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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 Manufacturer Application

EUDRAGIT E PO Ready Mix Poly(butyl methacrylate-co-(2-dimethylaminoethyl) Biogrund Protective coatings


methacrylate-co-methyl methacrylate) 1:2:1
Acryl-EZE Poly(methacrylic acid-co-ethyl acrylate) 1:1 Colorcon Enteric coating
Aquapolish E Acrylic acid copolymer Biogrund Enteric coating
Aquapolish R Ammonio methacrylate copolymer (type A and type Biogrund Sustained release
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 Fig. 1. Film formation mechanism from aqueous dispersions (Hofmann and Stahl,
were developed and marketed in 1972 to replace organic coat- 2012).
ing solutions. Over the years, numerous oral dosage forms using
poly(meth)acrylate coatings have been introduced, employing not a cosmetic improvement. The polymers themselves are pharma-
only simple coatings but also combining poly(meth)acrylates to cologically inactive and are compatible with skin and mucosal
achieve specic release proles. Advances have included inno- membranes.
vative formulations as well as new technologies in product
development. One example is ready-to-use polymer mixtures com- 3. Properties and coating composition
bined with color matching possibilities, which are quicker to
prepare and allow customization. These types of polymer systems 3.1. Film formation
contain all the necessary excipients in a powder mixture that only
needs to be stirred into a solution prior to coating. Besides the polymer and the dispersing or dissolving medium
Ready-to-use products are listed in Table 1. (organic solvents or water), poly(meth)acrylate coating formula-
tions can contain several additives such as surfactants, plasticizers,
2. Poly(meth)acrylates glidants and pigments. In order to select the appropriate coat-
ing excipients, an understanding of the mechanisms behind lm
Poly(meth)acrylates are synthetic (co)polymers prepared by formation is necessary. There is a fundamental difference in
free-radical polymerization. They exhibit extremely low batch-to- lm-formation between aqueous polymer dispersions, where the
batch variations when compared to natural, raw material polymers. polymer and the liquid phase are in a heterogeneous system, and
Synthetic polymers have very narrow specications due to their polymer solutions, where the polymer and the liquid phase are in
excellent reproducibility and are monographed in the European a homogeneous system.
Pharmacopoeia, the USP/NF and the Japanese Pharmaceutical Whereas lm formation from a solution simply occurs upon
Excipients. Drug master les for the entire range exist at the solvent evaporation (sol to gel transition), lm formation from
US Food and Drug Administration (FDA). Poly(meth)acrylates are aqueous dispersions is more complex (Fig. 1). Here, minimum lm-
available in different forms: as aqueous dispersions, organic solu- forming temperature (MFT) and glass transition temperature (Tg)
tions, granules or powders. Their physicochemical properties are are key parameters for efcient lm formation. The MFT is the tem-
determined by functional groups, and their solubility in the diges- perature above which a continuous lm is formed under dened
tive tract results from monomer variations and polymerization drying conditions. Upon drying, the particles come into direct
reaction. Acidic or alkaline groups of soluble poly(meth)acrylates contact with each other and form dense sphere packaging, due to
enable pH-dependent release through salt formation. Insoluble but evaporation and the surface tension between water and polymer.
permeable cationic or neutral (co)polymers, by contrast, enable During further evaporation, capillary forces lead to coalescence of
delayed release applications through pH-independent swelling the particles and the forming of a homogeneous lm. Coalescence
and diffusion-controlled dissolution. Due to their excellent lm- only occurs at temperatures above MFT. To achieve fast lm forma-
forming properties (supported by high exibility, low water vapor tion, the temperature should be 1020 K above MFT.
transition rates and high pigment uptake) their main application in The glass transition temperature is the temperature at which
the pharmaceutical industry is to achieve therapeutically necessary matter changes from a glassy state to a more rubbery state. Dur-
release proles or to protect the drug from surrounding inuences ing this transition, mobility of the polymer chains is increased
such as humidity or light. Furthermore, they are often used to (Jones, 2007). When lms are stored above the Tg, aging or fur-
avoid interactions between lm and core as well as to increase ther coalescence can occur and the free volume in the polymer
patient compliance, e.g. through sustained-release coatings or as lm is reduced. This leads to lower permeability of the lm, which
K. Nollenberger, J. Albers / International Journal of Pharmaceutics 457 (2013) 461469 463

results in decreased dissolution properties. These coatings there- compression forces. Moisture was found to be more effective than
fore require special post-processing (curing) to complete the the commonly used TEC.
