Detailed description of types of plasticizers, mode of selection, types of effects produced on polymers and optimization of plasticizers in aqueous/organic coating based systems.

1. PAS 243
Product formulation
Spring 2008
Instructor :- Dr.B.D.Rohera
Presented by
Deepa Nair
1
Effect of plasticizers in film coating
of tablets .

2. Outline
2
 Why do we need plasticizers?
 Introduction
 Mechanism of action of plasticizers
 Properties of plasticizers
 Classification of plasticizers
 Curing temperature & plasticizer.
 Selection of plasticizers
 Effect 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.
 Limitations
 Conclusion

3. 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 films
Produce intact films
3

4. 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. 4

5. 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
5

6. Introduction
6
 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

7. Cont'd
7
 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

8. Mechanism of action
8
 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 -

9. Cont'd
9
 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.

10. Classification of plasticizers
Depending on their properties they can be
classified as:-
 Polyols
Glycerol
Propylene glycol
PEG 200-6000 grades.
 Organic esters
Triacetin,
Diethyl phthalate (DEP),
Dibutyl phthalate (DBP) and
Tributyl citrate (TBC)
10

11. 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 11

12. 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 12

13. 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.
13

14. 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.
14

15. 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.
15

16. 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, 16

17. 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.
17

18. Classification on basis of water
solubility.
(A) Water soluble
PEG
TEC
Triacetin
(B) Water insoluble are
DEP
DBS
DBP
ATEC –Acetyl-triethyl-citrate.
18

19. 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. 19

20. 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
20

21. 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” .
21

22. Curing conditions and plasticizers
 Curing 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
22

23. 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 23

24. Cont’d
Fig.1. Shows relationship between the curing time and the percent
of plasticizer remaining in film.
24

25. Selection of plasticizers
 Selection 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
25

26. Critical aspects for selection
 The 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 the26

27. 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
27

28. Aquacoat CPD enteric coating onto
Aspirin tablets
 Recommended 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.
28

29. Cont’d
29

30. Effect of plasticizers on mechanical
properties of films.
30
 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.

31. Effect on residual internal stress
31
 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.

32. Effect on permeability of films
32
 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.

33. Characterization of plasticized films.
33
 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

34. Cont'd
34
 The Hildebrand equation is given by:-
∂ = (∆Ev ∕V) 1/2 - (∆HV RT ∕V)1/2
where ∆Ev molar energy of vaporization of plasticizers
V- molar volume of plasticizer
R- ideal gas constant
T -absolute temperature
∆HV -Latent heat of vaporization of plasticizer
 Mechanical methods:-
This is done by both indentation methods and tensile
methods.

35. Texture of plasticized films
 The 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.
35

36. 36

37. Viscoelastic property of plasticized
films (methylcellulose and cross
linked methyl cellulose)
37
 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.

38. Cont'd
38
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.

39. Cont’d
39

40. 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. 40

41. Cont’d
Table showing “Tensile strength and film elongation for
wet MC and dried MC films plasticized with PEG 400
at different concentrations”.
41
Amounts of
PEG 400
WET MC
Tensile
Strength
WET MC
Elongation
%
DRY MC
Tensile
Strength
WET MC
Elongation
%
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

42. Cont'd
42
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.

43. 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.
43

44. Cont’d
44

45. 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 effects45

46. Effect of plasticizers on release rates
of drug .
46
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.

47. Cont’d
47
 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.

48. Cont’d
48
 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.

49. Limitations
49
(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

50. Cont’d
50
 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.

51. Cont’d
51
 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.

52. Conclusion
 Plasticizers 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
52

53. THANK YOU
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