International Journal of Pharmaceutics 457 (2013) 461469

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

Review

Poly(meth)acrylate-based coatings
Kathrin Nollenberger , Jessica Albers
Evonik Industries AG, Kirschenallee, 64293 Darmstadt, Germany

a r t i c l e i n f o a b s t r a c t

Article history: Poly(meth)acrylate coatings for pharmaceutical applications were introduced in 1955 with the launch
Received 1 July 2013 of EUDRAGIT L and EUDRAGIT S, two types of anionic polymers. Since then, by introducing vari-
Received in revised form ous monomers into their polymer chains and thus altering their properties, diverse forms with specic
16 September 2013
characteristics have become available. Today, poly(meth)acrylates function in different parts of the gas-
Accepted 20 September 2013
trointestinal tract and/or release the drug in a time-controlled manner. This article reviews the properties
Available online 12 October 2013
of various poly(meth)acrylates and discusses formulation issues as well as application possibilities.
2013 Elsevier B.V. All rights reserved.
Keywords:
Coating
Polymer
Poly(meth)acrylates
Sustained release
Delayed release
Taste masking

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
2. Poly(meth)acrylates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462
3. Properties and coating composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462
3.1. Film formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462
3.2. Plasticizer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
3.3. Emulsiers/stabilizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
3.4. Glidants/anti-tacking agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
3.5. Pigments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
3.6. Solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
4. Polymer blends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
4.1. Target . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
4.2. Blends of GIT-insoluble polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
4.3. Blends of anionic poly(meth)acrylates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
4.4. Blends of GIT-insoluble and GIT-soluble polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
5. Application of poly(meth)acrylate coatings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
5.1. Moisture protection and taste masking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
5.2. Delayed release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
5.3. Sustained-release applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
6. Powder layering and dry powder coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468

1. Introduction

The success story of poly(meth)acrylates for pharmaceuti-

Corresponding author. Tel.: +49 6151 18 4292.
cal coatings began in 1933. That year saw the development of
E-mail addresses: Kathrin.nollenberger@evonik.com,
methacrylic acid co-polymer chemistry and the ensuing market
kathrin.nollenberger@gmx.de (K. Nollenberger), Jessica.albers@evonik.com launch of Plexiglas by Rhm and Haas. At the Paris World Expo-
(J. Albers). sition in 1937, visitors could view a violin made of Plexiglas ,

