International Journal of Pharmaceutics 457 (2013) 395–406

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International Journal of Pharmaceutics

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

Review

Film coatings for taste masking and moisture protection

S. Joshi a , H.-U. Petereit b,∗
a
R&D Formulation development Health Care Evonik India Private Limited, Krislon House Saki Vihar Road, Mumbai – 400072, India
b
Intellectual Property Management, Health Care, 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: Taste masking and moisture protection of oral dosage forms contribute significantly to the therapeutic
Received 30 August 2013 effect of pharmaceutical and nutraceutical formulations either by ensuring patient compliance or by
Received in revised form 2 October 2013 providing stability through shelf life of the dosage form. Among different types of taste, bitter taste is
Accepted 8 October 2013
the most relevant for patient acceptance because of the extremely high sensitivity. As hydrolysis is the
Available online 20 October 2013
most common mode of degradation of an active ingredient, moisture protection plays a vital role in the
stability of the active during manufacturing and storage. Optimized oral dosage forms need to reliably
Keywords:
hinder the release of bitter drug molecules in the mouth or ensure stability of the active compound,
Film coating
Taste masking
while also ensuring fast drug release in the stomach to enable early therapeutic onset. Besides different
Moisture protection formulation concepts, film coating is found to be the most effective and commonly used approach for
(Meth)acrylate copolymers taste masking and moisture protection. Film coating can be achieved through the use of water-soluble,
Cellulosics cationic, anionic or neutral insoluble polymers from different chemical structures. Cationic polymers
Permeability provide efficient moisture protection as well as taste masking without influencing the release of the
drug in the gastric fluids. Polymers may be sprayed onto various types of cores from dispersions or
solutions in organic, solvents or water in drum or fluidzed bed coaters. Applied quantities need insuring
complete coating thickness ranging from 0.5 to 50 ␮m or more finally. Insulating excipients, such as
hydrophobic plasticizers, lipids, pigments or other insoluble substances will influence the functionality of
films. Organoleptic tests are still common in testing the quality of taste-masked formulations. Recently,
multi-channel taste sensors have been developed to quantify different types of taste. Dynamic vapor
sorption technique and studies at elevated temperature provide effective concepts study the efficacy of
the formulations. Efficient taste masking and reliable moisture protection of solid oral dosage forms can
be achieved by film coating implementing the options of pharmaceutical polymers and processes.
© 2013 Elsevier B.V. All rights reserved.

Contents

1. Introduction: needs and concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395

1.1. Need and concepts of taste masking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395
1.2. Need and concepts of moisture protection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396
1.3. Mechanism of taste sensitivity and moisture uptake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396
2. Polymers and formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397
2.1. Polymers (Sohi et al., 2004) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397
2.2. Formulation principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
3. Relevant analytical testing and their challenges/limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
3.1. Thermogravemetric analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
4. Summary and conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405

1. Introduction: needs and concepts

1.1. Need and concepts of taste masking

∗ Corresponding author. The beneficial therapeutic effect of pharmaceuticals is depend-

E-mail address: hans-ulrich.petereit@evonik.com (H.-U. Petereit). ent on regular dosing following manufacturer advice. The oral,

