
gel penetration of water at 37oC. Moreover, the SEM photographs of the same
hydrogel sample at pH 8.0 swollen up to its equilibrium stage exhibits more or
less smooth surface which is due to the water retention inside the porous structure
of the gel. It is clear from the figures 3.7(a), 3.8(a), 3.9(a) and 3.9(b) that at higher
magnification power, the surface is more uneven indicating the presence of pores
of variable size in the ter-polymeric hydrogels. We can conclude that the pore size
is not uniform inside the structure of the gel. The most probable reason may be the
presence of different moieties inside the gel structure due to the use of a variety of
monomers in composition of the hydrogels. The higher degree of freedom allows
the formation of cross-links at different distances thus creating a variety in size as
well as shapes of the pores. Whatever the size and shape of the pore are, it is
confirmed that the hydrogels present a porous structure capable of retaining and
transferring fluids after swelling, which is to be expected since the porosity of the
material yields a better swelling degree.
84
Fig. 3.7 (a): SEM structures of the optimized batch [E2] inner surface in dry state at
high magnification power.
Fig. 3.7 (b): SEM structures of the optimized batch [E2] inner surface in equilibrium
state at pH 8.0.
85
Fig. 3.8 (a): SEM structures of the optimized batch [D2] inner surface in dry state at
high magnification power.
Fig. 3.8 (b): SEM structures of the optimized batch [D2] inner surface in equilibrium
state at pH 8.0.
86
Fig. 3.9(a): SEM structures of the optimized batch [NiPAAm-1] inner surface in dry
state.
Fig. 3.9 (b): SEM structures of the optimized batch [NiPAAm-2] inner surface in
equilibrium state at pH 8.0.
87
3.2.3. Differential Scanning Calorimetry/Thermo gravimetric
Analysis (DSC/TGA)
Fig. 3.10 (a) presents the results from the thermo-gravimetric analysis of the ter-
polymeric hydrogels with four different concentrations of AA content of hydrogels.
Thermal degradation proceeds in two steps in all the cases. It was observed that no
significant degradation occurred before 200oC in any case. The temperatures, at which
the first step started and then ended, are in increasing order with the concentration of
AA in the hydrogel systems. This increasing order may be attributed to the fact that
with the concentration of AA, the number of inter-polymer hydrogen bonds is also
increased resulting in the higher thermal stability. As the concentration of AA exceeds
the certain stoichiometric limit, the formation of PAA may appear inside the hydrogel
systems. The formation of a variety of polymers inside the gel systems, not only
disturbs the surface morphology of the hydrogels but also the thermal properties. The
temperatures at which the complete weight loss (up to 97%) occurs, also exhibited the
similar trend just like the first step. In Fig. 10 (b), the thermo grams of samples AE1,
AE2, AE3 and AE4 having the concentration of acrylic acid as 0.6, 17.6, 32 and 40
mol % respectively, is observed. The figure indicates that all the gels are showing a
high Tg value approaching to 300oC. As we used the samples as xerogels and there
was no chain relaxation in the dry state, so covalently formed cross links as well as
the presence of hydrogen bonds are the key factors for the high values of T g.
88
Fig. 3.10 (a): DSC curves for poly (MA-co-VA-co-AA) having a range of AA, cross-
linked with EGDMA used as xerogels.
Fig. 3.10 (b): TGA curves for poly (MA-co-VA-co-AA) having a range of AA, cross-
linked with EGDMA used as xerogels.
89
Fig. 3.11 (a) and 3.11 (b) represent the thermo-grams of optimized batch of poly
(MA-co-VA-co-AA) cross-linked with EGDMA in xerogel and swollen gel
respectively. Whereas, the fig. 3.12 (a) and 3.12 (b) exhibit the thermal behavior of
poly (MA-co-VA-co-AA) cross-linked with DEGDMA in dry and equilibrium
swollen state respectively. In all cases, thermal degradation proceeds in two steps. No
significant degradation occurred before 200oC in any hydrogel sample in dry state.
The first process occurred at about 250oC with a weight loss of 10-11%
approximately. The complete weight loss up to 90% of these co-polymeric hydrogels
begins at 360oC and reaches a maximum near 460oC in both sample gels in dry state,
ultimately leading to complete degradation of the polymer complex. Different
behavior was observed in case of swollen gels. The first weight of about 89% ends at
157oC in the co-polymeric hydrogel having EGDMA (Fig. 3.11 b), whereas in
hydrogels cross-linked with DEGDMA, the initial weight loss of about 90% ended at
132oC as shown in the Fig. 3.12 (b). The figures 3.11 (b) and 3.12 (b) are indicating
almost complete degradation of swollen poly (MA-co-VA-co-AA) hydrogels at
284.59oC and 279.46oC respectively. It is illustrated from the corresponding figures
that the hydrogels cross-linked with EGDMA are comparatively more thermo-stable
than those of having DEGDMA as a cross-linking agent. If we survey the literature,
there are reports that the hydrogels may be thermally stable up to 200oC, following
two step degradation (Kim SJ et al, 2003).
The existence of intermolecular forces was confirmed using DSC method. Fig. 3.10
(b), 3.11and 3.12 show the DSC thermo-grams of poly (MA-co-VA-co-AA) co-
polymeric hydrogels. The glass transition temperature of pure PAA is reported 105oC
(Mun et al., 2004) and that of polyvinylacetate is 80oC (Brandrup et al., 1999). When
these two monomers were incorporated with methacrylate in the presence of various
90
cross-linkers, the co-polymeric hydrogels showed a single Tg in both dried form and
swollen at equilibrium state at pH 8.0, confirming the miscibility of all the
components with each other. Our polymers have Tg values higher than that predicted
by linear additivity rule using the Tg values of the component polymers. Some other
researchers have the same observation too (Jiang et al., 1999). The high T g has been
explained on the basis of higher interactions between the component polymer chains
reducing segment mobility. So high chemical and physical cross-linking results in a
higher Tg value, which confirms the polymer network complexation in poly (MA-co-
VA-co-AA) hydrogels. Moreover, it was also observed that the Tg values decreased
significantly in both the hydrogel samples when the gels were swelled up to
equilibrium at pH 8.0 and 37oC. The value changed from 275oC to 105oC when the
optimized poly (MA-co-VA-co-AA) cross-linked with EGDMA was swollen at pH 8
up to equilibrium, as shown in the Fig. 3.11 (b). On the other hand, poly (MA-co-VA-
co-AA) cross-linked with DEGDMA shifted its Tg to 85oC, as presented in the Fig.
3.12 (b). It is clear that the vitreous transition temperature diminished by
approximately 60 % indicating that the chains have been relaxed and the chain
interactions have been reduced. Our findings are also supported by the literature
(Murali et al., 2006a; Murali et al., 2006b).
The thermal stability and thermal decomposition of NiPAAm gels were investigated
using TGA as shown in Fig. 3.13 and 3.14. For these polymers the degradation took
place in two stages. The first stage occurred between (250oC-400oC) and the second
stage started up to 450oC and completed by 600oC. On the other hand the literature
shows that no significant degradation occurs before 250oC in homo-polymer poly
(NiPAAm)gels, showing the total degradation in a single step and was completed by
470oC (Kim et al., 2003). From the above discussion, it can be estimated that presence
91
of hydrophilic component acrylic acid not only increased the LCST of these gels from
32 to 33.6 and 33.3oC in NiPAam-1 and NiPAAm-2 respectively but also decreased
Tg from 275oC (Fig. 3.13) to 40 and 45oC respectively (Fig. 3.14). On the other hand,
the Tg of pure Poly (NiPAAm) gels, reported is 260oC (Kim et al., 2003), but when
incorporated with acrylic acid and methacrylate, the Tg reduced to 45oC. Literature
supports the idea that the incorporation of hydrophilic component can increase LCST
and decrease Tg of the co-polymeric hydrogels. The transition temperature (LCST) is
adjustable either through the co-polymerization of the hydrophobic/hydrophilic
monomers or through controlling the polymer molecular weight (Reul-Gariépy,
Leroux, 2004). For example, an increase of the hydrophobic monomers (i.e. butyl
methacrylate), results in decrease in LCST (Jeong, Gutowska, 2002). On the other
hand, the incorporation of hydrophilic monomers (for example, acrylic acid or
hydroxyethyl methacrylate) fosters the formaion of hydrogen bonds with thermo-
sensitive monomers which increases LCST (Kim et al., 2009). The co-polymers of
NiPAAm and hydrophilic entities (for example, acrylic acid), promotes the increase
of LCST to temperatures around 37ºC, i.e., the body temperature.
92
Fig. 3.11(a): DSC /TGA curves for optimized batch of poly (MA-co-VA-co-AA)
cross-linked with EGDMA in dry state.
Fig. 3.11(b): DSC /TGA curves for optimized batch of poly (MA-co-VA-co-AA)
cross-linked with EGDMA in equilibrium state at pH 8.0.
93
Fig. 3.12(a): DSC /TGA curves for optimized batch of poly (MA-co-VA-co-AA)
cross-linked with DEGDMA in dry state.
Fig. 3.12 (b): DSC /TGA curves for optimized batch of poly (MA-co-VA-co-AA)
cross-linked with DEGDMA in equilibrium state at pH 8.0.
94
Fig. 3.13: DSC /TGA curves for optimized batch of poly (MA-co-AA-co-NiPAAm)
cross-linked with DEGDMA in dry state.
Fig. 3.14(a): DSC /TGA curves for optimized batch of poly (MA-co-AA-co-
NiPAAm) cross-linked with EGDMA in equilibrium state at pH 8.0.
95
Fig. 3.14 (b) DSC /TGA curves for poly (MA-co-AA-co-NiPAAm) cross-linked with
DEGDMA in equilibrium state at pH 8.0.
96
3.2.4. Mechanical Analysis
The mechanical strength of the xerogels was determined, applying a maximum weight
on them. Surprisingly, not a single disk was broken down even the maximum force
(5000 gm) was applied on them. However, the polymers with low concentration of the
cross linker showed a little strain in them by isotropic increase in their diameter, thus
decreasing their thickness; but the observed strain was vanished away within a few
minutes after the applied stress was released (as shown in the Fig. 3.15). The fully
swollen hydrogels up to their equilibrium point at pH 8.0 and 37oC, exhibited a
regular increase in the mechanical strength with the concentration of the cross linker
(452, 490, 560 and 634 gm for the samples E1, E2, E3 and E4 respectively) and
decreased with the concentration of AA acid (625, 545, 480 and 452 gm) in p (MA-
co-VA-co-AA) cross-linked with EGDMA. Similar effect of the cross linker on the
mechanical strength was also observed by other authors (Kumar et al., 2010).
Fig. 3.15 (a): Xerogel before applying stress.
97
Fig. 3.15 (b): Xerogel after applying maximum stress.
Fig. 3.15 (c): Xerogel regained the original shape and size after the stress is removed.
Fig. 3.15: Xerogel showing the effect of applied stress.
98
3.3. Swelling Kinetics
3.3.1. Dynamic & Equilibrium Swelling
The swelling experiments were carried out at five different pH values (1.0, 4.0, 5.5,
7.4 and 8.0), changing the polymer composition. Being chief swelling agent in all
these hydrogels, the presence of free carboxylic groups provided by acrylic acid, in
the polymer structure is the measure of swelling capacity of the system (Omidian et
al., 2010). After a specific time of introduction of the sample disks into the
surrounding medium, three regions were distinguishable within the hyderogel matrix
(Fig. 3.16 a), which is also supported by the literature (Fig. 1.1), (Omidian et al.,
2010). The first region is highly swollen with water and obviously mechanically a
weaker region. The outer layer of the highly swelled region works as a barrier for the
new incoming water and now the second region appears that is moderately swollen
and relatively stronger whereas the innermost region remains almost in its glassy state
as mentioned in the Fig. 3.16a. It was also observed (Fig. 3.16b), most of the hydrogel
disks swelled iso-tropically in all directions. Such type of swelling indicates that no
internal stress was applied to the gel during their synthesis. In other word, isotropic
swelling indicates the isotropic synthesis of theses copolymers.
Effect of pH& concentration of AA
Furthermore, the rate of swelling as well as the equilibrium swelling was studied to
analyze the effect of pH, concentration of EGDMA, DEGDMA and AA and nature of
the cross-linker in NiPAAm gels on these specific parameters. It was found that all
the hydrogel samples showed accelerated dynamic (mt-mo/mo) and equilibrium
swelling ratio (me-mo/mo) n the basic media. This behavior of co-polymeric hydrogels
can be explained as follows: being pH-sensitive polymers, the key role played, is by
the ionizable weak acidic moieties attached to a hydrophobic backbone. The pendent
99
acidic functional group added to the polymer backbone, releases protons in response
to appropriate pH due to which the ionic strength changes in aqueous media (Langer
et al., 2003). When ionization occurs, the coiled chains extend dramatically,
responding to the electrostatic repulsions of the generated charges thus causing
changes in their dynamic and equilibrium swelling behavior. As the degree of
ionization of these hydrogels depends on the number of pedant acidic groups in the
hydrogels, the electrostatic repulsions also increase between negatively charged
carboxylic groups on different chains. This, consequently, increases the hydrophilic
ability of the network and the greater swelling ratio at high pH (Fig. 3.19, 3.22 and
3.24). Whereas, at the pH lower than the pKa value of AA, the number of ionized
carboxylic groups is not considerable and most of the free carboxylic groups are
present in the unionized form which results in the formation of inter-polymer
complexes based on inter-polymer hydrogen bonding (Khutoryanskiy et al., 2004). To
more confirm our findings, the results of similar gels reported by other authors were
also studied. Omidian and his co-workers synthesized super-porous hydrogels (SPHs)
based on poly (2-hydrogxymethylacrylate) (PHEMA) by adding minute amounts of
an ion-complexable hydrophilic acrylic acid. They reported that the incorporation of
acrylic acid into SPHs improved their swelling (Omidian et., 2010). Ranjha combined
non-ionic vinylacetate (VAC) with anionic acrylic acid (AA) or meth-acrylic acid
(MAA) monomers using ethylene glycol dimethacrylate (EGDMA) a cross-linking
agent. It was reported that high swelling was observed above pH 5.5 through chain
relaxation (Ranjha, 1999).
An unusual behavior was exhibited by NiPAAm-1hydrogels which underwent
insignificant swelling in the media having pH 1.0 and 4.0. This anomalous behavior
can be explained considering two factors. First, in acidic pH, almost all free
100
carboxylic groups, being unionized, may form hydrogen bonding with in the network,
so no water is allowed to pass into the hydrogel disks. Second, poly (n-
isopropylacrylamide) is a typical thermo-responsive hydrogel, having a lower critical
solution temperature (LCST≈32oC). These gels suddenly transit from a swollen form
to a shrunken form at the transition temperature (≈ 32oC) through an increase in
incubation temperature in water. As swelling experiments were carried out at 37oC
(higher than LCST), so the acidic pH and the temperature of the medium interfered
with each other constructively to block the swelling in NiPAAm-1 gels having
EGDMA as a cross-linker. In low pH, NiPAAm-2 gels may have bigger pores due to
the presence of DEGDMA which facilitates the penetration of water into the
polymeric network, due to concentration gradient. At pH 8.0, a reasonable swelling
is observed in all the NiPAAm gels indicating that the basicity of medium dominates
all other factors as shown in the Fig. 3.23.
Effect of concentration of cross-linker
It was observed that during swelling, the disks having low concentration of the cross-
linker showed faster rate of swelling especially at the pH 8.0 (Fig. 3.17 and Fig. 3.20).
The disks were de-shaped initially and became isotropic while attaining equilibrium
swelling. The de-shaping of disks was because the margins swelled with greater rate
than the middle portion, and with more media sorption, the swelling process became
uniform, resulting in well-shaped disks. It is assumed that at the lower concentration
of the cross-linker, almost all the cross-linking agent is incorporated in the polymeric
network. As AA in these hydrogels, is hydrophilic group and the cross-linker binds
AA, so the crosslink density is increased which lowers the average molecular weight
between the cross-links and this curtails the free volume accessible to the penetrant
101
water molecules. With the concentration of EGDMA, the rate of sorption and
equilibrium water content was decreased.
Effect of nature of cross-linker
When we compare the swelling in both the NiPAAm gels at pH 8.0, the sample with
DEGDMA is exhibiting higher swelling rate and equilibrium swelling (Fig. 3.23). It is
reported that pure Poly (NiPAAm) hydrogels do not show any sign of swelling at
37oC because it is above LCST of 32oC (Heskins and Guillet, 1968), whereas PAA
show pH dependence because of its ionizable –COOH groups. But the swelling ratio
is much higher for co-polymers having NiPAAm at basic pH 8.0 (fig. 3.24), may be
due to the presence of acrylic acid which has increased the LCST up to 33.6oC (as
discussed in thermo-gravimetric analysis) and the swelling capacity of NiPAAm gel,
indicating the dual-sensitivity of these gels. Similar results have been reported by
Diez-Pena et al. (2004). They attempted the copolymerization of N-
isopropylacrylamide with methacrylic acid and observed much higher swelling ratio
at neutral and basic pHs (Diez-Pena et al., 2004).
The figure 3.25 is representing the combined effect of EGDMA and AA on
equilibrium swelling of poly (MA-co-VA-co-AA), which increases with low cross-
linker to acrylic acid volume ratio. This behavior is consistent with the strength of
milkiness in hydrogel samples, given in Fig. 1.1.
102
Table 3.2: Summary of media penetration velocities, equilibrium media contents,
Schott,s model and power law parameters for the poly (MA-co-VA-co-AA) for
varying concentration of EGDMA.