lm-forming process and to achieve storage-stable lms. In sol- Ghanam and Kleinebudde (2011) investigated the compressibil-
vent coating, the processing temperature denes the evaporation ity of enteric-coated -carrageenan pellets into multiparticulate
speed of the solvent. If evaporation is too fast, the free volume in the tablets. Pellets containing bisacodyl, a highly acid soluble drug
lm is increased, leading to possible aging during storage. Curing is were prepared with either -carrageenan or MCC as pelletization
especially important for sustained-release coatings (conditions for aid. Pellets were subsequently coated with a mixture of Kollicoat
sustained-release poly(meth)acrylate coatings are described later). MAE 30 DP and EUDRAGIT NE 30 D to achieve enteric proper-
Films with Tgs above storage temperature generally do not require ties, and then compressed using silicied microcrystalline cellulose
a curing step, e.g. anionic polymers like EUDRAGIT L 100-55. In as an embedding powder. Multiparticulate tablets with adequate
contrast to curing, all poly(meth)acrylate coatings require a val- enteric resistance were only achieved when using a sufcient coat-
idated post-coating drying process to remove residual water or ing thickness for -carrageenan pellets whereas the inuence of
solvent from the lms or in case unsuitable processing conditions the compression pressure was negligible.
led to incomplete lm formation.
3.3. Emulsiers/stabilizers
3.2. Plasticizer
Excipients for stabilizing or partial neutralization are espe-
Plasticizers are used primarily to increase lm exibility (by cially recommended with colored formulations, in the presence
lowering the glass transition temperature) and to enhance lm of electrolytes, or if different anionic poly(meth)acrylates are
formation from aqueous dispersions (by lowering MFT). An effec- blended. For anionic dispersions such as EUDRAGIT L 30 D-55 alka-
tive plasticizer must be able to diffuse into and interact with the line substances, stabilizers such as sodium hydroxide (NaOH) are
polymer and should remain in the polymer lm during storage preferred. As an emulsier and stabilizer, common coating formu-
time. An unsuitable or insufcient amount of plasticizer leads to lations very often use polyvinylpyrrolidone, polysorbate, sodium
crack formation and thus loss of functionality. Polymers with low carboxymethyl cellulose (CMC-Na) or sodium lauryl sulphate (SDS),
glass transition temperatures exhibit sufcient exibility and thus in a range of 2.510% on dry polymer content.
require no plasticizer (e.g. EUDRAGIT E, EUDRAGIT NE 30 D),
whereas more brittle polymers require plasticizers in a range of 3.4. Glidants/anti-tacking agents
530% based on the dry polymer substance. In case of redispersion
of enteric polymers, much higher amounts are necessary, ran- Glidants are added to coating formulation to prevent tacki-
ging between 50% and 70%. Hydrophilic plasticizers like triethyl ness and agglomeration during coating, drying, or storage, as these
citrate (TEC) can be added directly to the dispersions and result would otherwise cause lm damage. Tackiness occurs through
in coatings with higher permeability. Generally, reduced perme- softening of the polymer due to plasticizers or humidity. Com-
ability is achieved with lipophilic plasticizers, which need to be monly used glidants are talc, glycerol monostearate, magnesium
emulsied in water prior to adding to aqueous dispersions. They stearate and precipitated silica. Talc is the most effective glidant
also require longer stirring times until an equilibrium distribu- for enteric poly(meth)acrylate coatings, as it does not inuence
tion between the phases is achieved; for example, dibutyl sebacate the gastro resistance of the coatings. As an alternative, magne-
emulsied with 1% polysorbate in water must be subsequently sium stearate as well as glycerol monostearate (GMS, 215% based
stirred for one hour. Plasticizers will vary in efcacy depending on on dry polymers) can be used. Since it is water insoluble, GMS
the poly(meth)acrylate used. needs to be dispersed into water with an emulsier (e.g. polysor-
In general, the effect of the plasticizer on the coating is more bate 80). Heating the water above 60 C facilitates the formation
complex when using polymer blends rather than only one polymer. of a GMS emulsion. To reduce preparation time of the spray-
Due to different afnities to the separate polymers in the blend, the ing suspension, the ready-to-use PlasacrylTM T20 and PlasacrylTM
plasticizers can be unevenly distributed in the dispersions or lm HTP20 suspensions were developed to be used with poly(methyl
(Sakellariou et al., 1987). Lecomte et al. (2004a,b) investigated the acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 and
inuence of lipophilic and hydrophilic plasticizers on the physico- poly(methacrylic acid-co-ethyl acrylate) 1:1, respectively. They
chemical properties and the release of propranolol hydrochloride contain GMS, triethyl citrate as a plasticizer and polysorbate 80.
