Polymers

Applications of
Polymers in Drug
Delivery Systems
ADITHYA J
MPHARM Pharmaceutics 2021

Historical aspects of Polymers: Then to Now

● Hierarchical progress in modern drug delivery begins with the use of polymer
carriers to elicit spatiotemporal release of therapeutics in both pulsatile dose
delivery products and implanted reservoir systems.
● Polymers have played an integral role in the advancement of drug delivery
technology by providing a Remote control of the drug release.
● Conjugation of the therapeutic to the polymer improves the pharmacokinetic and
pharmacodynamic properties of biopharmaceuticals through a variety of
measures, including increased plasma half-life, protection of the therapeutic from
proteolytic enzymes, reduction in immmunogenicity, enhanced stability of
proteins, enhanced solubility of low MW drugs, and the potential for targeted
delivery

DEFINITION:
o Polymers are high molecular weight compounds or macromolecules composed of
many repeating subunits called “Monomers”, connected by covalent bonds or
chemical bonds.
o The reaction involving combination of two or more monomer units to form a long
chain polymer is termed as POLYMERIZATION.
o A monomer is a small molecule that combine with other molecules of the same
type or different types to form a polymer.
o If two, three, four, or five monomers are attached to each other, the product is
known a dimer, trimer, tetramer, or pentamer.
o An oligomer contains from 30 to 100 monomeric units, and the products
containing more than 200 monomers are simply called a polymer.

CLASSIFICATION
1. Based on monomer composition.
2. Based on method of polymerization.
3. Based on polymer architecture.
4. Based on application.
5. Based on morphology.
6. Based on degradability of polymers.

1. Based on Monomer Composition
 Homopolymer
o Polymers formed from one kind of monomer are called a homopolymer like
-A-A-A-A-
Eg:- polyethylene, polystyrene.
o There are 3 types of homo polymers:-
 Linear polymer
 Branched polymer
 Cross linked polymer

 Linear polymer
● Molecules has definite backbone and does not
have long chain branches.
Eg:- Polyformaldehyde, polyesters,
polycarbonates etc.
 Branched polymer
● It has long chain branches that cannot be
defined. It may also have short chain branches.
Eg:- Polyethylene, HPLD polyethylene etc.

 Cross linked polymer
● In this type all molecules are chemically bonded
together, forming a three dimensional network.
● Cross-linked polymers are produced from linear and
branched polymers or directly from chemical precursor.
Eg:- Natural rubber, polyacryl amide gels, epoxies, alky
resins etc.

 COPOLYMER
o Polymers formed from more than one kind of monomer unit is called a co-polymer or
mixed polymer like -A-B-A-B-A-B-
Eg. silicone, ethyl cellulose.
1. Random copolymers: two monomers randomly distributed in chain.
eg: poly(acrylo nitrile -ran-butadiene)
2.Alternating copolymers: two monomers incorporated sequentially.
eg: poly(styrene-alt-malic anhydride)

2.Based on method of polymerization
ADDITION POLYMERS
o Addition polymers are formed when monomer units are separately added to form long
chains without elimination of any by-product molecules.
o Addition or chain-growth polymerization involves the rearrangement of bonds within
the monomer in such a way that the monomers link up directly with each other
o Eg:- Polyethylene, polypropylene, styrene butadiene, rubber etc.
A chemically active molecule (called an initiator) is needed to start the chain
reaction. The manufacture of polyethylene is a very common example of such a
process.
•It employs a free-radical initiator that donates its unpaired electron to the
monomer, making the latter highly reactive and able to form a bond with
another monomer at this site.
•In theory, only a single chain-initiation process needs to take place, and the
chain-propagation step then repeats itself indefinitely, but in practice multiple
initiation steps are required, and eventually two radicals react (chain
termination) to bring the polymerization to a halt.

CONDENSATION POLYMER
o A condensation polymerization is a form of step-
growth polymerization in which monomers and/or
oligomers react with each other to form larger
structural units while releasing smaller molecules as a
byproduct such as water or methanol.
o If both moieties are bifunctional, the condensation
product is a linear polymer, and if at least one of the
moieties is tri- or tetra-functional, the resulting
polymer is a crosslinked polymer (i.e. a three-
dimensional network).
o Condensation polymers are the result of the
transformation of functional groups on monomers
that are bi-functional so that each monomer can
connect with two others.
o Eg:- Nylon-66, polyester, bakelite etc.
The given figure shows the formation of
nylon 6,6 by the polycondensation of adipic
acid with 1,6-hexamethylenediamine.

