PAS 243Product formulation

Spring 2008Instructor :- Dr.B.D.Rohera

Presented by Deepa Nair

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Effect of plasticizers in film coating of tablets .

Outline

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Why do we need plasticizers?IntroductionMechanism of action of plasticizersProperties of plasticizersClassification of plasticizersCuring temperature & plasticizer.Selection of plasticizersEffect of plasticizer on permeability of film. Effect of plasticizer on mechanical properties of

film.Characterization of plasticized films.Study of viscoelastic effect of plasticizers on films. LimitationsConclusion

Why do we need plasticizers?Almost all the film forming agents or

polymers are brittle in nature do to their complex structure.

Most commonly used polymers are the cellulose derivatives or cellulose related compounds like HPMC, MC, EC, HPMCP etc.

These polymers are widely used as film forming materials as they:-Produce transparent filmsProduce intact films

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Cont’d They have lower values for water vapor

permeability rate.They have lower values for oxygen

transmission rates.They can be structurally modified to

achieve sustained release ,like HPMC can be converted to HPMCP for enteric coating.

But due to presence of multiple polymeric strands within a single molecule of polymer makes them brittle.

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Cont’d When such a material is applied as a film coat on

to tablet a smooth film is not be obtained.This condition necessitates the addition of

plasticizers to the coating dispersions.The addition of plasticizers to polymeric material

causes them to diffuse within the polymers and cause polymer deformation and coalescence into homogeneous films.

The effectiveness of plasticizers on polymeric dispersion depends upon polymer compatibility and the permanence of plasticizer during the course of shelf life, or when it comes in contact with physiological fluids.

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Introduction

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Plasticizers are relatively low molecular weight materials which have a capacity to alter the physical properties of a polymer to render it more useful as film forming agents.

The polymers used as film forming agents are relatively brittle in nature at room temperature and pressure.

The function of plasticizer is to make the polymer more pliable and soft and thereby enhancing the flexibility and plasticity to the films.

They modify the physical and mechanical properties of film by enhancing the mobility of the polymeric chain.

Cont'd

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Plasticizer are added in order to reduce the glass transition temperature, this addition of the plasticizer facilitates the thermal stability of the drug and other ingredients.

The intensity of particle coalescence and the quality of the resulting final film so formed entirely depends on the type and the concentration of plasticizer added to the coating dispersion.

The efficiency of a plasticizer is intensely related to its chemical structure and the extent and rate of interaction with the polymeric material present in the formulation.

Physicochemical properties of the films mainly the water uptake and erosion, solid-state crystallinity, thermal behavior and water vapor and drug permeability are modified to a greater extend.

Mechanism of action

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The mechanism of action of plasticizers is defined as to interpose between every individual strand of polymer and thereby causing breakdown of polymer -polymer interactions.

The tertiary structure of the polymer is modified into more porous, flexible and with less cohesive structure.

Plasticizers soften and swell the polymer (latex spheres) which aids in overcoming their resistance to deformation.

As a result the plasticized polymer would deform at a lower tensile force as compared to without plasticizer. This enhances the polymer -plasticizer interaction.

Cont'd

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This effect in turn enhances the film elongation effect.

This interaction to a greater extend depends upon the glass transition temperature of polymers. Glass transition temperature, Tg is the temperature at which hard glassy polymer is converted into a rubbery material.

All polymers have higher glass transition temperatures and addition of plasticizers reduces the glass transition temperature.

Classification of plasticizersDepending on their properties they can be classified as:-

PolyolsGlycerolPropylene glycolPEG 200-6000 grades.

Organic estersTriacetin, Diethyl phthalate (DEP), Dibutyl phthalate (DBP) and Tributyl citrate (TBC) 10

Cont’d Oils/ glycerides

Castor oil

Fractionated coconut oil

Acetylated monoglycerides.

Newer Plasticizers – DBS.

Can be used for the very plasticizing effect

in both aqueous and solvent based

pharmaceutical coatings.

Under this category both the hydrophilic as

well as lipophilic esters are available. 11

Properties of commonly used plasticizers.

(A) PEGs

These are hydrophilic substances and soluble in water.

In the conventional film coating the solid grades of PEGs are used alone as hydrophilic plasticizers.

Rate of release of water soluble drugs decreases with increase in the molecular weight of PEGs.

The PEG with molecular weight of 6000 and above decreases plasticizing effect and increases lubricant effect.

Migration of PEG can occur from the tablet film coating leading to interactions with core compounds.

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Cont’d

(B) DBS- Dibutyl Sebacate.

These are esters of n-butanol and saturated dibasic acids.

Principally used as plasticizers in film coating.For film coating as a plasticizer, DBS is used in

10-30% concentration by weight of polymer. Insoluble in water but soluble in ethanol,

mineral oil etc.Quite suitable for solvent based coating

dispersions.

