1

Chapter 1

Introduction

Hydrogels are three dimensional hydrophilic polymeric networks capable of

absorbing large amounts of water or biological fluids (20% of their dry mass).1,2

The

networks are composed of homopolymers or copolymers and are insoluble due to the

presence of chemical cross-links or physical cross-links such as entanglements or

crystallites3, hydrogen bonds and Van der Waals forces.

1.1. Properties and Classification of Hydrogels

The common and the most important property of hydrogels is the water uptake

property. The water uptake property of some hydrogels depend on temperature4-8

, pH9-12

,

ionic strength13-16

of the swelling medium, chemical architecture of the gel, types of solvent

or even in the presence of electric field17-19

, magnetic field20-23

, mechanical forces24,25

, ultra

violet light26-28

and presence or absence of specific molecules29-31

. The polymer which

posses this type of surrounding environment sensitiveness due to the presence of certain

functional groups along the polymeric chains are referred to as “intelligent ” or “smart

polymer”32

. The water containing hydrogels have other important biophysical properties

such as softness, rubbery texture, resemblance to the living organs and permeability to

various biomolecules33

.

Hydrogels can be classified as neutral and ionic on the basis of the nature of the side

groups. According to their mechanical and structural characteristics hydrogels can be

classified as affine or phantom networks hydrogel. They may be homopolymer, co-

polymer, grafted copolymer, multi-polymer and interpenetrating polymeric on the basis of

method of preparation. Again they can be amorphous, crystalline, hydrogen bonded

structure, hydrocolloidal aggregates and microgels on the basis of the physical structure of

the networks2,34,35

. Hydrogel can be classified as reversible or physical hydrogel and

2

permanent or chemical gel according to their cross-linking network. The networks of

physical hydrogel are held together by molecular entanglement and or secondary forces36,37

.

Physical hydrogels are not homogeneous, since clusters of molecule entanglement or

hydrophobically or ionically associated domains can create a non homogeneous structure.

The network of chemical hydrogel is covalently crosslinked. Finally hydrogels can be

classified on the basis of sensitiveness to stimuli38

as pH, temperature, ionic strength,

electromagnetic radiation, electric force, mechanical force and ultra sound sensitive

hydrogels.

Different macromolecular structures are possible, which includes: cross-linked or

entangled network of linear homopolymers, polyion -multivalent ion, polyion or H-bonded

complexes, hydrophilic networks stabilized by hydrophobic domains, IPNs or physical

blends. Hydrogel may have different physical forms, which includes: solid molded forms (

e.g. soft contact lenses), pressed power matrices (e.g. pill or capsules for oral insertion),

microgels( e.g. as bioadhesives carrier or wound treatments), coatings ( e.g. on implants or

catheters, on pill or capsules or coating on the inside capillary wall in capillary

electrophoresis), membranes or sheets ( e.g. as a reservoir in a transdermal drug delivery

patch or for 2D electrophoresis gels), encapsulated solids( e.g. in osmotic pumps) and

liquid (e.g. that form gels on heating or cooling).

1.2 Synthesis and Application of Hydrogels

1.2.1 Monomers in the Synthesis of Hydrogels

The choice of monomer for the preparation of hydrogel is very important. It

depends upon the application, properties, cost and availability. Many synthetic and

naturally derived materials have been reported to form well characterized hydrogels.

Among these materials gelatin has attractive feature as the staring material for

biodegradable, non carcinogenic and hydrophilic39

biopolymer containing large number of

functional groups. Gelatin readily undergoes chemical cross linking, which is very

important for its use as a biomaterial. For this advantage gelatin containing hydrogel has

large application in the field ranges from tissue engineering 40

to drug delivery, gene

3

therapy41-44

and wound dressing45

. Acrylamide (AM) and 2- acrylamido-2-methyl propane

sulfonic acid (AMPS) have good polymer formation properties. A surfactant-modification

of Poly(acrylamide-co-acrylamido propane sulphonic acid) hydrogel improves its

sensitivity towards salt concentration, pH and drug release behaviour46

. AM has most wide

and commercial applications as water soluble product47

. They are used in paper

manufacturing, water treatment, through oil recovery, soil modification and medical sector.

AM and AMPS based polymer have environmentally sensitive properties48

. AMPS is ionic

monomer and the polymer prepared from it has known for hydrophilicity, thermal stability,

stability over broad pH range and ionic character. These hydrogels have attractive

application as wound dressing materials49,50

since it adheres to healthy skin but not to

wound surface and is easily replaceable without damage to the heal wound. Poly(vinyl

alcohol) (PVA) is highly hydrophilic, nontoxic and biocompatible polymer with excellent

film forming property. PVA films have high mechanical strength, low fouling potential and

long-term temperature and pH stability. These properties of PVA have to lead their use in

bioseparations, biotechnology and in the pharmaceutical industry51,52

.

Poly(N-vinyl-2-pyrrolidone) (PVP) is a synthetic linear non-toxic, biocompatible

polymer, frequently used in food and cosmetic industries as well as in pharmaceutical

formulations53,54

. Their uses as a biomaterial in artificial blood plasma were prevalent in

World War II55, 56

. PVP has large applications in controlled release57,58

, tissue regeneration

and implants59

, wound and burn dressings60

, and other applications. Hydrogel dressings

have attracted much attention among researchers for their use in the medicinal field, chiefly

in the healing of burn wounds. It must be emphasized here that there are already numerous

natural and synthetic polymers being studied and/or applied as medicinal hydrogels, and

PVP is among them61,62

. But, beyond PVP as a unique polymer, other polymer systems

involving VP-monomers are also used in this application area: chemically modified PVP63-

65, copolymers containing units of N-vinyl-2-pyrrolidone in their chains - for example,

poly(methacrylamide-co-N- vinyl-2- pyrro-lidone-co-itaconic acid)66

; poly(N-vinyl-2-pyrr-

olidone-co-styrene)67

; poly(N-vinyl-2-pyrrolidone-co- acrylic acid)68

and blends of PVP

with other bio-compatible polymers (for example, PVP-CMC69

; PVP-PVA70

; PVP-k-

carrageenan71

; PVP-chitosan72

.

4

The water sorption property as well as the mechanical strength of the hydrogel may

be improved by the introduction of a copolymeric system which has both hydrophilic and

hydrophobic monomers. This results in a change in the maximum hydration degree and

diffusion of the swelling agent into the gel as well as the organization of water molecules

depending on the chemical composition and distribution of the hydrophobic monomeric

units along the macromolecular chain. The introduction of hydrophobic monomer forms a

hydrophobic domain to reinforce the structure and provide higher tear, shear, and creep

strengths versus traditional hydrogels without sacrificing water content, low friction and

pliability. For instance, the water gain property of a polymer of 2-hydroxy ethyl

methacrylate was affected by means of the introduction of a hydrophobic monomer such as

furfyryl acrylate73

. Many researchers have used hydrophilic and hydrophobic combination

in hydrogel preparation.

