film coating with aqueous latex dispersions

7/29/2019 Film Coating with Aqueous Latex Dispersions

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ilm coating is a un it process that m ay serve one or m ore

of the following fun ctions: to mask odor or taste; to ease

the swallowing of the dosage form ; to improve mechan-

ical integrity; to enh ance produ ct identification and ele-gance; to improve produ ct stability; and to m odulate the re-

lease proper ties (e.g., sustained-r elease and enteric coatings).

With the decline of organic solventb ased systems, aqueou s-

based film coating is curren tly the metho d of choice for film

coating solid dosage form s. The intro duction of latex-based sys-

tems has resulted in film coat ing formu lations with lower vis-

cosities and decreased coating times, even with high polymer

(solids) content s, comp ared with aqu eous solventb ased sys-

tems. In add ition, latex systems have facilitated coating th rough

the use of water-insoluble polymers to mod ify the release char-

acteristics of the dosage form (1).

Latexes are aqueous polym eric dispersions in which the po ly-

mer part icles typically have a subm icron p article-size distri-bution. Therefore, they are subject to the factors that can in-

fluence the stability of colloids. The addition of electrolytes,

pigments, pH changes, temperature changes, or high-shear

forces can lead to irreversible coagulation, and such systems

mu st be discarded (2). Lehman n has discussed h ow the effects

of several of these factors on latex stability can be m inimized

(2). The form ulation of stable film coating form ulations re-

quires an un derstanding of the factors that are imp ortan t to

latex stability (see Table I).

Film coatings com mo nly are colored for iden tification and

aesthetic purp oses. Despite the widespread use of pigments in

film coating, very few papers have been pu blished in pharm a-

ceutical literatu re abou t th e aspects regarding their form ula-

tion. Some author s have reported that the addition of pigments

can result in latex coagulation ( 2,3). The interactions leading

to coagulation of aluminu m lake pigmen ts and Eudragit latex

dispersions were the subject of a recent p aper (4). This article

aims to provide an overview of some of the factors that should

be considered when formu lating latex dispersions with pig-

ment s for th e film coating of solid dosage form s.

Regulat ionAll color additives used in the United States are regulated by FDA

and mu st meet certain specifications before they are sold (5). In

8 Pharmaceutical Technology YEARBOOK 2001 w w w . p h a r m t e c h . c o m

Film Coat ing w it hAqueous Lat ex DispersionsGen era l Conside rat ions forForm ula t ing w it h P igm ent sNasser Nyamweya, Stephen W.Hoag, and Ketan A. Mehta*

N a s s e r N ya m w e y a is a graduate student

and S tephen W. Hoag , P hD , is an

associate professor in the Department of

Pharmaceutical Sciences, University of

Maryland, School of Pharmacy. K e tan A .

M eh ta , P hD, is a technical services manager

at Rhm Pharma Polymers, Degussa

Corporation, 2 Turner Place, Piscataway, NJ

08855, tel. 732.981.5366, fax 732.981.5484,

[email protected].

*To whom all correspondence should be addressed.

FLatex dispersions have proved to be very

useful in aqu eous-based film coat ing,

especially in contro lled-release app lication s.

Film coatings comm only are colored w ith

pigm ents to provide a means of product

identification and to enab le the

man ufacturer t o d istinguish similar

products. Colored film s allow t he

man ufacturer to imp art a distinct

appearance to the dosage form, which is

useful from a m arketing standpoint. The use

of pig m ent s in film coating s also facilitat es

patient recognition and m akes the prod uct

aesthet ically appealing. Because both t he

latex polymer and p igment part icles exist in

th e colloidal or near -colloidal state,

inte ractions caused by sur face pro per ties

may sometim es lead to un stable

form ulations. This article examines some of

the issues that are impo rtant to consider

when formu lating latex dispersions with

pigments.


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addition, color additives may be either certified (b y batch) orexempt from certification. The m ost comm only used colorants

for film coating are alumin um lakes,t itanium dioxide, and syn-

thetic iron oxides. Alum inum lakes must b e certified by FDA.

The aluminu m lakes that may be used for film coating (or in-

gested pharmaceuticals in general) fall into two categories

FD&C lakes (certified for use in food, dru gs, and cosmetics) and

D&C lakes (certified for u se in d rugs and cosm etics). Titanium

dioxide and synth etic iron oxides are exemp t from certification,

although iron oxides have a maximum ingestion limit of 5

mg/day (as elemental iron).