pellets in polymer blends of ethyl cellulose and EUDRAGIT L. Wesseling et al. (1999) found a correlation between minimum
Pellets were coated with different ratios of ethyl cellulose and lm-forming temperature and tackiness. In their study using differ-
EUDRAGIT L, and with either dibutyl sebacate or triethyl citrate ent aqueous polymer dispersions, talc and glycerol monostearate
as a plasticizer. The release was measured and the physicochemi- (GMS) were found to signicantly reduce tackiness of the lms,
cal properties of the lm coatings (e.g. mechanical resistance, water with GMS being more efcient at lower concentrations. Blending
uptake and dry weight loss) were determined. Results showed that the beads with talc prior to the curing step prevented agglom-
drug release strongly depended on the type of plasticizer used. This eration of coated theophylline beads during curing. Curing of
indicated that the chemical nature of the plasticizer has a high EUDRAGIT RS 30 D-coated theophylline beads at temperatures
impact on the underlying drug release mechanism by affecting both higher than 40 C led to an irreversible agglomeration of the beads
the slope and the shape of the release curves. Diffusion through and damage to the coating upon separation of the beads. This
the intact coating or water-lled cracks was observed as dominat- resulted in faster release than with uncured beads. Blending the
ing and was dependent on the polymer blend ratio and type of beads with talc just prior to the curing step eliminated the agglom-
plasticizer. eration and, therefore, lm damage, even at curing temperatures
Plasticization for increasing the exibility of lms is necessary of 60 C.
to compress coated particles. Brittle poly(meth)acrylates will
not withstand compression forces. Required are either higher 3.5. Pigments
amounts of plasticizer or mixtures with more exible polymers,
such as EUDRAGIT NE 30 D. Rujivipat and Bodmeier (2012) Poly(meth)acrylates have excellent pigment-binding capacities.
treated EUDRAGIT L 30 D-55-coated pellets with humidity before Without inuencing the lm properties, as much as two to three
compression, achieving exible lms sufcient to withstand 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 465

Table 2
Chemical names and compendia compliance of poly(meth)acrylates used for protective coatings.

Chemical/IUPAC name Commercial name Ph. Eur. USP/NF JPE Behavior in digestive
uids

Poly(butyl EUDRAGIT E PO/E Basic butylated Polymer conforms to Aminoalkyl Soluble < pH 5
methacrylate-co-(2- 100/E 12.5 methacrylate amino methacrylate methacrylate
dimethylaminoethyl) copolymer copolymer NF copolymer E
methacrylate-co-methyl
methacrylate) 1:2:1
Methyl methacrylate and Kollicoat Smartseal None None None Soluble < pH 5
diethylamino-ethyl 30D
methacrylate copolymer
dispersion

4.4. Blends of GIT-insoluble and GIT-soluble polymers coatings are listed in Table 2. Besides the listed products, in recent
years suppliers in India and China have started to serve their
Water-soluble or water-swellable substances such as cellulose domestic markets with products containing poly(meth)acrylates
ethers, poly(vinylpyrrolidone), poly(vinylalcohol), starch, lactose, (e.g. Instacoat).
sucrose, saccharides or PEG can be added to enhance the per- EUDRAGIT E was the rst poly(meth)acrylate polymer devel-
meability of GIT-insoluble lms. Furthermore, HPMC or sodium oped for protective purposes. By varying the amount applied
carboxymethyl cellulose can be used as pore formers for GIT- or by adding a specic excipient, the desired functionality can
insoluble poly(meth)acrylate polymers. However, the physical be obtained. EUDRAGIT E is a cationic copolymer based on
stability of such formulations must be examined on an individual dimethyl aminoethyl methacrylate, butyl methacrylate and methyl
basis, as they tend toward agglomeration and coagulation. methacrylate. Having a tertiary amino group, it rapidly dissolves
Especially for multiparticulates, which call for highly exible under salt formation at acidic pH values below 5, thus providing
polymer coatings, anionic and neutral poly(meth)acrylates can be gastro-soluble coatings that are insoluble/slightly permeable in the
combined. In lieu of using a large amount of plasticizer to overcome saliva.