Besides these monomers, many hydrophilic and hydrophobic monomers are used in

preparation of hydrogels. The most common monomers used in the synthesis of hydrogels

for the pharmaceutical applications are hydroxyethyl methacrylate(HEMA),

hydroxyethoxyethyl methacrylate (HEEMA), Hydroxydiethoxyethyl

Methacrylate(HDEEMA), Methoxyethyl methacrylate(MEMA), Methoxyethoxyethyl

Methacrylate(MEEMA), Methoxydiethoxyethyl methacrylate(HDEEMA) , Ethylene glycol

dimethacrylate(EGDMA), N-vinyl-2 pyrrolidone(NVP), N-isopropyl acryl

amide(NIPAAm), Vinyl acetate(VAc), Acrylic acid(AA), N-(2-hydroxypropyl)

Methacrylamide(HPMA), Methyl methacrylic acid (MMA), Ethylene glycol(EG), PEG

acrylate(PEGA), PEG methacrylate(PEGMA), PEG diacrylate(PEGDA), PEG

dimethacrylate(PEGDMA), Starch, Collagen, Hyaluronic acid(HA), Chitosan(CT),

Hydroxyapatite, Fibrin, Algibate, Poly(lactic acid), Methylmetha acrylic acid(MAA),

ply(isopropylacrylamide)(PNIPAAm) etc.

1.2.2 Preparation Methods of Hydrogel

Hydrogels are generally prepared from hydrophilic polymer matrices that are cross-

linked by several methods. One method is physical cross-linking which include hydrogen

5

bonds, crystallized domains, hydrophobic interaction, protein interaction,

stereocomplexation, temperature-induced, sol-gel transition, host-guest interaction,

aggregation and soft assembly. Schematic diagram of the formation of physical hydrogel is

given in fig.1.1. Another method involves chemical cross-linking in the presence of various

cross-linkers. Schematic diagrams of the formation of such hydrogels are given in fig.1.2

and 1.3. Though several methods are used for the preparation of the hydrogels, normally

they are prepared by thermal induced free radical74

, redox induced33

or radiation

induced75,76

polymerization/copolymerization in the presence of a suitable cross-linking

agent.

Fig.1.1 Schematic of methods for the formation of ionic (physical) hydrogel. (Adopted

from Ref77)

6

Fig1.2 Schematic of methods of formation physical and chemical hydrogel from

hydrophobic polymers. (Adopted from ref 77)

Fig.1.3 Schematic of formation of chemical crosslinked hydrogel. (Adopted from ref 77)

7

Hydrogel in the macroscopic network or confined to smaller dimension are called

microgels or nanogels. There are several methods for the preparation of microgels78

Photolithographic and micromodeling method.

Microfluidics precipitation

Fabrication of biopolymers:

Many methods have been developed for the preparation of microgels of

biopolymers like water in-oil (W/O) heterogeneous emulsion method. Inversion (mini)

emulsion, reverse miceller, membrane emulsification, aqueous homogeneous gelation,

spray drying, chemical cross linking etc.

Heterogeneous free radical polymerization:

Various heterogeneous polymerization reactions of hydrophilic and water soluble in

the presence of either diffusional or multifunctional cross-linker have been mostly utilized

to prepare microgels. They include dispersion, precipitation, inverse (mini) emulsion and

inverse microemulsion polymerization processes.

Heterogeneous controlled/ living radical polymerization

1.2.3 Application of Hydrogels

Since the pioneering work of Wichterle and Lim in 1960 on cross-linked HEMA

hydrogels79

, and because of their hydrophilic character, potential to be biocompatible,

hydrogels have been of great interest to biomaterial scientists for many years80-83

. The

important and influential work of Lim and Sun in 198084

demonstrated the successful

application of calcium alginate microcapsule for cell encapsulation. Later in 1980s, Yannas

and coworkers 85

incorporated natural polymer such as collagen and shark cartilage into

hydrogels for use as artificial burn dressings. Hydrogels based on both natural and synthetic

polymers have been continued to be of interst for encapsulation of cell86-88

and most

resently such hydrogels have become especially attractive to the new field of tissue

engineering as a matrix for repairing and regenerating a wide variety of tissues and

organs-89-100

.

Hydrogels have numerous applications particularly in medical and pharmaceutical

sector101,102

due to resemblance to the natural living tissue more than any other class of

8

synthetic biomaterials and biocompatibilities. Hydrogel can be used as contact lenses,

membranes for biosensors, for artificial skin, wound dressings and drug delivery devices103-

107. Besides biomedical applications hydrogels have other important applications in

agriculture, personal hygiene products, industrial absorbents and cosmetics108-111

.

Some important applications of hydrogel in medical sectors are given below:

1.2.3.1 Application in Drug Delivery

There are several numbers of stagiest to achieve a drug delivery system for

sufficient therapy. Among them hydrogels have attractive feature for controlled devices of

therapeutic agents. Hydrogel based delivery can be used for oral, rectal, ocular, epidermal

and subcutaneous.

● Oral Drug Delivery

Drug delivery through the oral rout has been the most common method in the

pharmaceutical application of hydrogels. Drug delivery to the oral cavity has useful

application in the local treatment of disease, stomatities, fungal and viral infections and oral

cavity cancers. For example “aftach” a bioadhesive tablet is used in oral treatment112

.

Several hydrogels are proposed for controlled release matrix in oral care113-116

.

● Transdermal Delivery

Drug delivery to the skin has been traditionally conducted for topical used of

dermatological drugs to treat skin diseases or for disinfection of skin itself. There are many

benefits to transdermal drug delivery that include drug can be delivered for a long duration

at a constant rate, drug delivery can be easily interrupted on demand by simply removing

the devices, and drug can bypass hepatic first pass metabolism and feeling in the skin in

comparison to conventional ointments and patches. Many hydrogel devices are therefore

proposed for transdermal delivery, for example PHEMA117

, BSA-PEG118

, methyl

cellulose119

, methotrexate delivery120

.

9

● Ocular Delivery

In conventional ocular drug delivery the drug solution is rapidly eliminated from the

eye and exhibit limited absorption, poor ophthalmic bioavailability due to eye protective

mechanisms such as effective tear drainage blinking and low permeability of cornea. These

problems are overcome by hydrogel delivery system. Due to their elastic properties

hydrogels show ocular drainage resistant device. In situ forming hydrogels are attractive as

an ocular drug delivery system because of their facility in dosing as a liquid and their long

term retention properties as a gel after dosing. For example in situ gelling system of

alginate with guluronic acid contents for pilocarpine is very useful for ocular delivery121

.

Many hydrogel contact lens and silicon hydrogel contact lenses122-124

are used in controlled

drug delivery.