3.Based on Polymer Architecture
STAR POLYMER
o Star shaped polymer consisting of several linear chains
connected to a central core. The core, or the center, of the
polymer can be an atom, molecule, or macromolecule.
o Ma et al. formed a star polymer consisting of a
poly(norbornene) core (via ROMP) and polystyrene arms
through RAFT.
COMB POLYMER
o A comb polymer molecule consists of a main chain with two or
more three-way branch points and linear side chains
o C.D. Neveu , et al., 2016 developed a novel comb polymer with
polar monomer containing PAMA, by combining the chemistry
of linear polyolefin and linear PAMA

LADDER POLYMER
o Ladder polymer is a type of double stranded polymer with the
connectivity of a ladder
o Eg: Some polysilicates like termolite
DENDRIMER
o Dendrimers are nano-sized, radially symmetric molecules with well-
defined, homogeneous, and monodisperse structure consisting of
tree-like arms or branches.
o Eg:Poly(amidoamine) or PAMAM

4.Based on Applications
PLASTICS
●Plastics are synthetic or semi-synthetic
polymers made from a wide range of moldable
organic polymers set into a rigid or semi-
elastic solid.
●They are routinely labelled as polymers, as
they are comprised of long chain polymers.
● Plastics are produced by condensation and
addition polymerization reactions.
●They can be used at a very wide range of
temperatures, are chemical- and light-
resistant and they are very strong and tough,
but can be easily worked as a hot melt.

THERMOPLASTICS
Thermoplastics consist of long, linear,
saturated carbon-carbon chains that
extend in one dimension.
LMW
Molecular chains of thermoplastics can
move independently because they are not
crosslinked.
Thermoplastics can be reused because
they can be repeatedly melted and
solidified by heating and cooling.
They are usually stored in the form of
pellets prior to the molding process.
Produced by addition polymerisation.
Eg: acrylic, polyester, polypropylene,
polystyrene, nylon and Teflon
THERMOSETTING PLASTICS/
THERMOSETS
Materials which remain in a permanent solid
state after being cured one time and extend in 3
Dimension.
HMW
Polymers within the material cross-link
during the curing process to perform an
unbreakable, irreversible bond.
This means that thermosets will not melt even
when exposed to extremely high temperatures.
Unlike thermoplastic pellets, the components
of thermoset polymers are stored in liquid form,
usually in large tanks or containers.
Produced by Condensation polymerisation.
Eg: epoxy, silicone, polyurethane and
phenolic.

ELASTOMERS
● The term “elastomer” is derived from “elastic polymer,” frequently interchanged with the term
“rubber.”
● An elastomer is a polymer that has extremely weak inter-molecular forces and, generally, a low
Young’s modulus.
Young’s modulus is a measure of the ability of a material to withstand changes in length when under
lengthwise tension or compression.
● It is viscoelastic, which means it has both elasticity and viscosity. Each one of the monomers that
have to link in order to form the polymer are typically made of hydrogen, carbon, silicon or oxygen.
ELASTOMERS
Diene Non Diene
Thermoplastic
elastomers

 Diene elastomers are polymerized from monomers containing two sequential double
bonds.
Eg: polyisoprene, polybutadiene, and polychloroprene.
 Non-diene elastomers have no double bonds in the structure, and thus, crosslinking
requires other methods than vulcanization such as addition of trifunctional monomers
(condensation polymers), or addition of divinyl monomers (free radical polymerization), or
copolymerization with small amounts of diene monomers like butadiene.
Eg: butyl rubber (polyisobutylene), polysiloxanes (silicone rubber), polyurethane
(spandex), and fluoro-elastomers.
 Thermoplastic elastomers (TPE) are a class of copolymers or a physical mix of
polymers (usually a plastic and a rubber) that consist of materials with
both thermoplastic and elastomeric properties. They contain rigid (hard) and soft (rubbery)
repeat units
Eg: SIS(Styrene-Isoprene-Styrene) and SBS [Poly(styrene-butadiene-styrene)]

COMMODITY PLASTICS
● Commodity plastic has a wide variety of
uses in the mass production of objects and
products that are designed to be single use
–examples include packaging film, bottles,
bags , cutlery, children’s toys and
electronic product casings, medical
trays,seeding trays, photographic and
magnetic tape etc.
● It is more cost-effective than other
alternative plastics.
● They are also chosen when a plastic’s
specific mechanical properties do not have
a negative impact on the performance or
functions of the product in question.
● E.g.: LDPE, LLDPE (Linear LDPE) HDPE,
PVC, Polypropylene(PP), Polystyrene (PS)
ENGINEERING PLASTICS
● Engineering plastics are different to commodity
plastics in that they are designed to withstand
mechanical and environmental conditions that
commodity plastics are not made to deal with.
● They are not mass produced in a comparable
level to commodity plastic.
● They are typically made in smaller quantities to
meet a businesses specific goal or outcome.
● Engineering plastics have favourable
characteristics, including high mechanical
strength, heat resistance, chemical stability and
self-lubrication – qualities that are highly
sought-after by different industries. These
distinctive properties have resulted in the
replacement of traditional materials like metals
and wood.
● Eg: Nylon, Teflon, PBT (Polybutylene
terephthalate), PET (Polyethylene terephthalate)

FIBRES
● polyamide nylon.
● PET or PBT polyester.
● phenol-formaldehyde (PF)
● polyvinyl chloride fiber (PVC) vinyon.
● polyolefins (PP and PE) olefin fiber.
COATING AND ADHESIVES
Coating :-
E.g: lacquer, vanishes, paint (oil or latex).
Adhesives :-
E.g: solvent based, hot melt, pressure sensitive, etc.