the brittleness of EUDRAGIT L 30 D-55 or Kollicoat MAE 30 DP, For a pediatric formulation of sodium benzoate, small, saliva-
up to 50% EUDRAGIT NE 30 D can be added to increase lm exi- resistant granules have been developed. EUDRAGIT E used as a
bility without changing the enteric properties of a sustained release coating was able to mask the bitter taste of the sodium benzoate for
prole (El-Malah and Nazzal, 2008). When preparing mixtures of at least ve minutes, while not delaying the release in hydrochloric
aqueous polymer dispersions, the differing pH values of the poly- acid (Breitkreutz et al., 2003)
mer dispersions must be considered. Prior to mixing, it is necessary Drug instability can be caused by various environmental inu-
to adjust both dispersions to the same pH value. ences such as temperature, light and moisture. Adding opaciers
Kranz and Gutsche (2009) investigated drug release patterns like titanium dioxide into a coating layer can circumvent the impact
and long-term stability of aqueous and organic coated pellets of light, whereas moisture protection is mainly provided by the
using blends of enteric and gastrointestinal insoluble polymers. The polymer in the lm coating. Due to their low water permeability,
major aim of this study was to identify an efcient tool for adjus- poly(meth)acrylates act as an effective barrier to prevent moisture
ting drug release patterns from aqueous and organic ethyl cellulose from penetrating into the core.
(a gastrointestinal insoluble polymer) coated pellets and to evalu- Bley et al. (2009a) compared the protective ability of various
ate the long-term stability of the lm coatings. Drug release was polymer coatings with respect to coating and curing conditions.
monitored during open and closed storage at 25 C/60% RH (ambi- Garlic powder was used as a moisture-sensitive drug to measure
ent conditions) and 40 C/75% RH (stress conditions) for up to 24 the degradation of aliin, the active amino acid, into allicin upon
months. Release of vatalanib succinate (a poorly soluble drug that moisture uptake. In parallel, the water uptake rates during process
demonstrates pH-dependent solubility) from pure ethyl-cellulose- and curing were determined. Besides poly(vinyl)alcohol, tablets
coated pellets was slow, irrespective of the type of coating and coated with EUDRAGIT E showed the lowest moisture uptake rate
release medium. Through addition of the enteric polymer to ethyl and a signicant improvement in drug stability. In a second study,
cellulose, broad ranges of drug release patterns could be achieved. the authors examined the mechanism behind water transport in the
For aqueous lm coatings, the addition of methacrylic acid/ethyl lm coatings by determining water content at differing tempera-
acrylate copolymer to ethyl cellulose dispersions resulted in unal- tures and relative humidities on coated tablets containing garlic.
tered drug release kinetics during closed storage at ambient and In differential scanning calorimetry (DSC), Opadry AMB showed
stress conditions. Compared to ethyl cellulose, the storage stabi- signicant physical changes and a strong dependence of vapor per-
lizing effect of the added enteric polymer might be explained by meability on the water content of the system, while EUDRAGIT E
its more hydrophilic nature, allowing it to trap water during lm PO remained unchanged. For Opadry AMB coatings stored at room
formation, thus improving polymer particle coalescence. temperature with elevated relative humidity, a glassy-to-rubbery
state transition was observed. This led to increased mobility of the
5. Application of poly(meth)acrylate coatings polymer chains, thus explaining the increased water uptake rates
(Bley et al., 2009b).
5.1. Moisture protection and taste masking The polymers listed in Table 2 are preferred as moisture-
protective coatings for immediate-release formulations. They
Protective coatings are applied for several reasons. First, they provide excellent protection without delaying the release of
protect the drug from environmental inuences affecting chemi- the drug and thus lowering bioavailability. However, other
cal stability such as moisture or light. Secondly, coatings increase poly(meth)acrylates exhibit low water permeability values as
patient compliance by masking the bitter taste or unpleasant well and are applied as moisture-protective coatings for enteric
odor of the dosage form. Poly(meth)acrylates applied as protective or controlled-release formulations. These are also applied for
466 K. Nollenberger, J. Albers / International Journal of Pharmaceutics 457 (2013) 461469

Table 3 high glass transition value and a high MFT, thus necessitating high
Water vapor permeability rates of EUDRAGIT lms.
plasticizer amounts of 5070%.
EUDRAGIT grade Water vapor permeability TEC was found to be the most efcient plasticizer for reduc-
rate [g/m2 d] ing MFT and Tg, providing enteric protection with mild coating
EUDRAGIT E 100 (organic) 350 temperatures (Lehmann and Petereit, 1993). Gutierrez-Rocca and
EUDRAGIT E PO (stearic acid formulation) 100 McGinity (1994) evaluated the inuence of different types and lev-
EUDRAGIT L 100/S 100 (redispersed) 150 els of plasticizers on the physical and mechanical properties of
EUDRAGIT L 30 D-55 (10%TEC) 100
casted lms with EUDRAGIT L 30 D-55 or EUDRAGIT L 100-55.
