SEMINARON

PLASTICIZERS

BY

NAGARAJU .JM.PHARM 1ST SEMESTER,

UNIVERSITY COLLEGE OF PHARMACEUTICAL SCIENCES

WARANGAL

CONTENTS INTRODUCTION

IDEAL PROPERTIES

CLASSIFICATION OF PLASTICIZERS

MECHANISM OF PLASTICIZATION

PLASTICIZERS USED IN

SOFTGELATIN CAPSULES AND TABLETS

EVALUATION OF PLASTICIZERS

APPLICATIONS

CONCLUSION

REFERENCES

INTRODUCTION

A plasticizer is a substance which when added to a material,usually a plastic, makes it flexible, resilient and easier tohandle.

They are colorless, odorless liquids produced by a simplechemical reaction, where by molecules of water are eliminatedfrom petrochemical products.

They are not just additives. They are major components thatdetermine the physical properties of polymer products.

DEFINITION :

A plasticizer or softener is a substance incorporated in amaterial (usually a plastic) to increase the flexibility,workability,dispensability.

It may reduce the melt viscosity, lower temperature of secondorder transition or lower the elastic modulus of the product.

There are more than 300 different types of plasticizersavailable.The most commonly used plasticizers are ester likephthalates, adipates and trimellitates.

IDEAL PROPERTIES OF PLASTICIZERS:

• It should be flexible resilient and easier to handle.

• It should be non volatile with high boiling point.

• It should not come out from materials to which it is added.

• Plasticizers used for internal purpose such as tabletcoating, capsule shell manufacturing should be non toxic.

• Lower the tensile strength and softening temperature, ofthe polymeric materials to which it is added.

• It should reduce the brittleness, improve flow,flexibility, and increase toughness, shear strength, andimpart resistance to the polymeric film coating.

• It should lower the glass transition temperature of thepolymeric film coating. It should reduce the viscosityof materials to which it is added.

• it should impart permanent properties such as liability,shock resistance, hand drop.

CLASSIFICATION OF PLASTICIZERS

These are two types

Internal plasticizers

External plasticizers:

Primary plasticizers

Secondary plasticizers

INTERNAL PLASTICIZERS:• A rigid polymer may be internally plasticized by chemically

modifying the polymer or monomer so that flexibility polymer isincreased.

• The process by which Tg of rigid polyvinylchloride is loweredthrough copolymerization, is called internal plasticization.

EXTERNAL PLASTICIZERS:• These are high boiling liquids, non volatile and having low vapor

pressure.

• They must soluble in polymer and reduce the Tg of polymer belowroom temperature rendering it softer and flexible

• They acts as lubricants between the polymer chains, facilitatingslippage of chain under stress.

PRIMARY PLASTICIZERS:Also called as chemical plasticizers, when added to

polymer, will cause the properties of elongation and softnessof the polymer to be increased.

SECONDARY PLASTICIZERS:Also called as plasticizing oils. They are not used

alone but when combined with primary plasticizers willenhance the plasticizing performance of the primaryplasticizer.

TYPES OF PLASTICIZERS:• Phthalates

• Adipates

• Citrates

• Phosphate esters

• Polymerics

• Esters of glycol and polyhydric alcohols

• Sebacate nad azelate esters

• Secondary plasticizers

• Trimellitates

PHTHALATES:• Both ortho-phthalic and terephthalic acids are used to react with

alcohol to produce phthalate esters

• Alcohol used in the range from methanol(c1 up to c17.)

• When added to vinyl, phthalate molecules are tightly bound upbetween the long vinyl molecules, making them slip and slideagainst each other without sacrificing strength.

ADVANTAGES:

• Migration is less

• Readily biodegradable

• Does not cause any harm to body.

A) DI-2-ETHYLHEXYL PHTHALATE:

• Also known as di-octyl phthalate.

• It is considered as the industry standard.

• It is phthalate ester of alcohol 2-ethylhexanol.

Advantages

• Low cost

• Posses reasonable plasticizing efficiency, fusion rate , viscosity

Disadvantages:

• It is toxic

B) DIISODECYL PHTHALATE(DIDP) AND DIISONONYLPHTHALATE (DINP) :

• These are prepared from oxo alcohols of carbon c9 and c10

• These are used for heat resistant electrical cards, leather for carinteriors and PVC flooring in concentration of 25 to 50%.

ADIPATES:• Adipates are prepared from alcohols in the c8 to c10 range.

• They are having improved low temperature performance and lowviscosity.

• They are highly volatile, having high migration rate and are highpriced.

CITRATES:• These include triethyl citrate, acetyl triethyl citrate, tributyl

citrate and acetyl tribuyl citrate

• Tri butyl citrate is heat stable and does not discolour whenprocessed in compound resins.