Formulat ionExamples of polymers th at are available as latex dispersion s in-clude cellulose acetate phthalate, ethylcellulose, and several acrylic

copolymers. The solids con tent of these dispersions is typically

2530% (w/w). Table II lists the compo nen ts of a typical latex-

based film coating form ulation for colored films from an acrylic

copolymer. The polymer and pigment d ispersions usually are

mad e separately and m ixed together just before coating. This

procedure is necessary because dispersing pigments requires the

use of high-shear forces that m ay lead to coagulation of the latex.

When m ixing the two dispersions, one shou ld slowly add th e

pigment dispersion to the po lymer dispersion while mixing

gently (6). Because both t he polymer and th e pigment are in-soluble in water,t hese form ulations are m ixed dispersions (sys-

tems containing more th an on e dispersed ph ase), and th e small

particle size of the comp onen ts will enhance the effects of inter-

particle interactions.

In add ition to its use as an opacifier, titanium dioxide often

is used as a white pigment. When u sed with colored pigments,

several pastel shades of a given color are p ossible depend ing on

the proportion of titanium dioxide to the other pigments. Bright

or d ark colors are difficult to obt ain when t itanium dioxide is

used because of its extreme whiteness (7). Talc (used to p revent

the do sage form from sticking when the coating is drying and

impar t a smoo thn ess to th e coating) also m ay serve as an ex-

tend er or filler. Polyethylene glycol also has sur factant an d plas-ticizing propert ies. The h igh-shear forces required to disperse

pigments may result in foam formation and air entrapm ent,

thereby necessitating the use of an ant ifoamin g agent such as

simethicone.

The viscosity of a film coating form ulation is an impo rtant

consideration, although th is is less of an issue for latex disper-

sions because of their relatively low viscosity, which is the re-

sult of the un dissolved polymer. Because of the low viscosity of

these systems, pigments tend to settle, and th e formulation

should be stirred well during spraying to ensure repro ducible

and un iform application of the film coating. The type of pump

used to deliver the formu lation m ay affect its stability, e.g., the

higher pressures or shear forces developed in gear and pistonpum ps can lead to coagulation of latex-based form ulations (8).

Me th ods for assessing stabi lit yLong-term stability of pigmented film coating formu lations is

not an issue because the formu-

lations usually are used soon after

they are made. However, the for-

mu lation shou ld be stable enou gh

to withstand the shear forces that

are encountered during the spray-

ing processes and stable long

enough for the coating to be ap-

plied. Because aggregation u su-

ally is man ifested b y changes in

the appearance of the film coat-

ing formu lation, visual observa-

tion may serve as a qualitative

measure of stability. For quanti-

tative assessments of stability, sev-

eral meth ods are available.Th ese

include microscopy, par ticle con-

tent (e.g., gravimetric and den-

sity measurements), particle-size

analysis, light- scattering tech-

Table I : Factors important to la tex stabi l i ty .Factor Relevance

Particle size Submicron particle size is required to prevent settl ing, but a large

specific surface area facilitates interparticle interactions.

Surface charge Decreasing surface charge can lead to aggregation;

zeta potential measurements are useful.

Surfactants Used for ster ic or electrosteric stabilization.pH Can alter surface properties by changing the ionization

of functional groups and/or the binding of surfactants.

Viscosity Affects the movement of dispersed particles.

Electrolytes Can destabilize ionic latex dispersions by charge

neutralization or double-layer compression.

Water-soluble Can stabilize or coagulate latex dispersions depending

polymers on nature of interactions and concentration.

Coagulation occurs by charge neutralization, bridging,

or depletion flocculation.

Insoluble additives Surface charge may lead to interactions with latex;

if opposite in sign, can cause coagulation.

Poten

tial

Shear plane

Distance from surface

Surface

Bulk medium

0

Sternlayer

Diffuselayer

Figure 1: Variation of potential from t he surface of a colloidal particle

to the bulk m edium. Symbols: zet a p otenti al , 0 su rf ace

potential.


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Pharmaceutical Technology YEARBOOK 2001 11

niques (e.g., turb idimetry, laser diffraction, and pho ton corre-

lation spectroscopy), electrochem ical meth ods (e.g., zeta po-

tential measurements), sedimentation, filtration, and rheology

(9). Because of the inherent limitations of each technique, a com-

bination of various techniques often is useful. It is imp ortant to

no te that b ecause latex-based film coating formu lations have

high solids conten ts, techniques such as light scattering and zetapotential measurements, which require sample dilution, may

give results that do not reflect th e state of the or iginal disper-

sion. Recently, electroacoustic techniqu es have been developed

that can be used to determine the particle size and zeta poten-

tial of highly concentrated dispersions (10). Chemical stability

can be stud ied by spectroscopic techn iques such as infrared and

nu clear m agnetic resonance spectroscopy.