EUDRAGIT FS 30 D (3% TEC). 100
EUDRAGIT NE 30 D 300 After triacetin, TEC was most effective in reducing the brittleness
EUDRAGIT NM 30 D 300 of the lms compared to other plasticizers. This was explained by
EUDRAGIT RS 100 (organic) 250 the smaller size of the molecules, which interacted more efciently
EUDRAGIT RL 100 (organic) 450
with the polymer chains. TEC content remained stable over 90 days,
whereas a loss in triacetin concentration was observed.
immediate-release coatings when interactions between the Coatings containing poly(methacrylic acid-co-ethyl acrylate)
cationic poly(meth)acrylates and actives may occur. In the latter 1:1 such as EUDRAGIT L 30 D-55 dissolve above pH 5.5 and are
case, thinner layers are employed than for achieving controlled mainly used for simple enteric coatings which dissolve quickly in
release, therefore ensuring no delay in the release of the dosage the intestine. To achieve more exible lms for coating of particles,
form. EUDRAGIT L 30 D-55 can be mixed with exible polymers such as
Water vapor permeability values of poly(meth)acrylates are EUDRAGIT NE 30 D or FS 30 D.
shown in Table 3. To accelerate the dissolution of enteric products and to provide
Prinderre et al. (1997) evaluated different coating agents a rapid drug release in the proximal small intestine, Liu et al.
for their protective ability and inuence on in vitro release. (2009a,b) and Liu and Basit (2010) developed a double-coating
These were Sepilm LP010 (hydroxypropylmethylcellulose), system The system consists of an enteric outer EUDRAGIT L 30 D-
Compritol 888 ATO (glyceryl behenate), and EUDRAGIT L 55 coating and an inner coating of partially neutralized EUDRAGIT
30 D-55 and RS 30 D (poly(methacrylic) acid-co-ethyl acry- L 30 D-55, plus an organic acid. The polymer dissolution and drug
late) 1:1 and poly(ethyl acrylate-co-methyl methacrylate-co- release rate were dramatically increased in pH 5.6, which are
trimethylammonioethyl methacrylate chloride) 1:2:0.1). Paracet- pH conditions reecting the proximal upper intestine. In a sec-
amol and josamycin granules were coated to weight gains of ond study the mechanism of the dissolution of the double coating
10% w/w in a uid bed system and moisture sorption studies was investigated via scanning electronic microscopy and energy-
were conducted at 20 C, 99% relative humidity. Cellulosic coat- dispersive X-ray spectroscopy. The inner coating dissolved prior
ing and poly(meth)acrylate coatings were applied as aqueous to the outer coating, accelerating the dissolution of the outer coat.
systems whereas wax-based coating was applied as an organic An increased buffer capacity and ionic strength, plus the migra-
coating with methylene chloride as a solvent. Water absorption tion of sodium ions from the inner to the outer layer, caused the
by the cellulose-based coating, the one with highest hydrophilicity, rapid dissolution of the system. The accelerated release of the
increased rapidly within ve days, whereas the poly(meth)acrylate double-coating system in vivo was proven in a two-way, cross-over
coatings showed much lower moisture absorption. The organic study in humans and compared with single enteric coatings using
applied wax showed the lowest water absorption due to its very gamma scintigraphy. The disintegration of the double-layer sys-
hydrophobic nature. The difference from the poly(meth)acrylate tem occurred within 28 6 min post-gastric emptying compared
coatings was below 1%. to 66 22 min for the single-layer enteric coating.
Higher exibility of coating lms is required for capsules, or for
5.2. Delayed release particles and pellets that are subsequently compressed into tablets.
To achieve more exible lms with EUDRAGIT L 100-55, either
Delayed release coatings are applied to inhibit the degrada- the addition of larger amounts of plasticizers or the admixture
tion of acid-labile drugs (such as proton pump inhibitors), to with a second, more exible polymer can be used. The disadvan-
decrease irritation of the gastric mucosa (e.g. NSAIDs), to target tage of high amounts of plasticizers is the increase in tackiness
a specic resorption window and to achieve colon targeting. This and an undesired inuence on the release. El-Malah and Nazzal
necessitates coatings that prevent the release of the drug in the (2008) conrmed these ndings and evaluated the mechanical
stomach yet disintegrate in the intestine or colon. Methacrylic acid and thermal properties of lms prepared from EUDRAGIT NE 30
copolymers with methyl methacrylate and ethyl acrylate as ester D/EUDRAGIT L 30 D-55 blends. Different ratios of EUDRAGIT NE
components dissolve at pH values starting in the range of 57. They 30 D and EUDRAGIT L 30 D-55 dispersions were blended at 50:50,
contain carboxylic groups, which remain in a unionized form in the 67:33, 75:25, and 80:20 ratios. Films were then casted as well as
acidic pH of the stomach and are ionized when the coated dosage coated on beads. An increase in the concentration of EUDRAGIT
forms enter the higher pH conditions in the intestine, facilitating NE 30 D showed decreased tensile strength and Youngs mod-
the dissolution of the coating. The dissolution pH of the polymers ulus, resulting in more exible lms. Increasing the amount of
depends on the content of carboxylic groups (see Table 4). EUDRAGIT NE 30 D with the ensuing weight gain led to an
Anionic poly(meth)acrylates can be used alone, in combination increased delay in drug release and therefore can be used to control
with a second anionic polymer to target a certain pH in the intes- drug release.
