Polymers

Polymers

Contents

• History

• Introduction

• Polymer synthesis

– Addition or free radical reaction

– Condensation reaction

• Classification of polymers

• Properties of polymers

• Ideal properties of polymers for pharmaceutical use

• Advantages of polymers

• Applications of polymers in pharmaceutical and biomedical field

Learning objectives

At the end of this chapter, student will be able to:

• Outline the historical development in polymer synthesis

• Define the terms, ‘polymer’, ‘monomer’, ‘degree of polymerization’

• Describe polymer synthesis by free radical addition and condensation reaction

• Classify polymers

• Describe the physical, mechanical and thermal properties of polymers

• Enlist the ideal requirements of polymers for pharmaceutical use

• Outline the advantages of polymers

• Discuss the applications of polymers in pharmaceutical and biomedical field

 History

• The first semisynthetic polymer ever made was guncotton (cellulose nitrate) by Christian F. Schonbein in 1845

– Highly explosive

– Poor processability

– Poor solubility

• Celluloid (plasticized cellulose nitrate)

• Cellulose acetate (cellulose treated with acetic acid)

• Hydrolyzed cellulose acetate soluble in acetone

• In 1872, Bakelite, a strong and durable synthetic polymer based on phenol and formaldehyde, was invented

• Other synthetic polymers invented later

– Polyethylene (1933)

– Poly (vinyl chloride) (1933)

– Polystyrene (1933)

– Polyamide (1935)

– Teflon (1938)

– Synthetic rubbers (1942)

Herman Staudinger, who received the Nobel Prize in Chemistry in 1953, coined the term “macromolecule” in 1922 and used it in reference to polymers.

What is the difference between ‘polymer’ and ‘macromolecule’?

Introduction

Single à MONO

Many àPOLY

Polymers are high molecular weight compounds or molecules composed of many repeating subunits called monomers, connected by covalent or chemical bonds

• Polymerization - Process of formation of macromolecules by linking of monomers together

• Degree of polymerization (DP) -Average molecular weight of the polymer divided by the molecular weight of the monomer

Polymer properties

Determined by

• Length

• Molecular weight

• Backbone structure

• Side chain

Can polymers exist in gaseous state?

Modifications in properties of polymers

 Changing molecular weight

 Changing structure of monomer building blocks

 Blending them with with other polymers

Polymer Synthesis

Methods

– Addition polymerization

– Condensation polymerization

Addition Polymerization/ Free-radical Polymerization

Monomer having a double bond

• The initiator is an unstable molecule that is cleaved into two radical- carrying species under the action of heat, light, chemical, or high-energy irradiation

• Each initiating radical has the ability to attack the double bond of a monomer

• The π bond in a monomer generally requires low energy to break; therefore, polymerization starts at this site by the addition of a free radical on the monomer

• The radical is transferred to the monomer and a monomer radical is produced. This step in polymerization is called initiation.

• The monomer radical is also able to attack another monomer and then another monomer, and so on and so forth. This step is called propagation by which a macroradical is formed.

• Macroradicals prepared in this way can undergo another reaction with another macroradical or with another inert compound (e.g., an impurity in the reaction) which terminates the macroradical.

Monomers such as acrylic acid, acrylamide, acrylic salts (such as sodium acrylate), and acrylic esters (methyl acrylate) contain double bonds and they can be polymerized via addition reactions.

Addition or free-radical polymerization of styrene

Condensation polymerization / step polymerization

• If  a  monomer  does  not  contain  a  double  bond  but  possesses functional groups such as hydroxyl, carboxyl, or amines, they can interact via condensation

• Example, monomer containing a reactive hydrogen from the amine residue can react with another monomer containing a reactive hydroxyl group (a residue of carboxyl group) to generate a new functional group (amide) and water as a side product

• Nylon is prepared via condensation polymerization of a diamine and diacid chloride