5. Based on their Morphology
AMORPHOUS
● Polymers with an amorphous morphology have
their atoms held together in a loose structure,
but this structure is never orderly or predictable
, i.e, amorphous solids have no long-range
order.
● The chains are arrayed randomly throughout
the material, making atomic positions quasi-
random-thus they are glassy ,brittle and ductile
polymers.
● Amorphous solids don’t melt suddenly when
they’re heated. Instead, they reach a range of
temperatures over which the material becomes
less glassy and more rubber-like or vice versa.
As a result, amorphous polymers don’t have a
melting point — they have a glass transition
temperature.

CRYSTALLINE
● They form orderly stacks of folded chains, known
as lamellae.
● Lamellae bring long-range order to polymers,
which is more like the orderly arrangement of
atoms in typical crystals.
● Crystallinity can range from 0 percent (entirely
amorphous) to 100 percent (entirely crystalline),
but most polymers fall somewhere between those
extremes.
● Different from small molecular materials
such as metals and organics, fully crystalline
polymers are impossible to obtain using
common processing conditions. A more
precise characterization of crystalline
polymers should be “semicrystalline
polymers.”
● Therefore, more than one phase exists,
namely, crystalline and amorphous phases in
semicrystalline polymers.

6.Based on Degradability of Polymer
BIODEGRADABLE POLYMERS
o Biodegradable polymers are polymers which degrade in biological fluids with progressive release of
dissolved or dispersed drug.
E.g.; Collagen, Polyglycolic acid etc.
o Biodegradable polymers are most commonly termed as “biopolymers,” as these polymers are mostly
derived from various natural sources. There are very few among the list of biopolymers that are
biodegradable in nature. Plastics such as PLA, PHA, and starch are the most frequently used biopolymers
that have minimum to least effect toward the rising environmental carbon footprint.
Biodegradable polymers can be classified in two:
1. Natural 2. Synthetic
o Natural biodegradable polymers:-
Albumin, Colaagen, Gelatin etc.
o Synthetic biodegradable polymers:-
Polyanhydrides, Polyaminoacides etc.
A synthetic biodegradable polymer are preferred more than the natural biodegradable polymer because
they are free of immunogenicity & their physicochemical properties are more predictable & reproducible.
It is important to understand that the biodegradability is a characteristic of polymers that is
independent of their origin and may be altered upon tuning at molecular level.

NON BIODEGRADABLE POLYMERS
●Polymer which cannot be biologically degraded by natural processes.
●These polymers are resistant to environmental degradation thus end up to accumulate in
form of waste.
●These are polymers which have long chains consisting of Carbon and Hydrogen atoms. The
interatomic bonding of these polymers is very strong and adamant, hence making them
resistant to microbes which try to break their bonds and digest them.
E.g.; Polythene, teflon, polypropylene

Tg: A Significant Property of Polymer to be considered
What is Tg?
What happens to the polymer at Tg?

Most common Polymers in DDS : A comparison of Tg/Tm/Crystallinity
Polymers Tg (°C) Tm(°C) Crystallinity (%)
HDPE -125 130-140 70-90
LDPE -130 85-125 45-60
PS 100 242 Low
PP -20 to-5 165-175 50-80
Nylon 6,6 50-60 245-265 80
PEG -63 64-66 30–50
PMMA 105°C 160 Low
Polyurethane(Used in
heart valves)
-63.15 56.85 Low
Chitosan 140 - 150 88 Low
HPMC 160-175 225-230 Low

Factors modifying the Tg of polymers
Plasticizer
● Plasticizers are low molecular weight and non-volatile materials added to polymers to
increase their chain flexibility. They reduce the intermolecular cohesive forces between
the polymer chains, which in turn decrease Tg.
● On addition of plasticizer to polymer, plasticizer gets in between the polymer chains
and spaces them apart from each other increasing the free volume. This results in
polymer chains sliding past each other more easily. As a result, the polymer chains can
move around at lower temperatures resulting in decrease in Tg of a polymer.
● Example of plasticizer includes, nitrobenzene, β-naphthyl salicylate, carbon disulphide,
glycerine, propylene glycol, triethyl citrate,triacetine,polyethylene glycol,etc.
● “At temperatures above the glass transition temperature an instant drug release of the
nanoparticles was observed, while at lower temperatures less drug was released.”