0378-5173/$ see front matter 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ijpharm.2013.09.029
462 K. Nollenberger, J. Albers / International Journal of Pharmaceutics 457 (2013) 461469
Table 1
Ready-to-use formulations with poly(meth)acrylates.
Name Polymer
EUDRAGIT E PO Ready Mix Poly(butyl methacrylate-co-(2-dimethylaminoethyl)
methacrylate-co-methyl methacrylate) 1:2:1
Acryl-EZE Poly(methacrylic acid-co-ethyl acrylate) 1:1
Aquapolish E Acrylic acid copolymer
Aquapolish R Ammonio methacrylate copolymer (type A and type
B)
a crystal-clear unbreakable organic glass of outstanding quality.
Since then, the properties of poly(meth)acrylates have been
altered for various applications, including for use in pharmaceuti-
cal coatings. These are produced by introducing diverse monomers
into the polymer chains, thus creating distinct variations with
specic characteristics. Trommsdorff and Grimm, for example,
described enteric coatings for solid dosage forms in a patent appli-
cation in 1952. Today, poly(meth)acrylates function in different
parts of the gastrointestinal tract and/or release the drug in a
time-controlled manner.
In 1955, the rst poly(meth)acrylates for pH-controlled release
became commercially available (EUDRAGIT L and EUDRAGIT S
as organic solutions in isopropyl alcohol). These were followed
in 1959 by those intended for immediate-release applications
(EUDRAGIT E). Only ten years later poly(meth)acrylates for
time-controlled drug release were launched. With growing
environmental and safety concerns, aqueous polymer dispersions
were developed and marketed in 1972 to replace organic coat-
ing solutions. Over the years, numerous oral dosage forms using
poly(meth)acrylate coatings have been introduced, employing not
only simple coatings but also combining poly(meth)acrylates to
achieve specic release proles. Advances have included inno-
vative formulations as well as new technologies in product
development. One example is ready-to-use polymer mixtures com-
bined with color matching possibilities, which are quicker to
prepare and allow customization. These types of polymer systems
contain all the necessary excipients in a powder mixture that only
needs to be stirred into a solution prior to coating.
Ready-to-use products are listed in Table 1.
2. Poly(meth)acrylates
Poly(meth)acrylates are synthetic (co)polymers prepared by
free-radical polymerization. They exhibit extremely low batch-to-
batch variations when compared to natural, raw material polymers.
Synthetic polymers have very narrow specications due to their
excellent reproducibility and are monographed in the European
Pharmacopoeia, the USP/NF and the Japanese Pharmaceutical
Excipients. Drug master les for the entire range exist at the
US Food and Drug Administration (FDA). Poly(meth)acrylates are
available in different forms: as aqueous dispersions, organic solu-
tions, granules or powders. Their physicochemical properties are
determined by functional groups, and their solubility in the diges-
tive tract results from monomer variations and polymerization
reaction. Acidic or alkaline groups of soluble poly(meth)acrylates
enable pH-dependent release through salt formation. Insoluble but
permeable cationic or neutral (co)polymers, by contrast, enable
delayed release applications through pH-independent swelling
and diffusion-controlled dissolution. Due to their excellent lm-
forming properties (supported by high exibility, low water vapor
transition rates and high pigment uptake) their main application in
the pharmaceutical industry is to achieve therapeutically necessary
release proles or to protect the drug from surrounding inuences
such as humidity or light. Furthermore, they are often used to
avoid interactions between lm and core as well as to increase
patient compliance, e.g. through sustained-release coatings or as
Manufacturer Application
Biogrund Protective coatings
Colorcon Enteric coating
Biogrund Enteric coating
Biogrund Sustained release
Fig. 1. Film formation mechanism from aqueous dispersions (Hofmann and Stahl,
2012).
a cosmetic improvement. The polymers themselves are pharma-
cologically inactive and are compatible with skin and mucosal
membranes.
3. Properties and coating composition
3.1. Film formation
Besides the polymer and the dispersing or dissolving medium
(organic solvents or water), poly(meth)acrylate coating formula-
tions can contain several additives such as surfactants, plasticizers,
glidants and pigments. In order to select the appropriate coat-
ing excipients, an understanding of the mechanisms behind lm
formation is necessary. There is a fundamental difference in
lm-formation between aqueous polymer dispersions, where the
polymer and the liquid phase are in a heterogeneous system, and
polymer solutions, where the polymer and the liquid phase are in
a homogeneous system.
Whereas lm formation from a solution simply occurs upon
solvent evaporation (sol to gel transition), lm formation from
aqueous dispersions is more complex (Fig. 1). Here, minimum lm-
forming temperature (MFT) and glass transition temperature (Tg)
are key parameters for efcient lm formation. The MFT is the tem-
perature above which a continuous lm is formed under dened
drying conditions. Upon drying, the particles come into direct
contact with each other and form dense sphere packaging, due to
evaporation and the surface tension between water and polymer.
During further evaporation, capillary forces lead to coalescence of
the particles and the forming of a homogeneous lm. Coalescence
only occurs at temperatures above MFT. To achieve fast lm forma-
tion, the temperature should be 1020 K above MFT.
The glass transition temperature is the temperature at which
matter changes from a glassy state to a more rubbery state. Dur-
ing this transition, mobility of the polymer chains is increased
(Jones, 2007). When lms are stored above the Tg, aging or fur-
ther coalescence can occur and the free volume in the polymer
lm is reduced. This leads to lower permeability of the lm, which
 K. Nollenberger, J. Albers / International Journal of Pharmaceutics 457 (2013) 461469
results in decreased dissolution properties. These coatings there-
fore require special post-processing (curing) to complete the
lm-forming process and to achieve storage-stable lms. In sol-
vent coating, the processing temperature denes the evaporation
speed of the solvent. If evaporation is too fast, the free volume in the
lm is increased, leading to possible aging during storage. Curing is
especially important for sustained-release coatings (conditions for
sustained-release poly(meth)acrylate coatings are described later).
Films with Tgs above storage temperature generally do not require
a curing step, e.g. anionic polymers like EUDRAGIT L 100-55. In
contrast to curing, all poly(meth)acrylate coatings require a val-
idated post-coating drying process to remove residual water or
solvent from the lms or in case unsuitable processing conditions
led to incomplete lm formation.
3.2. Plasticizer
Plasticizers are used primarily to increase lm exibility (by
lowering the glass transition temperature) and to enhance lm
formation from aqueous dispersions (by lowering MFT). An effec-
tive plasticizer must be able to diffuse into and interact with the
polymer and should remain in the polymer lm during storage
time. An unsuitable or insufcient amount of plasticizer leads to
crack formation and thus loss of functionality. Polymers with low
glass transition temperatures exhibit sufcient exibility and thus
require no plasticizer (e.g. EUDRAGIT E, EUDRAGIT NE 30 D),
whereas more brittle polymers require plasticizers in a range of
530% based on the dry polymer substance. In case of redispersion
of enteric polymers, much higher amounts are necessary, ran-
ging between 50% and 70%. Hydrophilic plasticizers like triethyl
citrate (TEC) can be added directly to the dispersions and result
in coatings with higher permeability. Generally, reduced perme-
ability is achieved with lipophilic plasticizers, which need to be
emulsied in water prior to adding to aqueous dispersions. They
also require longer stirring times until an equilibrium distribu-
tion between the phases is achieved; for example, dibutyl sebacate
emulsied with 1% polysorbate in water must be subsequently
stirred for one hour. Plasticizers will vary in efcacy depending on
the poly(meth)acrylate used.
In general, the effect of the plasticizer on the coating is more
complex when using polymer blends rather than only one polymer.
Due to different afnities to the separate polymers in the blend, the
plasticizers can be unevenly distributed in the dispersions or lm
(Sakellariou et al., 1987). Lecomte et al. (2004a,b) investigated the
inuence of lipophilic and hydrophilic plasticizers on the physico-
chemical properties and the release of propranolol hydrochloride
pellets in polymer blends of ethyl cellulose and EUDRAGIT L.
Pellets were coated with different ratios of ethyl cellulose and
EUDRAGIT L, and with either dibutyl sebacate or triethyl citrate
as a plasticizer. The release was measured and the physicochemi-
cal properties of the lm coatings (e.g. mechanical resistance, water
uptake and dry weight loss) were determined. Results showed that
drug release strongly depended on the type of plasticizer used. This
indicated that the chemical nature of the plasticizer has a high
impact on the underlying drug release mechanism by affecting both
the slope and the shape of the release curves. Diffusion through
the intact coating or water-lled cracks was observed as dominat-
ing and was dependent on the polymer blend ratio and type of
plasticizer.
Plasticization for increasing the exibility of lms is necessary
to compress coated particles. Brittle poly(meth)acrylates will
not withstand compression forces. Required are either higher
amounts of plasticizer or mixtures with more exible polymers,
such as EUDRAGIT NE 30 D. Rujivipat and Bodmeier (2012)
treated EUDRAGIT L 30 D-55-coated pellets with humidity before
compression, achieving exible lms sufcient to withstand
463
compression forces. Moisture was found to be more effective than
the commonly used TEC.
Ghanam and Kleinebudde (2011) investigated the compressibil-
ity of enteric-coated -carrageenan pellets into multiparticulate
tablets. Pellets containing bisacodyl, a highly acid soluble drug
were prepared with either -carrageenan or MCC as pelletization
aid. Pellets were subsequently coated with a mixture of Kollicoat
MAE 30 DP and EUDRAGIT NE 30 D to achieve enteric proper-
ties, and then compressed using silicied microcrystalline cellulose
as an embedding powder. Multiparticulate tablets with adequate
enteric resistance were only achieved when using a sufcient coat-
ing thickness for -carrageenan pellets whereas the inuence of
the compression pressure was negligible.
3.3. Emulsiers/stabilizers
Excipients for stabilizing or partial neutralization are espe-
cially recommended with colored formulations, in the presence
of electrolytes, or if different anionic poly(meth)acrylates are
blended. For anionic dispersions such as EUDRAGIT L 30 D-55 alka-
line substances, stabilizers such as sodium hydroxide (NaOH) are
preferred. As an emulsier and stabilizer, common coating formu-
lations very often use polyvinylpyrrolidone, polysorbate, sodium
carboxymethyl cellulose (CMC-Na) or sodium lauryl sulphate (SDS),
in a range of 2.510% on dry polymer content.
3.4. Glidants/anti-tacking agents
Glidants are added to coating formulation to prevent tacki-
ness and agglomeration during coating, drying, or storage, as these
would otherwise cause lm damage. Tackiness occurs through
softening of the polymer due to plasticizers or humidity. Com-
monly used glidants are talc, glycerol monostearate, magnesium
stearate and precipitated silica. Talc is the most effective glidant
for enteric poly(meth)acrylate coatings, as it does not inuence
the gastro resistance of the coatings. As an alternative, magne-
sium stearate as well as glycerol monostearate (GMS, 215% based
on dry polymers) can be used. Since it is water insoluble, GMS
needs to be dispersed into water with an emulsier (e.g. polysor-
bate 80). Heating the water above 60 C facilitates the formation
of a GMS emulsion. To reduce preparation time of the spray-
ing suspension, the ready-to-use PlasacrylTM T20 and PlasacrylTM
HTP20 suspensions were developed to be used with poly(methyl
acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 and
poly(methacrylic acid-co-ethyl acrylate) 1:1, respectively. They
contain GMS, triethyl citrate as a plasticizer and polysorbate 80.
Wesseling et al. (1999) found a correlation between minimum
lm-forming temperature and tackiness. In their study using differ-
ent aqueous polymer dispersions, talc and glycerol monostearate
(GMS) were found to signicantly reduce tackiness of the lms,
with GMS being more efcient at lower concentrations. Blending
the beads with talc prior to the curing step prevented agglom-
eration of coated theophylline beads during curing. Curing of
EUDRAGIT RS 30 D-coated theophylline beads at temperatures
higher than 40 C led to an irreversible agglomeration of the beads
and damage to the coating upon separation of the beads. This
resulted in faster release than with uncured beads. Blending the
beads with talc just prior to the curing step eliminated the agglom-
eration and, therefore, lm damage, even at curing temperatures
of 60 C.
3.5. Pigments
Poly(meth)acrylates have excellent pigment-binding capacities.
Without inuencing the lm properties, as much as two to three
parts by weight of solid additives (in specic cases up to 10 parts)
464 K. Nollenberger, J. Albers / International Journal of Pharmaceutics 457 (2013) 461469

can be incorporated. Pigments such as iron oxide, titanium dioxide

or aluminum lakes are added to improve the appearance of coatings
or for differentiation purposes. Hydrophilic excipients for increas-
ing permeability of lms can be added when required to facilitate
or enhance drug release.