tine or colon, or in combination with controlled-release polymers EUDRAGIT L 100 L1 12.5 is soluble above pH 6 (targeting the
or polysaccharides. Anionic polymers are brittle and require the jejunum), while EUDRAGIT S100/S 12.5 is soluble above pH 7
addition of plasticizers to lower the glass transition temperature (targeting the ileum and colon). Both polymers can be mixed to
and the elastic modulus. Poly(methacrylic acid-co-ethyl acrylate) tailor drug release for specic pH values, as aqueous or organic
1:1 is a relatively soft polymer requiring the 1020% addition of mixtures. For pharmaceutical forms that release the drug in the
plasticizer to achieve good lm formation at low coating temper- colon, EUDRAGIT grades with a dissolution pH of 7 (EUDRAGIT
atures of 2530 C. Suitable plasticizers are triethyl citrate, dibutyl S or FS) are used (Cole et al., 2002). EUDRAGIT S is the choice for
sebacate, polyethylene glycol and propylene glycol. In contrast, coating tablets, while the exible EUDRAGIT FS 30 D dispersion is
redispersed poly(methacrylic acid-co-methyl acrylate) 1:1 has a preferred for the coating of particles.
K. Nollenberger, J. Albers / International Journal of Pharmaceutics 457 (2013) 461469 467

Table 4
Chemical names and compendial compliance of poly(meth)acrylates used for delayed release coatings.

Chemical/IUPAC Commercial name Ph. Eur. USP/NF JPE Behavior in digestive uids
name

Poly(methacrylic EUDRAGIT Methacrylic acidethyl Methacrylic acid Dried methacrylic acid Soluble > pH 5.5
acid-co-ethyl L30D-55/L100-55 acrylate copolymer (1:1) copolymer, type C NF copolymer LD
acrylate) 1:1 Kollicoat MAE 30DP/100 type A
Poly(methacrylic EUDRAGIT Methacrylic acidmethyl Methacrylic acid Methacrylic acid Soluble > pH 6.0
acid-co-methyl L100/EUDRAGIT L 12.5 methacrylate copolymer copolymer, type A NF copolymer L
methacrylate) 1:1 (1:1)
Poly(methacrylic EUDRAGIT Methacrylic acidmethyl Methacrylic acid Methacrylic acid Soluble > pH 7.0
acid-co-methyl S100/EUDRAGIT S 12.5 methacrylate copolymer copolymer, type B NF copolymer S
methacrylate) 1:2 (1:2)
Poly(methyl EUDRAGIT FS 30D Soluble > pH 7.0
acrylate-co-methyl
methacrylate-co-
methacrylic acid)
7:3:1

Traditionally, colonic delivery has been used in the treatment The release was lowest at concentrations of 20% w/w. When the
of local diseases, e.g. ulcerative colitis or Crohns disease, deliv- pectin concentration in the complex exceeded 20%, theophylline
ering anti-inammatory drugs such as mesalazine to the colon. release from the coated pellets was slower in the presence of the
Currently, colon cancer has also been identied as a disease pectinolytic enzymes in the media, but increased when the con-
where local, site-specic treatment is predicted to be bene- centration was in the range of 10.0 and 15.0%, w/w.
cial. Various approaches have been employed in recent years Schellekens et al. (2008) incorporated disintegrants into
to achieve colon-targeted, controlled-release, bacterial-triggered, EUDRAGIT S lms to achieve pulsatile drug delivery to ileo-colonic
pH-responsive delivery systems and combinations. Most com- segments. Ac-di-sol appeared to be the best-performing swelling
mercial products for colon delivery are based on pH-dependent agent in vitro and was tested in vivo by coating capsules containing
release. EUDRAGIT S was rst used in 1982 by Dew et al. (1982) the stable isotope (13)C(6)-glucose. The occurrence of (13)CO(2) in
as a colon drug delivery system. Since then, numerous drug breath was measured. The coating passed the stomach and duode-
products coated with EUDRAGIT S have been developed. Other num intact and pulsatile release took place in the deeper parts of
poly(meth)acrylates for colon delivery are EUDRAGIT L 100 and the intestine.