● Rectal Delivery

The rectal rout has been used for local treatment of disease associated with the

rectum such as hemorrhoids. In conventional drug delivery, drugs diffusing out of the

suppositories in an uncontrolled manner are unable to be sufficiently retained in a specific

position in the rectum, and sometimes migrate upwards to the colon. This often leads to a

variation of the bioavailability of certain drugs, in particular, for drugs that undergo

extensive first-pass elimination. Ryu et al125

, Miyazaki et al126

, Watanable et al127

, Koffi et

al128

had reported for rectal delivery hydrogel devices.

●Subcutaneous Delivery

Among many pharmaceutical applications of hydrogels their substantial application

may be found in implantable therapeutics. Subcutaneously inserted exogenous materials

may more or less evoke potentially undesirable body responses, such as inflammation,

carcinogenicity and immunogenicity. So hydrogel biocompatible material has larger

application in that field. For example several hydrogel used for the subcutaneous delivery

of anticancer drugs crossed-linked PHEMA is used to cystabine (AraC)129

and

methotrexate130

, poly(AAM-co-monomethyl or monoproptl itaconate) is used to Ara-C131

and 5-flurouracil132,133

delivery.

10

1.2.3.2 Application of Hydrogel in Tissue Engineering

In tissue engineering, the partly or whole part of the damage tissue or failure organs

are repaired or replaced with synthetic or nature substituted or regeneration. Tissue

engineering has emerged as a promising technology for the design of an ideal, responsive,

living substitute with properties similar to that of the native tissue134

. Hydrogel constituents

are the most useful in tissue engineering. For examples Collagen based hydrogels are used

in soft tissue repairing, cell differentiation, capillary engineering, dermis engineering,

vascular adipose tissue135-139

; hyaluronic acid gel in regeneration of skin, cartilage,

pattering cell growth140

; Collagen-HA gel in control of vascular sprouting141

, chitosan

based in integrated scaffold, cartilage engineering142,143

; fibrin based gel in vessel

engineering, release of fibroblasts144,145

; gelatin based gel in trachea engineering, bone

engineering146,147

; poly(glycolic acid) in musculoskeletal tissue148,149

; polylactide-co-

glycolide, oligo(poy(ethylene glycol) fumarate) and etherified hyaluronan gels are used in

cartilage engineering148,150

; Poly ethylene glycol and tricalciumphosphate base gel in bone

formulator substituted151-153

; hydroxyapatite and cross linked thiolated hyaluronic acid in

neurite growth and support vocal fold repair154,155

. Many more hydrogels are proposed for

application in tissue engineering156-159

.

1.2.3.3 Application of Hydrogel as a Contact Lens

Hydrogels are well known polymer for the manufacturing of soft contact lenses.

The cornea of the eye is a precisely formed transparent structure of protein fibers

containing about 80% water and 20% formed materials160

. Hydrogels have such type of

similar property, making it suitable to use as a contact lens. Besides biocompatibility and

softness, inter-connected microstructures of hydrogels help oxygen transfer to the cornea.

Certain hydrogels possess high refractive index, modulus, and transparency, required to fit

for this application. Contact lenses are made from a group of hydrophilic monomers like

dimethylacrylamide (DMAAm), N-vinyl pyrrolidone (NVP) and methacrylic acid (MAA)

and hydrophobic monomers like perfluoro polyethers (PFPE), methyl methacrylate (MMA)

and silicon-containing monomers are utilized to design contact lenses161,162

. Hydrogel

contact lens has great advantages and usefulness because of its softness that easily fit to

11

eye, giving more comfort and more oxygen transfer to the cornea. Besides this usefulness

one of the most important applications of hydrogel contact lens can be used in controlled

drug release 163-165

.

1.2.3.4 Application of Hydrogel in Wound Dressing.

Hydrogels are widely used in wound dressing. Wound dressings are cross linked

polymer gels that are often shaped into sheets to provide and maintain a moist wound

environment. By increasing moisture content, hydrogels have the ability to help clean and

debride necrotic tissue. Hydrogels are non adherent and can be removed without trauma to

the wound. Hydrogel dressing have more benefit than general wound dressing166

. The

important benefit includes its use as therapeutic agents for controlled drug delivery to the

wound sit167-170

.

1.3 Network Structure of Hydrogels

The applications of hydrogel in pharmaceutical and medical purpose arise from the

properties of cross-linked structure of hydrogels. The cross-linked structures of the gel

determine the nature of monomer, method of preparation and nature of cross-linking agent.

Out of many theories, the best method for understanding the cross-linked structure of

hydrogel is to study the swelling of the hydrogel and calculation of some parameters. The

most important parameters that define the structure and properties of swollen hydrogels are

the polymer volume fraction in the swollen state, υ2,s, the effective molecular weight of the

polymer chain between cross-linking points, and correlation distance between two

adjacent crosslinks 171

. Schematic representation of cross-linked structure of hydrogel

showing and is given in fig.1.4.

12

Fig.1.4 Schematic representation of cross-linked structure of hydrogel showing and

● Polymer Volume Fraction

The Polymer volume fraction in the swollen state υ2,s describes the amount of liquid

that can be imbinded in hydrogels and is defined as the ratio of the polymer volume (Vp) to

the swollen volume (Vg). It is also reciprocal to the densities of the solvent (1) and

polymer (2 ) and mass swollen ratio Qm172

.

● Molecular Weight between Cross-links

The effective molecular weight of the polymer chain between cross-linking points

is related with physical and mechanical properties of cross-linked polymers. According

to the modified version of Flory-Rehner theory35

, can be determined by the following

equation.

13

Here is the molecular weight of the polymer chain prepared under identical

condition, but in the absence of the crosslinking agent, is the specific volume of the

polymer, V1 is the molar volume of water and χ is the polymer-solvent interaction

parameter. The value of can also be determined by following equation derived from

rubbery elasticity theory35,173

.

Where R is the gas constant, T is the absolute temperature (K), E is the Young’s

modulus (Pa) and is the specific density of the hydrogel (gm/ cm3). The effective

molecular weight of the polymer chain between cross linking point is commonly related to

the degree of cross linking in the gel X as174

.

Here, Mo is an estimate of the molecular weight of the units.

● Mesh Size

is the distance between sequential cross linking point, which represent an estimate

of available space between the macromolecular chain accessible for the following

equation35

14

Where Cn is the Flory characteristic ratio which is a constant for a given polymer-

solvent system, l is the carbon-carbon bond and Mr is the weight of the repeating units from

which the polymer chain is composed.

1.4 Swelling Behaviour of Hydrogel

The most important properties of the hydrogel are their ability to swell when in

contact with compatible solvent. When a hydrogel in its initial state is in contact with

solvent molecule, the solvent affects the hydrogel surface and penetrates into the polymeric

network. In this case a transition of polymer chain from glassy to rubbery takes place.

Regularly the meshes of the network in the rubbery phase will start expanding, allowing the

solvent molecule to penetrate within the hydrogel network causing swelling of hydrogel.

The hydrogel continuously swells until there is a balance between the osmotic force and

elasticity of the polymer.