• These esters used in electrical coatings, food industry, hairsprays and inks.

PHOSPHATES:• They show good compatibility with PVC.

• They are having good low temperature performance, migrationresistance and improved fire retardency relative to phthalates.

POLYMERICS:

• These are produced by reacting a dibasic carboxylic acidswith one or more glycols.

• These are manufactured in a wide range of viscosities. Withincreasing viscosity, handling become more difficult.

• The optimum viscosities of some acids areadipates-5600 cps, glutarates-12000 cps.

ESTERS OF GLYCOLS AND POLYHYDRICALCOHOLS:

• polyhydric alcohols are propylene glycol, glycerol,polyethylene glycol and Esters of glycols are glyceryltriacetate, tri ethyl citrate.

• These are water soluble and used in aqueous film coatings.

SECONDARY PLASTICIZERS:

• They are also known as extenders.

• The majority of these plasticizers include chlorinatedparaffin's, which are hydrocarbons chlorinated to a level of 30-70%.

• The fire retardency and viscosity increases with chlorinecontent.

• Other materials used are epoxidised soya bean oil andepoxidised linseed oil.

• They acts as lubricants to pvc due to their epoxy content.

TRIMELLITATES:• Common esters in these family are tris-2

ethylhexyltrimellitate,L810TM, an ester of mixed c8 and c10linear alcohols.

Advantages:

• Low volatility

• Low migration rate.

SEBACATE AND AZELATE ESTERS:• Di-2-ethylhexyl sebacate (DOS) and di-2-ethylhexyl azelate

(DOZ) are the most common members of this group, butDiisodecyl Sebacate (DIDS) is also used. They give superior lowtemperature performance than adipates.

GLASS TRANSITION TEMPERATURE(Tg):

• The temperature at which the glassy polymer becomes rubberyon heating and rubbery polymer reverts to glassy on cooling iscalled the glass transition temperature.

• Polymer in rubbery state are very viscous liquids withrelatively high freedom of rotation round the carbon-carbonbonds in the backbone with in the constraint of tetrahedralbond angle.

• The temperature is high enough so that most bonds capable ofovercoming potential energy barrier against rotation. Thisrotational freedom results in very flexible chains.

plaPlasticizer10% plasticizer 20%plasticizer

Triethyl citrate

Acetyl triethyl citrate

Tributyl citrate

Acetyl tributyl citrate

Triacetin

Tg of unplasticizedfilm is 55ºc

34.3

37.0

38.5

38.2

42.2

12.8

17.5

20.5

22.2

27.4

Tg of Eudragit RS 30D(ºc)

GLASS TRASITION TEMPERATURE OF EUDRAGIT RS 30 D POLYMERIC FILMS

MECHANISM OF PLASTICIZATION:

• Some involve detailed analysis of polarity, solubility andinteraction parameters and the thermodynamics of polymerbehavior, whilst others treat plasticization as a simple lubricationof chains of polymer, analogous to the lubrication of metal partsby oil.

• The following steps are involved in the incorporation of aplasticizer into a PVC product.1. Plasticizer is mixed with PVC resin.

2. Plasticizer penetrates and swells the resin particles.

3. Polar groups in the PVC resin are freed from each other.

4. Plasticizer polar groups interact with the polar groups on theresin.

5. The structure of the resin is re-established, with fullretention of plasticizer.

Theories of plasticization are :

The Lubricity Theory

The Gel Theory

The Free-Volume Theory

LUBRICITY THEORY: A “dry” polymer, a resin without plasticizer, is rigid

because friction exists between its chains, binding theminto a network.

When the polymer is heated in order to be plasticized, thebinding is weakened and the smaller plasticizer moleculesare able to slip in between the chains.

When the polymer cools, the plasticizer molecules act as alubricant between the chains, allowing them to “slip.”

GEL THEORY: The plasticizer molecules break up the polymer-polymer

interaction by getting in between the chains and“obscuring” these interaction sites from the polymermolecules.

THE FREE VOLUME THEORY:

• The free volume of a polymer can be described as the “emptyinternal space” available for the movement of the polymerchains.The free volume of a polymer greatly increases when itreaches the glass transition temperature.

• At the glass transition temperature, the molecular motionbegins to occur, which corresponds to an increase in the freevolume of the polymer.

• These plasticizer molecules are having low glass transitiontemperature than the polymer, so that Tg of the resultingmixture will be lower.

PLASTICIZERS USED IN CAPSULEMANUFACTURE

The most common plasticizers used in manufacturing of hard andsoft gelatin capsules polyvinyl alcohols, sorbital and propyleneglycols.

