International Journal of Pharmaceutics 465 (2014) 239254

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

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

Review

Taste-masking assessment of solid oral dosage formsA critical review

Miriam Pein , Maren Preis, Carolin Eckert, Florian E. Kiene
Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine University Duesseldorf, Universitaetsstr. 1, 40225 Duesseldorf, Germany

a r t i c l e

i n f o

Article history:
Received 17 August 2013
Received in revised form
15 December 2013
Accepted 16 January 2014
Available online 6 February 2014
Keywords:
Human taste panel
UV spectroscopy
Electronic taste sensing system
Sample pretreatment
Sampling
Standardized protocols

a b s t r a c t
Approaches to improve the taste of oral dosage forms that contain unpleasant tasting drugs are versatile.
Likewise, the analytical in vitro and in vivo methods to assess taste-masking efcacy are diverse. Tastemasking has gained in importance since the EU legislation on medicines for children came into force in
2007, and taste-masking attributes are often required by regulatory authorities. However, standardized
guidance for the analytical evaluation is still poor. Published protocols rarely consider real conditions,
such as the volume of saliva or the residence time of solid oral dosage forms in the mouth. Methodological
limitations and problems regarding time point of evaluation, sampling or sample pretreatment are hardly
ever addressed. This critical review aims to evaluate and discuss published strategies in this context.
2014 Elsevier B.V. All rights reserved.

Chemical compounds studied in this article:

Acetaminophen (PubChem CID: 1983)
Diclofenac (PubChem CID: 3033)
Diclofenac sodium (PubChem CID:
5018304)
Doxycycline (PubChem CID: 54671203)
Metformin hydrochloride (PubChem CID:
14219)
Theophylline (PubChem CID: 2153)
Quinine sulphate (PubChem CID: 13119)

Contents
1.
2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
In vivo evaluation of taste-masking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.
Panelists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.
Administration and inuence of pretreatment of drug formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.
Time points of taste assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.
Taste assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
In vitro evaluation of taste-masking efcacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Determination of taste-masking properties by UV spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.1.
Dissolution step . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.2.
Sampling procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.3.
Analytical assessment and data evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Determination of taste-masking properties by electronic taste sensing systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.1.
Commercially available electronic taste sensing systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.2.
Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Corresponding author. Tel.: +49 211 8114225; fax: +49 211 8114251.
E-mail addresses: Miriam.Pein@hhu.de (M. Pein), Maren.Preis@hhu.de (M. Preis), Carolin.Eckert@hhu.de (C. Eckert), Florian.Kiene@hhu.de (F.E. Kiene).
0378-5173/$ see front matter 2014 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ijpharm.2014.01.036

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5.

M. Pein et al. / International Journal of Pharmaceutics 465 (2014) 239254

3.2.3.
Dissolution step . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.4.
Sampling procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.5.
Analytical assessment and data evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Correlation of in vivo and in vitro taste assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction
For drug therapy adherence and patient convenience, tastemasking of unpleasant tasting active pharmaceutical ingredients
(APIs) is desirable. Many research and developing groups spend
tremendous effort on developing taste-masked formulations,
whereof several approaches have been derived (Momin, 2012).
One taste-masking approach is to construct physical barriers as
realized in coated tablets or granules. As tablets are intended to
remain shortly in the oral cavity, a coating layer can shield the
unpleasant taste of the API from the taste buds in the oral cavity
until the tablet has been completely swallowed (Malik et al., 2011;
Nakano et al., 2013). Other common approaches are based on the
addition of sweeteners, ion exchange resins (Fu Lu et al., 1991) or
cyclodextrins (Mady et al., 2010; Preis et al., 2012; Suthar and Patel,
2011). As a substance needs to be dissolved for perception by the
receptors located in taste buds on the human tongue, a lower solubility is tantamount to a less bad taste. Therefore, pH modiers
converting a substance into its less soluble or even insoluble form
are also used to achieve taste-masking effects (Ogata et al., 2012).
With regard to the chemical stability of drug substances, consideration of the effects of mixing corresponding drug formulations
with food or beverages is important. For example, some antibiotics
are sensitive to a decreased pH (e.g. azithromycin) like present in
apple sauce, or to multivalent cations (e.g. tetracycline) present
in milk products. Nevertheless, this approach enables a simplied administration to children and elderly patients (Sadrieh et al.,
2005), because these groups often face problems in swallowing
solid dosage forms. Moreover, increased viscosity of a drug formulation might help to achieve a taste-masking effect by inhibiting
drug diffusion to the taste receptors.
Masking unpleasant tasting APIs is doubtlessly desirable, if they
are incorporated in solid oral dosage forms, which potentially
release the API within the oral cavity. This is even intended for
orodispersible solid dosage forms (European Pharmacopoeia, 2008;
Food and Drug Administration, 2008). Standardized testing protocols and specication limits are provided by the pharmacopoeia
such as adequate disintegration times (Ph. Eur.: 3 min European
Pharmacopoeia, 2008, FDA: 30 s (Food and Drug Administration,
2008)), but criteria for disintegration are not useful to judge about
the taste-masking efcacy. Drug release specications might be
feasibly adapted for the assessment of taste-masking effects. But
while, for example, immediate release dosage forms require a drug
release of 80% within the rst 45 min, such specications are not
provided for the drug release of orodispersible solid dosage forms.
Based on some taste-masking approaches, a delayed release behavior arises within the rst minutes of dissolution testing (Cerea et al.,
2004). According to a former FIP/AAPS guideline, a drug release
of 10% within the rst 5 min of dissolution indicates a successful taste-masking (Siewert et al., 2003). However, this arbitrary
threshold is highly dependent on the human perception threshold of each individual drug substance and dissolution methods as
such are not applicable to judge about taste-masking effects based
on the addition of sweeteners or avors.
So far, human taste panels are often used for the assessment
of taste-masking properties, e.g. in Refs. (Bhoyar et al., 2011b;
Cilurzo et al., 2011; Douroumis et al., 2011; Fukui-Soubou et al.,

