Hydrogels, introduction, historical background, properties, classification, difference between chemical and physical hydrogels, common uses, pharmaceutical applications, preparation methods, list of monomers used, analytical machines, advantages, disadvantages, conclusion

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Gono Bishwabidyalay
Nolam, Saver, Dhaka
8th
Semester
Assignment on: Industrial Pharmacy &
Pharmaceutical Technology-IV (Pharm- 4801)
Assignment Topic: Hydrogels
Submitted To:
Dr. Pijush Kumar Paul
Professor
Department of pharmacy, GB
Submitted By:
Group: G
Batch: 32nd
Semester: 8th
Department of pharmacy, GB
Submission date: 25th
April 2021

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INDEX
Main
topic
Sub-topic Page no
Hydrogels
Abstract, introduction,
historical background,
properties, classification,
difference between
chemical and physical
hydrogels, common uses,
pharmaceutical
applications, preparation
methods, list of
monomers used,
analytical machines,
advantages,
disadvantages,
conclusion.
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Hydrogels
Abstract:
The method by which a drug is delivered can have a significant effect on its
efficacy. Some drugs have an optimum concentration range within which
maximum benefit is derived, and concentrations above or below this range can be
toxic or produce no therapeutic benefit at all.
To minimize drug degradation and loss, to prevent harmful side-effects and to
increase drug bioavailability and the fraction of the drug accumulated in the
required zone, various drug delivery and drug targeting systems are currently under
development.
Among drug carriers one can name soluble polymers, micro particles made of
insoluble or biodegradable natural and synthetic polymers, Microchips,
microcapsules, cells, cell ghosts, lipoproteins, liposome’s, and micelles. The
carriers can be made slowly degradable, stimuli-reactive (e.g., pH or temperature-
sensitive), and even targeted.
Introduction
Hydrogels are water-swollen, cross-linked polymeric structures produced by
reactions of monomers or by hydrogen bonding.
Hydrogels are composed of two constituents.
➢ One constituent is hydrophilic polymers like polyvinyl alcohol, sodium
polyacrylate, acrylate polymers and copolymers.
➢ second constituent is water.
Hydrogels can contain over 99.9% water, thus may absorb from 10-20% up to
thousands of times their dry weight in water.
Hydrogels possess the hydrophilic quality which makes them a good analog for
natural tissues and they even tend to mimic the flexibility and other textural
qualities of biological media.
Cross linked structure of hydrogels is characterized by junctions or tie points,
which may be formed from strong chemical linkages (such as covalent and ionic
bonds), permanent or temporary physical entanglements, micro crystallite
formation, and weak interactions (such as hydrogen bonds).

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Hydrogels are ideal for controlled drugs, proteins, hormones and growth factors
delivery.
Hydrogels under mechanical stress can exhibit a range
of responses from rapid, elastic recovery following an
applied stress or strain to a time-dependent recovery
approaching viscous behavior.
Thus, in short Hydrogels can be defined as “Three-
dimensional network of hydrophilic polymer chains
that do not dissolve but can swell in water and made of
natural or synthetic material”.
Historical background
• Hydrogels have existed for more than half century.
• Using Hydrogels have begun for therapeutic applications since the 1954. When
Lim and Wichterle Synthesized Polyhydroxy Methacrylate (PHEMA).
• Used in contact lens production.
• The history of hydrogels can be divided in three main blocks:
First generation: Chemical modifications of a monomer or polymer with an
initiator. The general aim is to develop material with high swelling, good
mechanical properties and relatively simple rationale. chemically crosslinked
networks of synthetic polymers.
Second generation of materials capable of a response to specific stimuli. starting
in the (1970s) seventies.