Surfa ce chem ist ryThe surface properties of both the latex particles and p igmen ts

are important for determining the n ature of interparticle inter-

actions. Because of their small size, they behave like colloidal

par ticles. Interaction s between colloidal particles depen d onthe att ractive and repulsive forces encoun tered when the p ar-

ticles interact. Charged par ticles develop an electrical dou ble

layer arou nd their surface so th e system can m aintain electri-

cal neutrality (see Figure 1). The charged p articles attract ions

of opposite charge (coun ter-ions), which are boun d strongly to

the sur face formin g the Stern layer. Beyond the Stern layer is

the diffuse layer, which consists of counter-ions and ions

of a charge similar to the charge on the particle surface. The

distribution o f ions in th is outer layer is more diffuse because

of repulsion from t he charged surface and the coun ter-ions in

the Stern layer. The existence of the d ouble layer creates a po-

tential that decreases from the surface of the par ticle un til the

bulk medium is reached. The zeta potential is the potential atthe shear plane (a region in the do uble layer within which th e

particle and associated ion s move as a unit). The zeta potential

is useful for determ ining how par ticles interact with on e an-

oth er and for pr edicting the stability of dispersed colloidal sys-

tems. Interparticle interactions th at result in coagulation are

mo re likely to occur when the p articles have opposite surface

charges. In addition , factors that decrease the zeta potential (e.g.,

electrolytes) also will enh ance the likelihood of instability. Sta-

bilization of colloidal par ticles will involve either providing th e

par ticles with a sufficiently large like-surface charge, which leads

to mutu al repulsion; the adsorpt ion of mo lecules that prevent

the par ticles from approachin g each o ther closely enough forattractive forces to predom inate (steric stabilization); or a com -

bination th ereof.

Pigmen t considerat ionsPigment s are insoluble colorants that color by dispersion, as

opp osed to dyes that exhibit colorin g power when they are dis-

solved ( 7). Insoluble colorants have been preferred m ore than

dyes because they do n ot m igrate with th e solvent as it evapo-

rates during the drying of the film coating, although recently

Signorino et al. have developed uniform non mo ttled coatings

using dyes with the addition of an imm obilizing agent (11). The

absence of color m igration results in produ cts that are less pron e

to m ottling and easier control of batch-to-batch consistency ofthe film coating color (12). In addition, pigments tend to be

more stable than dyes. Most of the pigments used are (or are

based on) metal oxides or hydroxides, e.g., iron oxide, titanium

dioxide, and aluminum lakes (alum inum hydroxide substrate).

When dispersed in aqueous media, these compo un ds acquire

a sur face charge, with H and OH as the potential-determ in-

ing ions (see Figure 2). Therefore, they m ay have a po sitive or

a negative surface charge depending on th e pH of the m edium

(9). The isoelectric point (IEP) is the pH at which the zeta po-

Tab le I I : Typ ica l f i lm coa t ing fo r mu la t ion fo r co lo r ed f i lms o f an ac r y l i c copo lymer .

Polymer Dispersion Example % (w / w ) Pigment Dispersion Example % (w / w )Latex Eudragit 40 Pigment Aluminum 5

(30% solids w/w) RS 30 D lake

Plasticizer* TEC** 2.4 Glidant Talc 15

Water 57.6 Opacifier Titanium dioxide 7

Glossing agent PEG 2

Antifoaming Simethicone 0.1

agent emulsion

Water 70.9

* For a 20% (w/w) plasticizer content on a polymer dry-weight basis** triethyl citrate polyethylene glycol

zeta

poten

tial

pH

OH2M

OH2M

OH2M

OHM

OHM

OHM

OM

OM

OM

OH

H

H2O

Figure 2: Effect of pH on the zeta potent ial of a met al (M) oxide or

hydroxide.


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tent ial is zero. In system s in wh ich electrostatic repu lsion is the

sole stabilization m echanism, the p articles will be least stable

at the IEP because of the absence of repulsive charges.

Because pigmen ts are insoluble, their coloring power is a

function of how well they are dispersed (13). When pigment s

are used in p owder form , they often tend to agglomerate be-

cause of their small particle size and large surface area. The useof suitable dispersion techniques such as high-shear mixers, ho-

mo genizers, and/o r m ills is required to ensure that agglom er-

ates are broken d own so th at a un iform ly colored coating is

achieved. If dispersion is a problem, predispersed color con-

centrates (dispersions) m ay be used.