The swelling of the hydrogel is affected by several factors like cross-linking ratio,

chemical structure of hydrogel and environmental condition of the swelling medium. The

cross-linking ratio is one of the most important factors that affect the swelling of the

hydrogels. The higher the cross linking ration, more the cross-linking agent incorporating in

the hydrogel structure. Highly cross linked hydrogels have a tighter structure and will have

less swelling compared with lower cross link hydrogels, because, cross-linking hinders the

mobility of the polymer chain. Hydrogels containing hydrophilic groups swell to higher

degree compared to those containing hydrophobic groups. Hydrophobic groups collapse in

the presence of the water molecules. The swelling of some hydrogels may depend on the

environmental condition of the swelling medium. The swelling is affected by temperature,

pH, ionic strength or even presence of electric or magnetic field or ultraviolet

light4,9,13,20,24,26

.

1.4.1 Kinetics of Hydrogel Swelling

1.4.1.1 Rate of Swelling

One of the most important feature of hydrogel swelling is the rate of swelling which

is determined by several physicochemical parameters particularly the extent of porosity and

15

the type of porous structure. In this relation, hydrogel may be classified into four classes,

non porous, microporous, macroporous and super porous hydrogel as given in table1.1

Table1.1 Rate of swelling on the basis of porosity of the Hydrogels.

Type Morphology Type of

absorbe

d water

Major

swelling

mechanism

Swelling

rate

Application

Non-porous

Microporous

Macroporous

Super porous

Without

network

porosity

Various

porosity with

closed cell

structure

(100-1000Å)

Various

porosity with

closed cell

structure (0.1-

1 μm)

Highly

porosity with

interconnecte-

d open cell

structure

Mostly

bound

Mostly

bound

Mostly

bound

Mostly

bound

Diffusion

through free

volume

Combination

of molecular

diffusion and

convection in

the water

filled pores

Diffusion in

the water

filled pores

Capillary

forces

Very slow,

sample

size

dependent

Slow

sample

size

dependent

Fast,

sample

size

dependent

Vary fast

sample

size-

dependent

Various uses

from contact

lenses, artificial

muscles etc.

Mainly in

biomedical

application and

controlled

release

technology

Mainly in form

of super

absorbent in

baby diapers etc

DDS(particularly

in the

gastrointestinal

tract) tissue

engineering etc

16

1.4.1.2 Fickian and non-Fickian Swelling

Swelling is a process of transition from glassy or partially rubbery state to a relaxed-

rubbery region. It is well known that sorption processes of polymer cannot be explained

completely with the classical theory of diffusions175

. The most commonly used empirical

equations to determine the polymeric networks are given below176, 177

.

Where, Wt and W∞ are the swelling ratios at time t and equilibrium time

respectively. K is the swelling rate front factor and n is the swelling exponent describing

the Fickian and non-Fickian swelling mechanism. If the value of n = 0.5 then the diffusion

process is Fickian and if the value of n lies between 0.5 to 1.0 than the diffusion process is

non-Fickian. Taking the logarithm of the equation (1.6)

ln (Wt/ W∞)= ln k + n lnt ----------(1.7)

From this equation the value of k and n can be calculated from the slope and

intercept in ln(Wt/ W∞) against ln t plot respectively. The following equation can be used to

calculate the diffusion coefficient D178

.

Where D is the coefficient constant of water (cm2/s) and l is the thickness of the dry

hydrogel. The slope of the straight line obtained from a plot between Wt/ W∞ and √t gives

the value of D.

Diffusion coefficient179

is very sensitive to substances which diffused in the

polymer than the viscosity of liquids. The factor which affects the diffusion are the

segmental mobility of the polymer chain, temperature, pressure, crystallinety, of the

polymer glass transition, viscosity, solute size etc.

17

1.4.1.2.1 Fickian Diffusion:

Fickian or case I transport is often observed when the glass transition temperature of

the polymer Tg is well below the experimental temperature. In this case the polymer chains

have a high mobility and the water penetrates more easily in the rubbery polymer network.

Therefore, the solvent diffusion rate Rdiff is slower than the polymer chain relaxation rate,

Rrelax ( Rdiff<< Rrelax ). The diffusion distance is proportional to the square root of time.

Mt = kt1/2

----------- (1.9)

1.4.1.2.2 Non-Fickian Diffusion

Non-Fickian diffusion is generally observed in glassy polymer i.e. when Tg of

polymer is well above the experimental temperature. In this case the polymer chains are not

adequately mobile to permit fast penetration of water into the polymer core180

. Non –

Fickian diffusion process has been studied by many groups181-184

. Depending on the relative

rate of chain relaxation and diffusion, non-Fickian diffusion is classified into two types

“case II diffusion” and “anomalous diffusion” (fig.1.5).

Case II diffusion is often observed when the diffusion rate is faster the than polymer

chain relaxation ( Rdiff>> Rrelax). Here, the rate of mass uptake of diffusion is commonly

observed when solvent have higher activities185

. Here, the diffusion is directly proportional

to time.

Mt = kt ---------------------(1.10)

The anomalouse diffusion is observed when the diffusion and chain relaxation rate

are comparable same order. ( Rdiff ~ Rrelax).

18

Fig.1.5 Mechanism of caseII and anomalous diffusion. (Adopted from Ref 186)

1.4.2 Theories for Explaining the Swelling

There are several theories for the explanation of the swelling behaviour of the

hydrogels. Some of them are mentioned below-

Earlier the swelling of hydrogels is explained on the basis of global macroscopic

and microscopic theories187

. For instance, the swelling ratio of polyelectrolyte gels is well

explained through statical theory. The macroscopic theory is applied to chemical and also

thermal stimulation188,189

. For example the experimental results of swelling of N-

isopropylacrylamide hydrogels in water and aqueous solution of the ethanol and acetone are

well analyzed by statical theory189

.

Theory of porous media is an example of macroscopic or mesoscopic continuum

theory. This theory is based on the theory of mixtures extended by the concept of volume

fraction190

. Through this homogenized model, all physical and geometrical quantities are

considered as the averages of the real data. This theory is formulated simply by the

conservation equation for the different constituents, while the local porous microstructure

and the real geometrical distribution of all the elements are unknown.

19

The discrete element theory describes the micromechanical behaviour of hydrogels.

The hydrogel network is characterized by distributing particle interacting with each other

mechanically191

.

Recently, the swelling behaviour of polyelectrolyte gels under electrochemical

stimulation was investigated by Wallmersperger et al. applying different modeling

strategies187

. In the statistical analysis, the porous media and the discrete element theory

models only the hydrogel network was investigated.

Based on the work of Wallmersperger, a chemoelectromechanical model was

developed by Li et al, to simulate the swelling and shrinking of hydrogels180

. The ionic

fluxes within both the hydrogel and solution, the coupling between the electric field, ionic

fluxes and mechanical deformations of the hydrogel are well accounted in this model.