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Third generation of hydrogels focusing on the investigation and development of
stereo complexed materials (e.g. PEG-PLA interaction (poly lactic acid)) hydrogels
cross linked by other physical interactions (e.g. cyclodextrines), metal-ligand
coordination It leads to the construction of smart hydrogels and starting in the
2010s.
Properties of Hydrogels
Swelling property:
Hydrogels are the swollen polymeric networks, interior of which is occupied by
drug molecules; therefore, release studies are carried out to understand the
mechanism of release over a period of application
➢ Swelling property is influenced by:
• type and composition of monomers
• other environmental factors such as :
- temperature,
- pH,
- ionic strength
- light radiation
- ultrasonic radiation
- magnetic field
- electrical field
• cross-linking (mechanical strength and permeability)

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Rs =
(𝐖𝐬−𝐖𝐝)
𝐖𝐝
Here,
Rs = Swelling ratio
Ws =Weight of swollen hydrogels
Wd = Weight of dried hydrogels
Mechanical properties of hydrogels are very important for pharmaceutical
applications. For example, property of maintaining its physical texture during the
application of drug delivery (both solid like & liquid like)
• Changing the degree of crosslinking has been utilized to achieve the desired
mechanical property of the hydrogel.
Biocompatible properties: It is important for the hydrogels to be biocompatible
and nontoxic in order to make it applicable in biomedical field
• Cell culture methods, also known as cytotoxicity tests, can be used to
evaluate the toxicity of hydrogels.
Classification:
On the basis of Preparation
A. Homo-polymer
B. Copolymer
C. Semi-interpenetrating network
D. Interpenetrating network

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A. Homo-polymer
• Homopolymers are referred to polymer networks derived from single species of
monomer
• It is the basic structural unit and comprising of any polymer network
• Homopolymers may have cross-linked skeletal structure depending on the nature
of the monomer and polymerization technique
• Cross linked homopolymers are used in drug delivery system and in contact
lenses
• Polyetheleneglycol (PEG) based hydrogels are responsive towards external
stimuli and hence these smart hydrogels are widely used in drug delivery system.
B. Co-polymeric hydrogel
• Co-polymeric hydrogels are composed of two types of monomer in which at least
one is hydrophilic in nature.
• Synthesized the biodegradable triblock poly(ethylene glycol)-poly(caprolactone)-
poly(ethylene glycol) (PEG) co-polymeric hydrogel for the development of drug
delivery system.
• The mechanism involve here is the ring-opening copolymerization of
caprolactone (Nylon 6).
C. Semi- Inter Penetrating Network (Semi-IPN)
• If one polymer is linear and penetrates another cross-linked network without any
other chemical bonds between them, it is called a semi-inter penetrating network.
• Semi-IPNs can more effectively preserve rapid kinetic response rates to pH or
temperature due to the absence of restricting interpenetrating elastic network.
• While still providing the benefits like modified pore size & slow drug release etc.
• This pH sensitive semi-IPN was synthesized by co-polymerization in the
presence of N, N′-methylene bisacrylamide as a cross-linking agent.
• The network contained both covalent and ionic bonds.
• The covalent bonds retained the three-dimensional structure of hydrogel and the
ionic bonds imparted the hydrogel with higher mechanical strength and pH
responsive reversibility.

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D. Inter Penetrating Network (IPN)
• IPNs are conventionally defined as intimate combination of two polymers, at
least one of which is synthesized or cross-linked in the immediate presence of the
other.
• This is typically done by immersing a pre-polymerized hydrogel into a solution of
monomers and a polymerization initiator.
• IPN method can overcome thermodynamic incompatibility occurs due to the
permanent interlocking of network segments and limited phase separation can be
obtained.
• The main advantages of IPNs are relatively dense hydrogel matrices can be
produced which feature stiffer and tougher mechanical properties, controllable
physical properties and more efficient drug loading compared to other hydrogels.
On the basis of cross linking
I. Chemical hydrogels
II. Physical hydrogels
Differences between Chemical hydrogels & Physical hydrogels
Chemical Hydrogels Physical Hydrogels
Covalently cross linked Noncovalently crosslinked
• Hydrogen bonding
• Hydrophobic interaction
• Stereo complex formation
• Ionic complexation
Thermoset hydrogels Thermoplastic hydrogels
Volume phase transition Sol-gel phase transition
Reliable shape stability and memory Limited shape stability and memory