Lakes are form ed by the precipitation and adsorption of a

water-soluble dye onto an insoluble substrate such as aluminum

hydroxide (7). Several colors are available depend ing on the

type and amoun t of dye used. The stability of aluminum lakes

in aqueou s dispersions is pH depen dent because of the disso-

lution of the aluminum hydroxide substrate at high and low

pH values (14).Th e dissolution of the substrate leads to the re-

lease of the water-solub le dyes, which are electrolytes becauseof the presence of ionic functional groups. The dye content of

the lake shou ld be considered for two reasons: First, when bleed-

ing occurs, lakes with higher d ye cont ents can release greater

amo un ts of dye, which will have a greater destabilizing effect

on latexes that are sensitive to electrolytes. Second , the po int of

zero charge (th e pH at which th e surface char ge is zero) is re-

lated inversely to the dye content ( 15). Therefore, it is possible

that lakes made with t he same dye but with different dye con-

tent s may interact differently with t he same latex.

Iron oxides are available in yellow, brown, red, and b lack.

These colorants are prepared by the precipitation of iron salts

(black and yellow iron oxides), calcination (red iron oxide), or

by blending mixtures of the other iron oxides (brown iron oxide)(5). The synthetic forms of iron oxide are used because of the

difficulties involved in pu rifying the n atur al form s (5). The color

of the film coating may be a function of the particle size of the

iron oxide (16,17). In such cases, consistent and reprodu cible

dispersion pro cedures are required if the same color is to be

maintained.

Interactions with latex particles (and o ther p articles in the

formu lation) that lead to coagulation will be favored when the

pigmen ts have a surface charge that is opp osite to that of the

latex particles (4). On e way to avoid such interactions is to ad-

ju st th e p H of th e m ed ium to a r egio n in wh ich bo th th e p ig-

m ent an d the latex par ticles have like charges. Altern atively, sur-

factants or dispersant s may be used. Polyethylene glycol and

pro pylene glycol have been u sed to prevent th e coagulation of

m ethacrylic acidethyl acrylate copolym er latex dispersions,

which occurs when the latex is formu lated with red iron oxide

(3). Sodium car boxymeth ylcellulose has been used to stabilize

m ethacr ylic acidethyl acrylate copo lymer latex dispersion s that

coagulated in the presence of red iron oxide (18). When u sing

water-soluble polymers for stabilization, their effect on t he vis-

cosity of the formulation should be taken into accoun t.

Latex considerationsIn certain conditions, latex dispersions of any type (cationic,

anionic, and no nionic) may form u nstable formulations in the

presence of pigments, as illustrated by the following examples:

q Eudragit RS 30 D (poly[ethyl acrylate, m ethyl met hacr ylate]

trim ethylamm onioethyl methacrylate chloride, 1:2:0.1) has

quaternar y amm onium functional groups that are used to

stabilize the latex particles without any requirement for sur-

factants. Because these group s are cationic, this latex is sen-sitive to the addition of anionic agents such as many of the

dyes used to manu facture alum inum lakes.D issolution of the

lakes occurs outside the pH r ange of 47, which leads to the

release of water-soluble dyes that can neu tralize the stabil-

izing quaternary amm onium groups and lead to coagulation

of the latex part icles (4). However, no coagulation is observed

if the pH is kept within the region of lake stability. The dyes

can d estabilize latex particles of similar charge such as th e an-

ionic latex Eudragit L 30 D-55 (poly[m ethacr ylic acid, ethyl

acrylate], 1:1) by doub le-layer comp ression (4). This is be-

cause of the shielding effect of electrolytes on t he repulsive

electro static forces that stabilize this latex. Because Eudra git

L 30 D-55 has a pH- depen dent sur face charge, increasing thepH of the dispersion will increase its zeta potential and make

the latex more stable in th e presence of electrolytes (4).

q Non ionic colloids usually will acquire a n egative charge in

aqueous media because of the preferential adsorption of OH

ions on non -ionogenic colloidal particles because of the ion-

indu ced dipole interaction ( 19). This can lead to electrostatic

interactions, e.g., Eudragit NE 30 D (poly[ethyl acrylate, methyl

met hacrylate], 2:1) with positively charged lakes, that can re-

sult in aggregation (4). These systems can be stabilized by th e

addition of surface active agents such as ethylenediaminete-

traacetic acid, polysorbate 80, or n onoxynol 100 (4,20).