Examples of condensation polymerization

Classification of Polymers

Polymers can be classified based on the following

Nature of monomers

1. Homopolymers

2. Copolymers

Arrangement of monomers

1.   Random

2.   Graft

3.   Block

Structure of polymer

1.   Linear

2.   Branched

3.   Crosslinked                                                                                               

Thermal response

1.   Thermoplastic

2.   Thermosetting

3.   Elastomer

Source

1.   Natural

2.   Semisynthetic

3.   Synthetic

Copolymers and Homopolymers

• If one monomer is involved, the process is called polymerization and the product is a homopolymer

• Copolymerization refers to a polymerization reaction in which more than one type of monomer is involved

• Generally, copolymerization includes two types of monomers

Other Terminologies

Interpenetrating Polymer Networks

Thermoplastic and Thermoset Polymers

Thermoplastic

• Polymers with a linear or branched structure

• Can undergo melting

• The process of thermomelting and solidification can be repeated indefinitely

Thermoset

• Cross-linked polymers

• There is no reversible melting and solidifying

• Once formed, it does not soften upon heating and decomposes with further application of heat

Elastomers

• Rubbery polymers that can be easily stretched without application of heat

• On releasing the applied stress, they return to original dimensions

• Have low density of crosslinking

Biodegradable and Nonbiodegradable polymers

• Based on the ability of the polymers to undergo degradation in natural environment and biological systems

• Biodegradable – slowly get degraded from the site of administration

• Non-biodegradable – inert in the environment of use

Polymer properties

Thermal              

Physical                               

Mechanical

Thermal

• Melting point

• Glass transition temperature 

Physical              

• Molecular weight

• Molar volume                               

• Density

• Degree of polymerization        

• Crystallinity of material

Mechanical

•   Stretching

•   Bending

•   Hard or soft

•   Response to application of repeated load

Physical Properties - Degree of Polymerization and Molecular Weight

• The degree of polymerization (DP)-n in a polymer molecule is defined as the number of repeating units in the polymer chain − (−CH_𝟐 − CH₂−)−_n

• The molecular weight of a polymer molecule is the product of the degree of polymerization and the molecular weight of the repeating unit 

Average Molecular weight

• The polymer molecules are not identical but are a mixture of many species with different degrees of polymerization, that is, with different molecular weights. Therefore, in the case of polymers we talk about the average values of molecular weights

Significance of polymer molecular weight

• The physical properties (such as transition temperature, viscosity, etc.) and mechanical properties (such as strength, stiffness, and toughness) depend on the molecular weight of polymer

• The lower the molecular weight, lower the transition temperature, viscosity, and the mechanical properties

• Increased entanglement of chains with increased molecular weight, the polymer gets higher viscosity in molten state, which makes the processing of polymer difficult

Physical Properties - Polydispersity Index (PDI) or Heterogeneity Index

•   The dispersity measures heterogeneity of sizes of molecules or particles in the mixture

• The mixture is called monodisperse if the molecules have the same size, shape, or mass

• If the molecules in the mixture have an inconsistent size, shape and mass distribution, the mixture is called polydisperse

 The PDI is equal to or greater than 1

 As the polymer chains approach uniform chain length, the PDI approaches to unity

Physical Properties – Polymer crystallinity

Semi-crystalline polymer

Crystalline and amorphous polymers

Crystalline Polymer

• If the structure of polymer is linear, polymer chains can pack together in regular arrays

Amorphous polymer

• In many cases, the structure of a polymer is so irregular that crystal formation is thermodynamically infeasible

Physical Properties – Polymer crystallinity

Amorphous   O% ß Polymer Crystallinity à >9O% Crystalline

• Lamellar crystalline form - the chains fold and make lamellar structure arranged in the regular manner

• Amorphous form -the chains are in the irregular manner

• Tie Molecules – The lamellae are embedded in the amorphous part and can communicate with other lamellae via tie molecules

Significance of polymer crystallinity

Slow cooling + Simple structural chains

â

Sufficient time is available for crystallization to take place

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High degree of Crystallinity

Rigid and have high melting point, but their impact resistance is low

Examples: polyethylene, and PET polyester

 

  Amorphous polymers are soft and have lower melting points

  Solvent can penetrate the amorphous part more easily than the crystalline part

  Examples: polystyrene and poly(methyl methacrylate)