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Cont’d (C) DEP- Di ethyl Phthalate.

Used both as a solvent and plasticizer.Non toxic, non irritant.DEP is used as a plasticizer in film coating

of tablets , beads and granules at a concentration of 10-30% W/W of polymers.

Its is insoluble in water, soluble in ethanol, ether and orgainc solvents.

It is volatile in nature.

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Cont’d (D) DBP- Dibutyl Phthalate.

Also known as kodaflex DBP.Very soluble in acetone, benzene, ethanol,

ether and soluble in water. Is principally used as a plasticizer.But it has limited compatibility with the

cellulose acetate polymers.

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Cont’d

(E) Triacetin

Also known as Triethyl glycerin or glycerol triacetate.Used as both plasticizer and a solvent. Its an hydrophilic plasticizers.This plasticizer is suitable for both aqueous and

solvent based polymeric coating of tablets, granules and beads in concentration of 10-35% by weight of polymer.

Miscible with water as well as in ether, ethanol, chloroform etc.

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Cont’d

(F) TEC- Triethyl Citrate.

It is a citric acid ethyl esters.Also known as Citroflex 2. Its is principally used as plasticizer. It is effectively used in aqueous based coating

in Oral sustained or enteric coated tablets .Miscible with water.

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Classification on basis of water solubility.

(A) Water soluble PEGTECTriacetin(B) Water insoluble areDEPDBSDBPATEC –Acetyl-triethyl-citrate.

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Cont’d Water soluble plasticizers make solutions whereas

the insoluble plasticizers are emulsified into dispersions.

With insoluble plasticizers, their dispersion is described as a 3 phase systems containing water phase, polymer phase and plasticizer emulsified droplets.

The rate and the extend of plasticizers uptake by the colloidal polymers was explained by conducting the effect of type and concentrations of plasticizers on Aquacoat and the plasticized films so formed were characterised by HPLC.

It showed that the water soluble plasticizers like triacetin was in higher concentrations in the aqueous phase due to higher solubility in aqueous phase. 19

Cont’d Whereas the water insoluble plasticizers

i.e. DBS partitioned about 90% or more into the polymer phase. And the rest form was present as emulsified droplets.

Under such conditions when the plasticized droplet containing coating dispersions are sprayed onto the tablets they generate rough, brittle and uneven films which potentially alters mechanical properties and release profile of drug from the coated dosage forms.

The rate of uptake of plasticizers by the polymers is a function of plasticizing time. But in case of water soluble plasticizers like triacetin or TEC uptake is not affected by the agitation time or mixing time.

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Cont’d But for water insoluble plasticizers like

DBS incomplete plasticizing is observed even after long plasticization time for ethylcellulose latex.

To overcome this undesired effect we carry out an additional step called “Curing Step” .

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Curing conditions and plasticizersCuring is a thermal treatment following the

application of coat .The coalescence of colloidal polymer particles from

the aqueous coating dispersions is usually incomplete.

As a result coalescence of particles during the storage temperature and time can occur which can in turn modify the release of drug from the coated products.

To overcome this ; curing which is a thermal treatment is followed. In this the coated dosage forms are kept at elevated temperatures for short period of time. This promotes further coalescence of the polymer particles before the long term storage periods.  22

Cont’d During the curing conditions the coated dosage

forms are subjected to temperatures higher than the glass transition temperatures of the polymer immediately after the coating is over.

Usually curing temperature is about 100C above the minimum film forming temperature (MFT).

It facilitates uniform distribution of plasticizers and improves polymer particle coalescence.

Both retardation and increase in drug release can achieved depending upon the drug type and the curing conditions.

Curing e.g.- the curing of Aquacoat coated CPM showed a retarded drug release from the product.

Very high curing temperatures can lead to excessive tackiness in the dosage form.

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Cont’d

Fig.1. Shows relationship between the curing time and the percent of plasticizer remaining in film.

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Selection of plasticizersSelection of the plasticizer is very critical. Plasticizer selection depends upon two major

criteria:- 1)Glass transition temperature and 2)Solubility

parameter.For a controlled release dosage form the polymer

plasticizer interaction in the latex emulsion must be considered as affecting primarily the drug and substrate and nature of rate limiting system.

The type and the concentration of plasticizers actually controls the desired flexibility and permeability in the finished film.

Thus type and concentration of plasticizer can eventually modifies the release rate of the drug from the coated product. Like increasing concentrations of DBS or triethyl citrate decrease the drug release from the Aquacoat coated dosage forms.

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Critical aspects for selectionThe capacity of the plasticizer molecule to modify

the polymer-polymer interaction.

The ability to solvate or solubilize the polymer.