The amount and choice of the plasticizer help to detemine thehardness of the final product, and may also affect the dissolution ordisintegration the Soft gel, as well as its physical and chemicalstability.

The ratio of dry plasticizers to dry gelatin determines the hardnessof the shell and can vary from 0.3-1.0, for a very hard shell 1.0 to1.8 for a very soft shell up to 5% sugar may be may be included togive chewable quality to shell.

Typical shell hardness ratios and their uses

Hardness Ratio of dryglycerin/dry gelatin

Usage

Hard 0.4/1 Oral, oil based or shellsoftening products andthose destined primarilyfor hot, humid areas.

Medium 0.6/1 Oral tube, vaginal oilbased, water-misciblebased or shell hardeningproducts and those

destined primary

Soft 0.8/1 Tube, vaginal, watermiscible based or shellshardening products andthose destined primaryfor cold, dry areas.

PLASTICIZERS IN TRANSDERMAL DRUG DELIVERY

PATCHES:

• Acrylic-acid matrices with plasticizers have been used tomake drug–polymer matrix films for transdermal deliverysystems. Some of the polymers that have been reported areEudragit RL PM, Eudragit RS PM, Eudragit S-100.

• Ethyl cellulose and pvp matrix films with 30% dibutylphthalate as a plasticizer have been fabricated to deliverdiltiazem hydrochloride and indomethacin.

• The addition of hydrophilic components such as PVP to aninsoluble film former such as ethyl cellulose tends to enhanceits release-rate constants.

PLASTICIZERS IN FILM COATING:The commonly used plasticizers can be categorized into three groups:1. Polyols:

(a) Glycerol (glycerin);(b) Propylene glycol;s(c) Polyethylene glycols PEG (generally the 200–6000 grades).

2. Organic esters:(a) Phthalate esters (diethyl, dibutyl);(b) Dibutyl sebacete;(c) Citrate esters (triethyl, acetyl triethyl, acetyl tributyl);(d) Triacetin.

3. Oils/ glycerides:(a) Castor oil;(b) Acetylated monoglycerides;(c) Fractionated coconut oil

Plasticizers used in controlled release drugs such as

Dibutyl sebacateDiethyl phthalate

Triacetin

Triethylcitrate

Acetylated monoglyceride

Plasticizer acts as a film forming aid by reducing the glasstransition temperature of the polymer, thereby promoting thecoalescence of the latex particle.

The degree of plasticization of a polymer is dependent ton theamount of plasticizer added, interactions between the polymer andplasticizer.

EFFECT OF PLASTICIZERS ON THE MECHANICALPROPERTIES OF THE FILM:

Common methods used to evaluate mechanical properties ofpolymeric films include microindentor probe analysis, and sheartests, and stress relaxation.

The stress–strain test is probably one of the most popular andwidely used technique to determine the mechanical properties ofpolymeric materials.

Stress–strain testing generally consists of applying an axial load toan isolated free film and measuring the load and deformationsimultaneously. The stress–strain test will provide a generalizedcurve from which several useful properties can be determined .

The basic requirements to be met by a plasticizer arepermanence and compatibility.

Compatibility, demands that the plasticizer must be miscible

with the polymer and exhibit similar intermolecular forces tothose present within the polymer.

Permanence is an attribute to be taken into consideration asloss of plasticizer, It leads to the cracking of the coating underinappropriate storage.

Permanence is obviously related to plasticizer volatility;however a change to a more non volatile plasticizer bychanging to a higher molecular weight plasticizer is not alwaysan advantageous move.

EFFECT OF PLASTICIZERS ON PERMEABILITY OF FILMCOATINGS:

water vapour transmission cell

• These water vapor transmission cells rely on a vapor pressuregradient to achieve a linear weight gain. From the daily weightgains, the water vapor permeability constant can be calculatedusing equation

• where Perm is the moisture permeability constant, W is the amountof moisture transmitted per unit time, L is the thickness of the film,A is the area of the film exposed, and DP is the vapor pressure

gradient.

• Water vapors have been shown to permeate more rapidly through

films containing hydrophilic plasticizers, whereas the inclusion ofa hydrophobic plasticizer in the coating has been found to exert nosignificant effects on water vapor permeability.

]

EVALUATION OF FILM PROPERTIES:

The free films were cut into strips of 70 mm × 10 mm forevaluation of mechanical properties or circular pieces with diameterof 7.46 cm for determination of water vapour permeability.

Film thickness was determined by measuring the thickness at fivescattered points on the film, using a digital micrometer (Mitutoyo,Japan) and the values averaged.

Only film samples with mean thickness within the range of 180 to220 mm and thickness value variation less than 10 % in each filmwere used for the above tests.

