Polymers Adds

8/10/2019 Polymers Adds

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POLYMER SCIENCE

MRUGESH RAIYANI

FIRST M. PHARM.

DEPT. OF PHARMACEUTICS.


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Polymer Science

Polymers play an important role in drugdelivery systems

The selection of a particular polymer is

primarily determined by the intended use.

Diluents : STARCH, MCC, EC, HPMC

Disintigrating Agents : SSG, STARCH


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Polymers used should be

Inexpensive

Readily available

Easily processed on a large scale

Biocompatible

Non-toxic


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Polymers are defined as very large molecules consisting of

many repeating units and are formed by a processes calledpolymerization , which links together smaller molecules

known as monomers,

Polymer also know as macromolecules.

monomers can be linked together in various ways to give

1. linear

2. branched

3. cross linked polymers .

Definition


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Linear and branched polymers are alsoknown as thermoplastic polymers bcos theycan flow when heated thus can be fabricated

by the application of heat and pressure theyare also soluble in certain solvents.

Crossed linked polymers are known as

thermosetting polymers as they dont flowwhen heat or pressure is applied and hencecannot be fabricated by application of heatand pressure since all the polymer chains areinter connected by covalent cross links , they

cannot dissolve and only swell to the extentallowed by crossed linked density


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Polymers Structure

Branched

branched

Cross linked


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POLYMER NAMES

A polymer is generally named based on the monomer it is synthesized

from. For example, ethylene is used to produce poly(ethylene) (PE).

Similarly PMMA (Poly Methyl MethAcrylate)

HOMOPOLYMER

(one monomer)


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Polymers

Terminology (contn): copolymer: polymers of two monomer types

random -B-A-B-A-B-B-A-

alternating-A-B-A-B-A-B-A-

block -A-A-A-A-B-B-B-

heteropolymer: polymers of many momomer types

COPOLYMER


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Polymer Classification

They are classified based on

1 The Method of polymerization Addition polymers

Condensation polymers

2 The Polymerization Mechanism

Chain (addition) polymerization Step growth (condensation) polymerization

3 The Origin polymers Natural

Semi Synthetic

Synthetic4 Degradable properties Biodegradable

Non Biodegradable


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THE METHOD OF

POLYMERIZATION

Addition polymers;The repeating units of thepolymer have the same molecular formula as the

monomer .

They are prepared by the polymerization of the

monomers bearing one or more double or triple bonds

or by the ring opening of cyclic structures.

C d ti P l


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Condensation Polymers

They are formed

by successive

reactions of

functional

groups . since

the by-productformed is a

smaller

molecule , the

repeating unit ofthe polymer are

fewer atoms

than the

monomer.


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How ever the above classification does

not include / accommodate

condensation reaction where no small

molecules split up.

Like for e.g.

poly urethanes

Poly ureas


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Polyurethanes

A urethane has an ester groupand amide groupbonded to the same carbon.

Urethanes can be prepared by treating an isocyanate with an alcohol.

RN C O ROH RNH C

O

OR+

an isocyanate an alcohol a urethane

Polyurethanesare polymers that contain urethane groups.

O C N

CH3

N C O

toluene-2,6-diisocyanate

+ HOCH2CH2OH

ethylene glycol

C

O

NH

CH3

NH C

O

OCH2CH2O C

O

NH NH C

O

OCH2CH2O C

OCH3

n

a polyurethane


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Classification based on The

Polymerization Mechanism

1.Chain (addition) polymerization:Reactions proceed via discrete initiation , propagation andtermination steps.

Once the polymerization reaction starts each polymer chainundergoes rapid preferential growth in terms of molecular

weight and a steady decrease in the monomer concentrationis evident.

Chain polymerizations divided into following four types:

Free radical

Anionic

Cationic

zieger-natta

copolymerization (random co polymer, alternating copolymer,block co polymer, graft copolymer)


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The Chemistry of Free Radical Polymerization

Radical Generation

Initiator Radicals

I I 2 I

Initiation

Monomers

I CH2 CH2 I CH2 CHR

Propagation I CH2 CHR + CH2 CHR

CH2 CHR CHRI

Termination I CH2 CHR + CH ICH2R

I CH2 CHR CH2CHR

CH2

I

Polymer

-

+


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Anionic polymerization :

Initiation: B M B + M

Propagation: B-CH2-CHR M + CH2 = CHR

B-CH2-CHR-CH2-CHR M

To high polymer


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Cationic polymerization :

Initiation : CH3HX + CH3 - C = CH2

CH3 CH3

CH3CCH3 CH3C= CH2 X

X H


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Propagation :

CH3 CH3

CH3CCH3 + CH3C= CH2

CH3 CH3

CH3CCH2C

CH3 CH3

To high polymer


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Step-Growth Polymerization

Step-Growth PolymersPolymers that are formedby a series of reactions between functional groups of

adjacent multifunctional molecules, often with the

loss of some small molecule such as H2O or CH3OH.