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Other various criteria for the classification of Hydrogels
Based on Types
Origin Natural
Synthetic
Structure
Amorphous hydrogels
Semi-crystalline hydrogels
Hydrogen bonded hydrogels
Charge
Neutral hydrogels
Anionic hydrogels
Cationic hydrogels
Ampholytic hydrogels
Water content or degree of swelling
Low swelling
Medium swelling
High swelling
Superabsorbent
Porosity
Nonporous
Microporous
Macro-porous
Super-porous
Mechanism of drug release
Diffusion Controlled Release System
Swelling Controlled Release System
Chemically Controlled Release System
Environment Controlled Release System
Biodegradability Biodegradable
Nondegradable
Common Uses for Hydrogels
Biotechnological use:
• Used as Biosensors that are responsive to specific molecules, such as glucose or
antigens.
Sanitary purpose:
• Used in disposable diapers where they absorb urine, or in sanitary napkins.
Miscellaneous:
• Used as Medical electrodes in ECG.
• Used as Breast implants.

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Pharmaceutical Applications of Hydrogels:
 Peroral Drug Delivery  Drug Delivery in The Oral Cavity
 Drug Delivery in the G.I.T  Ocular Delivery
 Transdermal Delivery  Subcutaneous Drug Delivery
 Hydrogels to Fix Bone Replacements  Protein Drug Delivery
 Topical Drug Delivery  Tissue Engineering
 In the Treatment Lower Extremity Diabetic ulcers.
Peroral Drug Delivery:
• Drug delivery through the oral route has been the most common method in the
pharmaceutical applications of hydrogels.
• In peroral administration, hydrogels can deliver drugs to four major specific sites;
mouth, stomach, small intestine and colon.
• By controlling their swelling properties or bio-adhesive characteristics in the
presence of a biological fluid, hydrogels can be a useful device for releasing
drugs in a controlled manner at these desired sites.
• Additionally, they can also adhere to certain specific regions in the oral pathway,
leading to a locally increased drug concentration, and thus, enhancing the drug
absorption at the release site.
Drug Delivery in The Oral Cavity:
• Drug delivery to the oral cavity can have versatile applications in local treatment
of diseases of the mouth, such as periodontal disease, stomatitis, fungal and viral
infections, and oral cavity cancers.
• Long-term adhesion of the drug containing hydrogel against copious salivary
flow, which bathes the oral cavity mucosa, is required to achieve this local drug
delivery.
Drug Delivery in the G.I.T:
• Hydrogel-based devices can be designed to deliver drugs locally to specific sites
in the GI tract. E.g.: Specific antibiotic drug delivery systems for the treatment of
H.pylori infection in peptic ulcer disease
• These Hydrogels protect the insulin in the harsh, acidic environment of the
stomach before releasing the drug in the small intestine.
Ocular Delivery:
• Silicone rubber Hydrogel composite ophthalmic inserts extended the duration of

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the Pilocarpine to 10 hr, compared to 3 hr when Pilocarpine nitrate was dosed as a
solution.
• In-situ forming Hydrogels are attractive as an ocular drug delivery system
because of their facility in dosing as a liquid, and long-term retention property as
a gel after dosing.
Advantages:
➢ Swollen Hydrogels can deliver drugs for long duration.
➢ Easy to remove.
➢ Patient compliance is high.
Transdermal Delivery:
• Drug delivery to the skin has been generally used to treat skin diseases or for
disinfections of the skin.
• Transdermal route is employed for systemic delivery of drugs.
• The possible benefits of transdermal drug delivery are
- drugs can be delivered for a long duration.
- drugs can be delivered at a constant rate.
- drug delivery can be easily interrupted on demand by simply
removing the devices.
- drugs can bypass hepatic first-pass metabolism.
• Furthermore, because of their high-water content, swollen hydrogels can provide
a better feeling for the skin in comparison to conventional ointments and patches.
Subcutaneous Drug Delivery:
• Subcutaneously inserted exogenous materials may more or less evoke potentially
undesirable body responses, such as inflammation, carcinogenicity and
immunogenicity.
• Therefore, biocompatibility is a prerequisite that makes materials implantable
• Due to their high-water content, hydrogels are generally considered as
biocompatible materials.
• They also provide several promising properties:
- minimal mechanical irritation upon in-vivo implantation, due to their
soft, elastic properties.
- Prevention of protein adsorption and cell adhesion arising from the low
interfacial tension between water and hydrogels;
- Broad acceptability for individual drugs with different hydrophilicities
and molecular sizes
- Unique possibilities to manipulate the release of incorporated drugs by
crosslinking density and swelling.