Sample Media penetration velocity Equilibrium media sorbed Schott’s Model Fick’s Model
(mm/min×10-6) (mg media/mg polymer) R2 n R2
__________________________________________________________________________________
pH =1
E1 318 0.1932 0.957 0.434 0.93
E2 420 0.1336 0.985 0.392 0.966
E3 493 0.1078 0.966 0.185 0.839
E4 620 0.1047 0.994 0.237 0.86
pH = 4
E1 285 0.0978 0.966 0.211 0.508
E2 323 0.0836 0.966 0.299 0.661
E3 412 0.0753 0.928 0.128 0.854
E4 420 0.0717 0.914 0.120 0.914
pH = 5.5
E1 3112 3.7578 0.998 0.671 0.996
E2 1626 1.114 0.970 0.557 0.983
E3 819 0.6341 0.948 0.555 0.977
E4 667 0.4117 0.937 0.505 0.990
pH = 7.4
E1 1834 1.9442 0.899 0.612 0.918
E2 684 1.0266 0.992 0.653 0.993
E3 667 1.051 0.851 0.701 0.993
E4 518 0.7568 0.850 0.621 0.970
pH = 8
E1 6977 8.1093 0.982 0.663 0.999
E2 3074 3.3486 0.985 0.589 0.996
E3 1656 2.1314 0.745 0.595 0.993
E4 1316 1.1731 0.979 0.566 0.994
103
Table 3.3: Summary of media penetration velocities, equilibrium media contents,
Schott,s model and power law parameters for the poly (MA-co-VA-co-AA) for
varying concentration of AA, crosslinked with EGDMA.
sample Media penetration velocity Equilibrium media sorbed Schott,s Model Fick’s Model
(mm/min×10-6) (mg media/mg polymer) R2 n R2
___________________________________________________________________________________
pH =1
AE1 212 0.057 0.988 0.486 0.965
AE2 272 0.060 0.964 0.475 0.925
AE3 594 0.084 0.989 0.386 0.911
AE4 637 0.124 0.975 0.790 0.721
pH = 4
AE1 281 0.049 0.959 0.494 0.996
AE2 382 0.07 0.985 0.225 0.976
AE3 357 0.074 0.964 0.441 0.976
AE4 577 0.094 0.981 0.286 0.991
pH = 5.5
AE1 160 0.130 .929 0.915 0.999
AE2 348 0.142 0.159 0.566 0.996
AE3 773 0.515 0.567 0.570 0.996
AE4 3550 0.924 0.927 0.432 0.992
pH = 7.4
AE1 272 0.085 0.902 0.347 0.999
AE2 645 0.394 0.565 0.595 0.996
AE3 1656 1.48 0.977 0.578 0.996
AE4 1518 1.51 0.455 0.702 0.992
pH = 8
AE1 331 0.197 0.762 0.638 0.999
AE2 1614 0.71 0.873 0.612 0.996
AE3 3499 1.671 0.928 0.545 0.996
AE4 6353 2.656 0.963 0.502 0.992
104
Table 3.4: Summary of media penetration velocities, equilibrium media contents,
Schott,s model and power law parameters for the poly (MA-co-VA-co-AA) for
varying concentration of DEGDMA.
Sample Media penetration velocity Equilibrium media sorbed Schott,s Model Fick’s Model
(mm/min×10-6) (mg media/mg polymer) R2 n R2
__________________________________________________________________________________ pH =1
D1 726 0.26997 0.961 0.461 0.948
D2 866 0.270784 0.992 0.442 0.959
D3 981 0.25115 0.933 0.474 0.899
D4 2586 0.095412 0.952 0.494 0.951
pH = 4
D1 770 0.153756 0.459 0.133 0.417
D2 654 0.107735 0.864 0.290 0.434
D3 650 0.098552 0.977 0.106 0.909
D4 450 0.090512 0.757 0.469 0.814
pH = 5.5
D1 3580 3.794443 0.983 0.722 0.998
D2 3440 2.895606 0.974 0.586 0.996
D3 1766 0.893382 0.939 0.514 0.963
D4 1248 0.67913 0.972 0.500 0.986
pH = 7.4
D1 2098 0.959736 0.998 0.510 0.922
D2 1125 0.890247 0.993 0.586 0.972
D3 1269 0.448158 0.937 0.539 0.952
D4 675 0.303726 0.974 0.520 0.887
pH = 8
D1 9486 7.703232 0.980 0.779 0.994
D2 6208 3.527171 0.994 0.502 0.944
D3 4849 0.9654 0.952 0.597 0.998
D4 2458 0.8825 0.946 0.531 0.987
105
Table 3.5: Summary of media penetration velocities, equilibrium media contents,
Schott,s model and power law parameters for the the poly (MA-co-VA-co-AA) for
varying concentration of AA, crosslinked with DEGDMA.
Sample Media penetration velocity Equilibrium media sorbed Schott,s Model Fick’s Model
(mm/min×10-6) (mg media/mg polymer) R2 n R2
_________________________________________________________________________________
pH =1
AD1 42.46 0.104 0.974 0.424 0.141
AD2 204 0.144 0.963 0.499 0.694
AD3 401 0.2072 0.953 0.424 0.775
AD4 868 0.2618 0.962 0.373 0.951
pH = 4
AD1 158 0.048 0.987 0.479 0.817
AD2 250 0.0589 0.976 0.467 0.930
AD3 367 0.2517 0.968 0.499 0.865
AD4 637 0.3132 0.982 0.561 0.987
pH = 5.5
AD1 171 0.0906 0.984 0.572 0.936
AD2 355 0.15 0.958 0.509 0.976
AD3 1165 0.8276 0.995 0.649 0.925
AD4 1752 0.8789 0.991 0.627 0.973
pH = 7.4
AD1 84.92 0.0554 0.960 0.693 0.962
AD2 108 0.0899 0.852 0.845 0.924
AD3 822 0.714 0.941 0.693 0.965
AD4 1328 0.8875 0.957 0.721 0.990
pH = 8
AD1 266 0.0896 0.929 0.551 0.942
AD2 544 0.2176 0.828 0.515 0.897
AD3 3204 1.146 0.908 0.516 0.985
AD4 4867 2.87 0.977 0.696 0.981
106
Table 3.6: Summary of media penetration velocities, equilibrium media contents,
Schott,s model and power law parameters for the poly (MA-co-NiPAAm-co-AA)
hydrogels.
Sample Media penetration velocity Equilibrium media sorbed Schott,s Model Fick’s Model
(mm/min×10-6) (mg media/mg polymer) R2 n R2
__________________________________________________________________________________
pH =1
NiPAAm-1 ---- ---- ---- ---- ----
NiPAAm-2 552.017 0.683168 0.960 0.690 0.974
pH = 4
NiPAAm-1 ---- ---- ---- ---- ----
NiPAAm-2 637 0.703704 0.975 0.582 0.916
pH = 5.5
NiPAAm-1 509.55 1.070922 0.980 0.577 0.757
NiPAAm-2 806.79 1.2285816 0.902 0.505 0.979
pH = 7.4
NiPAAm-1 637 1.304 0.985 0.862 0.967
NiPAAm-2 1019 1.605405 0.972 0.712 0.911
pH = 8
NiPAAm-1 2153 2.62122 0.898 0.535 0.789
NiPAAm-2 4034 6.947977 0.854 0.642 0.983
107
Fig. 3.16 (a): Hydrogel disk showing three regions during dynamic swelling process.
Fig. 3.16(b): Swollen at equilibrium state
Fig. 3.16 (c): Burst after equilibrium state
Fig. 3.16: Different stages of swelling of co-polymeric hydrogel disk.
108
Fig. 3.17: Effect of concentration of EGDMA on dynamic and equilibrium swelling
of poly (MA-co-VA-co-AA) co-polymeric hydrogels at pH 8.0.
Fig. 3.18: Effect of concentration of AA on dynamic and equilibrium swelling of poly
(MA-co-VA-co-AA) co-polymeric hydrogels cross-linked with EGDMA at pH 8.0.
0
100
200
300
400
500
600
700
800
0 500 1000 1500 2000
Sw
elli
ng %
time (min)
E1
E2
E3
E4
0
50
100
150
200
250
300
0 500 1000 1500 2000
Sw
elli
ng %
time (min)
EA1
EA2
EA3
EA4
109
Fig. 3.19: Effect of pH on optimized batch of poly (MA-co-VA-co-AA) co-polymeric
hydrogels cross-linked with EGDMA.
Fig. 3.20: Effect of concentration of DEGDMA on dynamic and equilibrium swelling
of poly (MA-co-VA-co-AA) co-polymeric hydrogels at pH 8.0.
0
50
100
150
200
250
300
0 500 1000 1500 2000
Sw
elli
ng %
time (min)
pH=1
pH=4
pH=5.5
pH=7.4
pH=8
0
100
200
300
400
500
600
700
800
900
0 500 1000 1500
Sw
elli
ng %
time (min)
D1
D2
D3
D4
110
Fig. 3.21: Effect of concentration of AA on dynamic and equilibrium swelling of poly
(MA-co-VA-co-AA) co-polymeric hydrogels cross-linked with DEGDMA at pH 8.0.
Fig. 3.22: Effect of pH on optimized batch of poly (MA-co-VA-co-AA) co-polymeric
hydrogels cross-linked with DEGDMA.
0
50
100
150
200
250
300
350
0 200 400 600 800
Sw
elli
ng %
time (min)
DA1
DA2
DA3
DA4
0
50
100
150
200
250
300
350
0 200 400 600 800
Sw
elli
ng %
time (min)
pH=1
pH=4
pH=5.5
pH=7.4
pH=8
111
Fig. 3.23: Effect of nature of the cross-linker on dynamic and equilibrium swelling of
poly (MA-co-AA-co-NiPAAm) co-polymeric hydrogels at pH 8.0.
Fig. 3.24: Effect of pH on NiPAAm-2 co-polymeric hydrogel sample.
0
100
200
300
400
500
600
700
800
0 20 40 60 100 140 180 240 300 360 480
Sw
elli
ng %
time (min)
NiPAAm-1
NiPAAm-2
0
100
200
300
400
500
600
700
800
0 200 400 600
Sw
elli
ng %
time (min)
pH 1
pH4
pH 5.5
pH 7.4
pH 8
112
Fig. 3.25: Effect of AA: EGDMA volume ration on equilibrium media sorbed at pH
8.0, at 37oC, in poly (MA-co-VA-co-AA) co-polymeric hydrogels.
-0.5
0
0.5
1
1.5
2
2.5
3
3.5
4
0.2:0.5 0.5:0.5 01:00.5 02:00.5 2:00 02:00.1 02:00.5 2:01 2:02
Qe
AA:EGDMA
113
3.3.2. Media Penetration Velocity
The rate of advancement of glassy to rubbery front from the surface to the center of
the polymer disk was determined by calculating the media penetration velocity (ν),
ν =1/2ρA.δw/δt (3.2)
Where “ρ” is the density of the media, “A” represents the area of the one disk face,
“w” is the mass gained by the polymer and “t” is the time. The early time data (t<15
min) was used to calculate the media penetration velocity. It has been reported that as
the media penetrates the glassy polymer, the solvent swells the polymer and produces
a rubbery region (Khutoryanskiy et al., 2004). Fig. 3.26 shows that the media
penetration velocity decreased by 75% at pH 5.5 and 73% at pH 8.0 and the
equilibrium media content decreased by an order of magnitude as the concentration of
EGDMA was increased from 1-10 mol % at all the pH values. Similarly, the
DEGDMA affected the media penetration velocity and equilibrium media content in
the same manner (Fig. 3.30). Our findings are in agreement with media penetration
velocity reported in other hydrophobic-hydrophilic copolymers like poly (HEMA-co-
MMA) as the proportion of hydrophobic monomer MMA was increased from 0-40%
(Khutoryanskiy et al., 2004). However, the media penetration velocity increased (46.6
%) with the concentration of EGDMA pH=1.0. It is assumed that pKa value of AA
(4.75) appeared to have a great impact on penetration velocity. It was concluded that
the equilibrium media content was directly proportional to the media penetration
velocity for poly (MA-co-VA-co-AA) cross-linked with EGDMA at the pH higher
than pKa value of AA. This trend has also been observed in poly (NIPA-co-FOSA)
copolymers (Tia et al., 2003). This relationship is also important because it suggests
that from the media penetration velocity, the equilibrium media content can be
predicted in very short experimental time (i.e. on the order of minutes vs. hours or
114
days) at a specific pH. But below pKa value the inverse trend was observed between
the media penetration velocity and equilibrium media content. The unexpected
behavior for these polymeric systems may be interpreted in such a way that the
carbonyl oxygen atoms of the EGDMA present on the surface of disks facilitate the
intermolecular hydrogen bonds with surrounding water molecules in pH 1.0, during
early times of exposure of hydrogels. However, as a continuous column of water is
developed from outside to inside of the disks, the increased crosslink density
predominates to cause a usual decrease in equilibrium media content. The formation
of hydrogen bonds by carbonyl oxygen with water molecules causing an increase in
media penetration velocity has also been reported (Mullerney et al., 2006). Fig. 3.28
illustrates the effect of concentration of acrylic acid on media penetration velocity of
poly (MA-co-VA-co-AA). It was found that the media penetration velocity increased
up to approximately 95% and the equilibrium media sorbed increased by an order of
magnitude as the concentration AA was increased from 0.6 to 40 mol % (Table 3.2).
The pH of the acidic medium appeared to have less effect on the media penetration
velocity and the equilibrium sorption but there was a pronounced increase in values of
ν as well as equilibrium media content at the higher AA concentrations. The sample
AE4 presented 90 % increase in the media penetration velocity when the pH was
increased from 1.0 to 8.0. Figure 3.32 represents the effect of acrylic acid in the poly
(MA-co-VA-co-AA) cross-linked with DEGDMA. The trend is same as indicated by
the gels cross-linked with EGDMA. The change in penetration velocity with AA
content and pH of the medium may be due to two possible mechanisms. First, if the
media traveled primarily through the hydrophilic acrylic acid regions of these
hydrogel, the increasing number of hydrophilic domains (-COOH) could facilitate the
media diffusive pathway through ionization of free carboxylic groups in the basic
115
media. Second, osmotic pressure caused by solvent molecules starts to relax the
polymer network chains more effectively in basic media at higher AA concentrations.
As far as the nature of the cross-liker is concerned, the media penetration velocity and
equilibrium media content were found to be higher in the NiPAAm gels cross-linked
with DEGDMA. The trend was consistent with of the swelling studies DEGDMA
containing hydrogels, owing to the presence of bigger pores inside the gel structures.
Fig. 3.26: Media penetration velocity at pH 1.0-8.0 in polymers comprised of 1-10
mol % EGDMA in poly (MA-co-VA-co-AA).
0
1000
2000
3000
4000
5000
6000
7000
8000
0 5 10 15
v (m
m/m
in ×
10
-6)
EGDMA Concentration ( mol %)
pH 1
pH 4
pH 5.5
pH 7.4
pH 8
116
Fig. 3.27: Equilibrium media content at pH 1.0-8.0 as a function of media penetration
velocity in polymers comprised of 1-10 mol % EGDMA in poly (MA-co-VA-co-AA).
Fig. 3.28: Media penetration velocity at pH 1.0-8.0 in polymers comprised of 6-40
mol % AA in poly (MA-co-VA-co-AA) cross-linked with EGDMA.
R² = 0.9784
0
1
2
3
4
5
6
7
8
9
0 2000 4000 6000 8000
Mas
s W
ater
/Mas
s P
oly
mer
(mg/m
g)
v(mm/min ×10-6)
0
1000
2000
3000
4000
5000
6000
7000
0 10 20 30 40 50
ν (
mm
/min
×10
-6)
Acrylic acid concentration (mol %)
pH=1
pH=4
pH=5.5
pH=7.4
pH=8
117
Fig. 3.29: Equilibrium media content at pH 1-8 as a function of media penetration
velocity in polymers comprised of 6-40 mol % AA in poly (MA-co-VA-co-AA)
cross-linked with EGDMA.
Fig. 3.30: Media penetration velocity at pH 1.0-8.0 in polymers comprised of 0.6-11
mol % DEGDMA in poly (MA-co-VA-co-AA).
R² = 0.9471
0
0.5
1
1.5
2
2.5
3
0 2000 4000 6000 8000
Mas
s W
ater
/Mas
s P
oly
mer
(mg/m
g)
ν (mm/min × 10-6)
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
0.6 3 5.8 11
v (m
m/m
in ×
10
-6)
DEGDMA Concentration ( mol %)
pH 8
pH 7.4
pH 5.5
pH 4
pH 1
118
Fig. 3.31: Equilibrium media content at pH 1.0-8.0 as a function of media penetration
velocity in polymers comprised of 0.6-11 mol % DEGDMA in poly (MA-co-VA-co-
AA).
Fig. 3.32: Media penetration velocity at pH 1.0-8.o in polymers comprised of 6-38.7
mol % AA in poly (MA-co-VA-co-AA) cross-linked with DEGDMA.
R² = 0.9258
0
0.5
1
1.5
2
2.5
3
3.5
0 2000 4000 6000
Mas
s W
ater
/Mas
s P
oly
mer
(mg/m
g)
v(mm/min ×10-6)
0
2000
4000
6000
8000
10000
12000
14000
16000
6 13.6 24 38.7
v (m
m/m
in ×
10
-6)
AA Concentration (mol%)
pH 8
pH 7.4
pH 5.5
pH 4
pH 1
119
Fig. 3.33: Equilibrium media content at pH 1.0-8.0 as a function of media penetration
velocity in polymers comprised of 6-38.7 mol % AA in poly (MA-co-VA-co-AA)
cross-linked with DEGDMA.
Fig. 3.34: Media penetration velocity at pH 1.0-8.0 in NiPAAm hydrogels.
R² = 0.838
-1
0
1
2
3
4
5
6
7
8
9
0 5000 10000
Mas
s W
ater
/Mas
s P
oly
mer
(mg/m
g)
v(mm/min ×10-6)
0
500
1000
1500
2000
2500
3000
3500
4000
4500
0 2 4 6 8 10
v (m
m/m
in ×
10
-6)
pH
NiPAAm-1
NiPAAM-2
120
Fig. 3.35: Equilibrium media content at pH 1.0-8.0 as a function of media penetration
velocity in NiPAAm-2 hydrogel.
R² = 0.998
0
1
2
3
4
5
6
7
8
0 2000 4000 6000
Mas
s w
ater
/Mas
s poly
mer
(mg/m
g)
v(mm/min ×10-6)
121
3.3.3. Swelling Mechanism
The kinetic order of swelling for all these hydrogels was determined using 1st order
model (Fick’s model i.e. Maxwell-Peppas model) and second order model (Schott’s
model). It is also likely that swelling of hydrogels at a certain time may follow both of
these kinetic orders (Mullerney et al., 2006). The mechanism of the media sorption
was estimated by calculating the diffusion exponent using Maxwell-Peppas model
(Jabbari and Nozari, 2008). The values are tabulated in tables 3.1-3.5. In our studies,
the Fick’s law was applied for the first swelling times; because for longer times, there
was a deviation in this behavior. So the swelling fraction values (W t/We) less than or
equal to 0.6 were established in accordance with bibliographic data (Hiratan et al.,
2005). On the other hand, the Schott’s model was applied for longer times when the
density of the sample has been increased. As indicated in the tables 3.1-3.4 that the
poly (MA-co-VA-co-AA) hydrogels followed the Schott’s model in acidic pH and
obeyed Maxwell-Peppas model in basic pH, with a few exceptions. So it was
concluded that poly (MA-co-VA-co-AA) hydrogels shifted their best fit from second
order swelling kinetics to the first order kinetics indicating the fact that the swelling
process for long times is not controlled by diffusion but by the relaxation of the
polymeric chains in acidic medium. On the other hand in basic medium, the swelling
mechanism should be controlled by the chain relaxations even in the early time of
swelling. Moreover, it was found that the increased pH values shift the mechanism
from diffusion-controlled (n<0.5) to an anomalous transport (0.5<n<1) in which both
the concentration gradient and erosion are governing the diffusion mechanism. It is
suggested that the polymer matrix maintains its structure in acidic conditions and the
media sorption is mainly controlled by diffusion, whereas the polymer chains get
relaxed in the basic media. It has been reported that in the anionic hydrogels like
122
having carboxylic groups attached with the polymeric chains, the H+ ions can
combine with OH- ions present in the basic solution to produce water. The cations
joined with other hydroxyl groups, may compensate the charge, going into the
polymeric network, thus leading to an osmotic pressure increase responsible for the
swelling of the hydrogels (Chen et al., 2000). At swelling equilibrium, the recovery
elastic force is equal to the osmotic pressure (Hiratani, 2005; Li and Chauhan, 2006).