Lai’s group developed a triphasic chemo electro-mechanical model to describe the

behaviour of soft tissue, such as charged hydrated tissues192

. This theory was verified for

the one dimensional equilibrium results of the swelling, while neglecting geometrical non-

linearities. In this model, an assumption of “electroneutrality” condition is made thereby

constraining the application range to a few particular cases193,194

.

1.4.3 Thermodynamics of Equilibrium Swelling

The thermodynamics of gel swelling has been investigated for many years. Interest

in this subject accelerated in the late 1990s upon reports by Tanaka et al of swelling

phenomena in polyacrylamide gels195

. The equilibrium swelling is obtained when the

solvent inside the network is thermodynamically in equilibrium with that outside. The

equilibrium state can be described by chemical potential of solvent in gel (g) and liquid (l)

phases respectively, which must be equal inside (µ1g) and outside (µ1

l) the gel

196.

µ1g = µ1

l …………………(1.11)

Based on Flory-Rehner theory197

free energy change of ionic hydrogel,

corresponding to the volume change during swelling ΔGtotal is the sum of change of free

20

energy of mixing ΔGmix, change of elastic free energy ΔGel and change of ion free energy

ΔGion.

ΔGtotal = ΔGmix + ΔGel + ΔGion …………….(1.12)

With the framework of Frory-Rehnar theory the osmotic pressure π for the swelling

of the hydrogel can be expressed as the component contribution to ΔG198

.

Where, V1 is the molar volume of the solvent. According to the Frory- Rehnar

theory197

, the osmotic pressure can be written as:

π= πmix + πelas + πion + πel ……………….(1.14)

Where πmix is the mixing free energy term, πelas is the elastic contribution connected

with the deformation of polymeric network, πion is the ionic contribution due to the

difference in ion concentration between the gel and the liquid phase, and πel is the

electrostatic contribution deriving from the repulsive effects between equal charges present

in the network. According to Flory-Huggins theory199

:

Where 2 is the polymer volume fraction, R is the universal gas constant, T is the

temperature, and is the Flory interaction parameter, related to the difference between the

free energies of a polymer segment-segment, and polymer-solvent interactions.

In the most general case, the elastic term could be calculated by assuming that the

real structural conditions of the polymeric network are somewhat intermediate between two

21

opposite ideal limits, corresponding to the affine and the phantom networks, respectively162-

200-203. The affine theory is the simplest one which can be expressed by following equation.

Where ρx is the crosslink density (mole/cm3) and 2

0 is the polymer volume fraction at the

reference state.

From Donnan equilibrium theory204,199,201

, the osmotic pressure of mobile ion within

the gel and external phase can be derived:

where i is the ionisation degree multiplied by the valence of the ionisable chain

groups, c2 is the polymer concentration cs* and cs are the salt concentrations in the external

solution and in the gel phase respectively, v(= v++v-) is the sum of the positive and negative

valences of the dissociating salt, and Z is the valence of the ions present in the polymer

chains. In the case of monovalent ions present both in solution and on the polymeric chains,

v = 2 and eq. (1.17) becomes:

Where Vu is the molar volume of the monomer. From the above assumptions the

equilibrium swelling of a polyelectrolyte gel/solution can be derived from the following

equation:

22

1.5 Hydrogel in Controlled Drug Delivery

In the last 100 years, drug delivery system has enormously increased their

performances, moving from simple pill to sustained/controlled release and sophisticated

programmable delivery systems. Meanwhile drug delivery has also become more specific

from system of organ and cellular targeting205

.

Traditional delivery systems are characterized by immediate and uncontrolled drug

release kinetics. Accordingly drug absorption is essentially controlled by the body’s ability

to assimilate the therapeutic molecule and thus drug concentrations in different body tissue

such as the blood, typically undergoes an abrupt increase followed by a similar decrease.

Therefore, drug concentration may dangerously approach to the toxic threshold to

subsequently fall down below the effective therapeutic level. Repeated administration does

not completely prevent above drawback206

. On the other hand controlled release systems

(CRS) overcome the drawback in the traditional delivery system.

Controlled release is a system that delivers the drug at a controlled rate or require

concentration in the blood or in the target tissues as long as possible. In other words, they

are able to exert on the drug release rate and duration and able to localize drug action to

where it is needed or to a particular cell type207

. CRS initially releases part of the dose in

such an order so that the target sites rapidly get the drug effective therapeutic concentration.

Then, drug release kinetics follows a well defined behaviour in order to supply the

maintenance dose enabling the attainment of the desired drug concentration. This step is

considerably influenced by drug removal kinetics due to different factors such as

metabolism206

. In the light of wide versatility CRS are unavoidable tools for the modern

concept of therapeutic treatment whose aim is to increase drug effectiveness and patient

compliance with less side effects of drug.

In the last 20 years, advanced controlled drug delivery system has become very

important. Because in many diseases such as diabetes208

, heat disease209

, thyroid disease210

23

the administration of drug is required only specific site and time interval. These leads to

stimuli sensitive drug delivery systems where drug is release only in response to metabolic

requirements or in the presence of specific stimuli. The major classes of biomaterials used

in advanced drug delivery system as a carrier matrix are hydrogels. Hydrogels have a

special attraction as a drug carrier matrix due to its softness, rubbery texture, resemblance

to the natural living tissue and biocompatibilities.

1.5.1 Types of Controlled Release System:

According to the release behaviour, controlled release system can be subdivided

into three categories207

.

(i) Passive pre-programmed:

Here release rate is predetermined and is responsive to external biological stimuli.

(ii) Active pre- programmed:

Here release rate can be controlled by a source of external to the body as in the case of

insulin delivery.

(iii) Active self-programmed:

This category representing the feature of CRS is characterized by delivery system whose

release rate is controlled by biological stimuli such as sugar concentration in blood211,212

.

Again on the drug release mechanism the controlled release system can be classified into

three categories35

:

(i) Diffusion controlled (drug diffusion from the non-degraded polymer)

(ii) Chemically controlled (enhanced drug diffusion due to polymer swelling)

(iii) Swelling controlled. (drug release due to polymer degradation and erosion)

1.5.2 Advantage of Controlled Release

The main advantages of controlled release system are its reproductive rate and can

deliver drugs for a prolonged period of time. A drug delivery vehicle positioned in the

proximity of the site of disease or injury can release the drug in the desired location, this

way reducing the side effects that usually result from systemic administration. Additionally,

depending on the crosslinking density, the hydrogels structure can restrict the diffusion of

24

macromolecules, being able to deliver the therapeutic agent over extended periods of time.

Indeed, improvement in patient compliance and extension of product life are major

advantages of the drug delivery systems213,214

.