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Hydrogels to Fix Bone Replacements:
• Provided orthopedic fasteners and replacements hip and knee replacements, etc.
are coated with Hydrogels which expand in the presence of liquids.
• Swelling of such coatings causes the fastener or replacement to be securely fixed
into position once inserted into bone material.
• Coating materials. Ex: Methacrylate, Hyaluronic acid esters.
• Replacements made of stainless steel, metal alloys, titanium or cobalt-chromium,
can be coated with these materials.
Protein Drug Delivery:
• Interleukins are conventionally given as injection.
• Hydrogels have the following advantages
- Better patient compliance.
- Hydrogels form insitu and release proteins slowly
- They are biodegradable and biocompatible.
Topical Drug Delivery:
• Hydrogels are used to deliver drugs like Desonide (synthetic corticosteroid)
usually used as an anti- inflammatory.
• Hydrogels with their moisturizing properties avoids scaling and dryness and has
better patient compliance.
• Antifungal formulations like Cotrimazole has been developed as Hydrogel
formulation for vaginitis and shows better absorption than conventional cream
formulations.
Tissue Engineering:
• Microgels (micronized Hydrogels) can be used to deliver macromolecules like
phagosomes in to cytoplasm of antigen-presenting cells.
• The release is because of acidic conditions. Hydrogels mold themselves to the
pattern of membranes of the tissues and have sufficient mechanical strength. This
property is also used in cartilage repairing.
In The Treatment Lower Extremity Diabetic ulcers:
• Diabetic ulcers are the primary cause of amputations of the leg, foot or toe.
NanoDOX™
• A topical doxycycline Hydrogel for chronic wounds
• NanoDOX™ contains 1% Doxycycline Monohydrate Hydrogel.
• Improve the topical delivery to increase local efficacy.

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Hydrogels Preparation:
Methods:
- Crosslinking
- Isostatic Ultra High Pressure
- Nucleophilic Substitution Reaction
- Using Gelling Agents
- Use of Irradiation
- Freeze Thawing
A. Crosslinking:
Purpose:
➢ To impart sufficient mechanical strength to these polymers
Examples:
➢ Glutaraldehyde,
➢ Calcium chloride
Advantage:
➢ Cross linkers prevent burst release of the medicaments
Drawbacks:
➢ Presence of residue.
Linear polymers
Crosslinking
Chemical compounds
Irradiation
Monomers used in the preparation of the
ionic polymer network contain an ionizable
group, gets ionized, or undergoes substitution
after the polymerization is completed.

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B. Isostatic Ultra High Pressure:
C. Nucleophilic Substitution Reaction:
D. Using Gelling Agents:
Examples:
- Glycophosphate. - 2 Propanediol.
- Glycerol. - Mannitol.
Suspension of natural biopolymers (starch)
5 or 20 min
Ultrahigh pressure of
300-700 MPs
Gelatinization of starch molecules occur.
IUHP brings about changes in the morphology of
the polymer. Whereas heat-induced
gelatinization (40 to 52°C) causes a change in
ordered state of polymer
Nucleophilic substitution
2-dimethylamino ethylamine
Methacyloyl chloride
N-2-dimethyl amino ethyl-methacryalmide (DMAEMA)
( a pH and temperature sensitive)