However, the behavior of NiPAAm gels was different from that of Poly (MA-co-VA-
co-AA) co-polymeric hydrogels. NiPAAm-1 hydrogels did not exhibit a reasonable
swelling in acidic medium as discussed earlier, and showed preference for Schott’s
model in basic medium. NiPAAm-2 co-polymeric hydrogels exhibited an alternative
model fit with the pH change from 1.0 to 8.0. It can be assumed that as the LCST for
these polymers were found to be not more than 33.6oC, so these should be shrinked at
37oC, the experimental temperature, especially in acidic medium where no support for
swelling is provided by acrylic acid. So at most of reaction conditions, NiPAAm co-
polymeric hydrogels showed best fit with Schott’s model, indicating the chain
relaxations in longer time on one hand and non-Fickian swelling mechanism on the
other side in all cases as shown in the table 3.5 and figures from 3.52 to 3.59 and from
3.76 to 3.83. Non-Fickian behavior for various hydrogels under similar conditions has
been reported by many authors (Liu et al., 2005; Vrentas and Vrentas, 2003; Afif and
Grame, 2002; Rajagopal, 2003).
123
Fig. 3.36: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample E1.
Fig. 3.37: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample E2.
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
0 2 4 6 8
ln W
t/W
e
ln t
-3
-2.5
-2
-1.5
-1
-0.5
0
0 2 4 6 8
ln W
t/W
e
ln t
124
Fig. 3.38: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample E3.
Fig. 3.39: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample E4.
-3
-2.5
-2
-1.5
-1
-0.5
0
0 2 4 6 8
ln W
t/W
e
ln t
-3
-2.5
-2
-1.5
-1
-0.5
0
0 2 4 6 8
ln W
t/W
e
ln t
125
Fig. 3.40: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample EA1.
Fig. 3.41: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample EA2.
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
0 2 4 6 8
ln W
t/W
e
ln t
-3
-2.5
-2
-1.5
-1
-0.5
0
0 2 4 6 8
ln W
t/W
e
ln t
126
Fig. 3.42: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample EA3.
Fig. 3.43: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample EA4.
-3
-2.5
-2
-1.5
-1
-0.5
0
0 2 4 6 8
ln W
t/W
e
ln t
-3
-2.5
-2
-1.5
-1
-0.5
0
0 2 4 6 8
ln W
t/W
e
ln t
127
Fig. 3.44: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample D1.
Fig. 3.45: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample D2.
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
0 2 4 6 8
ln W
t/W
e
lnt
-2.5
-2
-1.5
-1
-0.5
0
0 2 4 6 8
ln W
t/W
e
lnt
128
Fig. 3.46: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample D3.
Fig. 3.47: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample D4.
-1.8
-1.6
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
0 1 2 3 4 5
ln W
t/W
e
ln t
-2.5
-2
-1.5
-1
-0.5
0
0 2 4 6
ln W
t/W
e
ln t
129
Fig. 3.48: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample DA1.
Fig. 3.49: Graphic of Maxwell-Peppas Model at pH 8. for the hydrogel sample DA2.
-1.8
-1.6
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
0 2 4 6
ln W
t/W
e
ln t
-1.8
-1.6
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
0 2 4 6
ln W
t/W
e
ln t
130
Fig. 3.50: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample DA3.
Fig. 3.51: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample DA4.
-1.8
-1.6
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
0 2 4 6
ln W
t/W
e
ln t
-2.5
-2
-1.5
-1
-0.5
0
0 2 4 6
ln W
t\We
ln t
131
Fig. 3.52: Graphic of Maxwell-Peppas Model at pH 5.5 for the hydrogel sample
NiPAAm-1.
Fig. 3.53: Graphic of Maxwell-Peppas Model at pH 7.4 for the hydrogel sample
NiPAAm-1.
-3
-2.5
-2
-1.5
-1
-0.5
0
0 2 4 6
ln W
t/W
e
ln t
-3
-2.5
-2
-1.5
-1
-0.5
0
0 2 4 6
ln W
t/W
e
ln t
132
Fig. 3.54: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample
NiPAAm-1.
Fig. 3.55: Graphic of Maxwell-Peppas Model at pH 1.0 for the hydrogel sample
NiPAAm-2.
-1.8
-1.6
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
0 1 2 3 4 5
ln W
t /W
e
ln t
-2.5
-2
-1.5
-1
-0.5
0
0 2 4 6
ln W
t/W
e
ln t
133
Fig. 3.56: Graphic of Maxwell-Peppas Model at pH 4.0 for the hydrogel sample
NiPAAm-2.
Fig. 3.57: Graphic of Maxwell-Peppas Model at pH 5.5 for the hydrogel sample
NiPAAm-2.
-2.5
-2
-1.5
-1
-0.5
0
0 1 2 3 4 5
ln W
t/W
e
ln t
-2.5
-2
-1.5
-1
-0.5
0
0 1 2 3 4 5 6
ln W
t/W
e
ln t
134
Fig. 3.58: Graphic of Maxwell-Peppas Model at pH 7.4 for the hydrogel sample
NiPAAm-2.
Fig. 3.59: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample
NiPAAm-2.
-3
-2.5
-2
-1.5
-1
-0.5
0
0 1 2 3 4 5 6
ln W
t/W
e
ln t
-3
-2.5
-2
-1.5
-1
-0.5
0
0 2 4 6
ln W
t/W
e
ln t
135
Fig. 3.60: Graphic of Schott’s model at pH 1.0 for the hydrogel sample E1.
Fig. 3.61: Graphic of Schott’s model at pH 1.0 for the hydrogel sample E2.
0
5000
10000
15000
20000
25000
30000
0 10 20 30 40 50
t/W
t
t 1/2
0
5000
10000
15000
20000
25000
30000
35000
40000
45000
0 10 20 30 40 50
t/W
t
t 1/2
136
Fig. 3.62: Graphic of Schott’s model at pH 1.0 for the hydrogel sample E3.
Fig. 3.63: Graphic of Schott’s model at pH 1.0 for the hydrogel sample E4.
15000
20000
25000
30000
35000
40000
45000
15 20 25 30 35 40
t/W
t
t 1/2
10000
15000
20000
25000
30000
35000
40000
45000
50000
20 25 30 35 40
t/W
t
t 1/2
137
Fig. 3.64: Graphic of Schott’s model at pH 1.0 for the hydrogel sample EA1.
Fig. 3.65: Graphic of Schott’s model at pH 1.0 for the hydrogel sample EA2.
20000
30000
40000
50000
60000
70000
80000
90000
15 20 25 30 35 40
t/W
t
t 1/2
10000
20000
30000
40000
50000
60000
70000
15 20 25 30 35 40
t/W
t
t 1/2
138
Fig. 3.66: Graphic of Schott’s model at pH 1.0 for the hydrogel sample EA3.
Fig. 3.67: Graphic of Schott’s model at pH 1.0 for the hydrogel sample EA4.
5000
10000
15000
20000
25000
30000
35000
40000
45000
50000
10 20 30 40 50
t/W
t
t 1/2
5000
7000
9000
11000
13000
15000
17000
19000
21000
10 15 20 25 30
t/W
t
t 1/2
139
Fig. 3.68: Graphic of Schott’s model at pH 1.0 for the hydrogel sample D1.
Fig. 3.69: Graphic of Schott’s model at pH 1.0 for the hydrogel sample D2.
2000
4000
6000
8000
10000
12000
14000
16000
18000
10 20 30 40
t/w
t
t1/2
0
2000
4000
6000
8000
10000
12000
10 20 30 40
t/w
t
t1/2
140
Fig. 3.70: Graphic of Schott’s model at pH 1.0 for the hydrogel sample D3.
Fig. 3.71: Graphic of Schott’s model at pH 1.0 for the hydrogel sample D4.
1000
1500
2000
2500
3000
3500
4000
4500
5 10 15 20
t/w
t
t1/2
1000
1500
2000
2500
3000
3500
4000
4500
6 8 10 12 14
t/w
t
t 1/2
141
Fig. 3.72: Graphic of Schott’s model at pH 1.0 for the hydrogel sample DA1.
Fig. 3.73: Graphic of Schott’s model at pH 1.0 for the hydrogel sample DA2.
10000
12000
14000
16000
18000
20000
22000
24000
26000
28000
30000
10 15 20 25 30
t/W
t
t 1/2
4000
5000
6000
7000
8000
9000
10000
11000
12000
13000
14000
10 15 20 25 30
t/W
t
t 1/2
142
Fig. 3.74: Graphic of Schott’s model at pH 1.0 for the hydrogel sample DA3.
Fig. 3.75: Graphic of Schott’s model at pH 1.0 for the hydrogel sample DA4.
5000
5500
6000
6500
7000
7500
8000
8500
9000
9500
15 17 19 21 23 25
t/W
t
t 1/2
3500
3700
3900
4100
4300
4500
4700
4900
5100
5300
5500
15 17 19 21 23 25
t/W
t
t 1/2
143
Fig. 3.76: Graphic of Schott’s model at pH 5.5 for the hydrogel sample NiPAAm-1
.
Fig. 3.77: Graphic of Schott’s model at pH 7.4 for the hydrogel sample NiPAAm-1.
1000
1500
2000
2500
3000
3500
4000
10 15 20 25
t/W
t
t 1/2
1000
1200
1400
1600
1800
2000
2200
2400
2600
2800
3000
10 15 20 25
t/W
t
t 1/2
144
Fig. 3.78: Graphic of Schott’s model at pH 8.0 for the hydrogel sample NiPAAm-1.
Fig. 3.79: Graphic of Schott’s model at pH 1.0 for the hydrogel sample NiPAAm-2.
600
700
800
900
1000
1100
1200
1300
14 16 18 20 22 24
t/W
t
t 1/2
1000
1200
1400
1600
1800
2000
2200
2400
5 7 9 11 13 15
t/W
t
t 1/2
145
Fig. 3.80: Graphic of Schott’s model at pH 4.0 for the hydrogel sample NiPAAm-2.
Fig. 3.81: Graphic of Schott’s model at pH 5.5 for the hydrogel sample NiPAAm-2.
1000
1500
2000
2500
3000
3500
4000
4500
5000
5 10 15 20 25
t/W
t
t 1/2
2000
2200
2400
2600
2800
3000
3200
14 16 18 20 22 24
t/W
t
t 1/2
146
Fig. 3.82: Graphic of Schott’s model at pH 7.4 for the hydrogel sample NiPAAm-2.
Fig. 3.83: Graphic of Schott’s model at pH 8.0 for the hydrogel sample NiPAAm-2.
1000
1200
1400
1600
1800
2000
2200
2400
10 15 20 25
t/W
t
t 1/2
300
320
340
360
380
400
420
440
460
15 17 19 21 23 25
t/W
t
t 1/2
147
3.4. Loading of Tramadol HCl
Owing to preliminary swelling studies, the drug loading and release studies were
carried out at pH 8.0 where all the formulations attained the highest rate of sorption
and equilibrium media content. Fig. 3.84-3.90, exhibit the absorbency of Tramadol
HCl by the xerogels with different EGDMA content as well as drug concentration. It
is obvious from Fig. 3.84, when the mol % of the cross-linker in the co-polymer
hydrogels increases, less Tramadol HCl was absorbed because of low water up take.
The amount of the drug loaded in the hydrogel has a close relation with the cross-link
density of the hydrogels. As the increased concentration of the cross-linker increases
the cross-link density, so the amount of Tramadol HCl loaded decreases. Sung-Eun et
al. (2002) reported the similar effect of the cross-linker on the drug absorbency in
poly (ethylene glycolmethacrylate-co-acrylic acid) (Sung-Eun et al., 2002). The
increase in the initial concentration of the drug, results in more amount of drug to be
loaded in the polymeric network as indicated in Figs. 3.85-3.88. This can be explained
in terms of greater concentration gradient in the loading solution. Again, the Figs.
3.89 and 3.90 are showing the comparative absorbency of the drug with respect to the
nature of the cross-linking agent. It is clear from both the representative figures that
the absorbency of co-polymeric hydrogels cross-linked with DEGDMA is higher than
those having EGDMA as the cross-linking agent. It is due to the greater swelling
ability of DEGDMA, as already discussed (Section 3.2).
148
Fig. 3.84: Effect of the cross-linker concentration on absorbency of Tramadol HCl.
Fig. 3.85: Absorbency of Tramadol HCl by poly (MA-co-VA-co-AA) cross-linked
with EGDMA provided with various initial concentrations of the drug.
R² = 0.9968
106
108
110
112
114
116
118
120
122
0 2 4 6 8abso
rben
cy o
f T
ram
ado
l H
Cl
by t
he
xer
ogel
(m
g/g
)
EGDMA (mol %)
R² = 0.9872
0
100
200
300
400
500
600
700
800
0 2 4 6
abso
rben
cy o
f T
ram
ado
l H
Cl
by t
he
xer
ogel
(m
g/g
)
initial concentration of Tramadol HCl (mg/ml)
149
Fig. 3.86: Absorbency of Tramadol HCl by poly (MA-co-VA-co-AA) cross-linked
with DEGDMA provided with various initial concentrations of the drug.
Fig. 3.87: Absorbency of Tramadol HCl by NiPAAm-1 cross-linked with EGDMA
provided with various initial concentrations of the drug.
R² = 0.9867
0
50
100
150
200
250
300
0 0.5 1 1.5 2 2.5
abso
rben
cy o
f T
ram
adol
HC
l by t
he
xer
ogel
(m
g/g
)
initial concentration of Tramadol HCl (mg/mL)
R² = 0.9548
0
100
200
300
400
500
600
700
800
900
0 1 2 3 4 5
Ab
sorb
ency
of
Tra
mad
ol
HC
l b
y
xer
ogel
(m
g/g
)
initial concentration of Tramadol HCl(mg/mL)
150
Fig. 3.88: Absorbency of Tramadol HCl by NiPAAM-2 cross-linked with DEGDMA
provided with various initial concentrations of the drug.
Fig. 3.89: Effect of nature of the cross-linker on absorbency of Tramadol HCl in poly
(MA-co-VA-co-AA) hydrogels.
R² = 0.9909
0
100
200
300
400
500
600
700
800
900
1000
0 1 2 3 4 5
Abso
rben
cy o
f T
ram
adol
HC
l by
xer
ogel
(m
g/g
)
initial concentration of Tramadol HCl (mg/mL)
0
50
100
150
200
250
EGDMA DEGDMA
Abso
rben
cy o
f T
ram
ado
l H
Cl
by
xer
ogel
(m
g/g
)
0.8
1.6
151
Fig 3.90: Effect of nature of the cross-linker on absorbency of Tramadol HCl in
NiPAAm gels.
0
100
200
300
400
500
600
EGDMA DEGDMA
Abso
rben
cy o
f T
ram
adol
HC
l by
xer
ogel
(m
g/g
)
1.6
2.4
152
3.5. Drug Release Kinetics
3.5.1. Drug Release Profiles
Drug release studies were performed with respect to the concentration of the cross-
linker and the drug content available to be released by the system, because it has been
reported that the chemical structure and dissolution in water do not show a significant
influence on the drug release rate from the hydrogel networks; on the other hand the
cross link density and the amount of the drug loaded determine the drug release from
the system (Landner et al., 1996).
To analyze the effect of the concentration of the cross-linker on the release behavior
of the drug, only three samples E1, E2 and E3 were used for experiment as the sample
E4 was collapsed during the loading process. Fig. 3.91 is showing the release profile
for influence of the cross-linking agent concentration on the release rate of the drug
from the hydrogel network. As predicted from swelling studies, the drug release rate
decreases with increase in the cross-link density. Increasing the amount of cross-
linking agent, results in creation of more branches on network, decreasing the free
volume for water diffusion. Additionally, increasing the amount of the cross-linker
leads to a stronger but less flexible network, resulting in a decrease in the swelling
rate. Same effect of the cross linker’s concentration on the drug release rate has also
been reported by other authors (Kumar et al., 2010; Hekmat et al., 2009). On the other
hand, the release rate was enhanced by the amount of the drug loaded in the polymer
networks. The optimized formulations for every type of the polymeric hydrogels were
used to study the effect of amount of the drug loaded in the system as shown in fig.
3.92-3.95. In all representative figures, it is observed that at initial stages, the effect
was not pronounced. The difference in the drug release rate for various initial
concentrations of the Tramadol HCl, was negligible during first 30 minutes of
153
exposure of the drug loaded disks into the buffer solution at pH 8.0. However, with
passage of swelling time, the difference between the curves is becoming more and
more prominent especially for higher drug loading concentrations; the amount of the
drug released and the drug release rate were increased significantly. The root cause
for the observed effect might be the higher concentration gradient which is
responsible for a more efficient diffusion of the drug substance through the polymer
network, keeping all other conditions the same. Hence, variation in drug loading
concentration offers a real probability of controlling the drug release (Dimitrov et al.,
2003). The effect of nature of the cross-linker on release rate is shown in figs. 3.96
and 3.97. The release rate is faster in the gels cross-linked with DEGDMA, than those
cross-linked with EGDMA. However, the difference is more pronounced in NiPAAm
gels.
Fig. 3.91: Influence of concentration of the cross linking agent on release rate of
Tramadol HCl.
0
0.1
0.2
0.3
0.4
0.5
0.6
0 200 400 600 800
dru
g r
elea
sed
(m
g/m
l)
time (min)
E1
E2
E3
154
Fig. 3.92: Influence of amount of Tramadol HCl in the matrix on the release rate for
the hydrogel E2 at pH 8.0.
Fig. 3.93: Influence of amount of Tramadol HCl in the matrix on the release rate for
the hydrogel D2 at pH 8.0.
0
0.5
1
1.5
2
2.5
0 200 400 600 800
Dru
g r
elea
sed (
mg/m
l)
time (min)
TE1
TE2
TE3
TE4
TE5
TE6
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
0 50 100 150 200 250 300
dru
g r
elea
sed
(m
g/m
l)
time (min)
TD1
TD2
TD3
TD4
TD5
155
Fig. 3.94: Influence of amount of Tramadol HCl in the matrix on the release rate for
the hydrogel NiPAAm-1 at pH 8.0.