0378-5173/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ijpharm.2013.10.021
396 S. Joshi, H.-U. Petereit / International Journal of Pharmaceutics 457 (2013) 395–406
self-dosage route is the most common method for the application of
many drugs. However, patients tend to neglect instructions when
they are inconvenient or unpleasant. Particularly for oral pharma-
ceuticals, disagreeable taste – besides frequent daily dosing – is
one of the main reasons for patients to refrain from regular dos-
ing. Among the different taste sensations, bitterness is the most
repellent. For oral dosing in particular, compliance depends signif-
icantly on the taste of the dosage form. Thus, masking bitter taste is
the key parameter to improving patient compliance as well as the
therapeutic efficiency of oral pharmaceuticals (Valleri et al., 2004).
Measures to mask the taste of oral dosage forms must include effi-
ciency, but also avoid any negative effect of sensory awareness,
such as mucosa irritation, roughness in the mouth or hindered
swallowing. Another important aspect is to not negatively affect
the bioavailability of the active compound by hindering its release
or delaying its effect. This can be accomplished by designing a
release kinetic which functions over an extended time period after
ingestion.
Several concepts of taste masking for pharmaceuticals have
been developed and put into practice. Molecular concepts include
chemical modifications, such as the prodrug approach (i.e. ester-
ification with fatty acids, Brahmankar and Jaiswal, 1995), or salt
formation using either anions (i.e. organic acids, Sohi, 2004; JP,
1992) or cations such as magnesium (Nanda et al., 2002a) or inter-
action with ionogenic polymers, such as (meth)acrylates (EP, 2003;
WO, 2003a; Sharma and Lewis, 2010). Physical taste masking on a
molecular basis may be achieved by complexation (i.e. inclusion
in cyclodextrins, Swarbrick and Bolan, 1990), its derivatives (i.e.
hydroxypropyl-beta-cyclodextrin). Additionally practiced are con-
cepts of binding to ion exchange resins, which have been revealed
to be effective taste masking agents. Cross-linked polymers and
copolymers of methacrylic acid are available in pharmaceutical
grades – and optimized variations for different classes of drug
may be tested (Jain, 2001). Formulation concepts for taste masking
include the incorporation of specific flavor enhancers. Examples
may be sweeteners, i.e. aspartame (JP, 1990), amino acids and their
phosphate derivatives, natural products including fruit juices, aro-
matic oils, herbs, alkaline earth oxides, hydroxides and spices in
forms such as high concentrated extracts or dried solids, as well as
either alcoholic or aqueous solutions (Chatap, 2007). Further func-
tional excipients, which improve the organoleptic perception of
unpleasant oral formulations, are effervescent agents or rheological
modifiers, such as gel forming gums.
The type of taste masking suitable for final formulation is very
much influenced by the selected manufacturing process. Processes
for applying taste masking are melt and liquid extrusion, spray
or freeze drying to form solid dispersions or agglomerates, coat-
ing with lipids or waxes, formation of lipid vesicles or multiple
emulsions (preferably for oils, Rossof, 1988 or liposomes). Coating
processes are preferably used for taste masking of tablets or mini-
tablets. Commonly applied processes include liquid melt or powder
coating with lipids, waxes and polysaccharides. Compression coat-
ing is an unconventional, alternative method with limited practical
relevance. A modern variation of coating techniques is film coat-
ing particularly suitable for microencapsulation of small particles
to form taste masked multi-unit dosage forms. The functional coat-
ing is applied by spray processes from organic or aqueous solutions
or preferably from aqueous solutions or dispersions including nat-
ural or synthetic polymers. Among these varieties of formulation
designs, film coating provides the highest efficiency and has thus
gained the broadest importance.
1.2. Need and concepts of moisture protection
An active pharmaceutical ingredient in a dosage form needs to
be stable until the end of its shelf life, in order to ensure its efficacy
and safety for the patient. Degradation of the active ingredient can
occur though hydrolysis, thermal degradation, oxidation, light,
microorganisms or any other chemical reaction that renders the
active ineffective for its intended purpose (Ahlneck and Zografi,
1990). Of the various modes of degradation, hydrolysis is most
commonly found to influence the stability of the active. Amor-
phous forms of a material, which have a high internal energy and
a specific volume, are thermodynamically in a metastable form.
They are converted to a more stable crystalline form, which has
lower solubility and bioavailability as compared to the amorphous
states. Moisture influences the glass transition temperature and
thus affects the stability of such systems. Therefore, moisture is
considered to be one of the most important factors influencing the
stability of a pharmaceutical formulation.
Atmospheric humidity is one of the main sources of moisture
that influences the active ingredient chemically or physically. How-
ever, a formulator also needs to consider the inherent moisture
of some of the excipients, which could be potential contributors
of water molecules for hydrolysis. Many active ingredients are
hygroscopic in nature and need to be protected from moisture. In
addition, moisture protection is often needed when the cores are
hygroscopic (Prinderre et al., 1997a), as is the case with many herbal
products. Special attention needs to be given to the designing of
such formulations in order to prevent degradation due to hydroly-
sis (Luftensteiner et al., 1999). For most powders, residual humidity
modifies their mechanical and rheological properties. Hence, the
concept of water adsorption on the surface of solids is of utmost
importance in pharmaceutical studies.
A number of formulation approaches have been developed to
reduce hydrolytic degradation as well as to mask the taste of
the active pharmaceutical ingredient. These approaches have been
described below in detail.
Protecting a formulation from hydrolytic degradation is also
possible through appropriate packaging, however it does not
exclude moisture from seeping into the container during multi-
ple openings. Protecting the cores with a moisture barrier film is
found to be more appropriate, since it also eliminates the prob-
lem caused by multiple openings of the container. Thus, of all the
alternatives available, coating the formulations is found to be the
most appropriate and widely used technique.
Moisture-protective polymer coatings are often used to pro-
long the storage stability of water-sensitive drugs, including many
herbal extracts (Haleblian and Goodhart, 1975; Rudnic and Kottke,
1996; Du and Hoag, 2001).
While developing a coating formulation for a moisture sensi-
tive drug, the following strategies need to be considered during the
entire development process:
• Designing the dosage form with non-hygroscopic/low water-
activity excipients.
• Formulating the core with the least amount of inherent moisture.
• Providing the dosage form with a moisture protective coating.
• Packaging the dosage form with an appropriate moisture-
resistant material.
1.3. Mechanism of taste sensitivity and moisture uptake
To protect it, evolution has provided the body with taste in
response to dissolved substances in the oral cavity. Taste buds,
located primarily on the tongue, consist of open pores on the sur-
face. These are onion shaped organelles of receptor cells carrying
G-protein coupled receptors (GPCRs). The taste of compounds
is perceived by the binding of tastants (e.g. medicines or food)
with GPCRs in the taste buds. Interactions of tastants with the
receptor induce the release of the G-protein gustucin, which
 S. Joshi, H.-U. Petereit / International Journal of Pharmaceutics 457 (2013) 395–406
Fig. 1. Taste buds (Reineccius and Heath, 2006).
activates a multistep enzymatic process causing the release of
neurotransmitters that trigger nerve impulses to the brain (Fig. 1).
There are five basic types of taste: salty, sour, sweet, bitter
and umami (Mundada et al., 2008; Sugao et al., 1998). Often
a correlation of taste perception and chemical structure can be
observed. Low molecular salts (i.e. sodium chloride) taste salty,
while nitrogen containing substances (i.e. alkaloids) induce a mild
or even strong bitter perception. Compounds with hydroxyl groups
tend to taste increasingly sweet with higher numbers of OH-
groups. Among those, bitter taste is the most relevant for patient
acceptance because of an extremely low threshold concentration
(Table 1).
Quite recently, specific inhibitors of taste receptors have been
developed and will probably be used as functional excipients in the
future (Friend, 1992). It can be concluded that the human tongue is
ten thousand times more sensitive to a bitter taste than to a sweet
stimulant. As a consequence, masking bitter taste with different
flavors is not an efficient concept, because the necessary quantities
of natural or artificial aromas are extremely high and may not fit
the concept of a modern pharmaceutical dosage form.
As a general approach, efficient concepts of taste masking are
based on hindering or blocking interaction of tastants with GPCRs.
Any coating formulation that hinders the fast release of a bitter
tasting ingredient in the oral cavity – and its contact with taste
receptors in the tongue – will mask unpleasant taste. Film coating
is the most efficient mechanism to provide a barrier, hindering dis-
solved molecules from moving through the saliva toward the taste
receptors.
Understanding the mechanism of moisture passage through a
substrate will also reinforce the concept of film coating for moisture
protection. A water molecule’s path of movement from the surface
of a film to the surface of the drug substrate, is a 3-step mecha-
nism (Prinderre et al., 1997b): Starting with adsorption of water
molecules on the surface of the film. Followed by diffusion of the
molecules through the insulating membrane and finally desorption
on the film-substrate interface.
Table 1
Types of taste and threshold concentrations of dissolved tastants for primary taste
sensations (Guyton and Hall, 2007).
Taste Area of Tongue Threshold
Concentration [%]
Sweet (sucrose) Tip 0.5
Salt (NaCl) Tip and sides 0.25
Saur (HCl) Sides 0.007
Bitter (quinine) Back 0.00005
397
The permeability of the plastic membrane/polymer film thus
determines the speed and intensity of the diffusion of the water
molecules through the film. The rate of its diffusion is governed by
the coefficient of diffusion of water in that polymer. Chemisorption
through formation of irreversible hydrogen bonds with excipient
films has been established through thermodynamic studies. The
methods of Tabibi and Hollenbeck, based on the thermodynamic
theory developed by Copeland and Young, were used to study the
thermodynamics of water excipient film systems (Achanta et al.,
2001a).
Water vapor permeability has been shown to be dependent on
the relative polarity of the polymer (Banker, 1966). This is sup-
ported by the fact that the coefficient of permeability of a film
increases with the structural similarity between the polymer and
the diffusing molecule (Lefaux, 1971). Thus, the amount of mois-
ture sorbed (dissolved) by the polymer is a measure of the solubility
coefficient of water for that polymer (Mwesigwa et al., 2005a).
The rate of movement of moisture across a film is measured by
the water vapor transmission rate. This is best described by Fick’s
first law, which states that the amount of water vapor diffusing
across a film barrier at a given time is a function of the following
(Cech and Mistry, 2009):
• The moisture gradient, which can be calculated based on the
specific water activity of the core formulation and the ambient
humidity.
• The diffusion constant and the surface area of the tablet.
• The layer thickness of the film.
Water sorption often exhibits hysteresis. This is characterized
by isotherms showing a higher heat of desorption against that of
adsorption. Hysteresis is found when adsorption occurs by merging
clumps of molecules on separate sites. After merging, all molecules
are held by forces from all active sites touched by the merged clump.
Forces are therefore stronger than when the clumps were separate.
Hence the vapor pressures of all molecules are lowered and there
is desorption hysteresis (Pierce and Nelson Smith, 1950).
The period of a dosage form remaining in the mouth is quite
short. Generally, periods of a few seconds to half a minute or
a minute can be assumed. However after being swallowed, oral
dosage forms enter the stomach, the physiological section of the
gastro-intestinal tract targeted for drug release. Absorption of the
delivered active ingredient may take place in the stomach or,
preferably, in the upper small intestine. In order to ensure fast
and maximum therapeutic action, drug release kinetics have to be
as fast as possible after the delayed diffusion in the mouth. Any
release kinetic that masks unpleasant taste and protects the drug
against moisture but significantly delays drug release may cause a
prolonged onset of therapeutic action or even minimize the ther-
apeutic effect by reduced bioavailability of the active. This is the
basic compromise between the safeguarding therapeutic effect and
maximizing patient compliance. It needs to be optimized during
the development phase of an immediate-release oral dosage form.
Controlled-release dosage forms with enteric or colonic sustained-
release kinetics are generally not subject to specific taste masking
and moisture protection approaches.
2. Polymers and formulations
2.1. Polymers (Sohi et al., 2004)
Moisture protecting and taste masking polymers used in film
coating processes are based on polysaccharide, polypeptide or vinyl
polymer chemistry. Their physicochemical properties vary over a
398 S. Joshi, H.-U. Petereit / International Journal of Pharmaceutics 457 (2013) 395–406

Table 2
Water-soluble polymers used for taste masking and moisture protection by film coating.