Polymer Crystallinity - Spherulites

• If the molten polymer is cooled down, then the crystalline lamellae grow in radial direction from a nucleus along the three dimensions leading to a spherical structure called spherulite

• The amorphous region is in between the crystalline lamellae

• Due to highly ordered lamellae in the spherulite, it shows higher density, hardness, tensile strength, and Young’s modulus

Thermal Properties

Amorphous region in a polymer at different temperatures

Low temperatures

  Polymer are in, say, frozen state

  The molecules can vibrate slightly but are not able to move significantly. This state is referred as the glassy state

  The polymer is brittle, hard and rigid analogous to glass.

Hence the name glassy state

Higher temperatures

 The polymer chains are able to wiggle around each other, and the polymer becomes soft and flexible similar to rubber.

 This state is called the rubbery state

Glass transition temperature (Tg)

• The temperature at which the glassy state makes a transition to rubbery state is called the glass transition temperature (Tg)

• The glass transition occurs only in the amorphous region, and the crystalline region remains unaffected during the glass transition

• The glass transition temperature is the property of the amorphous region of the polymer, whereas the crystalline region is characterized by the melting point

• Glass transition temperature is the second order transition, whereas the melting point is the first order transition

Glass transition temperature and melting point

• The semi-crystalline polymer shows both the transitions corresponding to their crystalline and amorphous regions

•   Thus, the semi-crystalline polymers have true melting temperatures (Tm) at which the ordered phase turns to disordered phase

• The amorphous regions soften over a temperature range known as the glass transition (Tg).

• Note: Amorphous polymers do not possess the melting point, but all polymers possess the glass transition temperature

Factors affecting melting point

• The polymer melting point Tm is increased if the double bonds, aromatic groups, bulky or large side groups are present in the polymer chain, because they restrict the flexibility of the chain

• The branching of chains causes the reduction of melting point, as defects are produced because of the branching

Factors affecting glass transition temperature

1. Intermolecular Forces. Strong intermolecular forces cause higher glass transition temperature

2. Chain Stiffness. The presence of the stiffening groups (such as amide, sulfone, carbonyl, p-phenylene etc.) in the polymer chain reduces the flexibility of the chain, leading to higher glass transition temperature

3. Cross-Linking. The cross-links between chains restrict rotational motion and raise the glass transition temperature

4. Molecular Weight. Tg is increased with the molecular weight

5. Plasticizers. 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

6. Pendant groups

• Bulky pendant groups: the presence of bulky pendant group, such as a benzene ring, can restrict rotational freedom, leading to higher glass transition temperature

• Flexible pendant groups: the presence of flexible pendant groups, for example, aliphatic chains, limits the packing of the chains and hence increases the rotational motion, tending to less Tg value

Crystalline or amorphous – Pharmaceutical perspective

• Polymer strength and stiffness increases with Crystallinity as a result of increased intermolecular interactions

An amorphous polymer is preferred when the release of a drug or an active material is intended

• Crystallinity increases the barrier properties of the polymer.

• Small molecules like drugs or solvents usually cannot penetrate or diffuse through crystalline domains

•   Good barrier properties are needed when polymers are used as a packaging material or as a coating

Mechanical properties

1.   Strength

2.   Percentage elongation to break (Ultimate Elongation)

3.   Young’s Modulus (Modulus of Elasticity or Tensile Modulus)

4.   Toughness

5.   Viscoelasticity

Strength

• Strength is the stress required to break the sample

• There are several types of the strength, namely,

 Tensile (stretching of the polymer)

 Compressional (compressing the polymer)

 Flexural (bending of the polymer)

 Torsional (twisting of the polymer)

 Impact (hammering)

• The polymers follow the following order of increasing strength:

Linear < branched < cross-linked < network

Factors Affecting the Strength of Polymers

• Molecular Weight: In case of large molecular weight polymer, the chains become large and hence are entangled, giving strength to the polymer

• Cross-linking: The cross-linking restricts the motion of the chains and increases the strength of the polymer