Fig. 3.95: Influence of amount of Tramadol HCl in the matrix on the release rate for
the hydrogel NiPAAm-2 at pH 8.0.
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
0 100 200 300
dru
g r
elea
sed (
mg/m
l)
time (min)
TNE1
TNE2
TNE3
TNE4
TNE5
0
0.5
1
1.5
2
2.5
0 100 200 300
dru
g r
elea
sed
(m
g/m
l)
time (min)
TND1
TND2
TND3
TND4
156
Fig. 3.96: Effect of nature of the cross-linker on release rate of Tramadol HCl in poly
(MA-co-VA-co-AA) hydrogels having 1.6 mg/ml initial drug concentration.
Fig. 3.97: Effect of nature of the cross-linker on release rate of Tramadol HCl in
NiPAAm gels having higher drug concentration.
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
15 30 45 60 75 90 105 120 135 150 180 210 240
dru
g r
elea
sed(m
g/m
l)
time (min)
EGDMA
DEGDMA
0
0.5
1
1.5
2
2.5
2 4
10
15
20
25
35
45
55
70
85
100
130
160
190
220
250
270
dru
g r
elea
sed
(m
g/m
l)
time (min)
EGDMA
DEGDMA
157
3.5.2. Kinetic Order of Drug Release
Various mathematical equations have been proposed to describe the kinetics of the
drug release from the controlled release formulations. The zero order model equation
describes the systems, where the drug release does not depend on its concentration
(Najib , Suleiman, 1985) . The first order release kinetics describes the dependency on
the drug concentration in the polymeric networks (Desai et al., 1966). Higuchi model
proposes a direct relation of the drug release from the matrix to a square root of time
and is based on the Fickian diffusion (Higuchi, 1963). The Hixson-Crowell cube root
law describes the release rate from the systems depending on the change in surface
area and diameter of the particles or tablets, specifically is applied for the systems
which erode over time (Hixson and Crowell, 1931).
To describe drug release mechanism more precisely, there is a more comprehensive
but still very simple semi-empirical formula, called the Korsmeyer-Peppas power law.
So the drug release data were fitted to these kinetic models to analyze the release
kinetics and the mechanism from the hydrogels. Based on the best correlation
coefficient values, the most appropriate model was selected to explain the release
behavior of the drug. The values of the release exponent (n), kinetic rate constant (k)
and the correlation coefficient (R2) are tabulated in the tables 3.6, 3.7 and 3.8. In
general, the formulations with varying concentration of the cross-linker (E1, E2 and
E3) did not seem to obey a zero order kinetics based on the low R2 values obtained
compared to those of the first order profiles of the drug release. The values obtained
from other models were found to be very close to each other throughout the whole
series of formulations investigated. Nevertheless, with higher concentration of drug
loaded, the hydrogels (TE4, TE5 and TE6) were either following the zero order profile
or exhibiting very close R2 values to those of first order kinetics. It was concluded that
158
these formulations show drug concentration dependency up to a certain limit of drug
loaded (TE1, TE2 and TE3). After that threshold concentration of the drug loaded, the
release kinetics is observed by other factors like cross-link density, chain relaxation
and osmotic pressure. The co-polymeric hydrogels Poly (MA-co-VA-co-AA) cross-
linked with DEGDMA and all the NiPAAm gel samples exhibited the best fit model
for the first order kinetics for the entire initial drug loaded in the polymer networks. It
was concluded that in the Poly (MA-co-VA-co-AA) cross-linked with DEGDMA and
all the NiPAAm gel samples, the drug releasae rate was strictly depending upon the
drug loaded in the hydrogel disks. Applicability of Hixcon-Crowell model to the
formulations (TE4, TE5 and TE6) indicated a change in surface area and diameter of
the tablets with a progressive dissolution of matrix as a function of time (Mehrgan H,
Mortazavi SA, 2005). This result was similar to that obtained when the release
behavior of diltiezem HCl from matrix tablets was analyzed by other authors (Crohel
et al. 2002). However, co-polymeric hydrogels Poly (MA-co-VA-co-AA) cross-linked
with DEGDMA and all the NiPAAm gel samples followed the Higuchi model. The
correlation factor values and other concerned parameters are tabulated in the tables
3.7 and 3.8.
The values of “n” determined for chemically cross linked hydrogels studied, ranged
from 0.688 to 0.982 co-polymeric hydrogels Poly (MA-co-VA-co-AA) cross-linked
with EGDMA as shown in the table 3.6; and those for Poly (MA-co-VA-co-AA)
cross-linked with DEGDMA were lying between 0.515 and 0.961.The results
indicated that all the formulations exhibited anomalous transport (non-Fickian
diffusion mechanism), so the drug release was governed by both diffusion of the drug
and dissolution of the polymeric network. On the other hand, all NiPAAm gels
showed Fickian behavior with the values of the diffusion exponent (n) ranging from
159
0.199 to 0.265 for NiPAAm-1 and 0.155 to 0.290 for NiPAAm-2 as tabulated in the
table 3.8. The drug release mechanism was quite opposite to that exhibited during
swelling by NiPAAm gels, where they showd non-Fickian behavior as shown in the
table 3.5. This dramatic change undergone by the NiPAAm gels may be explained on
the basis of presence of dual-sensitivity in the gels towards temperature and pH, and
also there may be some strong interaction between the drug particles and the polymer
network. In fact all the NiPAAm hydrogels samples were collapsed during first 10
minutes of their exposure to the buffer solution. The initial uptake of water due to
diffusion developed some type of strong interaction with the drug, resulting greater
osmotic pressure to cause the burst release of the drug; ca. 40 % of the drug was
released during first 15 minutes due to the collapse of the hydrogel disks providing
greater surface area. That is the reason that NiPAAm gels followed Higuchi model
along with Fickian release mechanism.
In case of formulations containing low concentration of the drug loaded (TE1, TE2,
TE3, E1, E2 and E3) the R2 values obtained from the Higuchi model appeared to be
slightly, higher than those of Hixson-Crowell model. This indicates that the release
mechanism is principally being controlled by polymeric network. This fact is
supported by the values of diffusion exponent (n). For these systems, all the tablets for
P (MA-co-VA-co-AA) started to erode during the first two hours of their introduction
into a fixed volume of the phosphate buffer solutions. Even the samples with higher
drug concentrations were collapsed during the first hour of exposure of the
formulations to the dissolution medium.
160
Table 3.7: Kinetic parameters of tramadol HCl release from the matrix tablets of the
poly (MA-co-VA-co-AA) for varying concentration of EGDMA
Sample Zero-order First-order Higuchi Hixson-Crowell Korsmeyer-Peppas
ko (%min-1) R2 k1 (min-1) R2 kH(%min-1/2) R2 kHC(%min-1) R2
n R2 kKP(%min-n)
___________________________________________________________________________________
E1 0.339 0.957 0.007 0.990 7.715 0.989 0.009 0.965 0.907 0.987 0.007
E2 0.332 0.941 0.006 0.987 6.68 0.980 0.008 0.974 0.982 0.893 0.004
E3 0.23 0.942 0.004 0.981 4.921 0.983 0.005 0.974 0.691 0.990 0.016
TE1 0.332 0.941 0.006 0.987 6.83 0.980 0.008 0.974 0.982 0.893 0.004
TE2 0.131 0.963 0.002 0.973 3.803 0.967 0.003 0.949 0.713 0.914 0.009
TE3 0.123 0.978 0.002 0.986 3.827 0.989 0.002 0.984 0.748 0.969 0.007
TE4 0.146 0.996 0.002 0.973 4.309 0.978 0.003 0.990 0.832 0.994 0.004
TE5 0.096 0.991 0.001 0.989 3.155 0.983 0.002 0.990 0.688 0.988 0.007
TE6 0.0127 0.985 0.002 0.989 3.701 0.989 0.002 0.991 0.733 0.979 0.007
Table 3.8: Kinetic parameters of tramadol HCl release from the matrix tablets of the
poly (MA-co-VA-co-AA) for varying concentration of DEGDMA
Sample Zero-order First-order Higuchi Hixson-Crowell Korsmeyer-Peppas
ko (%min-1) R2 k1 (min-1) R2 kH(%min-1/2) R2 kHC(%min-1) R2
n R2 kKP(%min-n)
___________________________________________________________________________________
TD1 0.623 0.922 0.010 0.962 8.160 0.956 0.013 0.956 0.967 0.962 0.019
TD2 0.698 0.922 0.011 0.964 8.382 0.960 0.015 0.953 0.515 0.983 0.008
TD3 0.675 0.966 0.012 0.973 9.356 0.981 0.016 0.962 0.753 0.949 0.024
TD4 0.785 0.917 0.014 0.955 8.758 0.964 0.018 0.946 0.589 0.963 0.06
TD5 0.608 0.934 0.011 0.981 7.450 0.987 0.013 0.961 0.597 0.987 0.048
161
Table 3.9: Kinetic parameters of tramadol HCl release from the matrix tablets of
NiPAAm gels.
Sample Zero-order First-order Higuchi Hixson-Crowell Korsmeyer-Peppas
ko (%min-1) R2 k1 (min-1) R2 kH(%min-1/2) R2 kHC(%min-1) R2
n R2 kKP(%min-n)
___________________________________________________________________________________
TNE1 0.245 0.879 0.012 0.961 5.213 0.932 0.011 0.944 0.200 0.931 0.265
TNE2 0.240 0.815 0.012 0.980 7.340 0.977 0.020 0.971 0.265 0.992 0.223
TNE3 0.226 0.838 0.012 0.990 6.536 0.986 0.018 0.955 0.220 0.980 0.267
TNE4 0.221 0.832 0.010 0.971 5.809 0.986 0.016 0.978 0.199 0.970 0.280
TNE5 0.259 0.877 0.015 0.978 5.588 0.979 0.013 0.958 0.240 0.982 0.230
TND1 0.205 0.800 0.010 0.951 6.693 0.944 0.018 0.897 0.290 0.972 0.237
TND2 0.134 0.718 0.012 0.948 7.181 0.972 0.034 0.951 0.150 0.985 0.467
TND3 0.207 0.811 0.014 0.984 6.424 0.941 0.019 0.879 0.234 0.995 0.294
TND4 0.202 0.781 0.014 0.995 6.887 0.966 0.021 0.915 0.0.246 0.993 0.291
162
Fig. 3.98: Zero order release kinetics of Tramadol HCl from the sample E1 at pH 8.0.
Fig. 3.99: Zero order release kinetics of Tramadol HCl from the sample E3 at pH 8.0.
0
10
20
30
40
50
60
70
80
90
0 50 100 150 200
% c
um
ula
tive
dru
g r
elea
se (
Qt)
t (min)
0
10
20
30
40
50
60
70
80
0 50 100 150 200 250 300
% c
um
ula
tive
dru
g r
elea
se (
Qt)
t (min)
163
Fig. 3.100: Zero order release kinetics of Tramadol HCl from the sample TE4 at pH
8.0.
Fig. 3.101: Zero order release kinetics of Tramadol HCl from the sample TE5 at pH
8.0.
0
10
20
30
40
50
60
70
80
0 200 400 600
% c
um
ula
tive
dru
g r
elea
se (
Qt)
t (min)
0
10
20
30
40
50
60
70
80
0 100 200 300 400 500 600
% c
um
ula
tive
dru
g r
elea
se (
Qt)
t (min)
164
Fig. 3.102: Zero order release kinetics of Tramadol HCl from the sample TE6 at pH
8.0.
Fig. 3.103: Zero order release kinetics of Tramadol HCl from the sample TD5 at pH
8.0.
0
10
20
30
40
50
60
70
80
0 200 400 600 800
% c
um
ula
tive
dru
g r
elea
se (
Qt)
t (min)
0
10
20
30
40
50
60
70
80
90
0 20 40 60 80 100 120
% c
um
ula
tive
dru
g r
elea
se (
Qt)
t (min)
165
Fig. 3.104: Zero order release kinetics of Tramadol HCl from the sample TNE5 at pH
8.0.
Fig. 3.105: Zero order release kinetics of Tramadol HCl from the sample TND4 at pH
8.0.
0
20
40
60
80
100
120
0 100 200 300
% c
um
ula
tive
dru
g r
elea
se
Qt
t (min)
0
20
40
60
80
100
120
0 50 100 150 200 250 300
% c
um
ula
tive
dru
g r
elea
se
Qt
t (min)
166
Fig. 3.106: 1st order release kinetics of Tramadol HCl from the sample E1 at pH 8.0.
Fig. 3.107: 1st order release kinetics of Tramadol HCl from the sample E3 at pH 8.0.
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
0 50 100 150 200
ln %
cum
ula
tive
dru
g r
emai
nin
g
ln(1
00
-Qt)
t (min)
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
0 100 200 300
ln %
cu
mu
lati
ve d
rug r
emai
nn
ig
ln (
10
0-Q
t)
t (min)
167
Fig. 3.108: 1st order release kinetics of Tramadol HCl from the sample TE1 at pH 8.0.
Fig. 3.109: 1st order release kinetics of Tramadol HCl from the sample TE2 at pH 8.0.
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
0 50 100 150 200 250
ln %
cum
ula
tive
dru
g r
emai
nin
g
ln(1
00
-Qt)
t (min)
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
0 100 200 300 400 500 600
ln %
cu
mu
lati
ve d
rug r
emai
nig
ln(1
00
-Qt)
t (min)
168
Fig. 3.110: 1st order release kinetics of Tramadol HCl from the sample TE3 at pH 8.0.
Fig. 3.111: 1st order release kinetics of Tramadol HCl from the sample TD1 at pH 8.0.
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
0 200 400 600
ln %
cu
mu
lati
ve d
rug r
emai
nin
g
ln(1
00
-Qt)
t (min)
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
0 50 100 150
ln %
cu
mu
lati
ve d
rug r
emai
nin
g
ln (
10
0-Q
t)
t(min)
169
Fig. 3.112: 1st order release kinetics of Tramadol HCl from the sample TD2 at pH 8.0.
Fig. 3.113: 1st order release kinetics of Tramadol HCl from the sample TD3 at pH
8.0.
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
0 20 40 60 80 100 120
ln %
cu
mu
lati
ve d
rug r
emai
nin
g
ln(1
00
-Qt)
t (min)
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
0 20 40 60 80
ln %
cu
mu
lati
ve d
rug r
emai
nin
g
ln (
10
0-Q
t)
t (min)
170
Fig. 3.114: 1st order release kinetics of Tramadol HCl from the sample TNE1 at pH 8.
Fig 3.115: 1st order release kinetics of Tramadol HCl from the sample TNE2 at pH 8. 0.
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
0 100 200 300
% l
n c
um
ula
tive
dru
g r
emai
nin
g
ln (
100
-Qt)
t (min)
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
0 100 200 300
%ln
cu
mu
lati
ve d
rug r
emai
nin
g
ln (
10
0-Q
t)
t (min)
171
Fig. 3.116: 1st order release kinetics of Tramadol HCl from the sample TNE5 at pH 8.0.
Fig. 3.117: 1st order release kinetics of Tramadol HCl from the sample TND1 at pH 8.0.
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
0 50 100 150 200 250 300
% l
n c
um
ula
tive
dru
g r
emai
nin
g
ln (
100
-Q t)
t (min)
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
0 100 200 300
% l
n c
um
ula
tive
dru
g r
emai
nin
g
ln (
10
0-Q
t)
t (min)
172
Fig. 3.118: 1st order release kinetics of Tramadol HCl from the sample TND2 at pH 8.0.
Fig. 3.119: 1st order release kinetics of Tramadol HCl from the sample TND3 at pH 8.0.
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
0 50 100 150 200 250 300
% l
n c
um
ula
tive
dru
g r
emai
nin
g
ln (
100
-Qt)
t (min)
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
0 50 100 150 200 250 300
% l
n c
um
ula
tive
dru
g r
emai
nin
g
ln (
10
0-Q
t)
t (min)
173
3.5.3. Drug Release Models
Fig. 3.120: Hixson-Crowell kinetics of Tramadol HCl from the sample E1 at pH 8. 0.
Fi.g 3.121: Hixson-Crowell kinetics of Tramadol HCl from the sample E3 at pH 8.0.
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
0 50 100 150 200
(100
-Qt)
1/3
t (min)
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
0 50 100 150 200 250 300
(10
0-Q
t)1/3
t (min)
174
Fig. 3.122: Hixson-Crowell kinetics of Tramadol HCl from the sample TE5 at pH 8.0.
Fig. 3.123: Hixson-Crowell kinetics of Tramadol HCl from the sample TE6 at pH 8.0.
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
0 100 200 300 400 500
(10
0-Q
t)1/3
t (min)
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
0 100 200 300 400 500
(10
0-Q
t)1/3
t (min)
175
Fig. 3.124: Hixson-Crowell kinetics of Tramadol HCl from the sample TD5 at pH 8.0.
Fig. 3.125: Hixson-Crowell kinetics of Tramadol HCl from the sample TNE5 at pH 8.0.
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
0 20 40 60 80 100 120
(10
0-Q
t) 1
/3
t (min)
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
0 20 40 60 80
(10
0-Q
t) 1
/3
t (min)
176
Fig .3.126: Hixson-Crowell kinetics of Tramadol HCl from the sample TND4 at pH 8.0.
Fig. 3.127: Higuchi kinetics of Tramadol HCl from the sample E1 at pH 8.0.
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
0 10 20 30 40 50
(10
0-Q
t) 1
/3
t (min)
0
10
20
30
40
50
60
70
80
0 5 10 15
Qt
t1/2
177
Fig. 3.128: Higuchi kinetics of Tramadol HCl from the sample E3 at pH 8.0.
Fig. 3.129: Higuchi kinetics of Tramadol HCl from the sample TE1 at pH 8.0.
0
10
20
30
40
50
60
70
80
0 5 10 15 20
Qt
t 1/2
0
10
20
30
40
50
60
70
80
0 5 10 15 20
Qt
t 1/2
178
Fig. 3.130: Higuchi kinetics of Tramadol HCl from the sample TE2 at pH 8.0.
Fig. 3.131: Higuchi kinetics of Tramadol HCl from the sample TE3 at pH 8.0.
0
10
20
30
40
50
60
70
80
0 5 10 15 20 25
Qt
t 1/2
0
10
20
30
40
50
60
70
80
0 5 10 15 20 25
Qt
t 1/2
179
Fig. 3.132: Higuchi kinetics of Tramadol HCl from the sample TD1 at pH 8.0.
Fig. 3.133: Higuchi kinetics of Tramadol HCl from the sample TD2 at pH 8.0.
-10
0
10
20
30
40
50
60
70
80
0 2 4 6 8 10 12
Qt
t 1/2
0
10
20
30
40
50
60
70
80
0 2 4 6 8 10 12
Qt
t 1/2
180
Fig. 3.134: Higuchi kinetics of Tramadol HCl from the sample TD3 at pH 8.0.