Water or moisture content
● Increase in moisture content leads to increase in free volume due to formation of hydrogen bonds
with polymeric chains increasing the distance between polymeric chains. The increased free volume
between polymeric chains result in decreased Tg.
Pressure and free volume
● Increase in pressure of surrounding leads to decrease in free volume and ultimately high Tg. Free
volume is the unoccupied space arising from inefficient packing of disordered chains and is the
space available for polymer to undergo rotation.
Polymer film thickness
● Mobility of molecules increase when polymer film thickness decreases, resulting in decrease in Tg;
increase in film thickness increases compaction and results in an increased Tg.
● When a polymer is added to substrate, the Tg increases due to decreased mobility. In case of thin
free standing films, Tg decreases more due to high mobility than bulk polymer. In case of
sandwiched films, compaction leads to increase in Tg.
● Example: Polystyrene has shown decrease in Tg with decrease in its film thickness. Similar effect has
been observed in poly (methyl methacrylate) films on Au.

Other factors affecting Tg:
Molecular weight:
● In case of straight chain polymers, increase in molecular weight leads to decrease in chain end concentration. This results in decreased
free volume at end group region- and increase in Tg. If end groups of chain are changed molecular weight dependence of Tg can be
changed. Decrease in chain end concentration (low molecular weight) and stronger interactions at end groups increase Tg.
● Example: Effects of molecular weight of polyvinylpyrrolidone on glass transition temperature and crystallization of sucrose.
Molecular structure :
● Insertion of bulky, inflexible side group increases Tg of material due to decrease in mobility, viz: Poly-N-vinylcarbazole shows
increased Tg due to substitution of bulkier group (carbazole).
Length of side group:
● As length of side group increases the polymer chains move apart from each other and that increases free volume in the molecule
resulting in decreased Tg.
● Example: Polyvinyl n-butyl ether showed decreased Tg with increase in chain length.
Double bond in back bone
● Double bonds in backbone of molecule decrease bond rotation leading to increase in free volume and ultimately decrease in Tg.
● Example: Polybutadienes show low Tg (175°K), which is less than corresponding polybutane containing side chain double bond.
Chemical cross-linking
● Increase in cross-linking decreases mobility leads to decrease in free volume and increase in Tg.

Mechanical properties of the polymer v/s DDS
● To formulate any drug delivery system, a polymer must obtain optimized mechanical properties as per
the requirement.
Strength:
 The stress needed to break the sample.
 The polymers follow the following order of increasing strength: linear < branched < cross-linked <
network.
Young’s Modulus (Modulus of Elasticity or Tensile Modulus):
 Young’s Modulus is the ratio of stress to the strain in the linearly
elastic region .
 Elastic modulus is a measure of the stiffness of the material.
 E = Tensile Stress(𝜎) Tensile Strain(𝜀)

Toughness:
 The toughness of a material is given by the
area under a stress–strain curve
 Toughness = ∫ 𝜎 dE
 The toughness measures the energy
absorbed by the material before it breaks.
 A typical stress–strain curve is shown in
which compares the stress–strain behavior
of different types of materials.
 The rigid materials possess high Young’s
modulus (such as brittle polymers), and
ductile polymers also possess similar elastic
modulus, but with higher fracture
toughness.
 However, elastomers have low values of
Young’s modulus and are rubbery in
nature.

Polymer stress-strain curve
● Stress-strain curves show the response of a material to an applied (usually tensile) stress. They allow
important information such as a material's elastic modulus and yield stress to be determined.
Accurate knowledge of these parameters is paramount in engineering design.
● Polymer stress-strain curves are produced by stretching a sample at a constant rate through the
application of a tensile force.
● Polymers have a marked inherent time-dependence in their response to deformation, which sets their
behaviour apart from other classes of material.

● When a polymer is pulled at a (constant) strain rate the applied stress (or load) is
directly proportional to the observed strain (or elongation).
● The maximum stress up to which the stress and strain remain proportional is called
the proportional limit.
● If the material is loaded beyond its elastic limit, it does not return to its original shape
and size, i.e. a permanent deformation occurs.
● With increasing load a point is eventually reached at which the material starts yielding.
This point is known as the yield point. A further increase in strain occurs without an
increase in stress.
● At the yield point, the polymeric material undergoes strong irreversible plastic
deformation followed by necking and, in some cases depending on strain rate and
temperature.

Polymers for drug delivery purposes
 Thermo-responsive polymers
 pH responsive polymers
 Redox responsive polymers
 Ion responsive polymers
 Bio responsive polymers
SMART POLYMERS
“intelligent” delivery systems able
to release the entrapped drugs at
the appropriate time and site of
action, in response to specific
physiological triggers

Thermo-responsive polymers
● Unique property of sol–gel transition(Phase transition takes place) above certain
temperature.
● This property allows for unique manipulation of smart polymers via ‘on-demand’
remote control as well as ‘on–off’ switchable control by temperature.