3.6. Solvents

Due to environmental, safety and cost considerations, pharma-

ceutical manufacturing has been moving from organic to aqueous
coating systems. All poly(meth)acrylates are available in both sys-
tems, except for EUDRAGIT FS 30 D, EUDRAGIT NE 30 D and
EUDRAGIT NM 30 D, which are only available as aqueous dis-
persions. In some cases, replacing organic with aqueous systems
requires formulation adaptions to create bioequivalent release pro-
les. The difference between the two systems lies in lm density Fig. 2. Combinations of EUDRAGIT RL/RS and their inuence on the drug release
and variances in formulation excipients and volumes. Redispersed of coated theophylline pellets.
aqueous dispersions of EUDRAGIT L 100-55, L 100 and S 100
necessitate much higher plasticizer amounts (5070% on dry poly-
investigated, the formulation with 20% PG and 27% talc performed
mer substance) compared to respective organic coatings where no
best.
plasticizer is necessary. These higher plasticizer volumes lead to
faster dissolution speed in the buffer media (Bando and McGinity,
2006). With polymers such as EUDRAGIT RL, EUDRAGIT RS or 4. Polymer blends
EUDRAGIT E, organic coating formulations can be easily replaced
by an aqueous system. 4.1. Target
Coating formulation is a complex issue, which calls for thorough
examination. Flsser et al. (2000) investigated the effect of vari- With polymer-blend coatings it is possible to adjust release pro-
ations in talc concentration and plasticizer type and quantity on les, combine different properties of coating materials to achieve
the preparation and processing of a Kollicoat MAE 30 DP spray- new functionalities or improve the lm-forming process. More-
coating suspension. They also examined the properties of isolated over, poly(meth)acrylates with similar chemical structures can
lms and lm-coated caffeine tablets. During the preparation and be blended, either together or with polymers exhibiting different
processing of spray-coating suspensions, the plasticizers polyeth- chemical structures. Due to changes in the underlying drug release
ylene glycol (PEG) 400, PEG1500 and triethyl citrate (TEC) tended to mechanism, the slope as well as the shape of the release curves can
coagulate at all investigated concentrations, while Cremophor RH be varied (Lecomte et al., 2004a,b). Blends have a much higher com-
40 coagulated above 10% (expressed as a percentage of the mass of plexity compared to single polymer systems. The release prole is
the lm-forming agent used). On the other hand, analogous prepa- inuenced by pH values, mix ratios and the presence of additional
rations using propylene glycol (PG), PEG6000, and Lutrol F 68 were excipients in the coating suspension.
found to be stable at all concentrations. The instability was not
caused by the Kollicoat MAE 30 DP polymer dispersion as such, but
4.2. Blends of GIT-insoluble polymers
by interactions between the nely dispersed pigments and other
formulation ingredients. Equivalent non-pigmented preparations
Insoluble ionic poly(meth)acrylates, e.g. EUDRAGIT RL and
are stable and do not coagulate.
RS, can be blended to adjust the behavior of drug release in the
With all investigated plasticizers, the minimum lm-forming
gastrointestinal tract. As the main functional coating material,
temperature (MFT) fell, albeit to differing degrees, as the amount of
EUDRAGIT RL and RS can be mixed in any ratio to adjust the
plasticizer increased. Similarly, the tensile strength of isolated lms
permeability of the coating and thus the dissolution prole. Both
declined as plasticizer concentration increased, while the reverse
polymers can be mixed either as an organic solution or an aqueous
was true as regards their elongation at break. The subsequent dis-
dispersion. EUDRAGIT RL contains more quaternary ammonium
integration time and the rate of release of the active ingredient
groups, is more hydrophilic and shows a higher permeability. This
at pH 6.8 were not signicantly affected by the various plasticizer
means that an increased amount of EUDRAGIT RL accelerates the
additives. However, the different lm-coated tablet formulations,
drug release (Fig. 2), (Amighi and Moees, 1995).
with a core containing a powerful disintegrant, exhibited varying
In addition to the ratio of the polymers, the thickness of the lm
degrees of permeability to simulated gastric uid. With PEG6000,
also controls the release prole. Since the polymer with higher per-
permeability increased as the plasticizer concentration increased,
meability dominates the release characteristics, amounts of 510%
while with Lutrol F 68 an optimum barrier was provided at 20%,
are recommended for the blends.
and PG afforded a good barrier between 10% and 30%. No gastro
resistance was obtained with TEC at 10%.
Only the best performing plasticizer formulations were used 4.3. Blends of anionic poly(meth)acrylates
in the trials with different talc concentrations, namely, those for-
mulations with 20% PEG6000, 20% Lutrol F 68, 20% PG, and 10% Gastrointestinal targeting can be achieved by mixing organic
PG. When talc was added, the MFT rose, reaching its maximum anionic poly(meth)acrylates to adjust the dissolution pH of the
at 13% talc (as a proportion of the lm-forming agent). In the lm coating. EUDRAGIT L and EUDRAGIT S are often mixed
test for gastro resistance, lm-coated caffeine tablets without talc to adopt pH release proles to between pH 5.5 and 7.0. Com-
absorbed distinctly more acid than those containing talc. Above pared to organic solutions, the blending of aqueous dispersions
27% talc, the acid resistance was not signicantly improved. On will not produce the desired effect, due to the presence of poly-
the other hand, during this test, only a maximum of 3% of the mer domains in the lm, which act as pore formers (Skalsky and
active ingredient was released into the gastric juice. Of the variants Petereit, 2008).
 K. Nollenberger, J. Albers / International Journal of Pharmaceutics 457 (2013) 461469
Table 2
Chemical names and compendia compliance of poly(meth)acrylates used for protective coatings.
Chemical/IUPAC name Commercial name Ph. Eur.
Poly(butyl EUDRAGIT E PO/E Basic butylated
methacrylate-co-(2- 100/E 12.5 methacrylate
dimethylaminoethyl) copolymer
methacrylate-co-methyl
methacrylate) 1:2:1
Methyl methacrylate and Kollicoat Smartseal None
diethylamino-ethyl 30D
methacrylate copolymer
dispersion
4.4. Blends of GIT-insoluble and GIT-soluble polymers
Water-soluble or water-swellable substances such as cellulose
ethers, poly(vinylpyrrolidone), poly(vinylalcohol), starch, lactose,
sucrose, saccharides or PEG can be added to enhance the per-
meability of GIT-insoluble lms. Furthermore, HPMC or sodium
carboxymethyl cellulose can be used as pore formers for GIT-
insoluble poly(meth)acrylate polymers. However, the physical
stability of such formulations must be examined on an individual
basis, as they tend toward agglomeration and coagulation.