Polymer Trade name Monographs Manufacturer

HEC Natrosol, Oxycellulose EP, USP Ashland Aqualon

Hydroxyethyl cellulose

HPMC Methocel® E3/E5/E6/E15 EP, USP, JPE Dow Chemical

Hydroxypropyl methyl cellulose Pharmacoat® 603/645/606/615 Shin-Etsu
Walocel® HM 3 PA/HM 5 PA/HM 6 Wolff Celullosics
PA/HM 15 PA
SpectracelTM Sensient

Na CMC Walocel® CRT A EP, USP, JPE Wolff Cellulosics

Sodium carboxymethyl cellulose

PVP Kollidon EP, USP BASF

Polyvinyl pyrolidon
PVA-PEG copolymer Kollicoat® IR EP, USP, JPE BASF
(polyvinylalcohol–polyethylenglycol-copolymer) AquaPolish® BioGrund

Polyvinyl alcohol Opadry® AMB EP Colorcon

PVA–PEG: PVA Kollicoat® IR Protect EP, USP BASF

wide range, indicating enormous variability and different formula- were compared for their water uptake rates. Kollicoat® IR-coated
tion approaches. tablets showed higher initial water uptake rates (up to 2.97%/d.).
Knowledge of the physical state of the macromolecules in They also showed an increase in the extent of water uptake with
moisture-protective polymer coatings is important to understand- an increased coating level (Fig. 2). This can be attributed to the
ing the stability of the film. The macromolecules can be in either
the crystalline or the amorphous state. An amorphous polymeric
network can be in either the glassy or the rubbery state, depend-
ing on its glass transition temperature. The main physicochemical
parameter used to characterize amorphous polymers is the glass
transition temperature (Tg ). This is the temperature at which an
amorphous substance in the glassy state is transformed into the
rubbery state, resulting in rearrangement of the molecules into
a new, more highly energetic structure. This transition is mainly
induced by a change in temperature. A glass transition is observed
in all amorphous materials and in partially crystalline polymers
containing amorphous regions. The glass transition temperature
is mainly controlled by the polymer itself. Polymers containing
bulky side groups generally exhibit higher Tg values than polymers
without bulky side groups (Yazdani-Pedram et al., 1986) (Table 2).
Traditionally, water-soluble polymers are used for taste mask-
ing. However, some of them, like polyvinyl alcohol, are also used
for moisture protection. Expected is the enablement of fast drug
release independent of the dissolution medium, with no negative
effect on drug release or therapeutic effect. These polymers include
soluble starch derivatives, cellulose ethers and synthetic vinyl poly-
mers or hydrophilic block copolymers. Since these polymers do not
carry ionic groups, there is only a slight risk of chemical interaction
with the active drug. However, efficiency of blocking the interaction
of bitter drug molecules with taste receptors is somewhat limited.
Reliable taste masking needs coatings up to 10 ␮m in thickness or
more. The necessary polymer weight gain is high and the design
of the dosage form, i.e. particle size, may need to be questioned.
In addition, long process times will reduce the economy of the
manufacturing process. The Opadry® AMB system consists of partly
hydrolyzed polyvinyl alcohol, titanium dioxide, talc, lecithin soya
and xanthan gum. A study, which was conducted to check its mois-
ture protection ability, showed that an increase of the coating level
from 0% to 5% (w/w) led to higher water content in the tablets at the
beginning of the storage trial. A further increase up to 20% (w/w)
did not lead to additional water uptake. In contrast, it resulted in a
clear decrease in the water uptake rate during storage (from 1.00 to
0.31%/d), indicating the good moisture protective ability of this for-
Fig. 2. Water uptake of tablets containing 100 mg of freeze-dried garlic powder
mulation. Curing of tablets coated with 20% (w/w) Opadry® AMB at
coated with different types of poly(vinyl alcohol)-based formulations upon exposure
60 ◦ C for either three or 24 h had no effect on the water uptake rate to 75% RH: (A) Opadry® AMB, (B) Kollicoat® IR [coating level: 0–20% (w/w), Bley et al.,
(Bley et al., 2009a). Opadry® AMB and Kollicoat® IR coated tablets 2009b].
 S. Joshi, H.-U. Petereit / International Journal of Pharmaceutics 457 (2013) 395–406 399

Fig. 3. Water uptake of tablets containing 100 mg of freeze-dried garlic powder coated with different types of HPMC-based formulations upon exposure to 75% RH: (A)
Methocel® E5, (B) SepifilmTM LP 770, (C) SepifilmTM LP 761, (D) SepifilmTM LP 010 [coating level: 0–10% (w/w)] (Bley et al., 2009b).

different chemical structures of the polymers: the PVA (polyvinyl
alcohol) in Opadry® AMB is partially hydrolyzed, while the PVA
in Kollicoat® IR is co-grafted with PEG (polyethylene glycol), act-
ing as an internal plasticizer. PEG is hygroscopic, thus explaining
the higher rate and extent of water uptake of Kollicoat® IR-coated
tablets when compared to Opadry® AMB-coated tablets.
SepifilmTM LP is a ready-to-use formulation containing HPMC
(film-forming agent), cellulose (binder), stearic acid (hydrophobic
plasticizer) and, optionally, pigments. The SepifilmTM LP types dif-
fer in their composition: the LP 010 type contains no pigment and
low amounts of stearic acid, the LP 770 type contains low amounts
of pigments and stearic acid, and the LP 761 type contains high
amounts of stearic acid and pigments. A comparative study of the
three types of SepifilmTM is shown in Fig. 3.
Acid treated yeast cell walls have also been used as an aqueous
coating for moisture protection on formulations (Kasai et al., 2000)
(Table 3).
Films of entero-soluble polymers provide optimized functional-
ity for taste masking and moisture protection. Insoluble in water at
the neutral pH of saliva, they provide an effective barrier against the
movement of drug molecules to the surface and water molecules to
the core – thus providing taste masking and moisture protection.
EUDRAGIT® E is a cationic copolymer based on dimethylaminoethyl
methacrylate, butyl methacrylate and methyl methacrylate with a
ratio of 2:1:1. It is available as a micronized powder for aqueous
dispersion as EUDRAGIT® E PO and in granule form for organic solu-
tion preparation as EUDRAGIT® E 100. The tertiary amino groups
of EUDRAGIT® E polymer types become protonated in the acid
media of the human stomach and, hence, rapidly dissolve. Thus,
fast drug release is secured even if thicker coatings are applied
when needed for moisture protection. A comparative study of
the moisture protection properties of EUDRAGIT® E PO, HPMC,
SepifilmTM LP, Opadry® AMB and ethyl cellulose (Aquacoat® ECD)
was conducted. The time required to approach equilibrium was
longer for EUDRAGIT® EPO coatings compared to the other inves-
tigated formulations, indicating a good moisture protective ability
of this polymer. A curing effect was also studied for these films.
EUDRAGIT® EPO shows an improved resistance to water when
its films are cured at elevated temperatures of 60 ◦ C for 3–24 h
(Figs. 4–6).
Kollicoat® Smartseal 30 D is also a cationic polymer. It is
supplied as an aqueous polymer dispersion containing methyl

Table 3
Entero-soluble, cationic polymers used for taste masking and moisture protection by film coating.

Polymer Trade name Monographs Manufacturer

Amino dimethyl methacrylate EUDRAGIT® E EP, JPE, Evonik

copolymer EUDRAGIT® E PO DMF 1242 (USA)
EUDRAGIT® E 12.5
Amino diethyl-methacrylate Kollicoat® EP, USP BASF
copolymer Smartseal 30 D
400 S. Joshi, H.-U. Petereit / International Journal of Pharmaceutics 457 (2013) 395–406

Table 4
Enteric, anionic polymers used for taste masking and moisture protection by film coating.