• Crystallinity: The crystallinity of the polymer increases strength, because in the crystalline phase, the intermolecular bonding is more significant

Percent Elongation to Break (Ultimate Elongation)

• It measures the percentage change in the length of the material before fracture

• It is a measure of ductility

 Ceramics have very low (<1%)

 Metals have moderate (1–50%)

 Thermoplastic (>100%),

 Thermosets (<5%)

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

  

Toughness

• The  toughness  of  a  material  is  given  by  the  area  under  a stress–strain curve

• The toughness measures the energy absorbed by the material before it breaks

Mechanical Properties

The rigid materials possess high Young’s modulus (such as brittle polymers)

Ductile polymers also possess similar elastic modulus

Elastomers have low values of Young’s modulus and are rubbery in nature

Viscoelasticity

• There are two types of deformations: elastic and viscous

Elastic deformation

• In the elastic deformation, the strain is generated at the moment the constant load (or stress) is applied, and this strain is maintained until the stress is not released

• On removal of the stress, the material recovers its original dimensions completely, that is the deformation is reversible

Viscous deformation

• In viscous deformation, the strain generated is not instantaneous and it is time dependent

• The strain keeps on increasing with time on application of the constant load, that is, the recovery process is delayed

•When the load is removed, the material does not return to its original dimensions completely, that is, this deformation is irreversible

Ideal properties of polymer for pharmaceutical use

• Should be versatile and possess a wide range of mechanical, physical and chemical properties

• Should be non-toxic and have good mechanical strength and should be easily administered

• Should be inexpensive

• Should be easy to fabricate

• Should be inert to host and biodegradable  

Advantages of Polymers

• Polymers are more resistant to chemicals than their metal counterparts

• Polymer parts do not require post-treatment finishing efforts, unlike metal

• Polymer and composite materials are up to ten times lighter than typical metals

• Polymer materials handle far better than metals in chemically harsh environments.

This avoids problems associated with corroding metal components

• In  medical  facilities  polymer  and  composite  materials  are  easier  to  clean  and sterilize than metal

• Polymers with desirable properties can be synthesized by varying the monomers and their composition

Pharmaceutical applications of polymers

• The desirable polymer properties in pharmaceutical applications are

APPLICATION	PROPERTY
Coating	Film forming
Rheology Modifier	Thickening
Controlled Release	Gelling
Binding	Adhesion
Controlled Release	pH-dependent solubility
Taste Masking	Solubility in aqueous solvents
Protection And Packaging	Barrier properties

Binder

• In a traditional pharmaceutics area, such as tablet manufacturing, polymers are used as tablet binders to bind the excipients of the tablet

• Example: Poly(vinyl pyrrolidone) used as tablet granulation

Packaging materials for pharmaceutical products

• Flexible packages are made by the use of thin and flexible polymer films

• When they are wrapped around a product, they can easily adapt their shape to conform to the shape of the contents

• The thin, flexible films are usually produced from cellulose derivatives, Poly(vinyl chloride)  (PVC),  polyethylene,  polypropylene,  polyamide  (nylon),  polystyrene, polyesters, polycarbonate, poly(vinylidene chloride), and polyurethanes

• Heat sealable and are also capable of being laminated to other materials

• Rigid packages such as bottles, boxes, trays, cups, vials, and various closures are made from materials of sufficient strength and inflexibility

• Widely used polymers are high-density polyethylene, polypropylene, polybutene, poly(vinyl chloride), acrylic copolymers, polycarbonate, nylon, and polyethylene terephthalate (PET)

• Biodegradable PET is preferred due to environmental concerns, but it is expensive

Polyisoprene, ethylene propylene/dicylopentadiene copolymer, styrene/butadiene copolymer, polybutadiene, silicone elastomers, and natural rubber

Taste Masking

• Requirement for bitter drugs

• Applying polymer coatings

• It avoids direct contact of the bitter drug with the taste buds

A  water-soluble  polymer  such  as  a  cellulose  acetate,  cellulose  butyrate,  hydroxyethyl cellulose is used in taste masking of bitter drug