● Generally, thermo-responsive polymers exhibit a temperature dependent
miscibility or solubility gap in aqueous solutions that can be observed in phase
diagrams of temperature versus polymer fraction volume.
● This phase separation occurs due to hydrophobic interactions between
polymer chains, and this enables the self-assembly and aggregation of
polymers in aqueous solutions.
● LCSTs or UCSTs appear for thermo-responsive polymers when a polymer
solution is phase separated above or below a specific temperature.
● Eg: poly(Nisopropylacrylamide)s (PNIPAAMs)
o Below its lower critical solution temperature (LCST) near 32°C, PNIPAAm exists
as a hydrophilic coil, whereas above the LCST, PNIPAAm chains collapse
sharply into a hydrophobic globule .
o The nature of this volume phase transition stems from the
hydrophilic/hydrophobic balance of polymer chains, which is modulated by
continual establishment and disruption of intra- and intermolecular
electrostatic and hydrophobic interactions.
o Below the LCST, water molecules exist in an ordered state in the local
environment of polymer chains. As temperature rises above the LCST, polymer-
polymer hydrophobic interactions dominate.
o Consequently, polymer chains collapse and water molecules are released to the
bulk, resulting in a net entropic gain for the polymer/solvent system .

● For drug delivery applications, it may be desirable to shift the critical temperature for
volume phase transition to a specific temperature range.
● This can be accomplished through the inclusion of hydrophobic or hydrophilic moieties in
the polymer chain. Polymers with a larger hydrophobic hydration area possess stronger
hydrophobic interactive forces and undergo collapse at a lower temperature .
● Conversely, increasing the hydrophilic content of the polymer chain will increase the LCST.
Polymers that exhibit positive temperature-dependent swelling behavior, i.e., a globule-to-
coil transition with increasing temperature, possess an upper critical solution temperature
(UCST).
● Eg:poly(acrylic acid) and poly(acrylamide) interpenetrating networks (IPNs),

pH responsive polymers
● pH-Responsive polymers are a group of stimuli-responsive polymers that can respond to
solution pH by undergoing structural and property changes such as surface activity, chain
conformation, solubility, and configuration.
● The term “pH-responsive polymers” is commonly used to describe polymers having
ionisable acidic or basic residues whose ionization depends on solution pH.
● pH-Responsive polymers can have linear, branched or network structures. They may
show different responses to solution conditions and different self-assembly behaviors
depending on their structures.
● For example, a pH change may cause (de)protonation of functional groups in polymer
chains. In some cases, it may cause flocculation, chain collapse-extension, and
precipitation for homopolymers. It may also cause self-assembly such as formation of
micelles, unimers, gels, vesicles, swelling, deswelling, etc.
● There are two kinds of pHresponsive polymers: polymers with acidic groups and the
polymers with basic groups

pH-Responsive acidic polymers
● Polymers having weak acidic or basic residues are utilized as pH-responsive polymers.
● Such weak acidic/basic pendant groups (side group is a group of atoms attached to
a backbone chain of a polymer) accept protons at low pH and release them at high pH.
● Therefore, they gain polyelectrolyte nature at acidic or basic pH values depending on
their pKa values. Such an ionic/non-ionic transition allows us to tune their
hydrophilicity in the aqueous phase.
● This tuning results in precipitation/ solubilization of polymer chains,
swelling/deswelling of their hydrogels, or hydrophobic/hydrophilic characteristic
changes of such polymeric surfaces and their particles.
● Eg: Polycarboxylic acids:- PAAc and PMAAc
● Polysylfonic acids:- poly(2-acrylamido-2-methylpropane sulfonic acid) (PAMPS) and
poly(4-styrenesulfonic acid) (PSSA)

pH-Responsive basic polymers
● Weak polybases, which undergo ionization/deionization transitions from pH ∼7–11, are
utilized as pH-responsive polymers.
● The amine groups are located in their side chains and these groups accept protons at low
pH values by forming poly-electrolytes releasing them under basic conditions.
● Eg: poly[(2-dimethylamino)ethyl methacrylate] PDMA, poly[(2-diethylamino)ethyl
methacrylate] (PDEA), and poly[(2-diisopropylamino)ethyl methacrylate] (PDPA)
pH-Responsive natural polymers
● On suitable chemical modification, these polymers can provide better materials for drug
delivery systems.
● Eg: Alginic acid, Chitosan, CMC, HA

Ion Responsive Polymer
● The responsiveness to ionic strength is a typical property of polymers containing
ionizable groups in their structure.
● Variations in ionic strength may cause changes in the size of the polymeric micelles,
polymer solubility, swelling, fluorescence quenching kinetics of the chromophores bound
to electrolytes, among others.
● Effect of ionic strength in polymers is highly interrelated to the pH. For a nonionizbale
polymer, ionic strength will not affect its behavior.
● However, in an ionizable polymer, a different transitions occur at a specific sodium
chloride concentration in aqueous solution.
● Eg: Carbomer, Eudragit, CMC, Alginic acid, etc.