Polymer Trade name (selection) Monographs Manufacturer

Sodium alginate Keltone LV CR USP FMC biopolymers

Shellac SSB 55 Pharma USP SSB Pharm
Carboxymethyl cellulose CMC Akucell EP, USP Aqualon
Cellulose acetate phthalat CAP Aquacoat® CPD EP, USP/NF, JPE FMC
Eastman C-A-P NF EP, USP/NF Eastman
Cellulose acetat butyrate CAB CAB Eastman nf Eastman
Methacrylic acid copolymer, Type A EUDRAGIT® L 30 D-55/L 100-55 EP, USP/NF, JPE Evonik
Kollicoat® MAE 30 DP/100 P BASF
Eastacryl 30 D NF Eastman
Methacrylic acid copolymer, Type B EUDRAGIT® L 12,5/ EP, USP/NF Evonik
EUDRAGIT® L 100 EP, USP/NF, JPE
Methacrylic acid copolymer, Type C EUDRAGIT® S 12,5/ EP, USP/NF Evonik
EUDRAGIT® S 100 EP, USP/NF, JPE
Methacrylic acid copolymer EUDRAGIT® FS 30 D Evonik

methacrylate and diethylaminoethyl methacrylate co-polymer sta-
bilized with ∼0.6% macrogol cetostearyl ether and ∼0.8% sodium
lauryl sulfate. The solids concentration is approximately 30%. It
comes as a milky white liquid with a faint characteristic odor (Kolter
et al., 2011) (Table 4).
Shellac is a natural polymer, which is used as enteric coat-
ing material in pharmaceutical applications. It has a potential
for moisture-protective and taste-masking coatings as well as
extended-release matrix tablets. The efficiency of shellac to achieve
moisture protection and taste masking has been compared with
that of hydroxypropyl methylcellulose (HPMC), which is most fre-
quently used for these purposes. Shellac-coated tablets show lower
water uptake rates than HPMC-coated systems at the same coat-
ing level. The stability of acetylsalicylic acid, which was studied as
a prototype, was higher in tablets coated with shellac compared
with HPMC-coated systems, irrespective of the storage humid-
ity. Lower shellac coating levels are required to achieve the same
degree of drug protection. The resulting drug release in simulated
gastric fluid is not significantly altered by the thin shellac coatings,
which rapidly ruptured due to swelling of the coated tablet core.
In addition, shellac is also found to be a suitable matrix former for
extended-release tablets. The latter could be prepared by direct
compression or via wet granulation using ethanolic or ammoni-
ated aqueous shellac binder solutions. Anionic polymers include
natural polymers such as shellac and alginates, carboxymethyl
derivatives of cellulose, cellulose acetate derivatives of phthalic
acid and butyric acid, and specifically optimized methacrylates
carrying different amounts of carboxylic groups. These ensure tar-
geted drug release and controlled dissolution of the coating at a
defined pH. Primarily the polymers provide enteric functionality
and are used for taste masking and moisture protection due to their
efficiency in blocking drug release in the mouth and seepage of
moisture until the formulation is swallowed. The low volume and
low ionic strength of saliva followed by the acidic pH of gastric fluid
cause nothing more than swelling of the coating with little drug

Fig. 5. Allicin content (%) of uncoated and coated tablets [10% (w/w) coating level]
Fig. 4. Water uptake of tablets containing 100 mg of freeze-dried garlic powder containing 300 mg of freeze-dried garlic powder upon exposure to 75% RH at room
coated with: (A) Aquacoat® ECD, (B) Eudragit® EPO upon exposure to 75% RH [coat- temperature (the type of polymer coating is indicated in the figure) (Bley et al.,
ing level: 0–10% (w/w)] (Bley et al., 2009b). 2009b).
 S. Joshi, H.-U. Petereit / International Journal of Pharmaceutics 457 (2013) 395–406 401

Table 5
Insoluble polymers used for taste masking and moisture protection by film coating.

Polymer Trade name Monographs Manufacturer

EthocelTM EP, USP Dow Chemical

Ethyl cellulose Auqacoat® ECD FMC
Surelease® (Fertigprodukt) Colorcon
Cellulose acetate Eastman CA EP, USP Eastman
Poly(ethyl acrylate-co-methyl methacrylate) 2:1 EUDRAGIT® NE 30 D EP, JPE Evonik
EUDRAGIT® NM 30 D EP
Ammonio methacrylate Type A: EUDRAGIT® RL 30 D USP/NF Evonik
Poly(ethyl acrylate-co-methyl EUDRAGIT® RL 100/RL PO EP, USP/NF, JPE
methacrylate-co-trimethylammonioethyl methacrylate chlorid) EUDRAGIT® RL 12.5
1:2:0.2
Ammonio methacrylate Type B: EUDRAGIT® RS 30 D USP/NF Evonik
Poly(ethyl acrylate-co-methyl EUDRAGIT® RS 100/RS PO EP, USP/NF, JPE
methacrylate-co-trimethylammonioethyl methacrylate chlorid) EUDRAGIT® RS 12.5
1:2:0.1
Polyvinyl acetate Kollicoat® SR 30 D BASF

Table 6
Functional potential of different methacrylate coating levels, given as dry polymer weight gain per unit surface area of substrate (McGinity and Felton, 2008).

EUDRAGIT® E EUDRAGIT® L30 D-55 EUDRAGIT® RL

PO (mg/cm2 ) EUDRAGIT® L 100-55 (mg/cm2 ) 30 D (mg/cm2 )