1.5.3 Factors Affecting the Drug Release Rate

The release of drug depends on several factors like swelling of hydrogel, properties

of solvent or release medium, properties of drug etc. Swelling is the basic factor on which

drug release depends. Because the drug is released after the water molecule penetrate inside

the polymer matrix. Therefore the drug release rate is depended on solvent diffusion rate,

polymer chain relaxation rate, solubility of drug, hydrodynamic radius of drug and polymer

mesh size and general interaction between drug, polymer and solvent. Similarly properties

of solvent or release medium like strength of stimuli such as pH, temperature, light, electric

field, biological binding/ unbinding events and rate of change of polymer chain

salvation/modification can affect release rate. Properties of drug like multiplicity and

variability of chemical functionalities, monomer to template ratio can also affect the drug

release rate.

1.5.4 Drug Loading

The drug can be entrapped within the polymer by two methods. One method is

chemical entrapment and another is physical entrapment. In chemical entrapment the drug

is entrapped at the time of preparation of polymer by mixing required amount of drug with

monomer solution along with initiator and with or without crosslinker. In physical

entrapment the drug is entrapped by allowing the hydrogel to equilibrate at drug solution

till equilibrium. The physical entrapment method has some advantages over chemical

entrapment method, in case of activity of the drug. Sometimes the active site of the drug

may blocked by acetylation, methylation etc. The percentage of drug entrapment into the

hydrogel is calculated by following equation.

25

Where Wd and Wo are the weight of drug loaded and blank hydrogel respectively.

1.5.5 Kinetics of Drug Release

Drug release kinetics may be affected by many factors such as polymer swelling,

polymer erosion, drug dissolution/diffusion characteristic, drug distribution inside the

matrix, drug/ polymer ratio and system geometry (cylinder, sphere, film etc)215,216

. The

release of drug occurs only after when the solvent penetrate into the polymer matrix to

swell the polymer and dissolved the drug followed by diffusion along aqueous pathways to

the surface of the device. When the polymer contacts the release medium the swelling of

polymer and drug dissolution take place. As soon as the solvent concentration becomes

higher than the threshold value, glassy to rubbery polymer transition occurs in the polymer

chain and a gel like layer, surrounding the matrix dry core, begins to appear217-219

.This

transition implies a molecular rearrangement of polymeric chains that tend to reach a new

equilibrium condition as the old one was altered by the presence of the incoming solvent

220. So the release kinetics are related with the swelling of the hydrogel. The release kinetics

of drug can be explained with Ritger-Peppas model221

.

Mt/M∞= ktn ----------- (1.21)

In the above equation, Mt/M∞ is the fraction of drug release at time t, k is a constant

related to the properties of the drug delivery system and n is the diffusion exponent, which

characterizes the drug release mechanism. Peppas and coworkers were first introduced and

give the limitations of these equations222

. A value of n = 0.5 indicates the release follows

the Fickian diffusion (diffusion controlled drug release); when n = 1, case II transport

occurs (swelling controlled drug release) and when n value lies between 0.5 to 1 (0.5<n<1)

anomalous transport occurs. It is clear that when the value of exponent n is 1.0, the drug

26

release rate is independent of time (the case of the so called zero-order release kinetics)222

.

For spheres and cylinders different values have been derive223,224

as listed in Table1.2.

In case of anomalous transport Peppas-Sahilin model225

is applicable to describe

the release behaviour of dynamically swelling hydrogel.

Mt/M∞ = At1/2

+ Bt ----------

(1.22)

Where A and B are diffusion and erosion terms respectively. Where A>B, erosion

predominates. If A=B, then the release mechanism includes both diffusion and erosion

equally226

.

Table 1.2. Exponent n of the power law and drug release mechanism

from polymeric controlled delivery systems of different geometry

Diffusion exponent (n)

Drug release mechanism

Film Cylinder Sphere

0.5 0.45 0.43 Fickian diffusion

0.5<n<1.0 0.45<n<0.89 0.43<n<0.85 Anomalous transport

1.0 0.89 0.85 CaseII transport

1.5.6 Stimuli Sensitive (pH and temperature) Drug Delivery

Stimuli sensitive hydrogels have the ability to respond to changes with external

environments. They show a change in their swelling as well as drug release, network

structures, permeability, mechanical strength in response to pH, temperature, ionic strength,

electric and magnetic field, mechanical forces, ultraviolet light and the presence or absence

of specific molecules of the surrounding fluid35

. Because of these stimuli sensitiveness

hydrogel have a good application in pharmaceutical field.

27

Hydrogel containing ionic networks shows pH sensitivity. This ionic networks

contains either acidic or basic pendant groups35,227,228

. In aqueous media of appropriate pH

this pendant group can ionize, developed fixed charge on the gel. As a result electrostatic

repulsion between the charged groups along the chain and uptake of water in the network

increased. Ionic hydrogels containing pendant group such as carboxylic or sulfonic acid,

show certain or gradual changes in the equilibrium swelling behaviour to change to the

external environment. The ionization of this type of gel occurs when the pH of the

environment is above the pka of the ionization group. As the degree of ionization increase

the electrostatic repulsion and swelling of the hydrogel increases. On the other hand

cationic materials contain pendant group such as amines, ionize when the pkb value of the

environment is below the ionisable species35

. Thus at low pH the electrostatic repulsion

increases which causes a rise in swelling ratio.

The thermo sensitive hydrogel has attractive application in biomedical field due to

capability of swelling and deswelling with change in temperature. Thermosensitive

hydrogels can be classified as positive or negative temperature-sensitive systems. A

positive temperature- sensitive hydrogel has an upper critical solution temperature (UCST).

Such hydrogels contract upon cooling below the UCST. Negative temperature-sensitive

hydrogels have a lower critical solution temperature (LCST). These hydrogels contract

upon heating above the LCST. Many researchers have studied the release dynamic of pH

and temperature sensitive networks. Some of them are given below:

A novel pH-sensitive hydrogel based on dual crosslinked alginate/N-α-glutaric acid

chitosan (GAC) was prepared by Gong et al229

. The swelling behaviours of hydrogels and

protein Bovine serum albumin (BSA) release were investigated in simulated gastric fluid

(SGF), simulated intestinal fluid (SIF) and simulated colonic fluid (SCF). The amount of

BSA released from the beads at pH 1.2 was relatively low in comparison with pH 7.4.

Naiyan Zhang and his coworker230

had prepared semi-IPN hydrogels

based on poly((2-dimethylamino)ethylmethacrylate)/poly(N,N-diethylacrylamide)

(PDMAEMA/PDEA) by changing the initial PDMAEMA/DEA molar ratio at room

temperature and characterized by SEM and DSC. Equilibrium swelling ratio (ESR),

swelling and deswelling dynamics of the hydrogels study with respect to temperature and

28

pH shows fast swelling and deswelling rates in response to temperature and pH change.

The release behaviours of the model drug, aminophylline, were found dependent on

hydrogel compositions and environmental temperature.

Alginate(AG) hydrogels containing biocompatible Laponite (LP) were prepared and

studied the release behaviour of methylene blue (MB) as a model of a cationic drug by Li et

al231

. These hybrid hydrogels showed a greater encapsulation efficiency of MB and a better

sustained release. Their drug release properties at different pH values were greater for

hybrid hydrogel in comparison to the pure AG gels.

