Synthesis, Characterization and Swelling Kinetics of Co...

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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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DEDICATION

Dedicated to

All those

who are blessed with

intellect and wisdom

but

never get a chance

to

hunt out their hidden talent.

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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-

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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

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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



varying concentration of AA, cross-linked with EGDMA. 75



varying concentration of DEGDMA. 76


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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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


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


NiPAAm hydrogels in various pH media at 37oC. 166

Table 3.15: Rheological Properties of Hydrogels: Theremorheological Propeties. 174

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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

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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


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


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


(MA-co-VA-co-AA) co-polymeric hydrogels cross-linked with DEGDMA at pH

8.0. 82


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


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


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


velocity in NiPAAm-2 hydrogel. 92

Fig. 3.36: Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample

E1. 95


E2. 95


E3. 96


E4. 96


EA1. 97


EA2. 97

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EA3. 98


EA4. 98


D1. 99


D2. 99

Fig. 3.46 : raphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample

D3. 100


D4. 100

Fig. 3.48: G raphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample

DA1. 101


DA2. 101

Fig. 3.50 : Graphic of Maxwell-Peppas Model at pH 8.0 for the hydrogel sample

DA3. 102


DA4. 102

Fig.3.52: Graphic of Maxwell-Peppas Model at pH 5.5 for the hydrogel sample

NiPAAm-1 103


NiPAAm-1. 103

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NiPAAm-1. 104


NiPAAm-2. 104


NiPAAm-2. 105


NiPAAm-2. 105


NiPAAm-2. 106


NiPAAm-2. 106

Fig. 3.60: Graphic of Schott’s model at pH 1.0 for the hydrogel sample E1. 107




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. 3.72: Graphic of Schott’s model at pH 1.0 for the hydrogel sample DA1. 113

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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


NiPAAm-2. 116

Fig. 3.80 : Graphic of Schott’s model at pH 4.0 for the hydrogel sample

NiPAAm-2. 117


NiPAAm-2. 117


NiPAAm-2. 118


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


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


the hydrogel D2 at pH 8.0. 126


the sample NiPAAm-1 at pH 8.0. 127


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


8.0. 135


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


8.0. 139


8.0. 140

Fig. 3.111: 1st order release kinetics of Tramadol HCl from the sample TD1 at pH

8.0. 140

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8.0. 141


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


8.0. 144


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.3.132: Higuchi kinetics of Tramadol HCl from the sample TD1 at pH 8.0. 151



Fig.3.135: Higuchi kinetics of Tramadol HCl from the sample TNE1 at pH 8.0. 152



Fig.3.138: Higuchi kinetics of Tramadol HCl from the sample TND1 at pH 8.0. 154



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

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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. 3.149: Frequency- dependent property of ter-polymeric hydrogels at 10oC. 170




Fig. 3.153: Steady state viscosity of A1 as a function of shear rate at different

temperatures. 177


temperatures. 177


temperatures. 178


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. 3.162: Ostwald de-Waele model fit at 10oC. 185

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Fig. 3.166: Bingham model fit at 10oC. 187




Fig. 3.170: Modified Bingham model fit at 10oC. 189




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.


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


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


cross-linked with DEGDMA in dry state.


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



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



varying concentration of AA, crosslinked with EGDMA.

sample Media penetration velocity Equilibrium media sorbed Schott,s Model Fick’s Model


___________________________________________________________________________________

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



varying concentration of DEGDMA.

Sample Media penetration velocity Equilibrium media sorbed Schott,s Model Fick’s Model


__________________________________________________________________________________ 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


Schott,s model and power law parameters for the the poly (MA-co-VA-co-AA) for

varying concentration of AA, crosslinked with DEGDMA.



_________________________________________________________________________________

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


Schott,s model and power law parameters for the poly (MA-co-NiPAAm-co-AA)

hydrogels.



__________________________________________________________________________________

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.


(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


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


(MA-co-VA-co-AA) co-polymeric hydrogels cross-linked with DEGDMA at pH 8.0.


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


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


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


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


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


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.


-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



-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.


-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



-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.


-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



-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



-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


NiPAAm-1.


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


NiPAAm-1.


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


NiPAAm-2.


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


NiPAAm-2.


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.


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



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.


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



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.


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



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.


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



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



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



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



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.


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


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


the hydrogel E2 at pH 8.0.


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


the hydrogel NiPAAm-1 at pH 8.0.


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



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.



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


8.0.


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


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.


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. 3.111: 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.


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



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



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.


-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. 3.135: 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



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.


(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


the poly (MA-co-VA-co-AA) for varying concentration of DEGDMA in various pH

media at 37oC.


(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.


(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


the NiPAAm hydrogels in various pH media at 37oC.


(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



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. 3.149: 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



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


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


temperatures.


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


temperatures.


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.


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



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.


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



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.


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



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.


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



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.

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