Especially for multiparticulates, which call for highly exible
polymer coatings, anionic and neutral poly(meth)acrylates can be
combined. In lieu of using a large amount of plasticizer to overcome
the brittleness of EUDRAGIT L 30 D-55 or Kollicoat MAE 30 DP,
up to 50% EUDRAGIT NE 30 D can be added to increase lm exi-
bility without changing the enteric properties of a sustained release
prole (El-Malah and Nazzal, 2008). When preparing mixtures of
aqueous polymer dispersions, the differing pH values of the poly-
mer dispersions must be considered. Prior to mixing, it is necessary
to adjust both dispersions to the same pH value.
Kranz and Gutsche (2009) investigated drug release patterns
and long-term stability of aqueous and organic coated pellets
using blends of enteric and gastrointestinal insoluble polymers. The
major aim of this study was to identify an efcient tool for adjus-
ting drug release patterns from aqueous and organic ethyl cellulose
(a gastrointestinal insoluble polymer) coated pellets and to evalu-
ate the long-term stability of the lm coatings. Drug release was
monitored during open and closed storage at 25 C/60% RH (ambi-
ent conditions) and 40 C/75% RH (stress conditions) for up to 24
months. Release of vatalanib succinate (a poorly soluble drug that
demonstrates pH-dependent solubility) from pure ethyl-cellulose-
coated pellets was slow, irrespective of the type of coating and
release medium. Through addition of the enteric polymer to ethyl
cellulose, broad ranges of drug release patterns could be achieved.
For aqueous lm coatings, the addition of methacrylic acid/ethyl
acrylate copolymer to ethyl cellulose dispersions resulted in unal-
tered drug release kinetics during closed storage at ambient and
stress conditions. Compared to ethyl cellulose, the storage stabi-
lizing effect of the added enteric polymer might be explained by
its more hydrophilic nature, allowing it to trap water during lm
formation, thus improving polymer particle coalescence.
5. Application of poly(meth)acrylate coatings
5.1. Moisture protection and taste masking
Protective coatings are applied for several reasons. First, they
protect the drug from environmental inuences affecting chemi-
cal stability such as moisture or light. Secondly, coatings increase
patient compliance by masking the bitter taste or unpleasant
odor of the dosage form. Poly(meth)acrylates applied as protective
465
USP/NF JPE Behavior in digestive
uids
Polymer conforms to Aminoalkyl Soluble < pH 5
amino methacrylate methacrylate
copolymer NF copolymer E
None None Soluble < pH 5
coatings are listed in Table 2. Besides the listed products, in recent
years suppliers in India and China have started to serve their
domestic markets with products containing poly(meth)acrylates
(e.g. Instacoat).
EUDRAGIT E was the rst poly(meth)acrylate polymer devel-
oped for protective purposes. By varying the amount applied
or by adding a specic excipient, the desired functionality can
be obtained. EUDRAGIT E is a cationic copolymer based on
dimethyl aminoethyl methacrylate, butyl methacrylate and methyl
methacrylate. Having a tertiary amino group, it rapidly dissolves
under salt formation at acidic pH values below 5, thus providing
gastro-soluble coatings that are insoluble/slightly permeable in the
saliva.
For a pediatric formulation of sodium benzoate, small, saliva-
resistant granules have been developed. EUDRAGIT E used as a
coating was able to mask the bitter taste of the sodium benzoate for
at least ve minutes, while not delaying the release in hydrochloric
acid (Breitkreutz et al., 2003)
Drug instability can be caused by various environmental inu-
ences such as temperature, light and moisture. Adding opaciers
like titanium dioxide into a coating layer can circumvent the impact
of light, whereas moisture protection is mainly provided by the
polymer in the lm coating. Due to their low water permeability,
poly(meth)acrylates act as an effective barrier to prevent moisture
from penetrating into the core.
Bley et al. (2009a) compared the protective ability of various
polymer coatings with respect to coating and curing conditions.
Garlic powder was used as a moisture-sensitive drug to measure
the degradation of aliin, the active amino acid, into allicin upon
moisture uptake. In parallel, the water uptake rates during process
and curing were determined. Besides poly(vinyl)alcohol, tablets
coated with EUDRAGIT E showed the lowest moisture uptake rate
and a signicant improvement in drug stability. In a second study,
the authors examined the mechanism behind water transport in the
lm coatings by determining water content at differing tempera-
tures and relative humidities on coated tablets containing garlic.
In differential scanning calorimetry (DSC), Opadry AMB showed
signicant physical changes and a strong dependence of vapor per-
meability on the water content of the system, while EUDRAGIT E
PO remained unchanged. For Opadry AMB coatings stored at room
temperature with elevated relative humidity, a glassy-to-rubbery
state transition was observed. This led to increased mobility of the
polymer chains, thus explaining the increased water uptake rates
(Bley et al., 2009b).
The polymers listed in Table 2 are preferred as moisture-
protective coatings for immediate-release formulations. They
provide excellent protection without delaying the release of
the drug and thus lowering bioavailability. However, other
poly(meth)acrylates exhibit low water permeability values as
well and are applied as moisture-protective coatings for enteric
or controlled-release formulations. These are also applied for
466 K. Nollenberger, J. Albers / International Journal of Pharmaceutics 457 (2013) 461469
Table 3
Water vapor permeability rates of EUDRAGIT lms.
EUDRAGIT grade Water vapor permeability
rate [g/m2 d]
EUDRAGIT E 100 (organic) 350
EUDRAGIT E PO (stearic acid formulation) 100
EUDRAGIT L 100/S 100 (redispersed) 150
EUDRAGIT L 30 D-55 (10%TEC) 100
EUDRAGIT FS 30 D (3% TEC). 100
EUDRAGIT NE 30 D 300
EUDRAGIT NM 30 D 300
EUDRAGIT RS 100 (organic) 250
EUDRAGIT RL 100 (organic) 450
immediate-release coatings when interactions between the
cationic poly(meth)acrylates and actives may occur. In the latter
case, thinner layers are employed than for achieving controlled
release, therefore ensuring no delay in the release of the dosage
form.
Water vapor permeability values of poly(meth)acrylates are
shown in Table 3.
Prinderre et al. (1997) evaluated different coating agents
for their protective ability and inuence on in vitro release.
These were Sepilm LP010 (hydroxypropylmethylcellulose),
Compritol 888 ATO (glyceryl behenate), and EUDRAGIT L
30 D-55 and RS 30 D (poly(methacrylic) acid-co-ethyl acry-
late) 1:1 and poly(ethyl acrylate-co-methyl methacrylate-co-
trimethylammonioethyl methacrylate chloride) 1:2:0.1). Paracet-
amol and josamycin granules were coated to weight gains of
10% w/w in a uid bed system and moisture sorption studies
were conducted at 20 C, 99% relative humidity. Cellulosic coat-