Fig. 3.135: Higuchi kinetics of Tramadol HCl from the sample TNE1 at pH 8.0.
0
10
20
30
40
50
60
70
80
0 2 4 6 8 10
Qt
t 1/2
0
10
20
30
40
50
60
0 1 2 3 4 5 6 7
Qt
t 1/2
181
Fig. 3.136: Higuchi kinetics of Tramadol HCl from the sample TNE2 at pH 8.0.
Fig. 3.137: Higuchi kinetics of Tramadol HCl from the sample TNE4 at pH 8.0.
0
10
20
30
40
50
60
70
80
0 2 4 6 8
Qt
t 1/2
0
10
20
30
40
50
60
70
80
0 2 4 6 8
Qt
t 1/2
182
Fig. 3.138: Higuchi kinetics of Tramadol HCl from the sample TND1 at pH 8. 0.
Fig. 3.139: Higuchi kinetics of Tramadol HCl from the sample TND2 at pH 8.0.
0
10
20
30
40
50
60
70
80
0 2 4 6 8
Q t
t 1/2
0
10
20
30
40
50
60
70
80
0 1 2 3 4 5
Qt
t1/2
183
Fig. 3.140: Higuchi kinetics of Tramadol HCl from the sample TND3 at pH 8.0.
Fig. 3.141: Korsemeyer-Peppas kinetics of Tramadol HCl from the sample TE5 at pH
8.0.
0
10
20
30
40
50
60
70
80
0 2 4 6 8
Q t
t 1/2
-2.5
-2
-1.5
-1
-0.5
0
0 2 4 6 8
ln(Q
t/Q
e)
ln t
184
Fig. 3.142: Korsemeyer-Peppas kinetics of Tramadol HCl from the sample TD5 at pH
8.0.
Fig. 3.143: Korsemeyer-Peppas kinetics of Tramadol HCl from the sample TNE5 at pH
8.0.
-3
-2.5
-2
-1.5
-1
-0.5
0
0 1 2 3 4 5
ln (
Qt/Q
e)
ln t
-1.6
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
0 1 2 3 4
ln Q
t/Q
e
ln t
185
Fig. 3.144: Korsemeyer-Peppas kinetics of Tramadol HCl from the sample TND4 at pH
8.0.
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
0 1 2 3 4
ln Q
t/Q
e
ln t
186
3.6. Network Parameter
When a cross-linked polymer is placed in a good solvent, rather than dissolving
completely, it will absorb a portion of solvent and subsequently swells. To
characterize polymers, swelling is a simple and low cost technique. That is why; the
equilibrium swelling values of these hydrogels were used to determine the influence
of concentration and nature of EGDMA, DEGDMA and AA and pH, the major
factors affecting swelling in these gels, on their network parameters. The following
well known Flory-Rehner equation was used to calculate Mc, the molecular weight
between the cross links, one of the important parameters characterizing the cross
linked parameters:
Mc= -dp Vs / (v2, s1/3- v2, s /2) [ln (1- v2, s) + v2, s +χ v2, s 2] (3.3)
Whereas, the following equation was applied to calculate the volume fraction v2,s
v2, s = [1+ dp/ds (Wa/Wb-1)]-1 (3.4)
Where, dp and ds (1g/mL) stand for the densities of the polymer and the solvent
respectively. The density of the polymer was determined by the solvent displacement
method using n-hexane as a non-solvent. Mb and Ma represent the masses of xerogel
and the hydrogel after equilibrium swelling has been attained. Vs stand for the molar
volume of the solvent (18.0 mL/mol) and χ is the Flory-Huggins polymer-solvent
interaction parameter. To study the effect of pH of the medium on the network
parameters, equilibrium swelling results of poly (AA-co-MA-co-VA) hydrogels and
NiPAAm gels were used to determine Mc values at various pH values (1.0 – 8.0) at
37oC. Experimental values of Mc and other related parameters were tabulated in the
tables 3.10 to 3.14 for various hydrogels.
187
It is clear from the tables 3.10 and 3.12 that Mc value increased with increasing cross-
linking ratio and volume fraction of the swollen hydrogel. On the other hand, with the
concentration of acrylic acid, the molecular weight between the cross-links increased
with decreased cross-linking ratio and volume fraction of the polymer, as shown in
the tables 3.11 and 3.13. Moreover, the effect of nature of the cross-linker was also
estimated and it was found that Mc value was higher in the hydrogels cross-linked
with DEGDMA, as tabulated in the table 3.14. Additionally the effect of the external
medium pH on the network parameters was also investigated and it was found that, as
the pH was raised, the molecular weight between the cross links increased
significantly. For example Mc value of the sample AE4 reached 54450 g/mol from 63
g/mol, and 81368 g/mol from 113 g/mol for AD4 when the pH was changed from 1.0
to 8.0. The effect was even more pronounced when the least amount of the cross-
linker was used, changing from 65 to 132314 g/mol for poly (MA-co-VA-co-AA)
cross-linked with EGDMA and from 96 to 122927 g/mol for poly (MA-co-VA-co-
AA) cross-linked with DEGDMA, when the pH increased from 1.0 to 8.0. This
relatively higher change in Mc can be attributed to the fact that as the pH of the
swelling medium changes from 1.0 to 8.0, the –COOH groups attached to the polymer
chains ionize completely to produce charged carboxylate, –COO-, groups and H3O+
counter ions within the hydrogel. Since free counter ions remain inside the hydrogel
to neutralize the fixed charges on the polymer chain, a high osmotic pressure is
resulted which causes enhanced swelling percentage. Moreover, carboxylate groups
experience electrostatic repulsive force, which are responsible for the relaxation of the
polymer network. Same effect is shown by NiPAAm gels, as shown in table 3.14. It
was also determined that Mc changed depending upon the composition of the
hydrogel. Mole percent of ionizable monomer, AA, based on their total monomer, for
188
example AE1, AE2, AE3 and AE4 were 0.6, 17.6, 32 and 40 mol% respectively. Due to
the presence of the highest number of ionizable groups, the sample AE4 swelled to the
greatest extent and owing to this swelling behavior, its Mc value was found to be
54450 g/mol which is the highest one as compared to those of other related samples.
Similarly, the sample AD4 exhibited the highest Mc value of 81368 g/mol at pH 8.0.
As for as the effect of the cross-linking agent concentration is concerned, it was found
that the molecular mass between the cross-links was decreased from 132314 g/mol to
1826 for poly (MA-co-VA-co-AA) cross-linked with EGDMA, and from 122927
g/mol to 1683 g/mol for poly (MA-co-VA-co-AA) cross-linked with DEGDMA, with
increase in the concentration of the cross-linker, at pH 8.0. As already discussed, the
cross-linker increases the crosslink ratio of the co-polymeric hydrogels, thus
increasing the volume fraction and decreasing the Mc.
Characterizing cross linked polymers, is another significant parameter called cross
linking density, q
q= Mr /Mc (3.5)
Where Mr is the molar mass of the repeat unit and is calculated as
Mr = mVA MVA + mMA MMA+mAA MAA/ mVA+mMA+mAA (3.6)
Here mAAm, mMA and mAA are the masses of the monomers VA, MA and AA;
whereas, MVA, MMA and MAA are the molar masses of the monomers VA, MA and
AA respectively. In NiPAAm gels, the monomer VA was replaced with n-
isopropylacrylamide (NiPAAm), and the corresponding values were used to calculate
the cross-linking density.
189
The mesh size, ξ, describing the available space for solute transport within the
polymer network, is also an important parameter in analyzing cross linked polymers
and was calculated using following equation:
ξ = v2, s-1/3 (2Mc/Mr) 1/2 Cn1/2l (3.7)
Where, Mr represents the molecular weight of the repeating unit, l, the C-C bond
length (1.54 Ǻ for C-C) and Cn, the characteristic ratio taken 6.7 for AA (Gudman and
Peppas, 1995). ξ and q values for these hydrogel systems are represented in table 3.10
to table 3.14, as a function of pH and composition of hydrogels.. It is indicated that as
the swelling of the medium increased with pH, the values of ξ increased from 6.83 to
28093 Ǻ for the sample E1. Thus, with pH, greater swelling resulted in more space
available between the cross-links. It is also noticed that the cross linking decreased
with increasing external medium pH, again, indicating the availability of more space
for solute transportation. Moreover, the concentration of AA exhibited marked effect
on mesh size at all the pH of the media especially at pH 8.0, the value increased from
6.44Ao for A1 to 223.7 Ǻ for A4.
190
Table 3.10: Net work parameters determined from equilibrium swelling studies for
the poly (MA-co-VA-co-AA) for varying concentration of EGDMA in various pH
media at 37oC.
Sample Cross linking ratio Volume fraction Molecular weight Cross link density Mesh size
(102) (V2, s) (Mc) (q) (ξ)
_______________________________________________________________________________
pH =1
E1 0.702 0.826 65 1.2 6.83
E2 3.6 0.85 65 1.2 6.67
E3 7.26 0.877 54 1.5 5.56
E4 10.9 0.91 45 1.8 4.58
pH =4
E1 0.702 0.9 38 2.13 3.9
E2 3.6 0.9 45 1.8 4.59
E3 7.26 0.91 42 1.9 4.27
E4 10.9 0.91 45 1.8 4.58
pH =5.5
E1 0.702 0.195 14162 0.0057 2406
E2 3.6 0.41 1286 0.063 171
E3 7.26 0.55 442 0.18 53
E4 10.9 0.634 274 0.3 31.4
pH =7.4
E1 0.702 0.319 2632 0.031 380
E2 3.6 0.430 1085 0.075 142.5
E3 7.26 0.433 1066 0.076 139
E4 10.9 0.480 791 0.044 100
pH =8
E1 0.702 0.10 132314 0.00061 28093
E2 3.6 0.19 18126 0.0045 3106
E3 7.26 0.26 6298 0.0129 969
E4 10.9 0.38 1826 0.044 248
191
Table 3.11: Net work parameters determined from equilibrium swelling studies of
for the poly (MA-co-VA-co-AA) for varying concentration of AA, cross-linked with
EGDMA in various pH media at 37oC.
Sample Cross linking ratio Volume fraction Molecular weight Cross link density Mesh size
(102) (V2, s) (Mc) (q) (ξ)
___________________________________________________________________________________
pH =1
AE1 6.6 0.93 31 2.87 3.40
AE2 6 0.92 39 2.26 3.87
AE3 5.13 0.90 47 1.83 4.32
AE4 4.3 0.86 63 1.3 5.21
pH =4
AE1 6.6 0.925 32 2.78 3.45
AE2 6 0.91 43 2.05 3.95
AE3 5.13 0.90 47 1.83 4.17
AE4 4.3 0.88 57 1.44 4.90
pH =5.5
AE1 6.6 0.85 58 1.53 4.80
AE2 6 0.84 71 1.24 5.37
AE3 5.13 0.592 585 0.147 15.59
AE4 4.3 0.445 997 0.08 25.89
pH =7.4
AE1 6.6 0.89 50 1.78 4.41
AE2 6 0.65 232 0.379 10.53
AE3 5.13 0.5 655 0.131 19.71
AE4 4.3 0.48 765 0.107 35.91
pH =8
AE1 6.6 0.79 98 0.9 6.44
AE2 6 0.65 289 0.304 11.81
AE3 5.13 0.30 3989 0.021 57.36
AE4 4.3 0.27 54450 0.0015 223.7
192
Table 3.12: Net work parameters determined from equilibrium swelling studies for
the poly (MA-co-VA-co-AA) for varying concentration of DEGDMA in various pH
media at 37oC.
Sample Cross linking ratio Volume fraction Molecular weight Cross link density Mesh size
(102) (V2, s) (Mc) (q) (ξ)
pH =1
D1 1.2 0.769 96 0.83 6.75
D2 6 0.745 124 0.64 7.75
D3 11.6 0.745 131 0.61 7.97
D4 22 0.88 75 1 5.7
pH =4
D1 1.2 0.85 56 1.43 5
D2 6 0.88 51 1.57 4.7
D3 11.6 0.884 52 1.54 4.74
D4 22 0.886 53 1.5 4.78
pH =5.5
D1 1.2 0.19 15853 0.00 138.16
D2 6 0.215 12250 0.006 116.57
D3 11.6 0.457 940 0.085 25
D4 22 0.5089 643 0.124 20
pH =7.4
D1 1.2 0.428 960 0.08 26
D2 6 0.470 893 0.09 24.26
D3 11.6 0.6266 285 0.028 12.446
D4 22 0.698 186 0.43 9.7
pH =8
D1 1.2 0.104 122927 0.0006 249.36
D2 6 0.227 10186 0.008 104.38
D3 11.6 0.3276 3094 0.026 50.90
D4 22 0.391 1683 0.047 35.4
193
Table 3.13: Net work parameters determined from equilibrium swelling studies of
for the poly (MA-co-VA-co-AA) for varying concentration of AA, cross-linked with
DEGDMA in various pH media at 37oC.
Sample Cross linking ratio Volume fraction Molecular weight Cross link density Mesh size
(102) (V2, s) (Mc) (q) (ξ)
___________________________________________________________________________________
pH =1
DA1 1.2 0.891 44 1.932 4.22
DA2 6 0.855 58 1.448 4.94
DA3 11.6 0.800 84 0.988 6.24
DA4 22 0.754 113 0.7168 7.32
pH =4
DA1 1.2 0.95 41 2.073 4
DA2 6 0.98 17 4.941 2.5
DA3 11.6 0.767 103 0.806 6.87
DA4 22 0.72 59 1.373 5.58
pH =5.5
DA1 1.2 0.90 41 2.073 4.06
DA2 6 0.85 60 1.46 5.04
DA3 11.6 0.50 585 0.142 19.21
DA4 22 0.48 657 0.123 20.60
pH =7.4
DA1 1.2 0.94 29 2.931 3.36
DA2 6 0.90 42 2 4.137
DA3 11.6 0.54 438 0.189 3.63
DA4 22 0.48 657 0.123 5.11
pH =8
DA1 1.2 0.90 41 2.073 4.06
DA2 6 0.79 88 0.954 6.25
DA3 11.6 0.42 1098 0.076 27.40
DA4 22 0.223 81368 0.001 290
194
Table 3.14: Net work parameters determined from equilibrium swelling studies for
the NiPAAm hydrogels in various pH media at 37oC.
Sample Cross linking ratio Volume fraction Molecular weight Cross link density Mesh size
(102) (V2, s) (Mc) (q) (ξ)
___________________________________________________________________________________
pH =1
Ne 3.84 ----- 96 0.83 6.75
Nd 3.73 0.4732 124 0.64 7.75
pH =4
Ne 3.84 ----- 96 0.83 6.75
Nd 3.73 0.4658 124 0.64 7.75
pH =5.5
Ne 3.84 0.3415 96 0.83 6.75
Nd 63.73 0.3226 124 0.64 7.75
pH =7.4
Ne 3.84 0.2989 96 0.83 6.75
Nd 3.73 0.2765 124 0.64 7.75
pH =8
Ne 3.84 0.1732 96 0.83 6.75
Nd 3.73 0.0811 124 0.64 7.75
195
3.7. Rheological Studies
3.7.1. Flow Curves
The ter-polymeric hydrogels with the varying concentration of acrylic acid were
considered as control samples. Their rheograms were obtained at different
temperatures (10, 20, 30 and 37oC). At all the temperatures except 37oC, the highest
shear stress is observed in A3 hydrogels, whereas at 37oC the sample A2 is leading.
Again, it is observed from Figs.3.145-3.148 that the lowest shear stress is observed in
case of A1 which is having the least concentration of acrylic acid. It can be estimated
that shear stress values increase roughly with the increase in the concentration of
acrylic acid up to a certain stoichiometric limit. According to S. Chatterjee and H. B.
Bohidarm, regardless of the chemical or physical nature of the hydrogels, all the gels
have a threshold polymer concentration, called the overlap concentration, C* above
which the networks are formed signaling the onset of the gelation (Rudraraju and
Wyandt, 2005). In present studies, the anomalous behavior of A4 may be explained in
the way that the optimum amount of acrylic acid that can be polymerized with the
selected concentrations of the other two monomers is lying in A3 whereas in the
sample A4, the concentration of acrylic acid exceeds the threshold concentration or
overlap concentration, C* and remains un-polymerized in the ter-polymeric chains of
the hydrogel system. These free acrylic acid monomers may combine to form poly
acrylic acid macro-molecules, leading to the improper alignment of variety of
polymeric chains which ultimately cause a decline in the values of shear stress and
increase in the viscosity. This is clear from the viscosity-shear rate rheograms, shown
in the figs 3.149-3.153. Every curve exhibits a power law relationship between
viscosity (η) and shear rate (γ). It is clear that non- Newtonian flow regime (a constant
viscosity regime) is observable either at higher or lower shear rate (γ). The presence
196
of a low shear rate plateau can be attributed to the shorter relaxation times of the gels.
At low shear rates, initially, the viscosity increases at all temperature and
concentrations of acrylic acid. The chain closeness may result in the closure of free
carboxylic groups, introducing the inter-polymer as well as intra-polymer hydrogen
bonding in the gel structure. But very soon at higher shear rates, the repulsions appear
among similarly charged polar ends, decreasing the viscosity with a greater steep
which appeared in the rheograms. Moreover, it is assumed that at higher shear rate,
the existing hydrogen bonds are broken down and as a result, hydrogel chain
segments deform and align themselves in the direction of flow and so the topical gels
exhibit pseudo plastic behavior.
Fig. 3.145: Shear stress vs shear rate at 10oC.
0
500
1000
1500
2000
2500
3000
3500
0 10 20 30 40
shea
r st
res
(Pa)
shear rate(s-1)
A1
A2
A 3
A 4
197
Fig. 3.146: Shear stress vs shear rate at 20oC.
Fig. 3.147: Shear stress vs shear rate at 30oC.
0
200
400
600
800
1000
1200
1400
1600
1800
2000
0 10 20 30 40
shea
r st
ress
(P
a)
shear rate (s -1)
A1
A2
A3
A4
0
200
400
600
800
1000
1200
0 10 20 30 40
shea
r st
ress
(P
a)
shear rate (s-1)
A1
A2
A3
A4
198
Fig. 3.148: Shear stress vs shear rate at 37oC.
Fig. 3.149: Frequency- dependent property of terpolymeric hydrogels at 10oC.
0
100
200
300
400
500
600
700
800
900
1000
0 10 20 30 40
shea
r st
ress
(pa)
shear rate(s -1)
A1
A2
A3
A4
1
10
100
1000
0.01 0.1 1 10 100
visc
osi
ty (
η)
shear rate, frequency (s -1)
ɳ1
ɳ2
ɳ3
ɳ4
199
Fig. 3.150: Frequency- dependent property of terpolymeric hydrogels at 20oC.
Fig. 3.151: Frequency- dependent property of terpolymeric hydrogels at 30oC.