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2011; Kasliwal and Negi, 2011; Liew et al., 2012; Mady et al., 2010;
Makwana et al., 2010; Malik et al., 2011; Shah and Mashru, 2008a;
Sharma et al., 2012; Sharma and Chopra, 2012). But due to ethical and toxicological concerns, conducting human taste panels is
questionable, if the drugs of interest are still in the early stage of
development. On the contrary, analytical methods offer safe and
objective results. Thus, spectroscopic drug dissolution analysis and
electronic tongue measurements are often applied to assess the
efciency of taste-masking effects. Using UV spectroscopy, either
the dissolution prole of a sample is evaluated or the amount of
released drug after a predened dissolution time is determined. In
investigations with electronic taste sensing systems (e-tongues),
taste-masking effects are treated by univariate and/or multivariate
methods (Guhmann et al., 2012; Hoang Thi et al., 2012; Tokuyama
et al., 2009; Woertz et al., 2011b; Zheng and Keeney, 2006).
In contrast to the well-established pharmaceutical techniques
to obtain taste-masked formulations, taste assessment lacks precise description. This imbalance is due to the lacking denition of
taste-masking and missing standard evaluation tests and specications. Although some reviews have dealt with the assessment of
taste-masking effects in recent years (Anand et al., 2007; Datrange
et al., 2012; Sagar et al., 2012; Shet and Vaidya, 2013), the critical
aspects coming along with the according evaluation of solid oral
dosage forms are rarely discussed (Gittings et al., 2014; Woertz
et al., 2011a).
As the application of analytical methods for taste-masking
assessment gained importance, since the EU legislation on
medicines for children came into force in 2007 (Breitkreutz, 2008;
European Union, 2006), this review assembles and critically discusses recent approaches of assessing taste-masking properties
of solid oral dosage forms (granules, microspheres, pellets, tables
and lm formulations). Manuscripts have been considered, if the
assessment was performed with human taste panels (dened
as in vivo evaluation) and/or UV spectroscopy and/or electronic
tongue measurements (dened as in vitro measurements). UV
spectroscopy measurements comprise in this context on-line and
in-line UV-monitoring of the drug dissolution as well as off-line UV
detection or high performance liquid chromatography (HPLC) measurements after sampling. Electronic tongue measurements have
only been considered, if they were carried out with at least one of
the commercially available instruments (Insent or Astree).
2. In vivo evaluation of taste-masking
Although there are standardized protocols for taste evaluation (DIN10959, 1998; DIN10961, 1996; DIN10969, 2001; ISO3972,
1991), so far no standardized protocol exists for the evaluation of
taste-masking. Rather, the protocols described in literature differ
in their procedures, particularly with regard to the panelists, the
administration of the drug formulation and the time point(s) to
assess the taste-masking effects (Table 1).
2.1. Panelists
As summarized in Table 1, investigated studies have been conducted with 430 healthy adult human volunteers. If the ages of the
gender-mixed panelists were reported, they varied between 18 and