Redox responsive polymers
● The basic principle of redox-responsive polymeric drug delivery systems is to utilize the
distinct differences in redox potentials between tumors and normal tissues.
● It has been demonstrated in many papers that GSH/glutathione disulfide (GSSG) is the
most abundant redox couple in animal cells. In the cytosol and nuclei, the
concentration of GSH reaches 10 mM under the reduction of NADPH and glutathione
reductase, while outside the cell the concentration drops to about 2–20 mM.
● Disulfide linkages are well known to be unstable in a reductive environment as the
disulfide bond is readily cleaved in favor of corresponding thiol groups.
● Polymers with disulfide cross-links have been synthesized as polymersomes , nanogels
and core-cross-linked polyplexes and degrade when exposed to cysteine or glutathione,
reductive amino-acid based molecules present at intracellular concentrations 50–1000
fold greater than those of the extracellular milieu.
● Eg: Disulfide-linked dextran-b-poly(3-caprolactone) amphiphilic block copolymer
prepared using the thiol–disulfide exchange reaction under mild conditions.

● Apart from the direct disulfide linkage
formation reaction, one of the most
common strategies was cross linking
through disulfide-containing cross-
linkers.
● Up to now, there have been numerous
structures built on the basis of cross-
linking reactions.
● Eg: Dithiodipropionic acid, bis(2,20 -
hydroxyethyl)disulfide, cystamine and
their derivatives
● The resulting cross linked micelle was
observed to efficiently prevent drug
leakage in circulation before reaching the
target.

Bio responsive Polymers
● They can respond to the stimuli that are inherently present in the natural system.
● Bioresponsive polymeric systems mainly arise from common functional groups that are known to
interact with biologically relevant species, and in other instances the synthetic polymer is conjugated to a
biological component.
● Bioresponsive polymers are classified into antigen responsive polymers, glucose-sensitive polymers, and
enzyme responsive polymers.
● Glucose responsive polymers have the ability to mimic normal endogenous insulin secretion which
minimises diabetic complications and can release the bioactive compound in a controlled manner.
● The major limitations are its short response time and possible non-biocompatibility.

HYDROPHILIC POLYMER
● Hydrophilic polymers are those
polymers which dissolve in, or are
swollen by, water.
● These stable, robust systems offer
a wide range of achievable release
profiles for a wide range of API
behaviors.
● A significant feature of several
types of hydrophilic polymer is
the ability to interact with
biomacromolecules, e.g., with
DNA or proteins .
● Eg: HPMC, HPC, HEC, Sodium
Alginate, Cross linked
homopolymer, Poly (ethylene
oxide), Copolymer of Acrylic acid

HYDROPHOBIC POLYMERS
● Hydrophobic (water-resistant) polymers are materials that are not soluble in water or
other polar solvents.
● Eg: acrylics, epoxies, polyethylene, polystyrene, polyvinylchloride,
polytetrafluorethylene, polydimethylsiloxane, polyesters, and polyurethanes
Drug release from a hydrophobic matrix

Properties of an ideal polymer used in DDS
● Low Density.
● Low coefficient of friction.
● Good corrosion resistance.
● Good mould ability.
● Excellent surface finish can be obtained.
● Can be produced with close dimensional tolerances.
● Economical.
● Poor tensile strength.
● Low mechanical properties.
● Poor temperature resistance.
● Can be produced transparent or in different colours

Targets of polymeric drug delivery systems
1.Localized delivery of drug : The product can be implanted directly at the site where drug
action is needed and hence systemic exposure of the drug can be reduced. Especially for
toxic drugs which are related to various systemic side effects.
2. Sustained delivery of drug : The drug encapsulated is released over extended period and
hence eliminates the need for multiple injections. This feature can improve patient
compliance especially for drugs for chronic indications, requiring frequent injection.
3.Stabilization of the drug : The polymer can protect the drug from the physiological
environment and hence improve its stability in vivo. This feature makes this technology
attractive for the delivery of labile drugs like proteins

General Criteria followed in Polymer Selection:
● The polymer should be soluble and easy to synthesis.
● It should have finite molecular weight.
● It should be compatible with the biological environment.
● It should be biodegradable.
● It should provide good drug-polymer linkage.
Selecting a Polymer for drug release in a DDS