Linear Step-Growth Polymers: Made from

difunctional monomers of the type X-R-Y

(bifunctional monomer) or X-R-X + Y-R-Y where

X and Y are the functional groups. X and Y must becapable of condensing with one another.


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POSSIBLE DRUG RELEASE MECHANISM

FOR POLYMERIC DRUG DELIVERY

Drug Release

Diffusion Polymer Degradation combination

Enzymatic degradation Hydrolysis Combination

Surface erosion

Bulk erosion


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Various devices can be classified into,

1. Diffusion controlled devices

2. Solvent controlled devices

3. Chemically controlled devices


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Diffusion controlled devices :

Release from monolithic devices

Release from reservoir devices

Examples :

pilocarpine reservoir as occular

therapeutic system

Pesticide release in laminated controlled

release structure.


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Solvent controlled devices :

Osmotically controlled devices.

Swelling controlled devices.

Examples :

Capsule type osmotic pump

Elementary osmotic pump


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Chemically controlled devices :

Polymer erosion mechanism.

Type -1, Type-2, Type-3 erosion.

Drug release mechanisms.


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Biodegradable polymers

They are polymers in which the monomers

are linked to one another through functionalgroups

They are biologically degraded or eroded byenzymes

The concept of biodegradable polymersgenerated interest because of two reasons.

1. It was realized that drug depleted deliverysystem could cause toxicological reactionsin the body if retained.

2. Biodegradable polymers are applicable for awider range of drugs.


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Biodegradable

V

Non Biodegradable

They are degraded in thebody to the simple moleculeslike water and co2which areeasily eliminated in the urine.

They are mainly used forparental drug delivery systembut can also be used for oraldrug delivery system.

like liposomes, nanoparticles,microspheres etc.

e.g. poly(glycolic acid)

poly(para-diaxanone) etc.

They are non bio

degradable in the body.

Used only for oral

administration.

SR, ER, etc.

They cannot be used for

parental drug delivery of

drugs.

e.g. ethyl cellulose,

HPMC, methyl cellulose

etc.


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Classification Of Biodegradable

Polymers

Natural polymers

Proteins :Albumin , collagen , gelatin

Polysaccharides :collagen , dextran , hyaluronic acid , starch

Synthetic polymers

Aliphatic poly (esters)

Poly (lactic acid)

Poly (-caprolactone ) Poly ( para - dioxane )

Poly ( hydroxy butyrate)

Poly (- malic acid)

Poly ( phospho esters)

Poly anhydride

Poly phosphazene

Pseudo amino acids

Poly (ortho esters)


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Biodegradable Polymers Used for

Medical Applications

Natural polymers Fibrin

Collagen

Chitosan

Gelatin Hyaluronan ...

Synthetic polymers

PLA, PGA, PLGA, PCL, Polyorthoesters

Poly(dioxanone)

Poly(anhydrides)

Poly(trimethylene carbonate)

Polyphosphazenes ...


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PROTEINS


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HUMAN ALBUMIN

It is a major plasma protein component

accounts for 55% of the total proteins in thehuman plasma

It is sterile non pyrogenic preparation of serum

albumin obtained by fractionating material(source ; blood, plasma, serum, or placenta )

from healthy human donors . It is made by

process that yields product safe for ivuse . Mol.wt about 66500

It is a single peptide chain consisting of 585

amino acids


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Advantages of ALBUMIN

Biodegradation into natural products

Easily available

Absence of toxicity and antigenicity

It is soluble in water

Application of ALBUMIN

1. It is primarily used as an excipient inparentral pharmaceutical formulations whereit is used as a stabilizing agent for theformulations containing proteins and

enzymes in the conc range of 1% to 5%2. It is a also used a cryoprotectant during

lyophilization


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Albumin microspheresare used to deliver drugs like

inulin , sulphadiazine , 5-fluorouracil , prednisolone.

These are exploited mainly for chemotherapy

because with them high local drug conc. can beachieved for relatively longer time.

Factors affecting drug release from albumin

microspheres

1. Physicochemical properties and conc. of the drug2. Interaction b/w drug and the albumin matrix

3. Nature and the degree of cross linking

4. Presence of enzymes and ph of the environment

The release pattern from albumin microspheres is

biphasic . The initial burst release is followed by a

comparatively slower first order release.


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GELATIN

It is a purified protein fraction obtained either by partial

acid hydrolysis (type A gelatin) or by partial alkaline

hydrolysis (type B gelatin) of animal collagen. Mol.wt 15000-250000

Structural unit

Gelatin contains a large number of glycine (almost 1 in 3 residues,

arranged every third residue), proline and 4-hydroxyproline residues.