The ability to add flexibility to the material by

reducing its rigid characteristics or brittleness.

Should have optimum viscosity in the coating

solution.

Should have controlled and desired effects on the

film permeability, tackiness, flexibility, solubility,

taste etc 26

Cont’d Should be nontoxic and compatible with other

components.

Should have desired stability.

Optimizing the type of plasticizer and its ratio in the

formulation depends upon the chemical structure of

the polymer, method of application, and the other

ingredients present in the system.

Recommended concentration of plasticizers in film

coating material is 1-45% weight of the film former.

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Aquacoat CPD enteric coating onto Aspirin tabletsRecommended plasticizers include diethyl

phthalate (DEP), triethyl citrate (TEC) and triacetin (GTA or glyceryl triacetate).

The film forming temperature is reduced by decreasing the glass transition temperature (Tg) which is the temperature at which the polymer undergoes marked changes in physical properties.

The glass transition temperatures for Aquacoat CPD with various levels of plasticizer was determined .

Recommended levels of plasticizers are 20-24% of the latex solids.

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Cont’d

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Effect of plasticizers on mechanical properties of films.

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Decrease in tensile strength

Decrease in elastic modulus

Increase in film elongation.

E.g. the effect of plasticizers on the mechanical

properties of cast film of HPMC i.e.; Methocel ES

was studied and it was found that the low

molecular weight PEGs had a better plasticizing

effect as compared to higher molecular weight

due to viscoelastic effect of former.

Effect on residual internal stress

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Plasticizers reduce internal stress within the films.

They also decrease the surface tension at the

polymer surface.

When the effect on residual internal stress of

plasticizer was evaluated on CAP films , the

triacetin among the triacetin, DEP and Citroflex 2A

had the best plasticizing effect due to lowering of

residual internal stress within the films.

Effect on permeability of films

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Plasticizers play a very significant role in

optimizing the permeability characteristics of

film coat to retard the entry of water vapor

and other gases .

As plasticizers modify the structure of

polymers, they can alter the diffusion or the

dissolution of permeants across the polymers.

E.g.; the water absorption coefficient for

HPMC films plasticized with PEG 400 and

1000 for both the plasticizers are higher.

Characterization of plasticized films.

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Thermal methods

Determination of plasticizer activity by determing

the glass transition temperature Tg.

Thermomechanical methods

DSC, LVDT trace.

Solubility methods

For a polymer to dissolve in plasticizer , the Gibbs

free energy has to be negative and the solubility

can be obtained by the Hildebrand's and

Scott(1950).

 

Cont'd

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The Hildebrand equation is given by:-

∂ = (∆Ev ∕V) 1/2 - (∆HV RT ∕V)1/2

where ∆Ev molar energy of vaporization of plasticizersV- molar volume of plasticizerR- ideal gas constantT -absolute temperature∆HV -Latent heat of vaporization of plasticizer

Mechanical methods:-This is done by both indentation methods and tensile methods.

Texture of plasticized filmsThe texture of Aquacoat films varied with

the type of plasticizers used. Aquacoat films plasticized with DBP

appeared to be more flexible, smoother and homogeneous while those plasticized with DEP and ATEC had raised spots and undulating surfaces.

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Viscoelastic property of plasticized films (methylcellulose and cross linked methyl cellulose)

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Films of methylcellulose (MC), poly(ethylene

glycol)400 (PEG400) plasticized MC, and MC gels

(MC crosslinked with glutaraldehyde (GA)) were

prepared by casting from aqueous solutions.

The swelling test has shown that the MC gels

were insoluble in water and that their cross

linking density increased with increasing GA and

HCl concentrations.

Cont'd

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The DMA analysis of PEG400/MC blends:-The effect of the addition of PEG400 or GA to

MC was investigated through dynamic mechanical analysis (DMA).

PEG400 was compatible with MC and was an effective plasticizer since the curves of tan δ against temperature exhibited single peaks also they were displaced to lower values with increasing PEG400 content.

From the following graph its clear that the glass transition temperature decreases sharply with increasing concentrations of PEG400.

Cont’d

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Cont’d Tensile strength test.The tensile strength of the MC gels increased with

increasing GA and HCl concentrations, while the elongation decreased.

The wet MC gels, conditioned in a 50% relative humidity atmosphere for 48 h, had lower tensile strengths and higher film elongations than the vacuum-dried MC gels.

This result confirmed that water plasticized the polymer backbone of the gels, thus decreasing the tensile strength and increasing the elongation.

The PEG400 showed a decreased tensile strength with an increased film elongation effect with increasing concentration of PEG 400.

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Cont’d Table showing “Tensile strength and film

elongation for wet MC and dried MC films plasticized with PEG 400 at different concentrations”.