A new pH/temperature sensitive hydrogel bead (HME) with core-shelled structure

as a drug delivery system was prepared using N-acryloylglycinate and sodium alginate by

Deng et al232

. The caffeine release studies show that 62.2% drug was released from the

sensitive beads in pH 2.1 within 300 min, whereas 99.3% drug diffused into the medium at

pH 7.4 at 37℃. The significantly higher release was observed at higher temperature than at

lower temperature. In addition the release amount of drug was decreased with increasing

polymer content.

A novel pH-sensitive polyvinylpyrrolidone/acrylic acid (PVP/AA) hydrogels were

synthesized by free radical polymerization using ethylene glycol dimethacrylate (EGDMA)

as a cross-linker by Hussain et al233

and characterized by FT-IR, SEM and XRD. The

swelling of hydrogel increased with increasing pH from 1.2 to 7.5. The release of tramadol

hydrochloride from the PVP/AA hydrogel follows non-Fickian and the mechanism

followed diffusion controlled.

Liu and his co worker234

had prepared a novel pH/temperature sensitive hydrogel

bead (pTSB) with core-shelled structure from poly(N-acryloylglycine) (PAG), copoly(N-

acryloylglycine methyl este and N-acryloylglycine ethyl ester). The indomethacin release

shows 60.1 % within 500 mins was released in pH 7.4, but 22.3 % is achieved in pH=2.1.

The release rate of indomethacin was much faster at 18oC than that at 37

oC due to the

temperature sensitivity of poly(N-acryloylglycinates).

Semi-IPN composed of chitosan and PVP were prepared by crosslinking with

glutaraldehyde by Vaghani et al235

. These semi-IPNs were studied for their content

uniformity, swelling index (SI), mucoadhesion, wettability, in vitro release of repaglinide

29

and their release kinetics. The swelling ratio of hydrogel is higher at acidic medium and the

release of repaglinide completed at 12h and follows non Fickian diffusion mechanism. The

results of study suggest that semi-IPNs of Chitosan/PVP are potent candidates for delivery

of repaglinide in acidic environment.

Huynh and his coworker236

had prepared a low molecular weight biodegradable

pH/temperature-sensitive multiblock copolymer hydrogels composed of poly(ethylene

glycol) (PEG) and poly(β-amino ester urethane) (PAEU). The hydrogel was characterized

by 1H and

13C NMR, FT-IR and gel permeation chromatography. The non-cytotoxicity of

this hydrogel was confirmed by in vitro cytotoxicity test and the in vitro release of

doxorubicin from this hydrogel was sustained for more than 5 weeks. This novel injectable

biodegradable pH/temperature-sensitive hydrogels can be a potential candidate as drug

carriers.

A novel jujube cake-like pH/temperature responsive hydrogel (PME), was obtained

from N-acryloylglycinate methyl ester (AGME) and N-acryloylglycinate ethyl ester

(AGEE), using sodium laurate (SL) as an emulsifier and MBA as a crosslinking agent. The

indomethacin release behaviours were investigated by Liu et al237

and found that 48%

indomethacin from the hydrogel PME was released in pH 7.4 PBS at 18oC within 600

minutes, whereas only 17% indomethacin diffused into pH 2.1 PBS.

A pH/temperature and degradable-responsive hydrogel (PSMEA) was prepared by

Deng et al238

from chitosan (CS), N-acryloylglycine methyl ester (NAGME), N-

acryloylglycine ethyl ester (NAGEE), acrylic acid (AA), and N-methylenebisacrylamide

(NMBA). The swelling study indicated that the gel is temperature and pH sensitive. The

caffeine-release behaviours showed that only 42.9% caffeine was released in pH 2.1 and

71.5% in pH 7.4 and release rate higher at 37.0°C than that at 14.0°C. The gel degrades at

pH 7.4 PBS at 37.0°C through the chemical cleavage of CS.

A series of pH/temperature sensitive hydrogel beads with semi-interpenetrating

polymer network (semi-IPN), composed of sodium alginate and poly(N-acryloylglycinate)

were prepared by Liu et al239

. The release amount of indomethacin is only 9% at pH 2,3,

but it rise to 68% in pH=7.4 PBS. The release rate of indomethacin was higher at 370C than

30

that at 200C . These results suggest that the stimuli-sensitive beads have the potential to be

used as an effective pH/temperature delivery system in bio-medical fields.

Poly (methacrylic acid)-chitosan (PMC) and poly(methacrylic acid-vinyl

pyrrolidone)-chitosan (PMVC) microparticles were prepared by an ionic-gelation method

by Sajeesh et al240

. Mucoadhesion behaviour study showed that the addition of NVP units

enhanced the mucoadhesion behaviour of PMC particles on isolated rat intestinal. Both

PMC and PMVC particles were found non-toxic on Caco 2 cell monolayers and PMC

particles was more effective in improving the paracellular transport of fluorescent dextran

across Caco 2 cell monolayers as compared to PMVC particles. NVP incorporation

improved the insulin release properties of PMC microparticles at acidic pH.

Yinjuan Huang1 and his cowork241

had prepared a novel triple-responsive poly (3-

acrylamidephenylboronic acid-co-(2-dimethylamino) ethyl methacrylate) /(β-cyclodextrin-

epichlorohydrin) (P (AAPBA-co-DMAEMA) /(β-CD-EPI)) semi-interpenetrating (semi-

IPN) and characterized by FT-IR and SEM. The results from swelling studies reveal that

the equilibrium swelling ratios of semi-IPN hydrogels are significantly affected by pH,

temperature, ionic strength and glucose concentration of the swelling media. Release

studies of aminophylline and ibuprofen, show that the drug loading ratio of hydrophobic

drugs is apparently higher than that of hydrophilic drugs. It is also depicted that the release

behaviours of hydrogels depend on pH, glucose concentration and solvent type of release

medium.

Delia et al and coworker242

used N-ethyl-N-(3-dimethylaminopropyl)-carbodiimide

hydrochloride (EDC) and N-hydroxysulfosuccinimide (NHSS) as coupling agents to

crosslink succinic derivatives of inulin (INU-SA) with two different degrees of

derivatization (20% and 30%, mol/mol) with α,β-polyaspartylhydrazide (PAHy) to obtain

INUPAHy hydrogels. All samples prepared were characterized by FT-IR analysis and

swelling measurements in different media. Glutathione (GSH) and oxytocin (OT), were

entrapped into a INUPAHy hydrogel and their release was evaluated in simulated

gastrointestinal fluids. The obtained results suggest that GSH- and OT-loaded INUPAHy

hydrogels are potentially useful for the oral treatment of inflammatory bowel disease.