ing and poly(meth)acrylate coatings were applied as aqueous
systems whereas wax-based coating was applied as an organic
coating with methylene chloride as a solvent. Water absorption
by the cellulose-based coating, the one with highest hydrophilicity,
increased rapidly within ve days, whereas the poly(meth)acrylate
coatings showed much lower moisture absorption. The organic
applied wax showed the lowest water absorption due to its very
hydrophobic nature. The difference from the poly(meth)acrylate
coatings was below 1%.
5.2. Delayed release
Delayed release coatings are applied to inhibit the degrada-
tion of acid-labile drugs (such as proton pump inhibitors), to
decrease irritation of the gastric mucosa (e.g. NSAIDs), to target
a specic resorption window and to achieve colon targeting. This
necessitates coatings that prevent the release of the drug in the
stomach yet disintegrate in the intestine or colon. Methacrylic acid
copolymers with methyl methacrylate and ethyl acrylate as ester
components dissolve at pH values starting in the range of 57. They
contain carboxylic groups, which remain in a unionized form in the
acidic pH of the stomach and are ionized when the coated dosage
forms enter the higher pH conditions in the intestine, facilitating
the dissolution of the coating. The dissolution pH of the polymers
depends on the content of carboxylic groups (see Table 4).
Anionic poly(meth)acrylates can be used alone, in combination
with a second anionic polymer to target a certain pH in the intes-
tine or colon, or in combination with controlled-release polymers
or polysaccharides. Anionic polymers are brittle and require the
addition of plasticizers to lower the glass transition temperature
and the elastic modulus. Poly(methacrylic acid-co-ethyl acrylate)
1:1 is a relatively soft polymer requiring the 1020% addition of
plasticizer to achieve good lm formation at low coating temper-
atures of 2530 C. Suitable plasticizers are triethyl citrate, dibutyl
sebacate, polyethylene glycol and propylene glycol. In contrast,
redispersed poly(methacrylic acid-co-methyl acrylate) 1:1 has a
high glass transition value and a high MFT, thus necessitating high
plasticizer amounts of 5070%.
TEC was found to be the most efcient plasticizer for reduc-
ing MFT and Tg, providing enteric protection with mild coating
temperatures (Lehmann and Petereit, 1993). Gutierrez-Rocca and
McGinity (1994) evaluated the inuence of different types and lev-
els of plasticizers on the physical and mechanical properties of
casted lms with EUDRAGIT L 30 D-55 or EUDRAGIT L 100-55.
After triacetin, TEC was most effective in reducing the brittleness
of the lms compared to other plasticizers. This was explained by
the smaller size of the molecules, which interacted more efciently
with the polymer chains. TEC content remained stable over 90 days,
whereas a loss in triacetin concentration was observed.
Coatings containing poly(methacrylic acid-co-ethyl acrylate)
1:1 such as EUDRAGIT L 30 D-55 dissolve above pH 5.5 and are
mainly used for simple enteric coatings which dissolve quickly in
the intestine. To achieve more exible lms for coating of particles,
EUDRAGIT L 30 D-55 can be mixed with exible polymers such as
EUDRAGIT NE 30 D or FS 30 D.
To accelerate the dissolution of enteric products and to provide
a rapid drug release in the proximal small intestine, Liu et al.
(2009a,b) and Liu and Basit (2010) developed a double-coating
system The system consists of an enteric outer EUDRAGIT L 30 D-
55 coating and an inner coating of partially neutralized EUDRAGIT
L 30 D-55, plus an organic acid. The polymer dissolution and drug
release rate were dramatically increased in pH 5.6, which are
pH conditions reecting the proximal upper intestine. In a sec-
ond study the mechanism of the dissolution of the double coating
was investigated via scanning electronic microscopy and energy-
dispersive X-ray spectroscopy. The inner coating dissolved prior
to the outer coating, accelerating the dissolution of the outer coat.
An increased buffer capacity and ionic strength, plus the migra-
tion of sodium ions from the inner to the outer layer, caused the
rapid dissolution of the system. The accelerated release of the
double-coating system in vivo was proven in a two-way, cross-over
study in humans and compared with single enteric coatings using
gamma scintigraphy. The disintegration of the double-layer sys-
tem occurred within 28 6 min post-gastric emptying compared
to 66 22 min for the single-layer enteric coating.
Higher exibility of coating lms is required for capsules, or for
particles and pellets that are subsequently compressed into tablets.
To achieve more exible lms with EUDRAGIT L 100-55, either
the addition of larger amounts of plasticizers or the admixture
with a second, more exible polymer can be used. The disadvan-
tage of high amounts of plasticizers is the increase in tackiness
and an undesired inuence on the release. El-Malah and Nazzal
(2008) conrmed these ndings and evaluated the mechanical
and thermal properties of lms prepared from EUDRAGIT NE 30
D/EUDRAGIT L 30 D-55 blends. Different ratios of EUDRAGIT NE
30 D and EUDRAGIT L 30 D-55 dispersions were blended at 50:50,
67:33, 75:25, and 80:20 ratios. Films were then casted as well as
coated on beads. An increase in the concentration of EUDRAGIT
NE 30 D showed decreased tensile strength and Youngs mod-
ulus, resulting in more exible lms. Increasing the amount of
EUDRAGIT NE 30 D with the ensuing weight gain led to an
increased delay in drug release and therefore can be used to control
drug release.
EUDRAGIT L 100 L1 12.5 is soluble above pH 6 (targeting the
jejunum), while EUDRAGIT S100/S 12.5 is soluble above pH 7
(targeting the ileum and colon). Both polymers can be mixed to
tailor drug release for specic pH values, as aqueous or organic
mixtures. For pharmaceutical forms that release the drug in the
colon, EUDRAGIT grades with a dissolution pH of 7 (EUDRAGIT
S or FS) are used (Cole et al., 2002). EUDRAGIT S is the choice for
coating tablets, while the exible EUDRAGIT FS 30 D dispersion is
preferred for the coating of particles.
 K. Nollenberger, J. Albers / International Journal of Pharmaceutics 457 (2013) 461469
Table 4
Chemical names and compendial compliance of poly(meth)acrylates used for delayed release coatings.
Chemical/IUPAC Commercial name Ph. Eur.
name
Poly(methacrylic EUDRAGIT Methacrylic acidethyl
acid-co-ethyl L30D-55/L100-55 acrylate copolymer (1:1)
acrylate) 1:1 Kollicoat MAE 30DP/100 type A
Poly(methacrylic EUDRAGIT Methacrylic acidmethyl
acid-co-methyl L100/EUDRAGIT L 12.5 methacrylate copolymer
methacrylate) 1:1 (1:1)
Poly(methacrylic EUDRAGIT Methacrylic acidmethyl
acid-co-methyl S100/EUDRAGIT S 12.5 methacrylate copolymer
methacrylate) 1:2 (1:2)
Poly(methyl EUDRAGIT FS 30D
acrylate-co-methyl
methacrylate-co-
methacrylic acid)
7:3:1
Traditionally, colonic delivery has been used in the treatment
of local diseases, e.g. ulcerative colitis or Crohns disease, deliv-