1
10
100
0.01 0.1 1 10 100
visc
osi
ty (
η)
shear rate, frequency ( s-1)
ɳ1
ɳ2
ɳ3
ɳ4
1
10
100
0.01 0.1 1 10 100
visc
osi
ty(η
)
shear rate, frequency (s-1)
ɳ1
ɳ2
ɳ3
ɳ4
200
Fig. 3.152: Frequency- dependent property of terpolymeric hydrogels at 37oC.
1
10
100
0.01 0.1 1 10 100
visc
osi
ty (
ɳ)
Shear rate, frequency (s-1)
ɳ1 (A1)
ɳ2 (A2)
ɳ3 (A3)
ɳ4 (A4)
201
3.7.2. Yield Stress
Yield stress is the minimum stress that must be applied before the proper alignment of
molecules of material required to start to flow (Barners, 1999). It is considered as a
good indicator for characterization of semisolid systems, affecting their spreadibility
and retention (Keiweg et al., 2004). In general, low values of the yield stress increase
spreadibility but decrease retention. The cross-linked hydrogel structures where
individual particles are closely packed with their neighbors produce a yield stress in
the gel systems. In this study, the rheological measurements were experienced in the
ter-polymeric hydrogels without any chemical cross-linker. The yield stress exhibited
by these gels is actually due to intermolecular and intra-molecular hydrogen bonding
and other valence forces. Importance of hydrogen bond as one of the molecular
interactions on gel formation is also discussed by different authors (Guan et al., 2010;
Khutoryanskiy etal. 2004). Different methods were explored to measure the yield
stress of these materials. In order to calculate the yield stress τo, Attapattu et al. (1990)
and Naguyen and Boger (1983) performed extrapolation of the flow curves at the low
shear rates (γ = 0.1 s−1) to zero shear rate to obtain the yield stress values. Using the
same method, we determined the yield stress values for the hydrogels. Although, the
correlation coefficient is excellent yet all the samples show negative yield stress
values having no physical meanings. Two other methods were applied to measure the
yield stress (Table 3.15). The Bingham yield stress (τB) was determined using the
Bingham equation for shear stress (τ = τB + μBγ) (Bird et al., 1987). The τ-γ
relationship at low shear rates (γ = 0.01 to 15 s−1) was found to be linear. By extra
plotting this linear relationship to zero shear rates, the Bingham yield stress (τB) was
determined the intercept. On the other hand, the third method was the application of
modified Bingham equation (τ = τMB + μMBγ + Cγ 2) (Yahia and Khayat, 2001). The
202
yield stress determined from the second order equation is approximately half the
corresponding Bingham yield stress (τB) values for all the hydrogel samples at all the
temperatures studied. The overall Bingham yield stress (τB) values range from 12.24
to 68.28 Pa whereas the values of the yield stress from Modified Bingham equation
(τMB) are between 5.836 and 42.12 Pa. The literature survey provides an information
about the yield stress values for the similar gels used for the drug delivery in the same
way as our hydrogels may be used. Kim et al. (2003) reported the (τB) values for
carbapol gels (Acrylic acid polymers cross linked with alkenyl polyether or divinyl
glycol) lying in the range from 10 to 66 Pa which is very closed to our (τB) values and
also support our hydrogel systems suitable to be used in the same way as they have
claimed. Again, it is ascribed by other authors that the yield stress values determined
by Bingham model are much higher than those determined by the other methods (Kim
et al., 2003; Larson, 1999). Our findings summarized in the table 3.9 are in agreement
with the literature. Moreover, a clear trend in the values of (τB) can be noticed at least
at two different temperatures (10 and 37oC). The values gradually increase up to the
threshold concentration of AA content (A3). It can be concluded that with the AA
content in the polymer networks, the gels are acquiring better retention time at body
temperature to facilitate the drug release at specific area. The sample A4 is behaving
exceptionally as happened in the case of flow curve interpretation too. The same
arguments may explain the distinct behavior of A4.
Table 3.15: Rheological Properties of Hydrogels: Theremorheological Propeties.
sample Power law index (n) Consistency (K) (Pa.sn) Correlation coefficient (R2)
10oC 20oC 30oC 37oC 10oC 20oC 30oC 37oC 10oC 20oC 30oC 37oC
A1 0.935 0.830 0.689 0.648 77.42 129.7 107.3 36.04 0.994 0.980 0.952 0.945
A2 0.715 0.928 0.850 0.813 153.5 59.61 60.17 60.51 0.963 0.994 0.996 0.993
A3 0.830 0.834 0.783 0.690 225.2 165.9 146.3 64.50 0.992 0.990 0.974 0.927
A4 0.896 0.838 0.816 0.811 111.7 89.95 75.04 58.98 0.996 0.991 0.992 0.989
203
3.7.3. Temperature dependence of Viscosity
Steady state viscosities of all the samples were measured for a temperature range
covering 10-37oC. The flow curves for various gel samples are shown in the Figs.
3.153-3.156. It is apparent from the figures that acrylic acid gels exhibit a remarkable
stability towards temperature. No appreciable change in viscosity appears with change
in temperature for a particular shear rate. Weak temperature dependency of acrylic
acid hydrogels is also supported by literature (Nae and Reichert, 1992). Moreover, the
temperature stability for the sample A2 continues even at higher shear rate. The
temperature insensitivity in A2 can be explained in terms of elastic or cross-link
structure of the hydrogels. Thermal fluctuation or increased thermal mobility of
polymer chain strands may be suppressed by more cross-link junctions in A2 but at the
same time is facilitated by more repulsion among ionized carboxylic groups in A4
assumed to be having acrylic acid units exceeding the balanced concentration. Thus,
viscosity does not change appreciably in A2 however, A4 being more active exhibits a
distinct change in viscosity with respect to temperature at higher rates. For different
temperatures, the flow curves were fitted with Ostwald’s model, τ=K γn. The fluidity
index (n) in this equation represents pseudo plastic or shear thinning extent of the
fluids as it exhibits departure from Newtonian behavior (n=1 for Newtonian fluids).
The interpretation of n can be used to analyze the rate of change of structure with
shear rate (γ) (Ramirez et al., 1999). The hydrogel network structure can be changed
due to deformation induced changes in alignment of macromolecular chain segments
and breakdown of particle aggregates, formed by hydrogen bonds or van der Waal
interactions (Alina et al., 2011). In case of stronger hydrogels the value of n will be
lower because of strengthened non-covalent forces of attraction between neighboring
particles, which increase life time of temporary entanglement junctions. As indicated
204
in the Table 3.10, the values of n lie between 0.715-0.935 at 10oC, 0.8-0.928 at 20oC,
0.689-0.850 at 30oC and 0.648-0.813 at 37oC (Table 3.10). For all the gel samples
investigated, the fluidity index (n) values decrease reasonably with the increase in the
temperatures, with the exception of A1 at 20oC and 30oC. So it can be concluded that
gels are becoming stronger at higher temperatures, facilitating the jellification of the
drug delivery system on the skin with a body temperature of 37oC (Fig. 3.156). At any
particular shear rate (γ=10 s-1), the viscosities can be used for quantifying the
temperature dependency of viscosity applying Arrhenius (Arrhenius- Frenkel- Eyring)
type of relations and for determination of physical processes responsible for the
observed changes. The Arrhenius formula considers the exponential form of
temperature dependency (Fergusen and Kemblowski, 1992). η = A exp (Eγ/RT)
Where Eγ stands for the activation energy of the flow process at the constant shear
rate, A is pre-exponential factor, T represents absolute temperature and R is the gas
constant. Fig. 3.157 shows the Arrhenius modeling of the exponential data for all the
four hydrogel samples. From the Fig. 3.157, the activation energies (Eγ) of A1, A2, A3
and A4 samples were estimated to be 29, 31, 38 and 23 kJ/mol with a correlation
factor value of 0.831, 0.949, 0.906 and 0.992 respectively. The Eγ increases from A1
to A3 and then decreases for the sample A4 at a particular shear rate. The increase in
the values of Eγ in first three samples can be explained in terms of a gradual increase
in the polymer chain rigidity and intermolecular forces of attraction based on
hydrogen bonding; the same argument has been used by other authors too (Islam et
al., 2004). However, the exceptional behavior of A4 can be attributed to the loss of
corresponding chain rigidity due to the repulsion among ionized carboxylic units thus
making it more active and more sensitive towards the applied temperature.
205
Fig. 3.153: Steady state viscosity of A1 as a function of shear rate at different
temperatures.
Fig. 3.154: Steady state viscosity of A2 as a function of shear rate at different
temperatures.
0
20
40
60
80
100
120
0 5 10 15 20 25
visc
osi
ty(P
a.s)
shear rate(ᵞ)
η2 ( 20oC)
η2 ( 30oC)
η2 ( 40oC)
0
50
100
150
200
250
300
350
0 5 10 15 20 25
visc
osi
ty (
Pa.
s)
shear rate (γ)
ɳ1(10oC)
ɳ1(20oC)
ɳ1(30oC)
ɳ1(40oC)
206
Fig. 3.155: Steady state viscosity of A3 as a function of shear rate at different
temperatures.
Fig. 3.156: Steady state viscosity of A4 as a function of shear rate at different
temperatures.
0
50
100
150
200
250
300
350
400
450
0 5 10 15 20 25
visc
osi
ty (
Pa.
s)
shear rate(γ)
ɳ3(10oC)
ɳ3(20oC)
ɳ3(30oC)
ɳ3(40oC)
0
20
40
60
80
100
120
140
160
180
0 5 10 15 20 25
visc
osi
ty (
Pa.
s)
shear rate(ᵞ)
ɳ4(10oC)
ɳ4(20oC)
ɳ4(30oC)
ɳ4(40oC)
207
Fig. 3.157: Modeling of viscosities of hydrogels samples at shear rate of 10 s-1 using
Arrhenius equation.
0
1
2
3
4
5
6
0.0031 0.0032 0.0033 0.0034 0.0035 0.0036
ln η
T -1 (K-1)
lnη1
lnη2
lnη3
lnη4
208
3.7.4. Flow curve Modeling
The flow behavior of the hydrogels is compared with the predictions of some well-
known constitutive models to determine their validity. Two forms of Ostwald’s model
i.e. τ=Koγ n and η=Koγ n-1 was applied to modulate the flow data: where Ko is often
known as the consistency coefficient. This represents the overall range of viscosities
across the part of the flow curve that is modeled. The exponent n is called the Power
Law Index or Rate Index or the Fluidity Index. For a shear thinning fluid, the value of
n should be 0<n<1. The more shear thinning the product, the closer is the value of n to
0. From the τ or η against shear rate (γ) plot at different temperatures (10, 20, 30 and
37oC), shown in Figs. 3.158-3.165, the magnitude of n can be estimated and are given
in the Table 3.10. The table clearly indicates that these hydrogels (A1, A2, A3 and A4)
are showing the shear thinning behavior according to the Ostwald’s model. However,
the Ostwald’s model assumes no yield stress, which is not certainly the case for these
hydrogel systems. As for as the consistency coefficient (Ko) is considered, it is clear
from the Table 3.10 that the sample A3 has the highest consistency at all the
temperatures except 37oC. Moreover, it is noted in the Table 3.10 that the consistency
coefficient (Ko) increases with increasing AA content up to A3, at least at 10 and
37oC, and lowers with increasing temperature for A3 and A4 formulations. The
consistency coefficient values are ascribed to enhanced polymeric entanglements in
the sample A3 which also agrees with the previous interpretation of the flow curves.
In order to strengthen the above discussion, the rheological data were modeled
applying Bingham model as well as Modified Bingham model. The Bingham model is
presented as τ = τB + μγ. It has two parameters; yield stress τB and plastic viscosity μ.
Applying this model at low shear rates (up to 31.7 s−1), a good linear relationship is
observed between τ and γ (Table 3.16). In all the cases, a positive yield stress is
209
indicated. Again, it is clear that at most of the temperatures, again the sample A3
shows the highest yield stress values which are in strong agreement with the highest
consistency coefficient values for the same sample A3. The modified Bingham model
(τ=τMB + μMBγ+Cγ 2) (Yahia and Khayat, 2001) has been applied at low shear rates
(up to 31.7 s-1) to investigate the yield stress of the hydrogels at different
temperatures. All the samples exhibit an excellent fit to the model at all the
temperatures at low shear rates. In the case of the yield stress, a trend similar to that
according to the Bingham model is shown by the modified Bingham model. However,
the yield stress is half the corresponding value in the Bingham model as has been
discussed earlier. Considering the whole range of shear rate (100 s-1) , the flow curve
modeling for gel samples at 37oC shows that the Modifird Bingham model can
explain the yield stress, shear thinning behavior of the hydrogel and all the other
parameters having some physical meaning covering the overall flow behavior of the
ter-polymeric hydrogels.
210
Table 3.16: Rheological Properties of Hydrogels: Application of different models to
calculate the yield stress values at low shear rate ( up to 14.7 s-1).
Temperature Sample Atapattu method Bingham model Modified Bingham
model
R2 τo R2 τo R2 τo
10oC A1 0.999 -0.086 0.972 23.8 0.985 11.43
A2 0.999 -0.955 0.966 42.95 0.974 28.29
A3 0.999 -0.181 0.988 60.88 0.993 42.12
A4 0.999 -0.365 0.996 17.19 0.999 8.121
20oC A1 0.999 -0.188 0.953 50.92 0.988 26.26
A2 0.999 -0.162 0.967 19.48 0.995 5.836
A3 0.999 -0.816 0.983 47.40 0.996 24.66
A4 0.999 -0.220 0.991 22.25 0.997 12.96
30oC A1 0.997 -.502 0.906 52.11 0.939 38.83
A2 0.999 -0.025 0.994 12.24 0.999 6.438
A3 0.999 -0.811 0.911 68.28 0.965 39.32
A4 1 -0.017 0.985 21.64 0.995 12.81
37oC A1 0.999 -0.137 0.972 12.73 0.973 11.70
A2 0.999 -0.045 0.988 16.00 0.997 8.819
A3 0.999 -0.980 0.966 24.72 0.971 20.93
A4 0.999 -0.141 0.985 17.51 0.993 11.71
211
Fig. 3.158: Ostwald’s model fit at 10oC.
Fig. 3.159: Ostwald’s model fit at 20oC.
0
1
2
3
4
5
6
0 10 20 30 40
ln ɳ
Shear rate (s-1)
A1
A2
A3
A4
0
1
2
3
4
5
6
0 10 20 30 40
ln ɳ
Shear rate (s-1)
A1
A2
A3
A4
212
Fig. 3.160: Ostwald’s model fit at 30oC.
Fig. 3.161: Ostwald’s model fit at 37oC.
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
0 10 20 30 40
ln ɳ
Shear rate (s-1)
A1
A2
A3
A4
0
0.5
1
1.5
2
2.5
3
3.5
4
0 20 40 60 80 100 120
ln ɳ
Shear rate (s-1)
A1
A2
A3
A4
213
Fig. 3.162: Ostwald de-Waele model fit at 10oC.
Fig. 3.163: Ostwald de-Waele model fit at 20oC.
0
500
1000
1500
2000
2500
0 5 10 15 20
shea
r st
res
(Pa)
shear rate (s-1)
A1
A2
A3
A4
0
200
400
600
800
1000
1200
1400
1600
1800
0 5 10 15 20
shea
r st
ress
(P
a)
shear rate (s-1)
A1
A2
A3
A4
214
Fig. 3.164: Ostwald de-Waele model fit at 30oC.
Fig. 3.165: Ostwald de-Waele model fit at 37oC.
0
200
400
600
800
1000
1200
1400
0 5 10 15 20
shea
r st
ress
(P
a)
shear rate (s-1)
A1
A2
A3
A4
0
100
200
300
400
500
600
0 5 10 15 20
shea
r st
ress
(P
a)
shear rate (s-1)
A1
A2
A3
A4
215
Fig. 3.166: Bingham model fit at 10oC.
Fig. 3.167: Bingham model fit at 20oC.
0
500
1000
1500
2000
2500
0 5 10 15 20
shea
r st
res
(Pa)
shear rate (s-1)
A1
A2
A3
A4
0
200
400
600
800
1000
1200
1400
1600
0 5 10 15 20
shea
r st
ress
(P
a)
shear rate (s-1)
A1
A2
A3
A4
216
Fig. 3.168: Bingham model fit at 30oC.
Fig. 3.169: Bingham model fit at 37oC.
0
100
200
300
400
500
600
700
800
900
1000
0 5 10 15 20
shea
r st
ress
(P
a)
shear rate (s-1)
A1
A2
A3
A4
0
100
200
300
400
500
600
0 5 10 15 20
shea
r st
ress
(P
a)
shear rate (s-1)
A1
A2
A3
A4
217
Fig. 3.170: Modified Bingham model fit at 10oC.
Fig. 3.171: Modified Bingham model fit at 20oC.
0
200
400
600
800
1000
1200
1400
1600
1800
2000
0 5 10 15 20
shea
r st
res
(Pa)
shear rate (s-1)
A1
A2
A3
A4
0
200
400
600
800
1000
1200
1400
0 5 10 15 20
shea
r st
ress
(P
a)
shear rate (s-1)
A1
A2
A3
A4
218
Fig. 3.172: Modified Bingham model fit at 30oC.
Fig. 3.173: Modified Bingham model fit at 37oC.
0
100
200
300
400
500
600
700
800
900
0 5 10 15 20
shea
r st
ress
(P
a)
shear rate(s-1)
A1
A2
A3
A4
0
100
200
300
400
500
600
0 5 10 15 20
shea
r st
ress
(P
a)
shear rate (s-1)
A1
A2
A3
A4
219
Fig. 3.174: Application of Modified Bingham Model describing the overall flow
behavior of the acrylic acid ter-polymeric hydrogels at 37oC.
Conclusion
220
The chemically cross linked hydrogel copolymers comprised of a hydrophilic
monomer (AA) with MA, VA or NiPAAm have proven to be effective in controlling
the sorption of the swelling medium into the gel matrix. Copolymerizing the AA in
chemically cross linked hydrogel increased (1) the media penetration velocity through
the copolymers, (2) the change in disk volume during swelling, (3) the equilibrium
media content in the gel matrix, (4) and molecular weight between the cross links.
The effect was reversed when the concentration the cross-linker was changed in the
gel network structure. The pH of aqueous media showed a marked effect on the
dynamic as well as equilibrium swelling behavior of hydrogels. Increasing the media
pH enhanced the diffusion of swelling medium by increasing swell-ability of
hydrogels. This is a desirable attribute for a hydrogel when subjected to environments
of varying pH of human digestive tract. Diffusion models fitted to the experimental
data showed that the media diffusion rates through the copolymers were primarily
Fickian in acidic medium but non-Fickian in basic environment, in most of the cases
as shown by the values of the diffusion exponents. Furthermore, hydrogel mesh size is
of special significance in the drug release behavior because of the screening effect of
the hydrogel. So, the hydrogel mesh size should be large enough for the drug
molecules to pass through the hydrogel mesh. The mesh size range exhibited by most
of the gel systems is large enough for the most on peptide and protein drug molecules
will pass easily through the polymers.