Rheology Modifiers

Natural sources

Starch, cellulose, alginate, carrageenan, collagen, gelatin, guar gum, pectin, and xanthan gum

Synthetic

PVA, polyurethanes, acrylic polymers, CMC, HPMC, HMC

Gelling

• Acacia, alginic acid, bentonite, Carbopols (now known as carbomers), carboxymethylcellulose, ethylcellulose (EC), gelatin, hydroxyethylcellulose, hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose (MC), poloxamers, polyvinyl alcohol (PVA), sodium alginate, and xanthan gum

Poly (vinyl chloride)

Blood bag, hoses, and tubing

Contact lenses

Hard contact lenses

Poly (methyl methacrylate)

Soft contact lenses

Poly (hydroxyethyl methacrylate)

Polystyrene

Water-Soluble Synthetic Polymer

Poly (ethylene oxide) à Coagulant, flocculent, swelling agent

Poly (vinyl pyrrolidone) à Plasma replacement, tablet granulation

Poly (vinyl alcohol) à Water-soluble packaging, tablet binder, tablet coating

Poly (ethylene glycol) à Plasticizer, base for suppositories

Poly (isopropyl acrylamide) and poly (cyclopropyl methacrylamide) à Thermogelling acrylamide derivatives, its balance of hydrogen bonding, and hydrophobic association changes with temperature

Water-Insoluble Biodegradable Polymers

 (Lactide-co-glycolide) polymers à for protein delivery

Starch-Based Polymer

Sodium starch glycolate à Superdisintegrant for tablets and capsules in oral delivery

Starch à Glidant, a diluent in tablets and capsules, a disintegrant in tablets and capsules, a tablet binder

Plastics and Rubbers

Polycyanoacrylate à Biodegradable tissue adhesives in surgery, a drug carrier in nano- and microparticles

Polychloroprene à Septum for injection, plungers for syringes, and valve components

Polyisobutylene à Pressure-sensitive adhesives for transdermal delivery

Silicones à Pacifier, therapeutic devices, implants, medical grade adhesive for transdermal delivery

Polystyrene à Petri dishes and containers for cell culture

Poly (methyl methacrylate) à Hard contact lenses

Poly (hydroxyethyl methacrylate) à Soft contact lenses

Poly (vinyl chloride) à Blood bag, hoses, and tubing

Hydrocolloids

Carrageenan à Modified release, viscosifier

Chitosan à Cosmetics and controlled drug delivery applications, mucoadhesive dosage forms, rapid release dosage forms

Pectinic acid à Drug delivery

Alginic acid àOral and topical pharmaceutical products; thickening and suspending agent in a variety of pastes, creams, and gels, as well as a stabilizing agent for oil-in-water emulsions; binder and disintegrant

Cellulose based polymers

Hydroxypropyl methyl cellulose à Binder for tablet matrix and tablet coating, gelatin alternative as capsule material

Hydroxyethyl and hydroxypropyl cellulose à Soluble in water and in alcohol, tablet coating

Summary

• Historical evolution of polymers from guncotton to today’s generation of modern polymers can be recalled

• ‘Poly’ means many and ‘mer’ means part

• Polymers are synthesized from monomers                     

• Polymers can be synthesized by addition or condensationreactions

• Addition method is used when there are double bonds in monomers

• Condensation requires reactive groups in monomers

• Polymers are classified based on several factors like, nature and arrangement of monomers, structure, source and thermal response of polymer

• Physical properties of polymers include molecular weight, degree of polymerization, crystallinity etc.

• Thermal properties include glass transition temperature and melting point

• Mechanical properties include strength, elongation, young’s modulus, toughness and viscoelasticity

• There are some specific properties required of polymers for pharmaceutical use like, availability at affordable cost, non-toxicity, biodegradability, etc.

• Specific advantages of polymers lend themselves to specific applications in pharmaceutical and biomedical fields

• Polymers find applications in conventional and modified drug delivery systems

• Polymers also find use in packaging and medical device fabrications

• As pharmaceutical excipients in the form of binders, thickening agents, gelling agents, etc.

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