ering anti-inammatory drugs such as mesalazine to the colon.
Currently, colon cancer has also been identied as a disease
where local, site-specic treatment is predicted to be bene-
cial. Various approaches have been employed in recent years
to achieve colon-targeted, controlled-release, bacterial-triggered,
pH-responsive delivery systems and combinations. Most com-
mercial products for colon delivery are based on pH-dependent
release. EUDRAGIT S was rst used in 1982 by Dew et al. (1982)
as a colon drug delivery system. Since then, numerous drug
products coated with EUDRAGIT S have been developed. Other
poly(meth)acrylates for colon delivery are EUDRAGIT L 100 and
EUDRAGIT FS 30 D. The latter is a exible polymer, specially cre-
ated for the coating of particles and pellets for colon delivery.
Besides simple or polymer blend coatings, other more complex
formulation concepts are described in literature. Liu et al. (2010)
developed a double-coating system to improve pH-triggered
delivery to the ileo-colonic region of the gastrointestinal tract. Pred-
nisolon tablets were coated with partially neutralized EUDRAGIT
S and a buffer agent, followed by a second coating layer of standard
EUDRAGIT S. Dissolution was tested in 0.1 N HCl for two hours, fol-
lowed by a pH 7.4 physiological bicarbonate buffer (Krebs buffer).
The drug release from the EUDRAGIT S single-layer-coated tablets
in pH 7.4 was delayed for 120 min compared to 40 min from the
double-layer-coated tablets.
To ensure reliable release proles despite the variability of colon
physiology, combination approaches are discussed in literature.
In case one trigger fails, a second trigger ensures the release of
the drug. Bacterial trigger systems combined with pH-responsive
polymers are being discussed and examined using various coating
compositions.
Ibekwe et al. (2008) assessed the in vivo performance in humans
of a single-layer coating containing a mixture of EUDRAGIT S and
starch as a biodegradable polysaccharide. Tablets were radiola-
belled, lm-coated and administered in a three-way study (without
breakfast, with breakfast, or 30 min after breakfast) and the site
of disintegration was monitored with gamma scintigraphy. The
tablets were resistant to the stomach and intestinal environment
and disintegrated at the ileo-caecal junction/large intestine, all
independent of feeding.
Other studies describe the use of two-layer systems, apply-
ing an enzyme-dependent layer and subsequently coating with a
pH-dependent, releasing polymer such as EUDRAGIT F 30 D (Ji
et al., 2007) or EUDRAGIT S 100 (Ursekar et al., 2012) Semd
et al. (2000) studied mixtures of EUDRAGIT NE 30 D with pectin
HM/EUDRAGIT RL 30 D ionic complexes on theophylline pellets,
demonstrating that release was dependent on the pectin content.
467
USP/NF JPE Behavior in digestive uids
Methacrylic acid Dried methacrylic acid Soluble > pH 5.5
copolymer, type C NF copolymer LD
Methacrylic acid Methacrylic acid Soluble > pH 6.0
copolymer, type A NF copolymer L
Methacrylic acid Methacrylic acid Soluble > pH 7.0
copolymer, type B NF copolymer S
Soluble > pH 7.0
The release was lowest at concentrations of 20% w/w. When the
pectin concentration in the complex exceeded 20%, theophylline
release from the coated pellets was slower in the presence of the
pectinolytic enzymes in the media, but increased when the con-
centration was in the range of 10.0 and 15.0%, w/w.
Schellekens et al. (2008) incorporated disintegrants into
EUDRAGIT S lms to achieve pulsatile drug delivery to ileo-colonic
segments. Ac-di-sol appeared to be the best-performing swelling
agent in vitro and was tested in vivo by coating capsules containing
the stable isotope (13)C(6)-glucose. The occurrence of (13)CO(2) in
breath was measured. The coating passed the stomach and duode-
num intact and pulsatile release took place in the deeper parts of
the intestine.
Enteric polymers were also examined as an acidifying substance
for maintaining the micro-environmental pH within dosage forms.
This is necessary to ensure a pH-independent release prole of
weakly basic drugs, which show a decrease in aqueous solubility at
higher pH values, leading to pH-dependent release or incomplete
release in controlled-release dosage forms. Krber et al. (2011)
compared three different approaches to creating pH-dependent
release proles of a weakly basic drug. Layering an organic acid
on pellets and coating with ethyl cellulose and EUDRAGIT L 30
D-55 were not effective in creating pH-dependent and complete
extended-release proles. However, a subcoating with EUDRAGIT
L 30 D-55 beneath an ethyl cellulose and hydroxyl propyl cellu-
lose coating led to a pH-independent release. This was explained
by the increase in acidication, thus avoiding the precipitation
of the drug in the core. A pH-independent release of verapamil
HCl using a poly(methacrylic acid-co-ethyl acrylate)polymer dis-
persion (Kollicoat MAE 30 DP) in combination with an extended
release polymer (Kollicoat SR 30 D) was achieved by applying the
two polymers in separate layers or as a blend only, in carefully
balanced ratios (Dashevsky et al., 2010).
Poly(meth)acrylates are suitable for the enteric coating of hard
capsules, using either exible polymers such as EUDRAGIT FS 30 D
(Dvorckov et al., 2011) or adding higher amounts of plasticizer to
the polymers. An important consideration when coating capsules
is the gap between cap and body. To ensure enteric functionality,
this should be closed by prior banding or by applying a sufcient
amount of coating.
5.3. Sustained-release applications
EUDRAGIT RL, EUDRAGIT RS, EUDRAGIT NE, and
EUDRAGIT NM are poly(meth)acrylates used for sustained-
release lm coatings. After contact with gastrointestinal uids,
the lm coatings swell, independent of pH, and release the active
by a diffusion-controlled mechanism. EUDRAGIT RL (highly
468 K. Nollenberger, J. Albers / International Journal of Pharmaceutics 457 (2013) 461469
permeable) and EUDRAGIT RS (slightly permeable) can be mixed
in any ratio in either organic or aqueous form to adjust permeabil-
ity and obtain specic release patterns. In these extended-release
formulations, the amount of EUDRAGIT RS polymer is usually
much higher, since the EUDRAGIT RL properties are dominant. A
good starting point for new developments is 10% EUDRAGIT RL,
which can then be adapted based on the solubility of the drug and
the targeted release prole. With EUDRAGIT NE and NM (both
permeable), all carboxylic groups are esteried so that they have no
reactive functional groups. Thus, drug release is mainly controlled
by the coating thickness. Depending on drug solubility, 520% of
dry polymer substance based on tablet weight is usually sufcient
to control drug dissolution and release over a period of 68 h.
Kllai et al. (2010) investigated the effect of the pellet core mate-
rials isomalt, sugar and microcrystalline cellulose on the in vitro
drug release kinetics of coated, sustained-release pellets. They