Table 1
In vivo evaluation of taste-masking (API: active pharmaceutical ingredient, CD: cyclodextrin, HPCD: hydroxpropyl--cyclodextrin, MDT: mouth dissolving tablets, No: number of panelists, n.s.: not specied, ODF: orodispersible
lm, ODT: orodispersible tablet, SRT: sustained release tablets, TM: taste-masking).
Dosage form

Taste-masking
strategy

Panelists

Perception
threshold
(mg/ml)

Panelist
training

Dose of the sample

(in mg API)

Administration of
the solid oral
dosage form

Time point of
evaluation

Taste-masking
assessment procedure
(see also Tables 2 and 3)

Ref.

Aceclofenac

ODT

No.: 9
age: n.s.
sex: n.s.

n.s.

n.s.

100

One tablet placed

onto the tongue

Immediately after
administration
and at several
intervals for 5 min

Time intensity method

followed by bitterness
scores

(Kasliwal and
Negi, 2011)

Acetaminophen

Granules

HPCD:API
complexes including
neotame
(sweetener), orange
& peppermint avor
Application of
different granulation
processes

No.: 6
age: n.s.
sex: n.s.

1.08

Yes

22.5

After the solution

was held for 5 s in
the mouth

<2

Yes

100

Scoring of pure API

solution against solution
of the formulation (3 min
dissolved)
Against standard solution

(Albertini et al.,
2004)

No.: 56
age: n.s.
sex: n.s.

As solution
(granules
dissolved over
3 min)
One tablet placed
onto the tongue
and chewed 10
times

No.: 20
age: n.s.
sex: n.s.

0.35

n.s.

268.3

n.s.

n.s.

Granules: time that the

granules remained
tasteless; bitterness
scores tablets: n.s.

(Sharma et al.,
2012)

No.: 4
age: n.s.
sex: n.s.
No.: 9
age: n.s.
sex: n.s.

n.s.

n.s.

510

One tablet placed

onto the tongue

n.s.

200

n.s.

Drug formulations were

compared with placebo
formulations
Bitterness scores of drug
resin complex against
pure drug

(Bhasin and
Ghosh, 2012)

n.s.

No.: 10
age:
1825y
sex: n.s.
No.: 10
age: n.s.
sex: n.s.

n.s.

With
10 mg of
pure API

10

n.s.

Bitterness scores

(Douroumis
et al., 2011)

n.s.

n.s.

13.4

As aliquots of
0.50 L solution

After full
disintegration of
the tablet
10 s after
administration
(taste was also
evaluated at
1050 s after
rejecting the
tablet)
10 s, 1, 2, 5, 7,
10 min after
disintegration of
the tablet
15 s after
administration

Bitterness scores

(Cilurzo et al.,
2011)

No.: 16
age:
2223y
sex: 50:50
No.: 30 (20
for doxycycline)
age:
2029y
sex: 50:50

n.s.

n.s.

10

One lm placed
onto the tongue

After
disintegration of
the ODF

Bitterness scores
acceptability, aftertaste,
mouth feel, handling

(Liew et al.,
2012)

n.s.

n.s.

Doxy: 100
cipro: 500
KI: 130

As crushed tablet,
mixed with
masking agents

10 s after
administration
and 1 min after
swallowing (after
taste)

Palatability scores

(Sadrieh et al.,
2005)

Tablets

Granules,
ODT

Addition of Witepsol
H-15 or cacao, cocoa
butter, sucrose, cocoa
powder and
Benecoat BMI-40
Coating with
Eudragit EPO,
addition of mannitol,
aspartame, cocoa &
strawberry avor
Coating with
Eudragit EPO

Atorvastatin
calcium

ODT

Cefpodoxime
proxetil

SRT

Addition of
cation-exchange
resin tulsion-344

Cetirizine HCl

ODT

Coating with
Eudragit RL-30D

Diclofenac
sodium

ODF

Donezepil HCl

ODF

Doxycycline
(doxy),
ciprooxacin
HCl (cipro),
potassium
chloride (KI)

Tablets

Addition of sucralose,
saccharine, xylitol,
mint, licorice and
soft fruit avor
Addition of
aspartame, sucralose,
saccharine sodium,
pineapple avor
Mixing with masking
agents

10 s after the
repeated chewing

(Suzuki et al.,
2003)

(Bhoyar et al.,
2011a)

M. Pein et al. / International Journal of Pharmaceutics 465 (2014) 239254

API

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Table 1 (Continued)
Dosage form

Taste-masking
strategy

Panelists

Perception
threshold
(mg/ml)

Panelist
training

Dose of the sample

(in mg API)

Administration of
the solid oral
dosage form

Time point of
evaluation

Taste-masking
assessment procedure
(see also Tables 2 and 3)

Ref.