Sealing ∼1 ∼1 ∼1
Taste masking 1–2 ∼1 ∼1
Moisture protection 4–10 ∼1 ∼1

release and moisture seepage by molecular diffusion. However,

Fig. 6. Water uptake of tablets containing 100 mg of freeze-dried garlic powder
coated with different types of poly(vinyl alcohol)-based formulations upon exposure
to 75% RH: (A) Opadry® AMB, (B) Kollicoat® IR [coating level: 0–20% (w/w)] (Bley
et al., 2009b).
the desired fast drug release after passage of the dosage from the
mouth requires only thin coatings in the range of 0.5–5 mg polymer
per cm2 surface area. Reproducible coating processes need an opti-
mized formulation of the coating suspension, i.e. a reduced amount
of solids and meaningful and narrow control of the coating process.
Furthermore, free carboxylic groups may adversely interact with
cationic groups of the active compound leading to instability. Isolat-
ing subcoats may be necessary to hinder this chemical interaction.
Cationic or anionic copolymers, particularly the (meth)
acrylates, may be partially neutralized, leading to improved drug
release more independent of pH while maintaining a barrier effect
for dissolved molecules in saliva. The adding of sodium hydrox-
ide to methacrylic acid copolymer type A in quantities neutralizing
more than 10 mol%, i.e. increases the threshold pH of the polymer
solution up to neutral levels (US, 2011). Cationic aminomethacry-
late copolymer, carrying tertiary amino groups, may be neutralized
with a combination of mono and dicarboxylic acids, such as malic
or tartaric acid in order to achieve solubility of the coating in water
(WO, 2003b). While maintaining a significant taste masking effect,
the instant therapeutic effect is maintained more independently
of the physiological influences of the human gastro-intestinal tract
(Tables 5 and 6).
The neutral ethyl acrylate and methyl methacrylate disper-
sions (EUDRAGIT® NE 30 D and EUDRAGIT® NM 30 D) provide
coatings with medium permeability while the ammoniomethary-
late copolymers form films of high (Type A) (EUDRAGIT® RL) and
low permeability (Type B) (EUDRAGIT® RS). Based on the physico-
chemical characteristics, the type A polymer may be the preferred
coating polymer, however, mixtures are often applied for optimized
functionality. Due to insolubility in water and low permeability the
polymers can efficiently mask unpleasant taste and provide mois-
ture protection, but fast drug release requires thin coatings similar
to the anionic polymers. Both types may ensure improved func-
tionality by adding further excipients for modification of solubility
or permeability.
Ethylcellulose-based formulations (Aquacoat® ECD) also
provide moisture protection. Improvement in moisture protection
is achieved with an increase in film thickness.
Hydrogenated rosin (HR), a yellow-colored, natural, product-
based biomaterial, also has film-forming and coating properties.
402 S. Joshi, H.-U. Petereit / International Journal of Pharmaceutics 457 (2013) 395–406
Hydrogented rosin has an Mw of 400 with a polydispersity index
close to 1. The Tg is 47 ◦ C, acid value 171.0, while the softening point
range is 54–56 ◦ C. Hydrogenated rosin is soluble in organic sol-
vents such as dichloromethane and chloroform but poorly soluble
(insoluble) in water, which is indicative of its hydrophobic nature.
Solubility in different buffer solutions is highly pH-dependent, with
solubility increasing with an increase in the pH of the solution. HR
is effective as a moisture-protecting film former when combined
with dibutyl sebacate as the plasticizer (Satturwar et al., 2003).
Abetic acid is a major constituent of rosin. Glycerol derivatives
of abetic acid also provide moisture protection to formulations
(Puranik and Dorble, 1991).
A further alternative of coating formulation design is a combina-
tion of different polymers in the coating. Preferably, water-soluble
and insoluble types of polymers are combined in various ratios.
As a result, the positive effect of blocking bitter tasting molecules
from interacting with receptors on the tongue and instant drug
release in the stomach can be linked. Publications mention film
coatings containing ethyl cellulose and low substituted hydrox-
ypropyl cellulose (DE, 1990) or hydroxypropyl methyl cellulose
(CA, 1995). The insoluble polymer of EUDRAGIT® NE 30 D was
combined with hydroxypropyl cellulose (EP, 1993) and insolu-
ble EUDRAGIT® RL 30 D dispersion was co-processed with water
soluble carboxymethylcellulose sodium in a 9–1 polymer ratio.
The resulting coating maintained efficient taste masking combined
with instant drug release due to rapid disintegration of the poly-
mer layer in water independent of pH (EP, 19999). Taste masking
of acetaminophen particles has been achieved by film coating with
EUDRAGIT® RL/Blanose (sodium CMC) in a 9–1 combination (Meier
and Workshop, 2002).
Cationic entero-soluble EUDRAGIT® E 100 may be combined
with swellable MCC and water soluble HPC (Ishikawa Ref. 27) or
with water insoluble cellulose acetate (US, 2003).
Kollicoat® IR protect is a blend of PVA/PEG graft copolymer and
PVA in a 6:4 ratio. The high capacity of this polymer mixture to bind
insoluble pigments, due to its low viscosity, has shown to be useful
for providing oxygen and moisture protection to formulations.
2.2. Formulation principles
Polymers may be applied by spray coating from organic or aque-
ous solutions. Preferred solvents are ethanol, isopropanol or its
mixtures with acetone. Safety and toxicological reasons, as well
as specific product and formulation development, changed coating
processes to aqueous fluids containing the polymer in dissolved or
dispersed form. Polymer dispersion may be prepared by emulsion
polymerization, solvent evaporation from emulsions or micronized
polymer particles. For moisture sensitive drugs, there are concerns
about moisture penetrating during the coating process itself when
using aqueous coating formulations. However, the latest coating
equipment offers better drying techniques, thus preventing this
moisture penetration during the coating processes. Thus, based
on optimized formulations, aqueous coatings provide equivalent
functionality to solvent based coatings.
Cores used for taste masking and moisture protection by film
coatings may have many different structures and a wide variety of
particle sizes. They can range from crystals or particles of a few ␮m,
to granules and pellets up to 2 mm, or tablets of different shapes up
to 15 mm or more. Traditionally, the preferred application process
for tablets needing taste masking and moisture protection has been
by film and spray coating in drums. Based on optimized formula-
tions in terms of shape and hardness, the coating process usually
involves little risk of complications and offers high reproducibility.
Additionally, the small specific surface area requires low polymer
weight gain and short process times for taste masking. Hygroscop-
icity of the cores also determines the sorption and desorption of
the moisture barrier films. A comparative study was conducted on
cores of different hygroscopicity on SepifilmTM LP, Opadry® AMB
and EUDRAGIT® L 30 D-55 and EUDRAGIT® L 100-55. EUDRAGIT®
cast films exhibited the fastest equilibration but was also the least
hygroscopic. SepifilmTM LP, had the fastest sorption and took up the
greatest mass of water. The rate of uptake for Opadry® AMB film
was similar to SepifilmTM LP. However, this film continued to sorb
moisture for a longer period. When returned to 0% RH Opadry® AMB
retained moisture in the film, showing that it had a high affinity for
moisture within the film (Mwesigwa et al., 2005b).
Recently, orodispersible tablets (ODTs) gained significant
importance in the fast-acting, oral dosage market. Advantages of
these formulations are fast disintegration in the oral cavity, easy
swallowing of the powder or small particles, and fast therapeutic
onset enabled by drug absorption through mucosa of the mouth or
in upper segments of the gastro intestinal tract. Therefore, compli-
ance is significantly increased. However, course particles of more
than 150 ␮m cause the mouth to feel rough and irritated, thus
neutralizing the positive acceptance of ODTs. As a consequence,
small particle coating was applied for taste masking by film coat-
ing. Particles may have significantly different shapes or structures.
Pure API crystals may be round and suitable for a coating process,
preferably in the fluidized bed. However, needle-shaped crystals
may break through a fluidized bed coating process, thus constantly
creating new surfaces and reducing the efficiency of taste mask-
ing. These types of crystals often need a reformulation to granules
or small pellets. By ensuring adequate hardness of these cores, a
coating process can be designed in a reliable and reproducible man-
ner. As the specific surface area of small particles is significantly
higher than that of tablets, the necessary polymer application is
significantly higher, often requiring longer process times for appli-
cations.
The thickness of the coating film and the composition of the