also evaluated the inuence of different ratios of polymethacry-
late copolymers exhibiting different permeability characteristics
on the drug release rate. For characterization of the drug release
process of pellets, the effect of osmolality was studied using glu-
cose as an osmotically active agent in the dissolution medium. The
pellet cores were layered with diclofenac sodium as a model drug
and coated with EUDRAGIT RS 30 D and EUDRAGIT RL 30 D at
varying ratios in a uid bed coater. Regardless of the ratio of the
coating polymers, the results demonstrated that the release mech-
anism was also inuenced by the type of starter core used. Sugar
and types of isomalt pellet cores demonstrated similar drug release
proles.
Although a pH-independent drug release is expected because
of the quaternary nature of the cationic groups in EUDRAGIT
RL 30 D and EUDRAGIT RS 30 D, a pH-dependent drug release
is observed in the presence of salts. Therefore, Bodmeier et al.
(1996) investigated pH-dependent drug release in various buffer
media with differing pH values and at differing concentrations with
coated diltiazem beads. The drug release in the diverse buffer media
was in the following order: pH 5.0 acetate > pH 3.5 formate > pH
7.4 phosphate buffer > 0.1 M HCl. This could be explained with an
anion exchange process: the chloride counterions of the quater-
nary groups were exchanged with the anionic buffer species during
the dissolution study. The water uptake of the coated beads cor-
related well with the drug release from the beads. Increasing the
buffer strength (acetate buffer) rst increased and then decreased
the drug release, while increasing the ionic strength of different
buffers with NaCl decreased the drug release and eliminated the
observed buffer effects because of the excess of chloride ions.
Glaessl et al. (2009) elucidated in more detail mass transport
mechanisms with EUDRAGIT RS-based lms containing tartaric
acid, metoprolol free base and metoprolol tartrate upon exposure
to
0.1 M HCl, phosphate buffer pH 7.4 and distilled water. Impor-
tantly, the diffusivity of metoprolol tartrate and metoprolol free
base signicantly increased with increasing initial drug content.
This illustrates the strong plasticizing capacity of these compounds
for the polymer. In contrast to EUDRAGIT RL-based lms, meto-
prolol free base precipitation occurred only at higher initial drug
loadings, due to the lower water uptake resulting from the lower
contents of quaternary ammonium groups. Negatively charged tar-
trate ions dispersed more rapidly from lms containing metoprolol
tartrate than positively charged metoprolol ions. This indicated
that lower molecular weight potentially over-compensates for
the attractive ionic interactions with positively charged macro-
molecules.
Poly(meth)acrylate coatings can furthermore be used as gastro-
retentive drug delivery systems with multiple-unit mini-tablets as
developed by Meka et al. (2009) The system consists of core units
prepared by direct compression. These are then coated with two
successive layers, one of which is an effervescent (sodium bicar-
bonate) layer and one an outer polymeric layer of EUDRAGIT RL 30
D. The tablets oated within pharmacopoeial time limits, whereas
the time to oat decreased as the amount of the effervescent agent
increased and the coating level of polymeric layer decreased. The
in vivo gastric residence time was examined by radiograms, where
it was observed that the units remained in the stomach for about
6 h.
6. Powder layering and dry powder coating
The majority of lm coatings are based on aqueous polymer dis-
persions or solvent polymer solutions. Recently, solventless coating
technologies such as powder coating are being investigated to
reduce processing time and/or due to environmental issues.
Pearnchob and Bodmeier (2003) dry powder coated propra-
nolol hydrochloride pellets by spraying EUDRAGIT RS PO and talc
and separately plasticizer and binder solution to achieve extended
release properties. For achieving complete lm formation, 40% plas-
ticizer and thermal treatment of the pellets was necessary. Storage
stable proles were achieved by curing the pellets.
Sauer et al. (2007) developed a dry powder coating process
based on EUDRAGIT L 100-55 for chlorpheniramine maleate, an
ionizable and highly water-soluble model drug. The intent was
to prevent the migration of the drug into the polymer lm dur-
ing aqueous coating. EUDRAGIT L 100-55 was pre-plasticized
with triethyl citrate using hot-melt extrusion at levels of 20%, 30%,
and 40%, based on the polymer weight. The extrudate was sub-
sequently cut into pellets and cryogenically ground into a ne
powder. Talc was incorporated into the coating powder as an anti-
tack agent. PEG 3350 was used as a primer for the powder coating
of tablets with pre-plasticized EUDRAGIT L 100-55. The addition
of polyethylene glycol 3350 to the pre-plasticized EUDRAGIT L
100-55 was necessary to enhance the adhesion of the coating pow-
der to the tablet cores. PEG 3350 also improved lm formation
and coalescence of the polymeric particles due to its plasticiza-
tion effects on the acrylic polymer. For comparison, theophylline
tablets were also coated with pre-plasticized EUDRAGIT L 100-55.
Theophylline was selected as a less water-soluble model drug. The
powder coating process was performed in a modied, laboratory
scale spheronizer. The drug release rate was dependent both on
the TEC content and the coating level. The stability of the powder-
coated tablets was conrmed at 25 C/60% RH over a storage time
of 12 weeks.
References
Amighi, K., Moees, A.J., 1995. Evaluation of thermal and lm forming properties of
acrylic aqueous polymer dispersion blends: application to the formulation of
sustained-release lm coated theophylline pellets. Drug Dev. Ind. Pharm. 21,
23552369.
Bando, H., McGinity, J.W., 2006. Physicochemical properties of enteric lms prepared
from aqueous dispersions and organic solutions. Int. J. Pharm. 313, 4348 (Epub
17 2006 17).
Bley, O., Siepmann, J., Bodmeier, R., 2009a. Protection of moisture-sensitive drugs
with aqueous polymer coatings: importance of coating and curing conditions.
Int. J. Pharm. 378, 5965.
Bley, O., Siepmann, J., Bodmeier, R., 2009b. Characterization of moisture-protective
polymer coatings using differential scanning calorimetry and dynamic vapor
sorption. J. Pharm. Sci. 98, 651664.
Bodmeier, R., Guo, X., Sarabia, R.E., Skultety, P.F., 1996. The inuence of buffer species
and strength on diltiazem HCl release from beads coated with aqueous cationic
polymer dispersions, EUDRAGIT RS, RL 30 D. Pharm. Res. 13, 5256.
Breitkreutz, J., Bornhft, M., Wll, F., Kleinebudde, P., 2003. Pediatric drug formula-
tions of sodium benzoate: I. Coated granules with a hydrophilic binder. Eur. J.
Pharm. Biopharm. 56, 247253.
Cole, E.T., Scott, R.A., Connor, A.L., Wilding, I.R., Petereit, H.U., Schminke, C., Beckert,
T., Cad, D., 2002. Enteric coated HPMC capsules designed to achieve intestinal