ConclusionsThe formulation of pigments with aqueous polymeric latex dis-

persions can be optim ized by un derstanding the factors that

control the stability of the components. In general, the inter-

actions that lead t o instability in latex dispersions are of a physi-

cal rather than a chemical nature an d u sually result from dif-

ferences in th e surface charge of the excipients used in th e film

coating form ulation.

References1. S.C. Porter, Coating of Pharmaceutical Dosage Forms, in Rem in g-

ton: The Science and Practice of Pharm acy, A.R. Gennaro, Ed.(Lip-

pincott Williams an d Wilkins, Baltimore, MD, 20th ed., 2000).

2 . K. Lehmann, Chemis try and Appl icat ion Proper t i es of Poly-meth acrylate Co ating Systems, in A qu eou s Polym eri c C oa ti n gs for

Pharm aceutical Dosage Forms, J.W. McGinity, Ed. (Marcel Dekker,New

York, NY, 2nd ed.,1997).

3. A.Flosser et al.,Variation of Comp osition of an Enteric Formulation

Based on Kollicoat MAE 30 D,Dru g D ev. In d. Ph arm . 26 , 177187

(2000).

4. N. Nyamweya, K.A.Mehta, and S.W.H oag, Characterizat ion of the

Interactions between Polymethacrylate Latices and Alum inum Lakes

in Aqueous Film Coating Form ulations,J. Ph arm . Sci. (in p ress).

5. D.M . Marm ion , H an db ook of U S Co loran t s for Food s,

Dru gs, an d Cosm eti cs (John Wiley and Sons, New York, NY, 2nd ed.,

1984).

6 . K.Lehm ann , Practical Course in Film Coat ing of Pharm aceutical Dosage

Continu ed on page 26


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Form s with Eudragit(Rhm GmbH, Pharma

Polymers, Darmstadt, Germany, 1999).

7. Warner Jenkinson Company, Inc.,Al l Abou t

Lak e Pigm ent s (Warner Jenkinson Company,

Inc., St. Louis, MO, 1999).

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cel Dekker, New York, NY, 2nd ed., 1997).

9 . E.Kissa ,D ispersion s: Ch aracteri za tion , Test-

Continued from page 12 ing, and M easurement(Marcel Dekker, NewYork, NY, 1999).

10. R.W.Obrien, D.W.Cannon, and W.N.Row-

lands,Electroacoustic Determination of Par-

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11. C.A.Signorino and H. Meggos, Dye Com-

posit ions and Methods for Fi lm Coating

Tablets and th e Like, US Patent No. 5411746(May 1995).

12. M.E. Aulton and M .H. Abdul-Razzak,The

Mechanical Propert ies of Hydroxypropyl

Methylcellulose Films Derived from Aque-

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Inclusions, D ru g D ev. In d . Ph ar m . 10 ,

541561 (1984).

13. L.L-S Wou and B.A. Mulley, Effect of Dis-

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14. A.D esai et al.,Th e Effect of Alum inum Hy-droxide Dissolution o n th e Bleeding of Alu-

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14581460 (1993).

15. A. Desai et a l ., "Ef fect of Dye Content on

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Drug D ev. Ind . Pharm . 17 , 14051409 (1991).

16. R.C.Rowe,The Effect of the Particle Size of

Synth etic Red Iron Oxide on t he Appearance

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19. J.W. Vanderhoff ,Theory of Colloids , in

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20. C.A. Signorino and H. Meggos,Stable, Fluid,

Aqueous Pigm ent Dispersions for Use in Film

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Circle/e INFO 10

Alexanderwerk Inc . . . . . . . . . . . . . . . . . IC . . . . . .1

BASF Corp . . . . . . . . . . . . . . . . . . . . . . . . .7 . . . . . .4

Domino Special ty Ingredients . . . . . . .21 . . . . . .8

Dow Chemical Co,The . . . . . . . . . . . . . . .5 . . . . . .3

Dr.Schleuniger Pha rmat ron Inc . . . . . .26 . . . . .10

Elizabeth Compan ies,The . . . . . . . . . . .BC . . . . .11

Glatt Contract Services . . . . . . . . . . . . . .3 . . . . . .2

Nato l i Engineer ing Co . . . . . . . . . . . . . . .9 . . . . . .5

Noveon . . . . . . . . . . . . . . . . . . . . . . . . . .27 . . . . . .9

Rhm America Inc . . . . . . . . . . . . . . . . .25 . . . . .12

Special ty Measurements Inc . . . . . . . .13 . . . . . .6

SPI Pharma Group . . . . . . . . . . . . . . . . .17 . . . . . .7

Ad I nd exAd I nd exCOM PA N Y PA GE e I N FO

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