excipients used in the film are important factors influencing the
movement of water molecules through the film. Increasing the film
thickness results in an improvement of the tensile strength of the
core (Porter, 1980a). Increasing film thickness results in greater
amounts of water retained in the film. This could result in larger
amounts of moisture condensing in the pores, either because of
chemisorption or because of the different nature of the internal
microporous structure of the thick film. In a typical coating process,
the particle size of the substrates is heterogeneous, and so is the
coating film thickness on each substrate. If films of varying thick-
ness retain different amounts of moisture, the process variables
should be closely controlled to achieve as uniform a coating thick-
ness as possible for satisfactory product performance. This is of vital
importance for sustained-release and moisture-protective coating
applications because the residual moisture in the coating film may
migrate into the core and interact with the active ingredient in an
adverse manner during storage.
Thicker moisture protection films result in prolonged dis-
integration in the gastric fluid. A double-layer coating of the
same polymers, with each layer constituting a thinner film,
showed improved disintegration with the same moisture protec-
tion (Kuriyama et al., 1970).
However polymers with different chemical structures and
physicochemical properties are applied for taste masking in film
coating processes. It is clear that specific and optimized formula-
tions have to be developed in order to provide reliable function.
With the exception of cationic entero soluble polymers, coat-
ing thickness is the major parameter influencing functionality.
Coatings generally provide efficient taste masking, but only thin
coatings enable fast drug release in the stomach and thus instant
therapeutic effects. The design of the spray process requires com-
plete coverage of the core surface and coating thickness in the range
of only 10–15 ␮m. Consequently optimization of taste masking
 S. Joshi, H.-U. Petereit / International Journal of Pharmaceutics 457 (2013) 395–406
effect and drug release rate is necessary to find the best compro-
mise.
The glass transition temperatures of the polymers used for
coatings affect the moisture protection ability and the stability of
the formulation. Polymers in the amorphous state have a higher
capacity for moisture sorption than in the crystalline state (Hancock
and Zografi, 1997). The up taken water may be thought of as “dis-
solving” into the amorphous structure and acting as a plasticizer
(Hancock and Zografi, 1994). Consequently, the glass transition
temperature of the polymeric system decreases with increasing
water content. Thus, water which permeates through a moisture
barrier film would also have an influence on the Tg of the film and
hence on the stability of the film and the formulation. In the pres-
ence of moisture, glassy-to-rubbery state transition occurred with
the polymeric system of Opadry® AMB as opposed to EUDRAGIT®
EPO, which did not show this transition under the test conditions.
Hence, the water uptake with the Opadry® AMB films tend to
increase with increasing temperature, due to the higher mobility
of the macromolecules (Bley et al., 2009b).
The plasticizer effect is based on molecular interaction with the
polymer chains, thus helping to open the polymer chains and help-
ing them interact with each other in order to develop more firm
bonds, which result in coalescence of the film and film formation.
Plasticizers are required to impart the essential flexibility to the
film. This is obtained through a reduction in the glass transition
temperature of the film, thus reducing its tensile strength (Felton
and McGinity, 1997). Plasticizer also helps with adhering the film to
the tablet surface. Appropriate concentrations of the plasticizer are
important in determining the moisture protection properties of the
final film. Quantities above the optimum level result in molecular
scale holes in the film, which help water molecules pass through
the structure, thus reducing the moisture protection property of
the film. The effects of the presence of different types of plasti-
cizers in polymeric coating formulations have been reported in
literature (Johnson et al., 1991; Heinamaki et al., 1994; Guo, 1993).
The nature of the plasticizer drastically influences the moisture-
resistance ability of the film. Films having a hydrophilic plasticizer
are found to permeate moisture more rapidly (Listand and Kassis,
1982). On the other hand, addition of hydrophobic plasticizers
helps to increase lipophilicity and thus the moisture resistance of
the film (Benita et al., 1986).
In addition to a plasticizer, pigments have an important role
to play in moisture resistant film coatings. Due to the presence of
intermolecular spaces in polymeric films, a complete barrier to the
movement of air or vapor is not possible. Insoluble additives are
hence used on the coatings in order to block these intermolecular
spaces (Mistry and Cech, 2011). Pigments, being discrete particles,
serve as a barrier to the diffusion of moisture through the film.
The moisture has to bypass these particles, thus increasing the pas-
sage time, thereby improving the moisture protection ability of the
film. This, however, depends on the concentration of the pigments,
referred to as critical pigment volume concentration. Above this
level pigment pores are generated, thus facilitating the movement
of moisture and resulting in poor moisture protection by the film.
Pigments added to a polymer need to be distributed uniformly in
order not to form agglomerates, which would interrupt film for-
mation and possibly result in weaker films. Inadequate pigment
distribution would also adversely affect film adhesion to the sur-
face. Polyhydric material such as film formers or plasticizers can
form hydrogen bonds with the water molecules, thus reducing the
possibility of water molecules to reach the core and in turn provide
moisture protection (Porter, 1980b). Water-soluble polymers like
polyvinyl alcohol have been used for such applications (Cech and
Mistry, 2009).
The masking effect of water-soluble coatings may be improved
by adding insoluble substances like Ca gluconate (Nanda et al.,
403
2002b) or fatty acid esters and pigments, i.e. titanium dioxide, in
case of colored coatings (Shirai, 1993). Higher film flexibility is
desirable in order to incorporate larger amounts of pigment in the
film.
As a reverse effect, water soluble or swelling excipients may
be added to coating suspensions of water insoluble polymers.
Causing permeability enhancement, the release of enrobed drugs
will be accelerated. Examples are microcrystalline cellulose (MCC)
(Ishikawa et al., 1999). In order to improve patient’s perception of
the dosage form, sweet carbohydrate may be added to coating sus-
pensions, or even dry syrups such as sucrose (JP, 1993) or mannitol
and lactose (Shimizu et al., 2003).
The agitation granulation method is an approach for moisture
protection. An agitation granulation of a very hygroscopic extract
of Hatium-ziogam, with the help of porous calcium silicate as an
excipient, resulted in adequate moisture protection (Khan et al.,
2009).
Complexation with ion exchange resins is one of the tech-
niques used for moisture protection. Weak cation exchange resins
like polacrilex with exchangeable hydrogen, polacrillin potas-
sium and strong cation exchange resins like sodium polystyrene
sulphonate have been evaluated for moisture protection of Raniti-
dine hydrochloride tablets through ion exchange (Mundada et al.,
2008).
Aqueous coating processes are normally associated with longer
drying times. Non-aqueous coatings are largely discouraged due
to the hazards associated with the environment and solvent han-
dlings. A solvent-free process with micronized powders for film
coating on tablets using acrylic polymers such as EUDRAGIT® E PO
has been developed. The coated tablets, observed using a scanning
electron microscope, exhibited a continuous and uniform film coat-
ing. The results of dissolution testing indicated that in pH 6.8 buffer
media, film coating resulted in a delay in the release of the drug,
while no delay was observed in acidic medium. On the basis of
these behaviors, taste masking, moisture protection and controlled
release applications are expected from such films (Cerea et al.,
2004a).
Lipidic/waxy excipients with low melting points (<373 K) are
also sprayed in their molten state to form a uniformly continuous
film that acts as the rate-controlling membrane for drug release
as well as for moisture protection. The hydrophobic wax coat-
ing presents a barrier for moisture ingress into the drug-laden
substrate. The most commonly used waxy excipient is glyceryl
behenate. With glyceryl behenate, there may be binding of water
molecules to the electronegative oxygen atom in the terminal
carboxylic group via hydrogen bonding. Further, as temperature