targeting. Int. J. Pharm. 231, 8395.
Dashevsky, A., Ahmed, A.R., Mota, J., Irfan, M., Kolter, K., Bodmeier, R.A., 2010.
Effect of water-soluble polymers on the physical stability of aqueous polymeric
 K. Nollenberger, J. Albers / International Journal of Pharmaceutics 457 (2013) 461469
dispersions and their implications on the drug release from coated pellets. Drug
Dev. Ind. Pharm. 36, 152160.
Dvorckov, K., Rabiskov, M., Muselk, J., Gajdziok, J., Bajerov, M., 2011.
Coated hard capsules as the pH-dependent drug transport systems to ileo-
colonic compartment. Drug Dev. Ind. Pharm. 37, 11311140 (Epub 21 March
2011).
Dew, M.J., Hughes, P.J., Lee, M.G., Evans, B.K., Rhodes, J., 1982. An oral prepa-
ration to release drugs in the human colon. Br. J. Clin. Pharmacol. 14,
405408.
El-Malah, Y., Nazzal, S., 2008. Novel use of Eudragit NE 30D/Eudragit L 30D-55 blends
as functional coating materials in time-delayed drug release applications. Int. J.
Pharm. 357, 219227.
Flsser, A., Kolter, K., Reich, H.B., Schepky, G., 2000. Variation of composition of an
enteric formulation based on Kollicoat MAE 30 D. Drug Dev. Ind. Pharm. 26,
177187.
Ghanam, D., Kleinebudde, P., 2011. Suitability of -carrageenan pellets for the for-
mulation of multiparticulate tablets with modied release. Int. J. Pharm. 409,
918.
Glaessl, B., Siepmann, F., Tucker, I., Siepmann, J., Rades, T., 2009. Charac-
terisation of quaternary polymethacrylate lms containing tartaric acid,
metoprolol free base or metoprolol tartrate. Eur. J. Pharm. Biopharm. 73,
366372.
Gutierrez-Rocca, J.C., McGinity, J.W., 1994. Inuence of water soluble and insoluble
plasticizers on the physical and mechanical properties of acrylic resin copoly-
mers. Int. J. Pharm. 103, 293301.
Hofmann, F., Stahl, H., 2012. Understanding particle coating: consideration for coat-
ing polymers. Pharm. Technol. 36, 96.
Ibekwe, V.C., Khela, M.K., Evans, D.F., Basit, A.W., 2008. A new concept in colonic drug
targeting: a combined pH-responsive and bacterially-triggered drug delivery
technology. Aliment. Pharmacol. Ther. 28, 911916.
Ji, C., Xu, H., Wu, W., 2007. In vitro evaluation and pharmacokinetics in dogs of guar
gum and Eudragit FS30D-coated colon-targeted pellets of indomethacin. J. Drug
Target. 15, 123131.
Jones, D.S., 2007. Thermorheological Characterization In: Thermal Analysis of
Pharmaceuticals. CRC Press, Boca Raton.
Kllai, N., Luhn, O., Dredn, J., Kovcs, K., Lengyel, M., Antal, I., 2010. Evaluation of
drug release from coated pellets based on isomalt, sugar, and microcrystalline
cellulose inert cores. AAPS PharmSciTech 11, 1.
Krber, M., Ciper, M., Hoffart, V., Pearnchob, N., Walther, M., Macrae, R.J., Bodmeier,
R., 2011. Enteric polymers as acidiers for the pH-independent sustained deliv-
ery of a weakly basic drug salt from coated pellets. Eur. J. Pharm. Biopharm. 78,
447454 (Epub 2 April 2011).
Kranz, H., Gutsche, S., 2009. Evaluation of the drug release patterns and
long term stability of aqueous and organic coated pellets by using blends
of enteric and gastrointestinal insoluble polymers. Int. J. Pharm. 380,
112119.
Lecomte, F., Siepmann, J., Walther, M., MacRae, R.J., Bodmeier, R., 2004 Sep 14. Poly-
mer blends used for the aqueous coating of solid dosage forms: importance of
the type of plasticizer. J. Control. Release 99, 113.
Lecomte, F., Siepmann, J., Walther, M., MacRae, R.J., Bodmeier, R., 2004 May. Polymer
blends used for the coating of multiparticulates: comparison of aqueous and
organic coating techniques. Pharm. Res. 21, 882890.
469
Lehmann, K., Petereit, H.-U., 1993. Filmberzge auf Basis wriger
Polymethacrylat-Dispersionen mit verzgertem Zerfall im Darmbereich.
Pharm. Ind. 55, 615618.
Liu, F., Basit, A.W., 2010. A paradigm shift in enteric coating: achieving rapid release
in the proximal small intestine of man. J. Control. Release 147, 242245 (Epub
22 July 2010).
Liu, F., Moreno, P., Basit, A.W., 2010. A novel double-coating approach for improved
pH-triggered delivery to the ileo-colonic region of the gastrointestinal tract. Eur.
J. Pharm. Biopharm. 74, 311315 (Epub 20 November 2009).
Liu, F., Lizio, R., Meier, C., Petereit, H.U., Blakey, P., Basit, A.W., 2009a. A novel concept
in enteric coating: a double-coating system providing rapid drug release in the
proximal small intestine. J. Control. Release 133, 119124.
Liu, F., Lizio, R., Schneider, U.J., Petereit, H.U., Blakey, P., Basit, A.W., 2009b. SEM/EDX
and confocal microscopy analysis of novel and conventional enteric-coated sys-
tems. Int. J. Pharm. 369, 7278.
Meka, L., Kesavan, B., Kalamata, V.N., Eaga, C.M., Bandari, S., Vobalaboina, V., Yamsani,
M.R., 2009. Design and evaluation of polymeric coated mini tablets as multiple
unit gastroretentive oating drug delivery systems for furosemide. J. Pharm. Sci.
98, 21222132.
Pearnchob, N., Bodmeier, R., 2003. Dry powder coating of pellets with micronized
Eudragit RS for extended drug release. Pharm. Res. 20, 19701976.
Prinderre, P., Cauture, E., Piccerelle, Ph., Kalantzis, G., Kaloustian, J., Joachim, J.,
1997. Evaluation of some protective agents on stability and controlled release
of oral pharmaceutical forms by uid bed technique. Drug Dev. Ind. Pharm. 23,
817826.
Rujivipat, S., Bodmeier, R., 2012. Moisture plasticization for enteric Eudragit L30D-
55-coated pellets prior to compression into tablets. Eur. J. Pharm. Biopharm. 81,
223229 (Epub 16 January 2012).
Sakellariou, P., Rowe, R.C., White, E.F.T., 1987. The interactions and partitioning of
low molecular weight polyethylene glycols and diethyl phthalate in ethylcellu-
lose/hydroxypropyl methylcellulose blends. J. Appl. Polym. Sci. 34, 25072516,
2520.
Sauer, D., Zheng, W., Coots, L.B., McGinity, J.W., 2007. Inuence of processing param-
eters and formulation factors on the drug release from tablets powder-coated
with Eudragit L 100-55. Eur. J. Pharm. Biopharm. 67, 464475 (Epub 7 March
2007).
Schellekens, R.C., Stellaard, F., Mitrovic, D., Stuurman, F.E., Kosterink, J.G., Frijlink,
H.W., 2008. Pulsatile drug delivery to ileo-colonic segments by structured incor-
poration of disintegrants in pH-responsive polymer coatings. J. Control. Release
132, 9198 (Epub 23 August 2008).
Semd, R., Amighi, K., Devleeschouwer, M.J., Mos, A.J., 2000. Studies of pectin
HM/Eudragit RL/Eudragit NE lm-coating formulations intended for colonic
drug delivery. Int. J. Pharm. 197, 181192.
Skalsky, B., Petereit, H.U., 2008. Chemistry and application properties of poly-
methacrylate systems. In: Aqueous Polymeric Coatings for Pharmaceutical
Dosage Forms, third ed. Informa Healthcare.
Ursekar, B.M., Soni, P.S., Date, A.A., Nagarsenker, M.S., 2012. Characterization of soy
polysaccharide and its in vitro and in vivo evaluation for application in colon
drug delivery. AAPS PharmSciTech 13, 934943 (Epub 28 June 2012).
Wesseling, M., Kuppler, F., Bodmeier, R., 1999. Tackiness of acrylic and cellulosic
polymer lms used in the coating of solid dosage forms. Eur. J. Pharm. Biopharm.
47, 7378.