Film samples used for mechanical testing, assay of plasticizer andmoisture content and determination of percent weight change werestored in controlled environment chambers of 30°C and 50 or 75 %RH.

• samples were equilibrated at ambient room condition of 22 + 2°Cand 55 +2 % RH for 1 hour prior to testing. This is to minimiseany variations in result due to room condition.

MECHANICAL PROPERTIES:• The mechanical properties of the films were evaluated using a

tensile testing instrument (EZ Test-100N, Shimadzu, Japan)mounted with a 100 N capacity load cell..

• Four mechanical properties, namely tensile strength, % elongationat break, elastic modulus and work of failure were computed fromthe load - strain profile, and film dimensions as shown below.

• t = Lmax/Ai (1)• e= ∆lb/li (2)

• EM =dL/dm/Ai ( 3)

• ω = AUC x δ/Ai (4)

PLASTICIZER CONTENT:

• The amount of plasticizer in the Aquacoat film was determinedusing gas chromatography (Model 5890 series II HewlettPackard) with a split/ splitless inlet, a 23.5 m by 0.32 mmfused silica-polyethylene glycol capillary column (HP-FFAPX-linked polyethylene glycol) and a flame ionization detector.

• About 200 mg of film sample were accurately weighed anddissolved in methanol. An internal standard of 1 ml was thenadded to the mixture. triethyl citrate (TEC) (5 mM) wasemployed as the internal standard for GTA while glycerintriacetate (GTA) (10 mM) solution was the internal standardfor the rest of the plasticizers.

• Using methanol, the mixture was made up to a final volume of20 ml for dibutyl phthalate (DBP) and 10 ml for the rest.Nitrogen was used as the carrier gas at a flow rate of 28.5ml/min, with injector temperature at 240°C and detectortemperature at 270°C.

• For the assay of DEP, TEC, ATEC and GTA, the columntemperature was increased from 150°C to 230°C at a rate of10°C/min and held at 230°C for 3 min.

• For the assay of DBP and acetyltriethyl citrate (ATEC) , thecolumn was heated up from 150°C to 240°C at a rate of10°C/min and held at 240°C for 5 min

APPLICATIONS: The plasticized PVC is used for life saving medical devices

such as medical tubing and blood bags,t o footwear, electricalcables ; packaging, stationary, and toys.

Phthalates are used in other non pvc applications such aspaints, rubber products, adhesives and some cosmetics.

The butyl benzyl phthalate- plasticized polymeric material hasconsumer and industrial uses such as flooring, sealants andcoatings

PHARMACEUTICAL APPLICATIONS

Used in functional and nonfunctional coating of solid dosageforms, including tablets, beads and granules, such as filmcoating, enteric coating, osmotic tablet coatings etc. to impartflexibility to the different types of coating materials.

In the production of soft gelatin capsules.

In the manufacture of life saving medical devises such as

• IV administration

• Dialysis

• Cardio-pulmonary bypass (CPB) procedures

Bags used to store and transport:

• Enteral nutrition formulae

• Total parenteral nutrition formulae

Tubings used in enteral nutrition:

Nasogastric tubes

Nasojejunal tubes

Also used in manufacturing of transdermal patches

CONCLUSION:

Plasticizers are necessary for almost all polymers that arecurrently used for film coating of tablets and beads.Plasticizers reduce the brittleness, improves flow, impartflexibility, and increase flexibility, and increase toughness,strength, tear resistance of polymers.

Although there are many plasticizers used in chemicalindustry, only a few plasticizers have been approved forpharmaceutical applications due to environmental and humanhealth concerns attributed to plasticizers toxicity.

REFERENCES:

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2.Porter S.“Coating of Pharmaceutical Dosage forms”,Remington's book of science, 1: 894-902.

3. “Encyclopedia of pharmaceutical technology” by JamesSwarbrick, 1734, volume-3.

4. Sakellariou, P., Rowe, R. C., and White, E. F., Int. J.Pharm., 31: 55 (1986).

5. Entwistle, C. A. and Rowe, R. C., J. Pharm • Pharmacol.31: 269(1979)

6. Porter, S. C., Pharm • Tech., 4(3): 66 (1980).

7. Aulton, M. E., Twitchell, A. M., and Hogan, J. E.,Proceedings of AGPI Conference, Paris (1986).

8.Crawford, R. R. and Esmerian, O. K., J. Pharm. set.60(2):312 (1971).

9. Entwistle, C. A. and Rowe, R. C., J. Pharm •Pharmacology. 31: 269(1979) .

10. Skultety, P.F. & Sims, S. Drug Dev. Ind. Pharm. 13:2209–2219 (1987)

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THAN’Q’