EUDRAGIT FS 30 D. The latter is a exible polymer, specially cre- Enteric polymers were also examined as an acidifying substance
ated for the coating of particles and pellets for colon delivery. for maintaining the micro-environmental pH within dosage forms.
Besides simple or polymer blend coatings, other more complex This is necessary to ensure a pH-independent release prole of
formulation concepts are described in literature. Liu et al. (2010) weakly basic drugs, which show a decrease in aqueous solubility at
developed a double-coating system to improve pH-triggered higher pH values, leading to pH-dependent release or incomplete
delivery to the ileo-colonic region of the gastrointestinal tract. Pred- release in controlled-release dosage forms. Krber et al. (2011)
nisolon tablets were coated with partially neutralized EUDRAGIT compared three different approaches to creating pH-dependent
S and a buffer agent, followed by a second coating layer of standard release proles of a weakly basic drug. Layering an organic acid
EUDRAGIT S. Dissolution was tested in 0.1 N HCl for two hours, fol- on pellets and coating with ethyl cellulose and EUDRAGIT L 30
lowed by a pH 7.4 physiological bicarbonate buffer (Krebs buffer). D-55 were not effective in creating pH-dependent and complete
The drug release from the EUDRAGIT S single-layer-coated tablets extended-release proles. However, a subcoating with EUDRAGIT
in pH 7.4 was delayed for 120 min compared to 40 min from the L 30 D-55 beneath an ethyl cellulose and hydroxyl propyl cellu-
double-layer-coated tablets. lose coating led to a pH-independent release. This was explained
To ensure reliable release proles despite the variability of colon by the increase in acidication, thus avoiding the precipitation
physiology, combination approaches are discussed in literature. of the drug in the core. A pH-independent release of verapamil
In case one trigger fails, a second trigger ensures the release of HCl using a poly(methacrylic acid-co-ethyl acrylate)polymer dis-
the drug. Bacterial trigger systems combined with pH-responsive persion (Kollicoat MAE 30 DP) in combination with an extended
polymers are being discussed and examined using various coating release polymer (Kollicoat SR 30 D) was achieved by applying the
compositions. two polymers in separate layers or as a blend only, in carefully
Ibekwe et al. (2008) assessed the in vivo performance in humans balanced ratios (Dashevsky et al., 2010).
of a single-layer coating containing a mixture of EUDRAGIT S and Poly(meth)acrylates are suitable for the enteric coating of hard
starch as a biodegradable polysaccharide. Tablets were radiola- capsules, using either exible polymers such as EUDRAGIT FS 30 D
belled, lm-coated and administered in a three-way study (without (Dvorckov et al., 2011) or adding higher amounts of plasticizer to
breakfast, with breakfast, or 30 min after breakfast) and the site the polymers. An important consideration when coating capsules
of disintegration was monitored with gamma scintigraphy. The is the gap between cap and body. To ensure enteric functionality,
tablets were resistant to the stomach and intestinal environment this should be closed by prior banding or by applying a sufcient
and disintegrated at the ileo-caecal junction/large intestine, all amount of coating.
independent of feeding.
Other studies describe the use of two-layer systems, apply- 5.3. Sustained-release applications
ing an enzyme-dependent layer and subsequently coating with a
pH-dependent, releasing polymer such as EUDRAGIT F 30 D (Ji EUDRAGIT RL, EUDRAGIT RS, EUDRAGIT NE, and
et al., 2007) or EUDRAGIT S 100 (Ursekar et al., 2012) Semd EUDRAGIT NM are poly(meth)acrylates used for sustained-
et al. (2000) studied mixtures of EUDRAGIT NE 30 D with pectin release lm coatings. After contact with gastrointestinal uids,
HM/EUDRAGIT RL 30 D ionic complexes on theophylline pellets, the lm coatings swell, independent of pH, and release the active
demonstrating that release was dependent on the pectin content. 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 successive layers, one of which is an effervescent (sodium bicar-
in any ratio in either organic or aqueous form to adjust permeabil- bonate) layer and one an outer polymeric layer of EUDRAGIT RL 30
ity and obtain specic release patterns. In these extended-release D. The tablets oated within pharmacopoeial time limits, whereas
formulations, the amount of EUDRAGIT RS polymer is usually the time to oat decreased as the amount of the effervescent agent
much higher, since the EUDRAGIT RL properties are dominant. A increased and the coating level of polymeric layer decreased. The
good starting point for new developments is 10% EUDRAGIT RL, in vivo gastric residence time was examined by radiograms, where
which can then be adapted based on the solubility of the drug and it was observed that the units remained in the stomach for about
the targeted release prole. With EUDRAGIT NE and NM (both 6 h.