Famotidine

ODT

Addition of
carboxymethyl--CD
and sulfobuthyether-CD
Addition of
sweetener
(aspartame), original
and generic products
Addition of
ion-exchange resin
tulsion-335

No.: 8
age:
2327y
sex: n.s.
No.: 11
age: n.s.
sex: n.s.

n.s.

Yes

20

One tablet placed

onto the tongue

After
disintegration of
the tablet

Bitterness scores

(Mady et al.,
2010)

n.s.

Yes

10

One tablet placed

onto the tongue

30 s after
administration

Sweetness and bitterness

scoring

(Tokuyama
et al., 2009)

No.: 6
age: n.s.
sex: n.s.

n.s.

n.s.

One tablet placed

onto the tongue

10 s after
administration

Bitterness level:
++/
+++

(Sharma and
Chopra, 2012)

10 min (seconds?)
after
administration
(taste was also
evaluated at
1050 min
(seconds?) after
rejecting the
tablet)
n.s.

Scores drug resin

complex against pure
drug

(Bhoyar et al.,
2011b)

Bitterness scores

(Malik et al.,
2011)

Y: recognition of bitter
taste
N: no perception of bitter
taste
Bitterness scores

(Bora et al.,
2008)

ODT

Levocetirizine
HCl

Granules,
MDT

Metformin HCl

SRT

Addition of
cation-exchange
resins indion 244,
254 and 264

No.: 9
age: n.s.
sex: n.s.

n.s.

n.s.

300

n.s.

Ooxacin

Microspheres
for ODT

Addition of Eudragit
E100

n.s.

n.s.

n.s.

n.s.

Ondansetron HCl

Microspheres

Spray drying with

Eudragit E100,
addition of Chitosan
and MethocelE15 LV
Addition of
ion-exchange resin
indion 204

No.: 5
age: n.s.
sex: male
No.: 7
age:
2128y
sex: 4m/3f
No.: 10
age:
1822y
sex: n.s.
No.: 5
age: n.s.
sex: n.s.

0.075

n.s.

0.006

As solution (1 ml)

30 s after
administration of
the solutions

n.s.

n.s.

Granules placed
onto the tongue

10, 30, 60, 90, 120

and 150 s after
administration

n.s.

n.s.

Granules placed
onto the tongue

10 s after
administration

n.s.

(Prajapati et al.,
2010)

No.: 29
age:
22.3 0.9 y
sex:
13m/16f
No.: 18
age: n.s.
sex: 9m/9f

n.s.

n.s.

30

n.s.

Immediately after
administration
and after
disintegrating

(Nakano et al.,
2013)

n.s.

n.s.

30

As dispersion
(one tablet
dispersed in
10 ml water)
n.s.

10 s after
administration

VAS scoring mouth feel,

bitterness, sweetness,
saltiness, astringency,
sourness, overall
palatability
Bitterness rating

Information on
acceptability, bitterness,
saltiness, sweetness

(Guffon et al.,
2012)

Taste-masking and
grittiness evaluation

(Singh et al.,
2012)

ODT

MDT

Piogliazone HCl

ODT

Pyridostigmine
bromide

Dispersible
tablet

Addition of
ion-exchange resin
indion 204,
sweetening agent
aspartame and
avoring agents
(peppermint, vanilla)
Coating of core
granules with
Eudragit EPO,
addition of
aspartame and NaCl
Addition of -CD and
avor

Sodium
phenylbutyrate

Granules
tablet

Coating,
composition: n.s.

No.: 13
age: n.s.
sex: n.s.

n.s.

n.s.

Tablet: 500
granules:
940

Sumatriptan
succinate

Granules

Addition of Eudragit
E100, -CD and
sweetener

No.: 12
age: n.s.
sex: n.s.

n.s.

n.s.