Selecting a Polymer for drug release in a DDS
The choice of polymer, in addition to its physicochemical properties, is dependent on the need for
extensive biochemical characterization and specific preclinical tests to prove its safety.
● Surface properties such as hydrophilicity, lubricity, smoothness, and surface energy govern the
biocompatibility with tissues and blood, in addition to influencing physical properties such as
durability, permeability, and degradability are considered . The surface properties also determine the
water sorption capacity of the polymers, i.e., hydrogels, that undergo hydrolytic degradation and
swelling. On the other hand, materials for long-term use, e.g., for orthopedic and dental implants,
must be water-repellent to avoid degradation or erosion processes that lead to changes in toughness
and loss of mechanical strength.
● Bulk properties that need to be considered for controlled DDSs include molecular weight, adhesion,
solubility based on the release mechanism (diffusion or dissolution controlled), and its site of action.
● Bioadhesiveness needs to be taken into account when DDSs are targeted to mucosal tissues, whereas
polymers for ocular devices have to be aqueous or lipid-soluble in addition to having good film-
forming ability and mechanical stability for good retention.
● Structural properties of the matrix, its micromorphology, and pore size are important with respect to
mass transfer of water into and out of the polymer containing drug.

Role of Polymers in CR-Release Systems
● Controlled Drug Delivery (CDD) occurs when a polymer, whether natural or synthetic, is judiciously
combined with a drug or other active agent in such a way that the active agent is released from the
material in a predesigned manner.
● The release of the active agent may be constant over a long period, it may be cyclic over a long period,
or it may be triggered by the environment or other external events. In any case, the purpose behind
controlling the drug delivery is to achieve more effective therapies while eliminating the potential for
both under the dose and overdosing.
● Controlled release can be achieved through several mechanisms, such as dissolution, diffusion,
solvent-activation (as the osmotic pumps) or chemical-trigger (by hydrolytic or enzymatic reactions).
● Many marketed CR products are diffusion or dissolution limited or a combination of both mechanisms.

● In diffusion-limited CR formulations, insoluble polymers are used for controlling drug delivery
and it is quite easy to obtain a zero-order kinetic, particularly in multiparticulate reservoir types.
Diffusion through swellable hydrophilic polymers is a second alternative used mainly in matrix
systems, easy to manufacture, and generally having a non-constant release rate.
● Dissolution-limited systems are either based on pH differential dissolution of a coating polymer or
in the dissolution/erosion of soluble polymers. The former alternative performance may be affected
by inter and intra individual variability on intestinal pH profiles. The later may need additives to
render the dissolution pH-independent.
● Frequently, CR forms combine dissolution and diffusion release mechanisms in matrix type forms.
In these cases, it is possible to say that if the drug is highly soluble, diffusion may be more relevant,
peradventure the drug has low solubility, and then, matrix erosion may be more important.
● The main physiological factors affecting CR performance are intestinal fluids pH, volume and
composition, physical forces, and transit times which determine the time of exposure to the
particular segment conditions. Food influence depends on release mechanism.

Role of Polymers in SR-release Systems
● Sustained release systems include any drug-delivery system that achieves slow release of drug over an
extended period of time.
● Sustained Release is also providing promising way to decrease the side effect of the drug by preventing
the fluctuation of the therapeutic concentration of the drug in the body.
● Design of a sustained-release dosage form must take into account the properties of both the rate-
controlling polymer and the drug.
● The mechanism most commonly used to achieve sustained release is controlled diffusion through a
polymeric matrix or membrane.
● For diffusion of the drug to occur it must have some limited solubility in the polymer; this is often the
case with low molecular weight drugs.

 Immediate drug release dosage form tablets: Polymers including polyvinyl pyrrolidone and
hydroxypropylmethylecellulose (HPMC) are found to be a good binder which increases the formation
of granules that improves the flow and compaction properties of tablet formulations prior to tableting
 Capsules: Many of the polymeric excipients used to “bulk out” capsules fills are the same as those used
in intermediate release tablets. For hard and soft shell gelatin has most often used. By recent advances
HPMC has been accepted as alternative material for hard and soft capsules.
 Modified drug release dosage forms: To achieve gastro retention mucoadhesive and low density,
polymers have been evaluated, with little success so far their ability to extend gastric residence time by
bonding to the mucus lining of the stomach and floating on top of the gastric contents respectively.
 Extended release dosage forms: Extended and sustained release dosage forms prolong the time that’
systemic drug levels are within the therapeutic range and thus reduce the number of doses the patient
must take to maintain a therapeutic effect there by increasing compliance. The most commonly used
water insoluble polymers for extended release applications are the ammonium ethacrylate copolymers
cellulose derivatives ethyl cellulose and cellulose acetate, and polyvinyl derivative, polyvinyl acetate.
A Brief Overview on the Applications of Polymers in DD