permeable), all carboxylic groups are esteried so that they have no
reactive functional groups. Thus, drug release is mainly controlled 6. Powder layering and dry powder coating
by the coating thickness. Depending on drug solubility, 520% of
dry polymer substance based on tablet weight is usually sufcient The majority of lm coatings are based on aqueous polymer dis-
to control drug dissolution and release over a period of 68 h. persions or solvent polymer solutions. Recently, solventless coating
Kllai et al. (2010) investigated the effect of the pellet core mate- technologies such as powder coating are being investigated to
rials isomalt, sugar and microcrystalline cellulose on the in vitro reduce processing time and/or due to environmental issues.
drug release kinetics of coated, sustained-release pellets. They Pearnchob and Bodmeier (2003) dry powder coated propra-
also evaluated the inuence of different ratios of polymethacry- nolol hydrochloride pellets by spraying EUDRAGIT RS PO and talc
late copolymers exhibiting different permeability characteristics and separately plasticizer and binder solution to achieve extended
on the drug release rate. For characterization of the drug release release properties. For achieving complete lm formation, 40% plas-
process of pellets, the effect of osmolality was studied using glu- ticizer and thermal treatment of the pellets was necessary. Storage
cose as an osmotically active agent in the dissolution medium. The stable proles were achieved by curing the pellets.
pellet cores were layered with diclofenac sodium as a model drug Sauer et al. (2007) developed a dry powder coating process
and coated with EUDRAGIT RS 30 D and EUDRAGIT RL 30 D at based on EUDRAGIT L 100-55 for chlorpheniramine maleate, an
varying ratios in a uid bed coater. Regardless of the ratio of the ionizable and highly water-soluble model drug. The intent was
coating polymers, the results demonstrated that the release mech- to prevent the migration of the drug into the polymer lm dur-
anism was also inuenced by the type of starter core used. Sugar ing aqueous coating. EUDRAGIT L 100-55 was pre-plasticized
and types of isomalt pellet cores demonstrated similar drug release with triethyl citrate using hot-melt extrusion at levels of 20%, 30%,
proles. and 40%, based on the polymer weight. The extrudate was sub-
Although a pH-independent drug release is expected because sequently cut into pellets and cryogenically ground into a ne
of the quaternary nature of the cationic groups in EUDRAGIT powder. Talc was incorporated into the coating powder as an anti-
RL 30 D and EUDRAGIT RS 30 D, a pH-dependent drug release tack agent. PEG 3350 was used as a primer for the powder coating
is observed in the presence of salts. Therefore, Bodmeier et al. of tablets with pre-plasticized EUDRAGIT L 100-55. The addition
(1996) investigated pH-dependent drug release in various buffer of polyethylene glycol 3350 to the pre-plasticized EUDRAGIT L
media with differing pH values and at differing concentrations with 100-55 was necessary to enhance the adhesion of the coating pow-
coated diltiazem beads. The drug release in the diverse buffer media der to the tablet cores. PEG 3350 also improved lm formation
was in the following order: pH 5.0 acetate > pH 3.5 formate > pH and coalescence of the polymeric particles due to its plasticiza-
7.4 phosphate buffer > 0.1 M HCl. This could be explained with an tion effects on the acrylic polymer. For comparison, theophylline
anion exchange process: the chloride counterions of the quater- tablets were also coated with pre-plasticized EUDRAGIT L 100-55.
nary groups were exchanged with the anionic buffer species during Theophylline was selected as a less water-soluble model drug. The
the dissolution study. The water uptake of the coated beads cor- powder coating process was performed in a modied, laboratory
related well with the drug release from the beads. Increasing the scale spheronizer. The drug release rate was dependent both on
buffer strength (acetate buffer) rst increased and then decreased the TEC content and the coating level. The stability of the powder-
the drug release, while increasing the ionic strength of different coated tablets was conrmed at 25 C/60% RH over a storage time
buffers with NaCl decreased the drug release and eliminated the of 12 weeks.
observed buffer effects because of the excess of chloride ions.
Glaessl et al. (2009) elucidated in more detail mass transport
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