As far as NiPAAm gels are considered, these hydrogels showed a volume phase
transition temperature greater than 32oC (the LCST of PNiPAAm). It was found that
the hydrophilic component AA shifted the LCST to the higher temperature and the
hydrophobic components such as MA, DEGDMA and EGDMA have provided a
necessary mechanical strength to resist against the peristaltic movement of the
221
stomach. Following the first order release kinetics, the release of Tramadol HCl from
most of the hydrogels is strongly influenced by the copolymer composition and the
amount of the drug loaded. Controlling the initial concentration of the drug loaded in
the polymer network structure allows tailoring of the release rate of the Tramadol
HCl.
It is concluded that these systems, most likely would prevent Tramadol HCl release in
the stomach, facilitating the drug release in the proximal part of gastrointestinal tract.
These findings indicate that the designed co-polymeric hydrogels are showing a
promising trend to be used as pH-modulated drug delivery systems.
Rheological characterization of systems designed for topical applications is important
because they can exert influence at technological level (entrapment of active and
auxiliary substances), at therapeutical level (rheological parameters can be correlated
with the composition of the system and therefore with their consistency and
bioavailability) and also on their stability and compliance. Rheological experiments
performed on the acrylic acid ter-polymeric hydrogels showed that the topical gels
exhibit a remarkable temperature dependency. Flow curves obtained at different
temperatures indicate acrylic acid hydrogels showing significant pseudo-plastic
behavior with a power law exponent ranging from 0.648 at 37oC to 0.935 at 10oC,
exhibiting a higher pseudo-plastic behavior at higher temperature. The temperature
dependency of the hydrogels can be explained well by Arrhenius model. Several
rheological techniques confirm that significant amounts of stress greater than the yield
stress values of the topical ter-polymeric hydrogels are required before the topical gels
start to flow. The yield stress values depend on the method used and range from 5.83
to 68.28 Pa. Comparison of the flow curves with the simple well-known constitutive
222
models were performed to estimate their validity. The visco-elastic nature of gel
systems with substantial yield strength suggests that such ter-polymeric gels may be
useful as topical and muco-adhesive delivery systems. The short relaxation time and a
remarkable temperature stability exhibited by gels having low acrylic acid
concentration make them suitable delivery systems requiring enhanced absorption in
short relaxation time.
Conclusively, the desirable pH and temperature sensitivity, suitable mechanical
behavior and the control on drug release mechanism indicate that the gels can
approach the target of colon saving themselves from the acidic medium and peristaltic
pressure of the stomach. So these systems may prove themselves very effective
targeted controlled drug delivery carriers. Moreover, the rheological behavior studies
of physically cross-linked hydrogels exhibit that these may be appropriate systems to
be used topically to release the drug on the target.
References
223
1. Adams, M., Lavasanifar A. and Kwon G. Amphiphilic block copolymers for
drug delivery. Journal of Pharmaceutical Sciences. 2003, 92, 1343-1355.
2. Afif A. E. and Grame M. Non-FickinTtransport in Polymers. J Rheol 2002,
46, 591-628.
3. Akkas P., Kavakh Y.Z. and Sen M. Investigation of Heavy Metal Ion
Adsorption, Characteristics of Poly (N,N Dimethylamino Ethylmethacrylate)
Hydrogels Separation Sci. Tech. 2007, 42, 1245-1254.
4. Albu M. G., Ghica M. V., Popa L., Leca M. and Trandafir V. Kinetics of In-
Vitro Release of Doxycyclin Hydrate from Collagen Hydrogels. Revue
Roumaine deChimie. 2009, 54, 373-379.
5. Alina O., Christina D.P., Mihaela V.J., Laidia M.P. and Lucian I. Rheological
Study of a Liposomal Hydrogel Based on Carbapol. Roman Biotech Lett.
2011, 16, 47-54.
6. Almeida H., Amaral M.H. and Lobão P. Temperature and pH Stimuli-
responsive Polymers and Their Applications in Controlled and Self-regulated
Drug Delivery. J. Applied Pharm. Sci. 2012, 02, 01-10.
7. Allcock H., Lampe F. and Mark J. Contemporary Polymer Chemistry. 3rd ed.
Pennsylvania: Prentice Hall, 2003.
8. Attapatu D.D., Chhabara R.P. and UhCherr D.H.T. Wall Effect for Spheres
Falling at Small Reynolds-number in a Viscoplastic Medium. J Non-
Newtonian Fluid Mech 1990, 38, 31-42.
9. Bajpai A.K., Shukla S.K., Bhanu S. and Kankane S. Responsive Polymers in
Controlled Drug Delivery. Prog Polym Sci 2008, 33, 1088-1118.
10. Bawa P., Pillay V., Choonara Y.E. and Toit L.C. Stimuli-responsive Polymers
and Their Applications in Drug Delivery. Biomed Mate. 2009, 4, 1-15.
224
11. Beebi D.J., Moore J.S., Bauer J.M., Yu Q., Liu R.H., Devadoss C. and Jo B.H.
Functional Hydrogel Structures for Autonomous Flow Control Inside
Microfluidic Channels. Nature 2000, 404, 588-590.
12. Bezerril L. M., deVascocelos C. L., Dantas T. N. C. Perira M. R. and Fonseca
J. L. Rheology of Chitosan-Kaolin Dispersions. Colloids and Surf. A. 2007,
287, 24-28.
13. Bird R.B., Armstrong R.C. and Hassager O. Dynamics of Polymer Liquids, 2nd
Ed.Wiley, New York 1987.
14. Brandrup J., Immergut E.H. and Grulk E.A. Polymer handbook. 4th Ed. Wiley,
New York, 1999.
15. Bussemer T., Peppas N.A. and Bodmeier R. Evaluation of Hydration and
Rupturing Properties of the Swelling Layer of a Rupturable Pulsatile Drug
Delivery System. Eur J Pharm Biopharm 2003, 56, 261-270.
16. Chasin M. and Langer R. (eds): Biodegradable Polymers as Drug Delivery
Systems, New York, Marcel Dekker, 1990.
17. Chein Y.W. Novel Drug Delivery Systems, New York, Marcel Dekker, 1982.
18. Chen J., Belvins W.E., Park H. and Park K. Gastric Retention Properties of
Superporous Hydrogels Composites. J. Control. Release. 2000, 64, 39-51.
19. Chen J., Belvins W.E., Park H., and Park K. Gastric Retention Properties of
Superporous Hydrogel Components. J. Control. Release. 2000, 64 (1-4), 39-
51.
20. Chen J. and Park K. Synthesis and Characterization of Superporous Hydrogel
Composites. J. Control. Release. 2000, 65 (1-2), 73-82.
225
21. Chen Q., Guan Y., Zhang Z.M., Peng Y.X. and Jian X.U. Cross-linking
Copolymerization of Acrylic acid and Multi-armed Cross-linkers, Chinese
chem. Let. 2001, 12, 1029-1032.
22. Dai Y.N., Li P., Zhang J.P., Wang A.Q. and Wei Q. A Novel pH-sensitive N-
succinyl chitosan/alginate Hydrogel Beads for Nifedipine Delivery. Biopharm.
Drug Disp. 2008, 29, 173-184.
23. Das A., Wahwa S. and Sri Vastawa A,K, Crosslinked Guargum Hydrogel
Discs for Colon-specufic Delivery of Ibuprofen: Formulation and in-vitro
Evaluation. Drug. Del. 2006, 13,139-142.
24. Desai S.J., Singh P., Simonelli A.P. and Higuchi W.I. Investigation of Factors
Influencing Release of Solid Drug Dispersed in Wax Matrices III. Quantitative
Studies Involving Polyethylene Plastic Matrices. J. Pharm. Sci. 1966, 55,
1230-1234.
25. Dhawan S., Medhi B. and Chopra S. Formulation and Evaluation of Diltiaze.
Hydrochloride Gels for the Treatment of Anal Fissures. Sci. Pharm. 2009, 77,
465-482.
26. Diez-Pena E., Fructose P., Frutose G., Quijada-Garrido I. and Barrales-Rienda
M. The Influence of the Copolymer Composition on Diltiazem Hydrochloride
Release from a Series of pH-sensitive Poly (N-isopropylacrylamide-co-
methacrylic acid)hydrogels. AAPS Pharm. Sci. Tech. 2004, 5, 1-3.
27. Dimitrov M., Lambov N., Shencov S. and Dossevav-Baranovski V.Y.
Hydrogels Based on Chemically Crosslinked Polyacrylic acid:
Biopharmaceutical Chacterization. Acta. Pharm. 2003, 53, 25-31.
226
28. Dogu Y. and Okay. Swelling-deswelling Kinetics of Poly (N-
isoprpylacrylamide) Hydrogels Formed in PEG Solutions. J. Appl. Polym. Sci.
2005, 99, 37-44.
29. Dorkoosh, F.A., Verhoef, J. C., Ambagts, M. H. C., Rafiee, T. M., Borchard,
G. and Junginger, H. E. oral delivery systems based on superporous hydrogels
polymers: release characteristics for the peptide drugs buserelin, octreotide
and insulin Euro. J. Pharma. Sci. 2002, 15, 433-439.
30. Dergunov S. and Mun G. Gamma-irradiated chitosan-polyvinyl pyrrolidone
hydrogels as pH-sensitive protein delivery system. Radiation Physics and
Chemistry. 2009, 78, 65-68.
31. El-hefian E. A., Nasef M. M., Yahaya A. and Khan R. A. Preparation and
Characterization of Chitosan/agar Blends. J. Chilean Chem. Soci. 2010, 55,
130-136.
32. Ende M. & Peppas N. Transport of ionizable drugs and proteins in crosslinked
poly(acrylic acid) and poly(acrylic acid-co-2-hydroxyethyl methacrylate)
hydrogels .1. Polymer characterization. J. Appl. Polym. Sci.1996, 59,673-685.
33. Fergusen J. and Kemblowski Z. Applied Fluid Rheology, Elsevier Applied
Science, London and New York 1992.
34. Fang J., Chen J., Lew Y. and Hu J. Temperature Sensitive Hydrogels
Composed to Chitosan and Hyaluronic acid as Injectable Carriers for Drug
Delivery. Eur. J. Pharm. Biopharm. 2008, 68, 626-636.
35. Fogueri L.R. and Singh S. Smart Polymers for Controlled Delivery of Proteins
and Peptides: A Review of Patents. Recent Pat. Drug Deliv. Formul. 2009, 3,
40-48.
227
36. Foss A.C., Goto T., Morishita M. and Pepas N.A. Development of Acrylic-
based Copolymers for Oral Insulin Delivery. Eur. J. Pharm. Biopharm. 2004,
57, 163-169.
37. Ganji F., Vasheghani-Farahani S. and Vasheghani-Farahani E. Theoretical
Description of Hydrogel Swelling: A review. Iranian Polym. J. 2010, 19, 375-
398.
38. Garala K. and Shah P. H. Influence of Crosslinking Agent on the Release of
Drug From the Matrix Transdermal Patches of HPMC/Eudragit RL 100
Polymer Blends. J. Macromol. Sci. Part A. 2010, 47, 273-281.
39. Gazzaniga A., Palugan L., Oppdi A. and Sangalli M.E. Oral Pulsatile Delivery
Systems Based on Swellable Hydrophilic Polymers. Eur. J. Pharm. 2008, 68,
11-18.
40. Gil E.S. and Hudson S.M. Stimuli-responsive Polymers and Their
Bioconjugates. Prog. Polym. Sci. 2004, 29, 1173-1222.
41. Gomez M. L., Williams R. J. J., Montejano H.A. and Previtali C.M. Influence
of the Ionic Character of the Drug on its Release Rate From Hydrogels Based
on 2-Hydroxymethylmethacrylate and Acrylamide Synthesized by Photo
Polymerization. eXPRESS Polym. Lett. 2012, 6(3), 189-197.
42. Grainger S.T. and El-Sayed M.E.H. Stimuli-sensitive Particles for Drug
Delivery. Biologically-responsive Hybrid Biomaterials: A Reference for
Material Scientists and Bioengineers. World Sci. Pub. Co. Pte Ltd, Danvers
2010, 171-189.
43. Guan L., Xu H. and Huang D. The Effect of Ions on Thermal Behaviors of
Poly (Acrylic acid)/Water Mixtures. Polym. (Korea) 2010, 34, 386-389.
228
44. Gudeman L.F. and Peppas N.A. pH-Sensitive Membranes from Poly (vinyl
alcohol)/Poly (acrylic acid) Interpenetrating Networks. J. Membr. Sci. 1995,
107, 239-248.
45. Gupta P., Vermani K. and Garg S. Hidrogels: From Controlled Release to pH-
responsive Drug Delivery. Drug Discov. Today. 2002, 7, 569-579.
46. Hekmat A., Barati A., Frahani E.V. and Afraz A. Synthesis and Analysis of
Swelling and Controlled Release Behavior of Anionic IPNs Acrylamide Based
Hydrogels. 2009, 56, 96-100.
47. Hamadan S., Hashim D.M.A., Ahmad M.B. and Abdullah W.F.W. Pakistan J
Applied Sci 2007, 3, 460.
48. Hennink W. and van Nostrum C. Novel crosslinking methods to design
hydrogels. Adv. Drug Delivery Rev. 2002, 54, 13-36.
49. Herandez R., Zamora-Mora V., Sibaja-Ballestero M., Vega-Baudrit J., Pez
D.L. and Mijangos C. Influence of Iron Oxide Nanoparticles on the
Rheologival Properties of Hydride Chitosan Ferrogels. J. Colloid. Interface.
Sci. 2009, 339, 53-59.
50. Heskins M. and Guillet J.E. Solution Properties of Poly (N-
isopropylacrylamide). J. Macromol. Sci. Chem. A2. 1968, 8, 1441-1455.
51. Hiemstra C., Zhong Z., Jommes R., Steenbergen M.J., Jacobs J. and Otter
W.A., Hennink W.E., Feijen. In vitro and In vivo Protein Delivery From In
situ Forming Poly (Ethylene glycol)-Polylactide Hydrogels. J. Control. Rel.
2007, 19, 320-327.
52. Higuchi T. Mechanism of Sustained Action Medication. Theoretical Analysis
of Rate of Solid Drugs Dispersed in Solid Matrices. J. Pharm. Sci. 1963, 52,
1145-1149.
229
53. Hiratani H., Mizutani Y. and Alvarez-Lorenzo C. Controlling Drug Release
From Imprinted Hydrogels by Modifying the Characteristics of the Imprinted
Cavities. Macromol. Biosci. 2005, 5,728-733
54. Hixson A.W. and Crowell J.H. Dependence of Reaction Velocity Upon
Surface and Agitation. Ind. Eng. Chem. 1931, 23, 923-931.
55. Houwei T., Yi Q., Xiaohua H., Yihua X., Hua Z., Peihu X. and Filiang X.
Study of the Sigmoidal Swelling Kinetics of Carboxymethyl Chitosan-g-
poly(acrylic acid) Hydrogels Intended for Colon-specific Drug Delivery.
Carbohydrate Polym 2010, 82, 440-445.
56. Islam M.T., Hornido N.R. and Ciotti S., Ackermann C. Rheological
Characterization of Topical Carbomer Gels Neutralized to Different pH.
Pharm. Research. 2004, 21, 1192-1199.
57. Jabbari E. and Nozari S. Synthesis of Acrylic Acid Hydrogel by γ-Irradiation
Crosslinking of Polyacrylic Acid in Aqueous Solution. Iranian Polym. J. 2002,
8, 264-270.
58. Jabbari E. and Nozari S. Strain Induced Clustring in Polyelectrolyte
Hydrogels. Euro. Polym. 2008, 36, 2685-2692.
59. Jeong B. and Gutowska A. Lessons From Nature: Stimuli-responsive
Polymers and Their Biomedical Applications. Trends Biotechnol. 2002, 20,
305-310.
60. Jiang M., Li M., Xiang M. and Zhou H. Interpolymer Complexation and
Miscibility Enhancement by Hydrogen Bonding. Adv. Polym. Sci. 1999, 146,
121-196.
230
61. Jianqi F. and Lixia G. PVA/PAA thermo-crosslinking hydrogel fiber:
preparation and pH-sensitive properties in electrolyte solution. European
Polym. J. 2002, 38, 1653-1658.
62. Keiweg, S. L., Geonnotti A. R. and Katz D. F. Gravity-induced Coating Films
of Vaginal Gel Formulations: In Vitro Experimental Analysis, J. Pharm. Sci.
2004, 93, 2941-2952.
63. Kempe S., Metz H., Bastrop M., Huilson A., Contri R. V. and Mader K.
Characterization of Thermosensitve Chitosan Based Hydrogels by Rheology
and Electron Paramagntyic Resonance Spectroscopy. Eur. J. Pharm.
Biopharm. 2008, 68, 26-33.
64. Khutoryanskiy, V. V., Dubolazov A. V., Nurkeeva Z. S., and Mun G. A. pH
Effects in Complex Formation and Blending of Poly (acrylic acid) With Poly
(ethylene oxide). Langmuir 2004, 20, 3785-3790.
65. Kim B., La Flamme K. and Peppas N.A. Dynamic swelling behavior of pH-
sensitive anionic hydrogels used for protein delivery. J. Appl. Polym. Sci.
2003, 89, 1606-1613.
66. Kim B. and Peppas N.A. Synthesis and Characterization of pH-sensitive
Glycopolymers for Oral Drug Delivery Systems. J. Biomater. Sci. Polym. Ed.
2002, 13, 1271-1281.
67. Kim B. and Peppas N.A. Poly (ethylene glycol) Containing Hydrogels for Oral
Protein Delivery Applications. Biomed. Microdevices. 2003, 5, 333-341.
68. Kim S.J., Park S.J., Shin M.S., Lee Y.H., Kim S.I. J. Appl. Polym. Sci. 2002,
85, 1956.
69. Kim S.J., Park S.J., Kim I.Y., Chung T.D., Kim H.C. and Kim S.I. Thermal
Characterization of Interpenetrating Polymer Networks Composed of Poly
231
(vinyl alcohol) and Poly (N-isopropylacrylamide). J. Appl. Polym. Sci. 2003,
90, 881-885.
70. Kim S., Kim J.H., Jeon O., Kwon I.C. and Park K. Engineered Polymers for
Advanced Drug Delivery. Eur. J. Pharm. Biopharm. 2009, 71, 420-430.
71. Kim S.W. Temperature Sensitive Polymers for Delivery of Macromolecular
Drugs, in Advanced Biomaterials, in Biomedical Engeneering and Drug
Delivery Systems, Ogata N, Kim SW, Feijen J, et al. (eds), Tokyo, Springer,
1996, 126-133.