A typical structure is -Ala-Gly-Pro-Arg-Gly-Glu-4Hyp-Gly-Pro-.


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Advantages of Gelatin

Easy availability

Low antigenic profile

Poor binding to drug molecules

Low temperature preparation technique

that reduces the chances of drug

degradation Solubility

Insoluble in acetone , chloroform , ethanol , ether , methanol

Soluble in glycerin , acids and alkali {ppt by strong acids and

alkali.}


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The properties of gelatin mainly depends on the source of collagen ,

extraction method , pH value , etc..

1. It is used as a

Coating agent

Gelling agent

Suspending agent

Tablet binder

Viscosity increasing agent

Raw material for the production of empty gelatin capsules2. it can be used as a biodegradable matrix material in an implantable

delivery system

3. Low mol.wt gelatin has been investigated for its ability to enhance

dissolution of orally ingested drugs

4. Gelatin micro pellets have been prepared for control release of drugs

5. Therapeutically gelatin has been used in the preparation of wound

dressings

6. Gelatin sponge has haemostatic properties


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GELATIN

Swelling properties

In water it gradually swells and softens gradually

absorbing water 510 times of its own weight.

It is soluble in hot water and forms a jelly or gel

on cooling (35-40 0).

At temp above 400 it remains as a solution.


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FIBRINOGEN

It is a soluble plasma protein having a

mol.wt of 340000 Fibrinogen mirospheres are prepared by

emulsification technique followed by

thermal denaturation Doxorubicin, 5-flurouracil , adriamycin ,

are delivered with fibrinogen microspheres


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CHITIN AND CHITOSAN

Chitin is a linear poly cationic polymer of N-

acetyl-D-glucosamine units linked by -d (1-4)

bonds

It is insoluble in common solvents and shows

resemblance to cellulose by having similar

solubility profile and low chemical reactivity

Industrial sources of chitin are shells ofshrimps , lobsters and crab


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CHITOSAN

It is a principle derivative of chitin and is obtained by alkaline

deacetylation

The characteristic properties of chitosan that make it suitable forpharmaceutical and biomedical application are

1. Antacid and anti ulcer activity , hypocholoesterolemic action and

wound healing properties.

2. Haemostatic property.3. Presence of reactive functional group and cationic character

opens up possibilities for their application in controlled drug

delivery

4. Favorable biological properties like biodegradability ,

biocompatibility , and non toxicity

5. Gel forming ability at low ph, so can be used for oral sustained

release delivery of drugs.

6. The chitosan matrix formulation floats and gradually swells in

acidic medium.


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O

CH2OH

HOH

H

H O

O

NH

H

C O

CH3

O

CH2OH

HOH

H

H O

O

NH2

H

chitin chitosan

alkaline

deacetylation


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As a direct tabletting agent .

It can be used as a diluents , binder , lubricant

and a potential disintigrant due to its wateruptake properties .

Ulcerogenic drugs can be effectivelyadministered with chitosan .

Reduces the gastric mucosal injuries.associated with diclofenac sodium.

Has antitumor activity .

Film forming capacity of chitosan --employedfor the development of contact lenses .

Used in ocular bandage lenses, as protectivedevice for acutely or chronically traumatizedeye.


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DEXTRAN

It is a polymer of glucose

It is obtained by the action of bacteriumleuconostoc mesenteroides

The crude high mol wt dextran is formed

is hydrolyzed and fractionated to yeild

dextran of desired mol wt.

Used in the form of gel for colonicdelivery of drugs


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ALGINATES

E.g, sodium alginate

Hydrophilic carbohydrates obtained from variousspecies of brown sea weeds by the use of dilute alkali.

Particularly beneficial as a carriers for peptidesandother sensitive drugs as the particulate carriers can beeasily prepared at the room temperature in a aqeous

solution Effectively used for oral delivery of vaccines.

Used as a binder , disintigrant, as a diluent forcapsules.

Used in sustained release of drugs as it delays thedissolution of the formulation.

The adhesiveness of the hydrogels prepared fromsod.alginate has been investigated (buccal tablets )


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SODIUM ALGINATE

USE CONCENTRATION[in %]

Pastes and

creams

5-10

Stabilizer in

emulsion

1-3

Suspending

agent

1-5

Tablet binder 1-3

Tablet disintigrant 2.5-10


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Biodegradable Polyesters


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Polyglycolide (PGA).

Polyglycolide is the simplest linear aliphatic polyester.

It was used to develop the first totally synthetic absorbablesuture, marketed as Dexon in the 1960s.

Glycolide monomer is synthesized from the dimerization ofglycolic acid.

Ring-opening polymerization yields high-molecular-weight

materials, with approximately 13% residual monomerpresent

PGA is highly crystalline (4555%), with a high meltingpoint (220225C) and a glass-transition temperature of 35

40C.