31

Ananthoji et al243

had prepared a novel composites of a hydrogel with a zeolite-like

metal–organic framework, rho-ZMOF, using 2-hydroxyethyl methacrylate (HEMA), 2,3-

dihydroxypropyl methacrylate (DHPMA), N-vinyl-2-pyrolidinone (VP) and ethylene

glycol dimethacrylate (EGDMA) by ultraviolet (UV) polymerization method and its

release behaviour was investigated by using procainamide (protonated, PH), an anti-

arrhythmic drug, in phosphate buffer solution (PBS) using UV spectroscopy.

Jun et al244

had synthesised poly(N,N-diethylacrylamide-co-(2-dimethylamino) ethyl

methacrylate) (poly(DEA-co-DMAEMA)) hydrogels by changing the initial

DEA/DMAEMA mole ratio. The hydrogels were characterized by FT-IR,SEM. The

deswelling and reswelling kinetics and cytotoxicity of the different composition ratios of

DEA to DMAEMA in the co-polymerized hydrogels were also investigated in detail. The

absorption and release behaviour of the model drug, bovine serum albumin, were found to

be dependent on hydrogel composition and environment temperature, which suggests that

these materials have potential application as intelligent drug carriers.

Moogooee245

and his coworker reported the synthesis and characterization of a

novel cross-linked N-isopropylacrylamide-acrylic acid-hydroxyethyl methacrylate [P

(NIPASM-AA-HEM)] hydrogel nanoparticles (NPs) containing amoxicillin. The

entrapment efficiency (EE%), mean diameter, and morphology of NPs was evaluated. The

profile of amoxicillin release from hydrogel was studied under various conditions and

found that the drug release is reduced as concentration of the polymer in the formulation

rises. Amoxicillin release rate was higher in pH 1 than pH 7.4.

Davaran et al246

modified bovine serum albumin (BSA) with poly(ethylene glycol)

citrate ester (PEG–CA) through amidation with its amino groups. Adriamycin (ADR)-

loaded PEG–CA–BSA hydrogels and microparticles were prepared, and the ADR released

from the hydrogels (pH 7.4) showed that hydrogels had lower ADR release rates with a

slight initial burst release. The release rates of ADR from the microparticles were

dependent on the amount of glutaraldehyde and PEG–CA/BSA molar ratio. Higher release

rates were observed for microparticles with a lower amount of BSA in the conjugates in a

pH-dependent manner.

32

A novel drug (ketorolac) loaded nanocomposite hydrogel film contact lens was

prepared by Xu et al247

with 2-hydroxyethyl methacrylate (HEMA). In the hydrogel matrix

MgAl-layered double hydroxide (MgAl-LDH) nanoparticles intercalated with the anionic

drug were well dispersed. TEM images show that these nanoparticles 40-200 nm were

evenly dispersed in the hydrogel matrix. In vitro release tests of hydrogel-LDH-drug in pH

7.4 PBS solution at 32 °C indicate a sustained release profile of the loaded drug for 1 week.

The drug release undergoes a rapid initial burst and then a monotonically decreasing rate up

to 168 h.

A novel pH-sensitive hydrogel system composed of itaconic acid (IA) and N-[3-

(dimethylamino) propyl] methacrylamide was prepared by aqueous copolymerization with

MBA as a chemical crosslinker and characterized by FTIR, XRD and SEM by Mishra et

al248

. Swelling experiments were carried out in buffer solutions at different pH values (1.2–

10) and temperature at 20–70°C. The hydrogels swells maximum at low pH and high

temperature. 5-Aminosalicylic acid (5-ASA) release experiments were carried out under

simulated intestinal and gastric conditions and was found to follow non-Fickian diffusion

mechanism under gastric condition and a super case II transport mechanism was found

under intestinal conditions.

Kevadiya et al249

has prepared an intercalation of lidocaine hydrochloride (LC), an

antiarrhythmic local anesthetic drug into montmorillonite (MMT) as a controlled release

drug carrier and characterized by powder X-ray diffraction, FT-IR, particle size,

electrokinetic mobility and thermal analysis. MMT-LC was compounded with alginate

(AL) to form a hydrogel composite and to study its release response in gastric

environments. The in vitro release experiments revealed that LC was released from

MMT/AL in a controlled way which was pH dependent.

A novel physically cross-linked, injectable poly(N-acryloylglycine) (PNAG)

hydrogel was synthesized by Deng et al250

and characterized by FTIR and1H NMR. The

swelling behavior of hydrogel PNAG was investigated at different temperatures and PNAG

concentrations. It was found that the PNAG hydrogel demonstrates distinct temperature

responsive nature. In vitro drug release behaviour of caffeine showed that the release rate of

33

caffeine from PNAG hydrogel apparently dropped as PNAG concentration of the system

was increased, while the temperature and pH decreased.

The hybrid hydrogel composed of Fmoc-diphenylalanine (Fmoc-FF) peptide and

konjac glucomannan (KGM) was prepared through molecular self-assembly of Fmoc-FF in

the KGM solution by Huang et al251

. This hybrid hydrogel exhibited a highly hydrated,

rigid and nanofibrous gel network in which self-assembled peptide nanofibers were

interwoven with the KGM chains. The results of a stability test and rheology study showed

that the hybrid hydrogel has much higher stability and mechanical strength compared to

Fmoc-FF hydrogel alone. The sustained and controlled drug docetaxel release from this

hybrid hydrogel was achieved by varying the KGM concentration, molecular weight, aging

time or β-mannanase concentration.

A novel hydrogels, composed of carboxymethylchitosan (CMCS), cellulose ethers

including hydroxyethylcellulose (HEC) and methylcellulose (MC) are prepared by Yan et

al252

and characterized by IR, XPS, WAXD, and SEM. The swelling and controlled drug

release behaviours study indicated the swelling and drug release rate of hydrogels decreases

as the interaction of component polymers increases. Both the swelling and drug release

from hydrogels can be controlled by component polymer ratio.

1.6 Objectives of the Present Work

While reviewing the literature of earlier works, it is observed that hydrogels have

large application in controlled drug delivery, artificial implants, soft contact lens, tissue

engineering, wound dressings and dialysis membrane. Looking at the great usefulness of

hydrogel matrices in biomedical and allied fields and realizing the physical significance of

APMS based hydrogels in this field the present work is aimed to synthesis AMPS based

polymer system which could exhibit good swelling behaviour with desired mechanical

strength and have potential applicability for controlled drug delivery. The main objectives

of the present research work include:

1. Preparation and characterization of AMPS based hydrogels.

34

2. Study of swelling behaviour of the prepared hydrogel and evaluation of various

kinetic parameters of the swelling process. It is also aimed to observe the effect of

different hydrophilic and hydrophobic monomers, pH, temperature and electrolytes

on the swelling behaviour of the gels.

3. Loading of drugs tetracycline, an antibiotic drug and brufen an analgesic drug into

the prepared hydrogels and study of their in-vitro drug release behaviour under

different experimental environment such as pH of the release medium,

concentration of monomers, loading of drug on device etc.

4. Preparation of nano composite hydrogel and compare their swelling and drug

release behaviour with prepared hydrogels.