 Gastro retentive Dosage forms: Gastro retentive dosage forms offer an alternative strategy
for achieving extended release profile, in which the formulation will remain in the stomach
for prolonged periods, releasing the drug in situ, which will then dissolve in the liquid
contents and slowly pass into the small intestine.
 Occular drug delivery systems: (eg:Temp resp polymers)
 Intraocular drug delivery systems allow the release of the drug, bypassing the blood-ocular
barrier. The main advantage of these preparations is that they can release the drug over a
long time with one single administration.
 They can be prepared from biodegradable or non biodegradable polymers. Biodegradable
polymers have the advantage of disappearing from the site of action after releasing the
drug.
 The majority of intraocular devices are prepared from non biodegradable polymers, and
they can release controlled amounts of drugs for months.
 The polymers usually employed to prepare nanoparticles for the topical ophthalmic route
are poly (acrylic acid) derivatives (polyalquilcyanocrylates), albumin, poly-ε-caprolactone,
and chitosan

 Transdermal Drug delivery sytems:
 Systems for transdermal delivery are fabricated as multilayered polymeric laminates in
which a drug reservoir or a drug–polymer matrix is sandwiched between two
polymeric layers: an outer impervious backing layer that prevents the loss of drug
through the backing surface and an inner polymeric layer that functions as an adhesive
and/or rate-controlling membrane.
 The polymers like cross linked polyethylene glycol, eudragits, ethyl cellulose,
polyvinylpyrrolidone and hydroxypropylmethylcellulose are used as matrix formers for
TDDS. Other polymers like, silicon rubber and polyurethane are used as rate controlling
membrane.

Hydroxypropylmethyl cellulose (HPMC)
● HPMC is a non-ionic derivative of cellulose ether, it is stable over pH range 3.0-11
● Hydroxypropylmethlcellulose (HPMC) is a semi-synthetic polymer and is used as first
choice for the formulation of hydrophilic matrix systems as it provides a robust mechanism
for controlled release of drugs and choice of viscosity grades.
● Its non ionic nature minimises interaction problems when used in acidic, basic or
electrolytic systems and provides reproducible release profiles. It is also cost effective.
● Matrices containing HPMC are not affected by the pH of fluid.
● HPMC matrix systems are classed as swelling controlled systems and are controlled by the
rate of penetration of media and erosion of the matrix
● In hydrophilic polymers the rate of swelling determines the presence of different fronts
within the matrix and when the movement of these front is synchronised then the drug
release rate is constant
● HPMC is a mixture of alkyl hydroxyalkyl cellulose ether containing methoxyl and
hydroxypropyl groups
● The rate of hydration of HPMC depends on the nature of the substituent’s that form the
polymer e.g. molecular structure, degree of substitution

 Effect of pH on HPMC-systems
● The gastro-intestinal (GI) pH is one of the major properties of GI fluids and varies
greatly along the digestive tract under fed and fasted conditions .It has an influence on
the dynamics of HPMC hydrophilic matrix systems and can affect the gel layer
formation.
● Due to its non ionic nature, the viscosities of HPMC polymers are generally stable over a
wide pH range of 3-11. This means if drug solubility is pH dependent, the drug release
from the HPMC matrix will also be pH.
 Effect of ionic strength on HPMC- systems
● Ionic strength is also a major property of GI fluids and can affect the rate of drug
release from HPMC matrices. Generally the ionic concentration strength of the GI tract
under both fed and fasted states is a range of 0-0.4 M
● Ionic strength increase, drug release also increase.

Sodium carboxymethyl cellulose (NaCMC)
● This is a polyelectrolyte ionic cellulose derivative which is sensitive to changes in pH
● On hydration, polymer chains of NaCMC sell and untangle forming a viscous gel layer
on the surface .
● Erosion of the gel has been found to be one of main mechanisms by which this polymer
releases drug.
Alginate
● Alginates are found in brown marine algae and are natural polymers that are used in
various areas such as the food industry used them as thickeners and in the
pharmaceutical industry they are used in tablet manufacture as binders and tablet
disintegration.
● Alginates have been used controlled release formulations due its ability to form a gel
upon hydration.
● Sodium alginate has a unique feature which enables gel formation in acidic media as
well as neutral media and these features need to be utilised when designing a controlled
release formulation.

Effect of Cations on NaAlginate –systems
● Polyvalent cations such as Al3+, Ca2+, Zn2+ and Mg2+ have been used to form cross-
links with alginate molecules.
● The presence of cations within a matrix containing alginate allows for bridges to be
formed between the anionic polymer chains forming a network known as a hydrogel.
● The link can also be described as the ‘egg-box model’.

● Aluminium ions on the other hand would
have a different interaction with alginate
molecules due them having an extra valence
available for bonding
● This allows cross-linking to a greater extent
than divalent cations as aluminium ions
have an extra positive charge per unit of
surface.
● The formation of hydrogels modulates drug
release from sustained release formulations
and has been used in microspheres, beads
and film coating.
● They are also used extensively in matrix
tablets to preserve the matrix structure and
avoid early disintegration of the matrix

Polymers

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