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PGA is absorbed within a few months

post implantation due to greater

hydrolytic susceptibility. Not soluble in most organic solvents.

Sutures lose about 50% strength after 2

weeks & 100% at 4 weeks , completelyabsorbed in 4- 6 months.


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Poly(-caprolactone )


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Poly(-caprolactone )

Ring-opening polymerization ofcaprolactone.

Melting point of 5964C and a glass-transition temperature of60C

Regarded as tissue compatible and used as abiodegradable suture in Europe.

Homopolymer has a degradation time on theorder of 2 years.

Slow degradation rate renders it suitable forlong term delivery system (1 year ).

High permeability to large no. of drugmolecules & has non-toxic profile.


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Poly(dioxanone)

The ring-opening polymerization ofp-dioxanoneresulted in the first clinically tested monofilamentsynthetic suture, known as PDS (marketed by Ethicon).

55% crystallinity, with a glass-transition temperature of-10 to 0C.

Has demonstrated no acute or toxic effects onimplantation.

The monofilament loses 50% of its initial breakingstrength after 3 weeks and is absorbed within 6 months


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Poly dioxanone)

Fibers made from polymers containing a highpercentage of polyglycolide are too stiff formonofilament suture.

Thus are available only in braided form abovethe micro-suture size range.

The first clinically tested mono-filamentsynthetic absorbable suture was made frompolydioxanone (PDS, Ethicon).


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Poly(dioxanone)


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Polylactic acid

PLA or polylactide, is prepared from the cyclicdiester of lactic acid (lactide) by ring openingpolymerization.

Lactic acid exists as two optical isomers orenantiomers.

Crystalline poly-L-lactide more resistant tohydrolytic degradation than the amorphous DLform.


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Polylactic acid

The rate of poly-L-lactide degradation has beenincreased by plasticization with triethyl citrate.

Time required for poly-L-lactide implants to beabsorbed is relatively long .

It depends on polymer quality, processing conditions,implant site, and physical dimensions of the implant.

Absorption time of about 1.5 years for 50 to 90 mgsamples.


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Polylactic Acid (PLA)


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Polylactic acid (PLA): Linear aliphatic polyester Produced by :

poly-condensation of naturally produced lactic acid (co-product of corn), or by

Catalytic ring opening of the lactide group.

The ester linkages in PLA are sensitive toboth chemical hydrolysis and enzymatic

chain cleavage.

PLA is fully biodegradable (whencomposted at 60C).



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Properties and uses of PLA

Packaging Packaging foam

Films

Containers (biodegradable)

Coatings for papers and boards

Fibres

Clothing

Carpet tiles (Interface Inc.)

Nappies

Bottles

Biodegradable bottles
http://www.biocorpusa.com/html/resource-ware.htmlhttp://www.biocorpusa.com/html/pla_clear_cup.html


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Poly hydroxybutyrate

Poly hydroxybutyrate (PHB) is a rare example of abiodegradable polymer that both occurs in nature.

High MW, crystalline, and optically active PHB has beenextracted from bacteria.

Polymer has been proposed for use as absorbable

suture.

Recent improvements in the extraction process haveresulted ins PHB for both medical and nonmedicalapplications.

.


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Non Degradable Polymers For Drug

Delivery

The various polymers are

Ethyl cellulose

Cellulose esters HPMC

Acrylic polymers

Silicones

Poly (ethylene oxides)


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ETHYL CELLULOSE

It is a cellulose ether prepared by reaction of alkali cellulose with

ethyl chloride.

Insoluble in water but soluble in organic solvents. Tasteless, odorless, inert, stable in pH 3-11 and compatible with

most drug substances.

Use Concentration(%)microencapsulation 10-20

Sustained release

tablet coating

3-20

Tablet coating 1-3

Tablet granulation 1-3


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CELLULOSE ACETATE ESTERS

Cellulose acetate(CA) , cellulose acetate

butyrate , cellulose acetate propionate CA is obtained by controlled esterification of

purified cellulose with acetic acid and

anhydride.

Cellulose triacetate has the highest acetate

content and higest MP of cellulose esters.

Decrease in the acetyl content increases the

hydrophilic properties of the polymer


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USES OF ETHYL CELLULOSE

The main use of ethyl cellulose in oral formulation

as a coating agent in order toi. Mask unpleasant taste

ii. Improve stability of the formulation

iii. To inhibit the oxidationiv. Modify the release

In matrix systems prepared by wet granulation and

direct compression

Thin films of EC are also used as a moisture

barrier to improve the stability of hydrolytically

unstable drug.


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CELLULOSE ACETATE

Used in sustained release formulations and

also for taste masking It is used as a semipermiable coating on the

tablets especially in osmotic pump type

tablets and implants Solubility

It is soluble in acetone -water blends of

various ratios.

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Polymers Adds