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Drawbacks:
- Turbidity.
- Presence of negative charged moieties pose problem of interaction with
the drug.
E. Use of Irradiation:
Advantages:
➢ Irradiation method is convenient.
➢ Hydrogels prepared by microwave irradiation are more porous than
conventional methods.
Drawbacks:
➢ Irradiation method processing is costly.
➢ Mechanical strength of such Hydrogels is less.
F. Freeze Thawing:
Advantages:
➢ Sufficient mechanical strength.
➢ Good Stability.
Drawbacks:
➢ Opaque in appearance
➢ Little swelling capacity.
List of monomers used in the synthesis of Hydrogels:
Monomer
abbreviation
Monomer Monomer
abbreviation
Monomer
HEMA Hydroxyethyl
methacrylate
EG Ethylene glycol
HEEMA Hydroxyethoxyethyl
methacrylate
EGDMA Ethylene glycol
dimethacrylate
HDEEMA Hydroxydiethoxyethyl
methacrylate
NVP N-vinyl-2-pyrrolidone
MEMA Methoxyethyl
methacrylate
AA Acrylic acid
MEEMA Methoxyethoxyethyl
methacrylate
PEGMA PEG methacrylate

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Hydrogels analytical machines:
Atomic Force Microscopy (AFM):
➢ A Multimode Atomic Force Microscope Form Digital Instrument is used to
study the surface morphology of the hydrogels.
X-ray Diffraction:
➢ Used to understand whether the polymers retain their crystalline structure or
they get deformed during the pressurization process.
FTIR (Fourier Transform Infrared Spectroscopy):
➢ Any change in the morphology of Hydrogels changes their IR absorption
spectra.
➢ Formation of coil or helix which is indicative of cross linking is evident by
appearance of bands near 1648 cm-1
.
Cone Plate viscometer:
➢ Hydrogels are evaluated for viscosity under constant temperature (4°C) by
using Cone Plate viscometer.
AFM machine
X-ray diffraction machine
FTIR
Cone plate viscometer

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Advantages:
• Effective in hydrating wound surfaces and liquefying necrotic tissue on the
wound surface.
• Non-adherent and can be removed without trauma to the wound bed.
• "Soothing" effect promotes patient acceptance.
• Easy to modify.
• Biocompatible.
• Good transport properties.
• Hydrogels provide suitable semi-wet, three-dimensional environments for
molecular-level biological interactions.
• Hydrogel mechanical properties are highly tunable, for example elasticity can be
tailored by modifying cross-link densities.
• Hydrogels can be designed to change properties (e.g. swelling/ collapse or
solution-to-gel transitions) in response to externally applied triggers, such as
temperature, ionic strength, solvent polarity, electric/magnetic field, light, or
small (bio) molecules.
Disadvantages:
• Hydrogels are expensive.
• Hydrogels causes sensation felt by movement of the maggots.
• The surgical risk associated with the device implantation and retrieval.
• Hydrogels are non-adherent, they may need to be secured by a secondary
Dressing.
• Hydrogels used as contact lenses causes lens deposition, hypoxia, dehydration
and red eye reactions.
• Hydrogels have low mechanical strength.
• Difficulty in handling.
• Difficulty in loading.

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Conclusion:
➢ Recent developments in the field of polymer science and technology has led
to the development of various stimuli sensitive hydrogels like pH,
temperature sensitive hydrogels
➢ A new way to create hydrogels has been developed by immobilizing
different proteins at the same time
➢ Hydrogels with novel properties will continue to play important role in drug
delivery
➢ New synthetic methods have been used to prepare homo- and co-polymeric
hydrogels for a wide range of drugs, peptides, and protein delivery
applications
➢ Hydrogels are also used in regenerating human tissue cells.
……………………..........……… Thank you ………...………….………………

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References:
1.Remington: The Science and Practice of Pharmacy.
➢ Published by Lippincott Williams & Wilkins, 2005.
➢ Twenty-First Editions. P.NO. 294,756,867,868.
2. Handbook of Pharmaceutical Excipients, A. Wade and P.J. Weller ed., The
Pharmaceutical Press, London, 1994, pp. 229–232.
3. British Pharmacopoeia 2002, the Stationary Office, London, 2002, p. 2092–
2094.
4. Kopeček J, Yang J. Polymer Int. 2007;56:1078–1098.
5. Dušek K, Prins W. Adv Polym Sci. 1969;6:1–102.
6. Sanjay k Jain & N.K Jain controlled & novel drug delivery system.
Dr. Rakesh S. Patel