increases and is closer to the melting temperature of the wax, the
intermolecular distances increase, leading to a greater number of
carboxylic groups becoming available. Thus the effective moisture
content (EMC) increases with increasing temperature for glyceryl
behenate film (Bley et al., 2009b).
As long term storage of oral dosage forms, often under elevated
temperatures and high humidity, create a high stress on dosage
forms during storage, packaging may be necessary additionally to
ensure storage stability of the dosage forms during an adequate
period of time. Thus plastic or metal containers may be used to
strengthen moisture protection over a longer period of time or plas-
tic foils out of polyethylene, polypropylene or polyester, probably
even laminated with aluminum.
3. Relevant analytical testing and their
challenges/limitations
A method for organoleptic testing of bitterness is described in
the European Pharmacopoeia. The method is designed for solid
404 S. Joshi, H.-U. Petereit / International Journal of Pharmaceutics 457 (2013) 395–406
powders dissolved or dispersed in water. Test substances need
to be processed and tested as fine powders. However, the taste
masking effect is linked to the design and structure of the dosage
form. So reducing the particle size to a powder will influence or
even eliminate the formulation effect. The US Pharmacopoeia does
not provide any test method but includes organoleptic character-
istics in the description chapter of monographs. Sensory testing is
expressively excluded from any identity verification (USP, 2012).
However, organoleptic testing of taste has been used tra-
ditionally for characterizing taste and odors of substances and
formulations. State-of-the-art panels of at least six persons are col-
lected, who judge taste perceptions and usually compare different
test substances with a standard. A well-controlled experimental
design is necessary to achieve the necessary accuracy and repro-
ducibility. Even quantitative evaluation procedures are described
in the literature (Wagh and Gadlinge, 2009). The method, although
still applied routinely, often lacks reproducibility and reliability.
Further, more toxic effects, particularly of highly potent drugs, can-
not be excluded. Thus, the practical and scientific benefit of panel
testing is in question.
Frog taste nerve response is a method practiced on intraperito-
nially anesthetized adult bullfrogs. The glossopharyngeal nerve is
dissected, cut proximally and linked to an amplifier with an elec-
tronic integrator. The set-up allows quantitative detection of the
nerve impulses and correlates the peak height with the intensity
of taste sensing when a test substance is applied (Katsurgi and
Kashiwayanagi, 1997). The method is challenging and has only
limited value for a larger number of test substances.
Multi-channel taste sensors, also described as an electronic
tongue, have been recently developed to quantify taste sensations
caused by a chemical substance. Sensors are available, including
several lipid and polymer membranes with different physicochem-
ical characteristics, allowing the detection and analysis of taste
sensations by a principle similar to human physiology. Electric sig-
nals, generated as a response of membrane potential by the test
substance, are analyzed for electric potential and correlated with
different taste qualities and their intensity. Three types of bitterness
sensors are available, besides a sensor for umami, saltiness, sour-
ness and astringency. Generally, ionic substances can be detected
with higher accuracy than neutral ones (Woertz et al., 2011). A qual-
ification of sensors for bitterness is published (Woertz et al., 2010).
A bitterness evaluation of famotidine tablets using a taste sensor in
comparison with the valuation of human volunteers resulted in cor-
relating results and indicated higher bitterness scores for generic
products compared with the original (Okamoto et al., 2009). The
method has the potential to provide a standard for quantitative
EUDRAGIT® EPO, 10%SLS,15% stearic acid
EUDRAGIT® L100-55
OPADRY AMB
EUDRAGIT® RS 100
EUDRAGIT® E100
EUDRAGIT® NE30
EUDRAGIT®EPO, 7%SLS, 10%DBS
EUDRAGIT® RL 100
HPMC
0 100
Fig. 7. Water vapor permeability of free polymeric films (ASTM E 95-96).
measuring of the bitterness strength of substances and to replace
sensory testing of human panels.
Spectrophotometric methods are based on an estimation of sub-
stance concentration in a filtered aqueous solution, prepared in a
reproducible manner. If the concentration is below a known thresh-
old, it can be concluded that no bitter taste will be perceived in
vivo. Spectrophotometric tests may be particularly suitable for rou-
tine quality control of manufactured dosage forms (Shirai and Sogo,
1997).
Moisture uptake studies are conducted by measuring the
increase in the weight of the coated formulations at various
constant temperature and humidity conditions. Saturated salt solu-
tions are used to obtain high humidity conditions. The conditions
most often used are 25 ◦ C with a relative humidity (99 ± 1%)
(Prinderre et al., 1997c). A saturated salt of potassium sulfate or
barium sulfate is used for this condition. Studies are carried out at
25 ◦ C at 84% relative humidity (RH) and at 25 ◦ C at 75% RH, pro-
duced with a saturated potassium chloride solution. The coated
and uncoated tablets are evaluated for their weight uptake at these
different humidity conditions. The studies are conducted until a
constant weight (equilibrium weight) is achieved. Some studies
are also carried out at elevated temperatures along with elevated
humidity, for example at 75% relative humidity at 45 ◦ C. The USP
suggests that for equilibrium moisture determinations, weighing
should be performed every hour until consecutive readings record
a mass change of less than 0.25%.
Since water acts as a plasticizer in polymeric films, it reduces
the Tg of the film. Thus, a measure of the Tg of the films stored
at elevated temperature and humidity conditions can also give an
estimate of the moisture resistant capacity of the film (Bley et al.,
2009c).
Casting films of the polymer is one of the methods for evaluating
a polymer. The free films are prepared according to The Ameri-
can Society for Testing and Materials (ASTM) standard practices for
producing films of uniform thickness of paint, varnish and related
products on test panels. The coating solution is spread onto flat
Teflon® plates using a manual applicator with a blade which is
10 cm wide, 5 mm thick and has a clearance of 0.63 mm. The plates
are stored in a static oven at different temperatures. The thick-
ness of the free films is measured in accordance with the ASTM
standard test method for the measurement of dry film thickness
using a micrometer. Further, electrogram micrographs of the film
are studied after exposure to elevated humidity conditions (Cerea
et al., 2004b). ASTM E 95 and 96 are used for the study of moisture
protection properties of films. Water vapor transmission rates are
determined using a water vapor permeability analyzer, which is
200 300 400 500 600 700 800 900 1000
Water vapour permeability (g water/m2 d)
 S. Joshi, H.-U. Petereit / International Journal of Pharmaceutics 457 (2013) 395–406
also described in the ASTM E 95 and 96. Examples of experimental
data from pharmaceutical polymers are summarized in Fig. 7.
Free films are also produced by spraying the coating solution
onto vinyl-coated cards, which are fitted to the inside of a coating
pan to represent the surface of a tablet. Once dry, the film samples
are removed from the card and stored flat between two index cards
prior to testing. Subsequently, the tensile strength of the film is
measured with the help of a tensile tester. Evaluating such free
films provides a good understanding of the behavior of the coating
when applied to an actual tablet surface. This information is often
useful, but should be used with caution, especially when the free
film preparation conditions vary considerably from actual coating
conditions.
3.1. Thermogravemetric analysis
Dynamic vapor sorption technique (DVST) is a fully automated
gravimetric sorption system used to rapidly measure uptake and
loss of moisture. This is done by allowing a carrier gas (nitrogen) to
flow at a specified relative humidity (RH) over the material spec-
imen suspended from an ultrasensitive microbalance capable of
measuring changes in mass lower than 1 part in 10 million. Com-
pared with traditional experimental approaches utilizing saturated
salt solutions, DVST offers fast equilibration times, high preci-
sion/sensitivity in mass determination and temperature control,
small sample size requirement, and full automation to facilitate
convenient and accurate moisture sorption/desorption investiga-
tions (Achanta et al., 2001b).
4. Summary and conclusion
Taste masking and moisture protection of oral dosage forms
contribute significantly to the therapeutic effect of pharmaceutical
and nutraceutical formulations either by ensuring patient compli-
ance or by providing stability through shelf life in order to provide