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Amounts of PEG 400

WET MCTensile Strength

WET MCElongation%

DRY MCTensile Strength

WET MCElongation%

0 48.0 2.0 67.3 1.6

2 46.5 11.2 57.0 8.5

3.8 45.1 14.6 51.8 11.5

7.4 44.3 17.1 46.6 14.3

13.8 33.5 25.1 36.7 16.5

Cont'd

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The Thermo Gravimetric Analysis (TGA) :-

The thermal stability of MC was not affected

by the chemical cross linking.

The tensile strength was slightly increased

through cross linking while the elongation was

slightly decreased.

The tensile strength decreased and the film

elongation was increased with the gradual

addition of PEG400.

Cont’d The Differential Thermo Gravimetric Analysis

The Differential Thermo Gravimetric Analysis curves for MC and for PEG400 plasticized MC was performed.

These Differential Thermo Gravimetric Analysis curves showed single peaks.

This indicates that MC and PEG400 are compatible and that the thermal stability of plasticized MC is far better and desired when compared to that of MC.

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Cont’d

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Cont’d The plasticizers here decreased the intermolecular

interactions among the functional groups of the backbone chains, thus increasing the mobility of the chains, resulting in increased flexibility and extensibility.

The polyethylene glycols (PEG) have certain advantages that they offer a higher plasticity than other compounds such as glycerol and sorbitol etc.

They possess some hygroscopic characteristics that helps in retaining a moderate moisture in the polymer.

This enables PEG to generate viscoelastic effects in films when added as a plasticizer.

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Effect of plasticizers on release rates of drug .

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Effect of plasticizer type and coat level on aqueous coating dispersions of ethylcellulose.

To optimize the most suitable plasticizer and in its most suitable concentration for ethylcellulose (EC).

The two plasticizers selected were DBS and GTC.The two commercial formulations, one Surelease/E-

7-7050 containing dibutyl sebacate (DBS) and formulation 2 was Surelease/E-7-7060 containing glyceryl tricaprylate/caprate (GTC).

The tablet was coated with 1%, 2%, 3% and 5% coat levels.

The release profile of the drug (Ibuprofen) was a function of coat thickness.

Cont’d

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The coated Ibuprofen tablets were evaluated for their drug release profile, coat reflectivity (gloss), surface texture, hardness, and elastic modulus.

At a coat of 2% the release of drug from with GTC plasticized formulation appeared to follow the non-Fickian release mechanism , whereas the tablets coated with DBS plasticized formulation appeared to follow apparent zero-order release.

At equal concentrations of both the plasticizers and coat levels, the GTC plasticized Surelease slower release rates, higher reflectivity (gloss), lower surface roughness, higher hardness( Brinell) and lower elastic modulus than those coated with DBS plasticized formulation.

Cont’d

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The film plasticized with GTC were intact and more elastic than those of DBS plasticized films.

Hence it was inferred that GTC was a better plasticizer as compared to DBS when both used in same concentrations.

The film elongation effect increase , tensile strength decreases and glass transition temperature decreases in GTC plasticized films.

Limitations

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(A) LEACHING EFFECT- The major trouble encountered during the

plasticizing of polymers is the leaching of the plasticizer from the film.

This leaching effect of Plasticizer is dependent on the type and concentration of dissolution medium.

This eventually results in drastic alteration of drug release patterns from coated dosage forms.

This tendency of plasticizers can be well demonstrated from the In vitro dissolution studies with cast films of Eudragit® RS/RL had leached out the water-soluble plasticizers when the amount of hydrophilic polymer in the film was increased than the normal.

Cont’d

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Permanence is an attribute taken in consideration as loss of plasticizer during storage of plasticizers which in turn can hamper integrity of coated tablets.

The mechanism by which permanence occurs is said to be migration via diffusion process.

The molecular size and shape of the plasticizer are highly important as small molecules migrate faster than large ones. Also linear molecules migrate faster than bulky, branched ones.

The highly solvating ones that produce an open gel structure migrate at a faster rate.

Cont’d

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Volatility was found to be one of the major cause.

Thus permanence due to leaching tendency of plasticizers can be controlled by diffusion control.

This diffusion of plasticizer can be controlled by incorporating a more non volatile plasticizer or switching to a higher molecular weight plasticizer.

ConclusionPlasticizers play a very significant role on

mechanical properties, permeability of films and release of drug from the coated products.

They do enhance flexibity and plasticity of films.Therefore, the selection of a plasticizer for a film-

coating formulation is very important in the process development and optimization of a coated dosage form.

Curing conditions can facilitate the uniform distribution of plasticizers.

Therefore, one needs to strike a balance between the desired and undesired effects of the plasticizer and optimize its concentration in the coating formulation. 52

THANK YOU

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