72. Kim S. H., Smith J., Claudi A. and Lin R. J. The purified yeast pre-mRNA
splicing factor PRP2 is an RNA-dependent NTPase. EMBO J. 1992 , 11,2319-
26.
73. Klouda L. and Mikos A.G. Thermo-responsive Hydrogels in Biomedical
Applications. Eur. J. Pharm. Biopharm. 2008, 68, 34-45.
74. Kopecek J. Hydrogel Biomaterials: A Smart Future? Biomaterials. 2007,
28(34), 5185-5192.
75. Krusic M.K. and Filipovic J. Copolymer Hydrogel Based on N-
isopropylacrylamide and Itaconic Acid. Polym, 2006, 47, 148-155.
76. Kubo M., Matsuura T., Morimoto H., Uno T. and Itoh T. Preparation and
Polymerization of a Water-soluble, Nonbonding Cross-linking Agent for a
Mechanically Cross-linked Hydrogel. J. Polym. Sci. Part A-Polym. Chem.
2005, 43, 5032-5040.
77. Kuckling D. and Urban M.W. Handbook of Stimuli-responsive Materials.
WILEY-VCH Verlag GmbH& Co. KGaA, Weinheim. 2011, 1-26.
78. Kulkarni S.S. and Aloorkar N.H. Smart Polymers in Drug Delivery: An
Overview. J. Pharm. Res. 2010, 3(1), 100-108.
232
79. Kumar A., Laluiris S. and Singh H. Development of PEGDMA: MAA Based
Hydrogel Microparticles for Oral Insulin Delivery. Int. J. Pharm. 2006, 323,
117-124.
80. Kumar A., Pandey M., Koshy M. K. and Saraf S. A. Synthesis of Fast
Swelling Superporous Hydrogels: Effect of Concentration of Crosslinker and
Acdisol on Swelling Ratio and Mechanical Strength. 2010, 2, 135–140.
81. Kumar A., Srivastata A., Galaev I.Y. and Mattiasson B. Smart Polymers:
Physical Forms and Bioengineering Applications. Prog. Polym. Sci. 2007,
32(10), 1205-1237.
82. Landner W.D., Mockel J.E. and Lippold B.C. Controlled Release of Drugs
From Hydrocolloid Embedding. Pharmazei. 1996, 51, 263-272.
83. Langer R. and Peppas N. A., Advances in biomaterials, drug delivery and
bionanotechnology. AlChEJ. 2003, 49, 2990-3006.
84. Larson, R. J. The Structure and Rheology of Complex Fluids, Oxford
University Press, New York, 1999.
85. Lee C.H., Moturi V. and Lee Y. Thixotropic Property in Pharmaceutical
Formulations: A Review. J Controlled Release. 2009, 136, 88-98.
86. Lee W.F. and Lin Y.H. Effect of Porosigen on the Swelling Behavior and
Drug Release of Porous N-isoprpylacrylamide/poly (ethylene glycol)
monomethylether acrylate Co-polymeric Hydrogels. J. Appl. Polym. Sci.
2006, 102, 5490-5499.
87. Lee Y.G., Kang H.S., Kim M.S. and Son T. Thermal Cross-linked Anionic
Hydrogels Composed of Poly (vinylalcohol) and Poly (gamma-glutamic acid):
Preparation, Characterization and Drug Permeation Behavior. J. Appl. Polym.
Sci. 2008, 109, 3768-3775.
233
88. Li, C.C. and Chauhan. Modeling Ophthalmic Drug Delivery by Soaked
Contact Lenses. Ind Eng Chem Res, 2006, 45, 3718-3734
89. Li S. Molina I. Martinez M. and Vert M. Hydrolytic and Enzymatic
Degradations of Physically Cross-linked Hydrogels Prepared from
PLA/PEO/PLA Triblock Copolymers. J. Mat. Sci. Mat. Medicine. 2002, 13,
81-86.
90. Liu Q., Wang Y. and Kee D.D. Mass Transport Through Swelling
Membranes. Int. J. Eng. Sci. 2005, 43, 1464-1470.
91. Liu Y. Vrana N. and McGuinness G. Physically Crosslinked Composite
Hydrogels of PVA With Natural Macromolecules: Structure, Mechanical
Properties, and Endothelial Cell Compatibility. J. Biomedical Mat. Res. Part
B Applied Biomaterials. 2009, 90, 492-502.
92. MacEwan S.R., Callahan D.J. and Chilkoti A. Stimulus-responsive
Macromulecules and Nanoparticules for Cancer Drug Delivery. Nanomedicine
UK. 2010, 5(5), 793-806.
93. Madrigal-Carballo S., Seyler D., Manconi M., Murasvila O. and Molina F. An
Approach to Rheological and Electrokinetic Behavior of Lipidic Vesicles
Covered With Chitosan Biopolymer. Colloids and Surf. A. 2008, 323, 149-
154.
94. Mahajan A. and Aggarwal G. Smart Polymers: Innovations in Novel Drug
Delivery. Int. J. Drug Dev. & Res. 2011, 3(3), 16-30.
95. Mahkam, M., Mohammadi, R. and Siadat, S.O.R. Synthesis and Evaluation of
Biocompatible pH-sensitive Hydrogels as Colon-specific Drug Delivery
Systems. J. Chinese Chem. Soc. 2006, 53, 727-733.
234
96. Martinez-Ruvalcaba A., Chornet A. and Rodrigue D., Viscoelastic Properties
of Dispersed Chitosan/Xanthan Hydrogels. Carbohydrate Polym. 2007, 67,
586-595.
97. Martinez-Ruvalcaba A., Sanchez-Diaz J.C., Becerra F., Cruz-Barba L. E. and
Gonzalez-Alvarez A. Swelling Characterization and Drug Delivery Kinetics of
Polyacrylamide-co-itaconic acid/Chitosan hydrogels. exPRESS Polym. Lett.
2009, 3, 25-32.
98. Morishita M., Lowman A.M., Takayama K., Nagai T. and Peppas N.A.
Elucidation of the Mechanism of Incorporation of Insulin in Controlled
Release Systems Based on Complexation Polymers. J. Control. Release. 2002,
81(1-2), 25-32.
99. Mullerney M.P., Seery T.A.P. and Weiss R.A. Drug Diffusion in
Hydrophobically Modified N, N-dimethylacrylamide Hydrogels. Polymer.
2006, 47, 3845-3855.
100. Mun G.A., Khutoryanskiy V.V., Akhmetkalieva G.T., Shamakov S.N.,
Dubolazou A.V., Nurkeeva Z.S. and Park K. Inter-polymer Complexes of Poly
(acrylic acid) With Poly (2-hydroxyethylacrylate) in Aqueous Solution.
Colloid. Polym. Sci. 2004, 283, 174-181.
101. Mundargi R.C., Patel S.A., Kulkarni P.A., Mullikarjuna N.N. and
Aminabhavi T.M. Sequential Interpenetrating Polymer Network Hydrogel
Microspheres of Poly (methacrylic acid) and Poly (vinylalcohol) for Oral
Controlled Drug Delivery to Intestine. J. Microencapsulation. 2008, 25, 228-
240.
102. Murali Y.M.., Keshava Y.M., Sudhakar Y.M., Kumar Y.M., Mohana
R.K. and Padmanabha R.M. Swelling and Diffusion Properties of Poly
235
(acrylamide-co-maleic acid) Hydrogels: A Study With Different Cross-
linking Agents, Int. J. Polym. Mat. 2006a, 55, 1-23.
103. Murali Y.M., Sudhakar K., Keshava P.S.M and Mohana R.K. Swelling
Properties of Chemically Cross-linked Poly (acrylamide-co-maleic acid)
Hydrogels. Int. J. Polym. Mat. 2006b, 55, 513-536.
104. Nae, H. N. and Reichert W. W. Rheological Properties of Lightly
Cross-linked Carboxy Copolymers in Aqueous Solutions, Rheol. Acta. 1992,
31, 351-361.
105. Naguyen, Q. D. and Boger D. V. Yield Stress Measurement for
Concentrated Suspensions, J. Rheol. 1983, 27, 321-349.
106. Najib N. and Suleiman M. The Kinetics of Drug Release From Ethyl
Cellulose Solid Dispersions. Drug Dev. Ind. Pharm, 1985, 11, 2169-2181.
107. Odian G. Principles of Polymerization. 4th ed. New York, NY: Wiley
Interscience, 2004.
108. Omidian H., Park K., Kandalam U. and Rocca J. Swelling and
Mechanical Properties of Modified HEMA-based Super-porous Hydrogels.
2010, 25, 483-497.
109. Oprea A., Neamta A., Stoica B., Vasile C. Cellulose/Chondroitin
Sulphate Hydrogels as Carrier for Drug Delivery Applications. Mol. Bio.
2009, 85-92.
110. Ortan A., Parvu C. D., Ghica M. V., Popescu L. M. and Ionita L.
Rheological Study of a Liposomal Hydrogel Based on Carbopole. Roman.
Biotech. Lett. 2011, 16, 47-54.
236
111. Owen, D. H., Peters J. J. and Katz D. F. Comparison of the
Rheological Properties of Advantage-S and Replens, Contraception 2001, 64,
393-396.
112. Pal K., Banthia A.K. and Majumdar D.K. Effect of Heat Treatment of
Starch on the Properties of the Starch Hydrogels. Mater. Lett. 2008, 62, 215-
218.
113. Pal K., Banthia A.K. and Majumdar D.K. Polymeric Hydrogels:
Characterization and Biomedical Applications----A mini review. 2009, 12,
197-220.
114. Patel A. and Murthy R.S.R. Preparation, Swelling Kinetics and Drug
Loading Studies of Cross-linked Polymeric Hydrogel Beads. 2001, 63, 222-
227.
115. Peppas J.B. and Peppas N.A. Dynamic and Equilibrium Swelling
Behavior of pH-Sensitive Hydrogels Containing 2-hydroxyethyl Methacrylate.
Biomaterials. 1990, 11, 635-649.
116. Peppas N.A., Buresa P., Leobendunga W. and Ichikawa H. Hydrogels
in Pharmaceutical Formulations. European J. Pharm. Biopharm. 2000, 50, 27-
46.
117. Povea M.B., Monal W.A., Cauich-Rodriguez J.V., Pat A.M., Rivero
N.B. and Covas C.P. Interpenetrating Chitosan Poly (acrylic acid-co-
acrylamide) Hydrogels: Synthesis, Characterization and Sustained Protein
Release Studies. Mater. Sci. Appli. 2011, 2, 509-520.
118. Ranjha N.M. Swelling Behavior of pH-sensitive Cross-linked poly
(vinylacetate-co-acrylic acid) Hydrogels for Site Specific Drug Delivery. Pak.
J. Pharm. Sci. 1999, 12, 33-41.
237
119. Rao M.A. Rheology of Fluid and Semisolid Foods. Principles and
Applications, Aspen Publishers, Gaithersburg, 1999.
120. Ramirez, A., Fresno M. J., Jimenenz M. M. and Selles E. Rheological Study
of Carbopoly (R) Ultrez (TM) 10 Hydro-alcoholic gels, I: Flow and
Thixotropic Behavior as a Function of pH and Polymer Concentration,
Pharmazei. 1999, 54, 444-447.
121. Rogero S. Malmonge S. Lugao A. Ikeda T. Miyamaru L. and Cruz A.
Biocompatibility study of polymeric biomaterials. Artificial Organs. 2003, 27,
424-427.
122. Rosiak J. and Yoshii F. Hydrogels and their medical applications. Nuclear
Instruments & Methods in Physics Research Section B-Beam Interactions with
Materials and Atoms. 1999, 151, 56-64.
123. Rudraraju V. S. and Wyandt C. M. Rheology of Micro-crystalline Cellulose
and Sodiumcarboxymethyl Cellulose Hydrogels Using a Controlled Stress
Rheometer: Part II. Int. J. Pharm. 2005, 292, 63-73.
124. Ruel-Gariépy E. and Leroux J. In situ Forming Hydrogels- Review of
Temperature-Sensitive Systems. Eur. J. Pharm. Biopharm. 2004, 58(2), 409-
426.
125. Schreyer H.B., Gebhart N., Kim K.J. and Shahinpoor M. Electrical
Activation of Artificial Muscles Containing Polyacrylonitrile Gel Fibers.
Biomacromolecules. 2000, 642-647.
126. Scott-Blair G.W. Elementary Rheology. Academic Press, New York, 1969.
127. Schott, H., J. Macromol. Sci. Phys. Part B. 31, 1 (1992).
238
128. Shaikh R.P., Pillay V., Choonara Y.E., Toit L.C., Ndesendo V.M.K., Bawa
P. and Cooppan S. A Review of Multi-responsive Membranous Systems for
Rate-modulated Drug Delivery. AAPS Pharmscitech. 2010, 2(1), 441-459.
129. Sen M. and Yakar A., 2005, 234, 226-
130. Shahinpoor M. and Kim K.J. Novel Ionic Polymer-metal Composites
Equipped With Physically Loaded Eith Physically Loaded Particulate
Electrodes as Biomimetic Sensors, Actuators and Artificial Muscles. Sens.
Actuayors. A. Phys2002, 96, 125-132.
131. Shahinpoor M. and Kim K.J. Ionic Polymrer-metal Composites:
Modeling and Simulation as Biomimetic Sensors, Acutators, Transducers and
Artificial Muscles. Smart Mater. Struct. 2004, 13, 1362-1388.
132. Singh B., Sharma N. and Chauhan N. Synthesis, Characterization and
Swelling Studies of pH-responsive Psyllium and Methacrylamide Based
Hydrogels for the Use in Colon Specific Drug Delivery. Carbohyd. Polym.
2007, 69, 631-643.
133. Slaughter, B. Khurshid S. Fisher O. Khademhosseini A. and Peppas N.
Hydrogels in regenerative medicine. Adv. Mat. 2009, 21, 3307-3329.
134. Steffe J.F. Rheological Methods in Food Process Engineering.
Freeman Press Michigan. 1992.
135. Stuart M.A.C., Huck W.T.S., Genzer J., Muiller M., Ober C., Stamm
M., Sukhorukov G.B., Szleifer I., Tsukruk V.V., Urban M., Winnik F.,
Zauscher S., Luzinov I. and Minko S. Emerging Applications of Stimuli-
responsive Polymer Materials. Nat. Mater. 2010, 9(2), 101-113.
239
136. Sung-Eun P., Young-Chang N. and Hyung K. Preparaion of Poly
(ethylene gl ycolmethacrylate-co-acrylic acid) Hydrogels by Radiations and
Their Physical Properties. Rad Phy Chem. 2002, 221-227.
137. Sutter M., Siepmann J., Hennnink W.E. and Jiskoot W. Recombinant
Gelatin Hydrogels for the Sustained Release of Proteins. J. Control. Rel. 2007,
119, 301-312.
138. Ta H.T., Dass C.R. and Dunstan D.E. Injectable Chitosan Hydrogels
for Localized Cancer Therapy. J. Controj. Rel. 2008, 126, 205-216.
139. Tamburic, S. and D. Q. M. Craig. The Effects of Aging on the
Rheological, Dielectric and Mucoadhesive Properties of Poly (acrylic acid)
Gel Systems, Pharm. Res. 1996, 13, 279-283.
140. Tang Y. F., Du Y. M., Shi X. W. and Kennedy J. F. Rheological
Characterization of a Novel Thermosensitive Chitosan/Poly (vinyl alcohol)
Blend Hydrogel. Carbohydrate Polym. 2007, 67, 491-499.
141. Taran E. and Caykara T. Swelling and Network Parameters of pH-
sensitive Poly (acrylamide –co-acrylic acid) Hydrogels. J. Appl. Polym. Sci.
2007, 106, 2000-2007.
142. Tia Q., Zhao Z., Tang X. and Zhang Y. Hydrophobic Association and
Temperature and pH Sensitivity of Hydrophobically Modified Poly (n-
Isopropylacrylamide-co-acrylamide) Gels. J Applied Polym Sci, 2003, 87,
2406-2413
143. Vrentas J.S. and Vrentas C.M. Steady Viscoelastic Diffusion. J Appl
Polym Sci 2003, 88, 3256-3263.
240
144. Wallmersperger T., Witte F.K., Ottavio M. and Kriplin B. Multiscale
Modeling of Polymer Gel-chemo-electric Model Versus Discrete Element
Model. Mech. Adv. Mater. Sruct. 2008, 15, 228-234.
145. Wang C. Stewart R. and Kopecek J. Hybrid hydrogels assembled from
synthetic polymers and coiled-coil protein domains. Nature. 1999, 397, 417-
420.
146. Xinming L. and Xingde C.U.I. Study on Synthesis and
Chloremphenicol Release of Poly (hydroxyethylmethacrylate-co-acrylamide)
Hydrogels. Chinese. J. Chem. Eng. 2008, 16, 640-645.
147. Yaszemski M. Trntolo D. Lewandrowski K-U. Hasirci V. Altobelli D.
and Wise D. (Eds.). Tissue Engineering and Novel Delivery Systems, CRC
Press, 2004.
148. Yahia A. and Khayat K. H. Analytical Models for Estimating Yield
Stress of High- performance Pseudo Plastic group. Cement Concrete
Research. 2001, 31, 731-738.
149. Yarimkaya S. and Basan H. Swelling Behavior of Poly (2-
hydroxyethylmethacrylate-co-acrylic acid-co-ammoniumacrylate) Hydrogels.
J. Macromol. Sci. Part A: Pure and Appl. Chem. 2007, 44, 939-946.
150. Ying Y. Gu X. and Yang, C. Abnormal pH sensitivity of polyacrylate-
polyurethane hydrogels. J. Appl. Polym. Sci. 1998, 70, 1047-1052.
151. Yin X., Hoffman and Stayton P.S. Poly (n-isopropylacrylamide-co-
acrylic acid) Co-polymers That Respond Sharply to Temperature and pH.
Biomacromolecules. 2006, 7, 1381-1385.
152. Yin Y., Yang Y. and Xu H. Swelling Behavior of Hydrogels for
Colon-site Drug Delivery. J Appl Polym Sci 2002, 83, 2835-2842.
241
153. You J., Almeda D. and Ye G.J.C. Auguste D.T. Bioresponsive
Matrices in Drug Delivery. J. Biol. Eng. 2010, 4(15), 1-12.
154. Yu X., Zhang X., Wang B., Cheng S., Zhuo R. and Wang Z.
Fabrication of a Novel Temperature Sensitive Poly (n-isopropyl-3-
buteneamide) Hydrogel. Colloid. Surface. 2007, 59, 158-163.
155. Zafar Z. I., Malana M.A., Pervez H., Shad M. A. and Momina K.
Synthesis and Swelling Kinetics of a Cross-linked pH-sensitive Ternary Co-
polymer Gel System, Polym. (Korea). 2008, 32, 1-11.
242
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