the desired efficacy to the end user. Among different types of taste,
bitter taste is the most relevant for patient acceptance because
of the extremely high sensitivity of taste buds on the back of the
tongue. As hydrolysis is the most common mode of degradation of
an active ingredient, moisture protection plays a vital role in the sta-
bility of the active. Moisture protection can be achieved by reducing
the initial moisture content of the formulation and inhibiting fur-
ther moisture seepage into the formulation during manufacturing
and storage. Optimized oral dosage forms need to reliably hinder
the release of bitter drug molecules in the mouth or ensure stability
of the active compound, while also ensuring fast drug release in the
stomach to enable early therapeutic onset.
Besides different formulation concepts, film coating is found to
be the most effective and commonly used approach for taste mask-
ing and moisture protection. Film coating can be achieved through
the use of water-soluble, cationic, anionic or neutral insoluble
polymers from different chemical structures. Use of water-soluble
polymers often results in a compromise of the isolation or moisture
protection ability of the film. Use of anionic or neutral polymers
necessitates thin films in order to ensure quick release in the gas-
tric fluid. Cationic polymers provide efficient moisture protection
without influencing the release of the drug in the gastric fluids.
Polymers may be sprayed onto various types of cores from disper-
sions or solutions in organic solvents or water. Organic solvents
offer the safest option. However, due to environmental concerns,
aqueous formulations are often preferred. Efficient drying with
coating equipment can ensure effective use of aqueous systems
without compromises. Coating thickness ranging from 0.5 to 50 ␮m
or more, represents the most important influence on the desired
405
function besides physicochemical properties of the coating mate-
rial.
Insulating excipients with the least affinity to moisture also taste
mask and ensure patient compliance as well as keeping the mois-
ture uptake to a minimum during storage. Hydrophobic plasticizers
would enhance the moisture protection ability of the film over the
hydrophilic ones. Close attention needs to be payed to the quantity
of the plasticizer. Pigments used for esthetics can be additionally
exploited for their ability to physically obstruct the passage of drug
or water molecules in the coating films.
Organoleptic tests are still common in testing the quality of
taste-masked formulations. Recently, multi-channel taste sensors
have been developed to quantify different types of taste. Dynamic
vapor sorption technique provides an effective system to study the
efficacy of the formulations. Studies at elevated humidity condi-
tions as obtained with saturated salt solutions also provide a good
option for the evaluation of the systems. Critical control of the
study system is, however, necessary to ensure reproducibility of
the results.
Efficient taste masking and reliable moisture protection of solid
oral dosage forms can be achieved by film coating implementing the
options of pharmaceutical polymers and processes, while also over-
coming possible interactions with the active compound or different
excipients.
References
Achanta, A.S., Adusumilli, P.S., James, K.W., Rhodes, C.T., 2001a. Drug Dev. Ind. Pharm.
27, 227–240.
Achanta, A.S., Adusumilli, P.S., James, K.W., Rhodes, C.T., 2001b. Drug Dev. Ind. Pharm.
27, 241–250.
Ahlneck, C., Zografi, G., 1990. Int. J. Pharm. 62, 87–95.
Banker, G.S., 1966. J. Pharm. Sci. 55.
Benita, S., Dor, P., Aronhime, M., Marom, G., 1986. Int. J. Pharm. 33, 71–80.
Bley, O., Siepmann, J., Bodmeier, R., 2009a. Int. J. Pharm. 378, 59–65.
Bley, O., Siepmann, J., Bodmeier, R., 2009b. Eur. J. Pharm. Biopharm. 73, 146–153.
Bley, O., Siepmann, J., Bodmeier, R., 2009c. J. Pharm. Sci. 98, 651–664.
Brahmankar, D.M., Jaiswal, S.B., 1995. Pharmaceutics Pharmacokinetics, 1st ed., pp.
162–165.
CA 1336819 (1995).
Cech, T., Mistry, M., 2009. Pharm. Technol. Eur. 21, 46–53.
Cerea, M., Zheng, W., Christopher, R., Young, McGinity, J.W., 2004a. Int. J. Pharm.
279, 127–139.
Cerea, M., Zheng, W., Young, C., McGinity, J.W., 2004b. Int. J. Pharm. 279, 127–139.
Chatap, V.K., 2007. Pharmainfo.net 5, vol. 4.
DE 3900811 (1990).
Du, J., Hoag, S.W., 2001. Pharm. Dev. Technol. 6, 159–166.
EP 0551820 (1993).
EP 0 955 041 B1 and US 6.656,507 B2 (1999).
EP1478344 B1 (2003).
Felton, L.A., McGinity, J.W., 1997. Int. J. Pharm. 254, 167–178.
Friend, D.R., 1992. J. Microencap. 9, 469–480.
Guo, J.H., 1993. Int. J. Pharm. 99, 1541–1555.
Guyton, C., Hall, J.E., 2007. The Chemical Senses – Taste and Smell Textbook of
Medical Physiology, 11th ed. W.D. Saunders Company, Hong Kong.
Haleblian, J.K., Goodhart, F.W., 1975. J. Pharm. Sci. 64, 1085–1148.
Hancock, B.C., Zografi, G., 1994. Pharm. Res. 11, 471–477.
Hancock, B.C., Zografi, G., 1997. J. Pharm. Sci. 86, 1–12.
Heinamaki, J.T., Lehtola, V.M., Nikupaavo, P., Yliruusi, J.K., 1994. Int. J. Pharm. 112,
191–196.
Ishikawa, T., Wattanabe, Y., Utoguchi, N., Masumoto, M., 1999. Chem. Pharm. Bull.
47, 1451–1454.
Jain, N.K., 2001. Advances in Controlled and Novel Drug Delivery, vols. 290–306., 1st
ed.
Johnson, K., Hathaway, R., Leung, P., Franz, R., 1991. Int. J. Pharm. 73, 197–208.
JP 02,056,416 (1990).
JP 04,327,526 (1992).
JP 05,097,664 (1993).
Kasai, T., Eguchi, T., Ishiwaki, N., Kaneshige, J., Ozeki, T., Yuasa, H., 2000. Int. J. Pharm.
204, 53–59.
Katsurgi, Y., Kashiwayanagi, M., 1997. Brain Res. Protoc. 1, 292–298.
Khan, S., Giradkar, P., Yeole, P., 2009. J. Pharm. Sci. Technol. 63, 226–335.
Kolter, K., Guth, F., Angel, M., 2011. CRS.
Kuriyama, T., Nobutoki, M., Nakanishi, M., 1970. J. Pharm. Sci. 59, 1341–1346.
Lefaux, R., 1971. Lab. Pharma. Probl. Technol. 203, 55.
Listand, P.H., Kassis, G., 1982. Pharm. Technol. 82, 21–33.
Luftensteiner, C.P., Viernstein, H., 1999. Wien. Med. Wochenschr. 149, 258–261.
406 S. Joshi, H.-U. Petereit / International Journal of Pharmaceutics 457 (2013) 395–406
McGinity, J.W., Felton, L.A., 2008. Drugs and the Pharmaceutical Sciences, 176., 3rd
ed., pp. 237–277.
Meier, C., 2002. EUDRAGIT Workshop, February.
Mistry, M., Cech, T., 2011. Drug Dev. Deliv. 11, 28–33.
Mundada, A.S., Jain, S., Chachda, N.O., Avari, J.G., 2008. Am. Pharm. Rev. 11.
Mwesigwa, E., Buckton, G., Basit, A., 2005a. Drug Dev. Ind. Pharm. 31, 959–968.
Mwesigwa, E., Buckton, G., Basit, A., 2005b. Drug Dev. Pharm. Ind. 31, 959–968.
Nanda, A., Kandarapu, Garg, S., 2002a. Indian J. Pharm. Sci. 64, 10–17.
Nanda, A., Kandarapu, R., Garg, S., 2002b. Indian J. Pharm. Sci 64, 10–17.
Okamoto, M., Sunada, H., Nakano, M., Nishiyama, R., 2009. Asian J. Pharm. Sci. 4, 1–7.
Pharm Eur 7.0/2.08.15.00, 2.8.15 Bitterwert (2011).
Pierce, C., Nelson Smith, R., 1950. J. Phys. Colloid Chem. 54, 784–794.
Porter, S., 1980a. Pharm. Technol. 80, 67–75.
Porter, S., 1980b. Pharm. Technol. 4, 67–75.
Prinderre, P., Cauture, E., Piccerelle, Ph., Kalantzis, G., Kalostiana, 1997a. J. Drug Dev.
Ind. Pharm. 23, 817–826.
Prinderre, P., Cauture, E., Piccerelle, Ph., Kalantzis, G., 1997b. Drug Dev. Ind. Pharm.
23, 817–826.
Prinderre, P., Cauture, E., Piccerelle, Ph., Kalantzis, G., Kalostiana, J., Joachim, J., 1997c.
Drug Dev. Ind. Pharm. 23, 817–826.
Puranik, P.K., Dorble, A.K., 1991. J. Microencap. 8, 247–252.
Reineccius, G., Heath, H.B., 2006. Flavor Chemistry and Technology, 2nd ed. Boca
Raton, Florida, USA.
Rossof, M., 1988. Pharmaceutical Dosage from Dispersed Systems, vol. 1. Marcel
Dekker, New York, pp. 245–283.
Rudnic, E.M., Kottke, M.K., 1996. In: Banker, G.S., Rhodes, C.T. (Eds.), Modern Phar-
maceutics. , 3rd ed. Marcel Dekker, New York, NJ, pp. 333–394.
Satturwar, P.M., Fulzele, S.V., Joshi, S.B., Dorle, A.K., 2003. Drug Dev. Ind. Pharm. 29,
877–884.
Sharma, S., Lewis, S., 2010. Int. J. Pharm. Pharm. Sci. 2, 6–13.
Shimizu, T., Kameoka, N., Iki, H., Tabata, T., Hamaguchi, N., Igari, 2003. J. Chem. Pharm.
Bull. 51, 1029–1035.
Shirai, Y., 1993. Biol. Pharm. Bull. 16, 172–177.
Shirai, Y., Sogo, K., 1997. Biol. Pharm. Bull. 16, 172–177.
Sohi, H., 2004. Drug Dev. Ind. Pharm. 30, 429–448.
Sohi, H., Sultama, Y., Khar, R.K., 2004. Drug Dev. Ind. Pharm. 30, 429–448.
Sugao, H., Yamazaki, S., Shiozawa, H., Yano, K.J., 1998. Pharm. Sci. 87,
96–100.
Swarbrick, J., Bolan, S.C., 1990. Encyclopaedia of Pharmaceutical Technology, vol. 2.
Marcel Dekker, New York, pp. 40–42.
US 6,586,012 (2003).
US 7,932,528 (2011).
USP 35, 1098, Decription and Solubility (2012).
Valleri, M., Mura, P., Maestrelli, F., Cirri, M., Bellerini, R., 2004. Drug Dev. Ind. Pharm.
30, 525–534.
Wagh, V.D., Gadlinge, S.V., 2009. J. Pharm. Res. 2, 1049–1054.
WO 2004/066976 (2003).
WO 2011/012161 A2 (2003).
Woertz, K., Tissen, C., Kleinebudde, P., Breitkreutz, J., 2010. J. Pharm. Biomed. Anal.
51, 497–506.
Woertz, K., Tissen, C., Kleinebudde, P., Breitkreutz, J., 2011. J. Pharm. Biomed. Anal.
55, 272–281.
Yazdani-Pedram, M., Tagle, L.H., Soto, E., Diaz, F.R., Gargallo, L., Radic, D., 1986.
Thermochim. Acta 105, 149–160.