Drug content
varied depending
on TM strategy

Granules placed
on posterior
lobe of tongue

Immediately after
administration,
0.5 and 2 h after
ingestion
46 s after
administration

(Makwana
et al., 2010)

(Tan et al.,
2012)

M. Pein et al. / International Journal of Pharmaceutics 465 (2014) 239254

API

Very good
Excellent

Highly
palatable
Good

Palatable
Fair
Tasteless

Poor

Aweful

Extremely
bitter
Very bitter

Intermediate
steps: 0.5, 1.5,
2.5, 3+
X = threshold
bitterness

Moderately
bitter
Intensely bitter

0.5 = threshold

Strong bitterness

Moderate

Moderate
bitter
Strong bitter

Slightly bitter

Moderately
bitter
Strongly bitter

Slightly
bitter
Bitter

Slightly
bitter
Bitter

Slightly
bitter/acceptable
Slightly
sweet/good
Very sweet/very
good

Moderately
bitter
Slightly bitter

Extremely
poor
Very poor
Strongly bitter
Bitter
Very bitter/poor
Bitter/poor
Palatable
Normal
Good
Tasteless
Tasteless
Slightly bitter
Pleasant
Tasteless
Tasteless
Slightly bitter
No bitterness
Slight

6
7
Additional
information

Moderately
bitter
Strongly bitter
4

No bitter taste
Acceptable
bitterness
Slightly bitter
0
1

(Makwana
et al., 2010)
(Douroumis et al.,
2011) (Kasliwal
and Negi, 2011)
(Cilurzo et al.,
2011)
(Bhoyar et al.,
2011b)

As described in Section 2.2, drug formulations have been administered with and without initial pretreatment for the taste-masking
evaluation. And as displayed in Fig. 1, the pretreatment time plays

Score

2.3. Time points of taste assessment

Table 2
Scoring systems for human taste panelslabeled with numbers from 07.

The most common way to administer drug formulations to panelists is the one that depicts reality most accurately: placing the
drug formulation directly onto the tongue (Table 1). In contrary,
some authors administered a prepared solution or suspension.
Administration of dissolved or dispersed drug formulations leads to
dened concentrations of unpleasant tasting API offered to the panelists. However, an increasing taste sensation over time is expected
when the drug formulation is placed directly onto the tongue. Pretreatment (dissolution/dispersion) times could offer safety margins
for evaluating taste-masking effects, if they were dened to be a little longer than the time needed to swallow a solid oral dosage form.
But on the contrary, the prognoses of the taste-masking efcacy
worsen, if the pretreatment times were too long.
Although the pretreatment (dissolution/dispersion) time obviously inuences the gustatoric sensation (especially of orodispersible drug formulations), detailed information was only given by
(Albertini et al., 2004) and (Shah and Mashru, 2008b): while Albertini et al. described a dissolution time over a period of 3 min (180 s)
followed by a ltration of the sample, Sha and Mashru administered 1 ml suspension prepared by dispersing equivalents of 1 g
primaquine for 15 s in water. For the taste-masking evaluation of
the four different drug formulations displayed in Fig. 1, these two
pretreatment procedures would cause signicant differences.
But although the pH and viscosity of the human saliva have a
great impact on the dissolution behavior and change with age and
food intake (Pfaffe et al., 2011), detailed information are lacking
concerning taste-masking evaluation in the perused literature.

(Malik et al.,
2011)

2.2. Administration and inuence of pretreatment of drug

formulations

Palatable taste
Used, but not
dened
Used, but not
dened
Used, but not
dened
Worst taste
sensation

(Shah and
Mashru, 2008a)

(Sharma
et al., 2012)

(Suthar and
Patel, 2011)

(Liew et al., 2012)

(Mady et al.,
2010)

(Patel and
Vavia, 2008)

(Sadrieh
et al., 2005)

29 years (Bhoyar et al., 2011a,b; Mady et al., 2010; Maniruzzaman

et al., 2012; Sadrieh et al., 2005; Shah and Mashru, 2008b). The taste
impression of humans differs based on their nationality, eating
habits and age (Breitkreutz and Boos, 2007). Thus, missing information about the compositions and age structures of the group
of panelists reduces the signicance of the results. Taste-masking
effects are moreover desired to improve the compliance of patients,
who are not limited to the described panelists gender and aging
structures. Especially transferring the results of human (adult)
taste panels to the taste impression of children can be accompanied with a signicant falsication, as their taste impression varies
tremendous over age (Mennella and Beauchamp, 2008). To ensure
reliability and comparability of panel results, two working steps
should be carried out before determining taste-masking properties:
threshold determination and training of the panelists. The human
perception threshold is the lowest concentration of a substance, a
human still perceives. Also called bitterness value, its determination is dened in detail in the (European Pharmacopoeia, 2008).
Similar procedures were described and conducted very detailed
by some working groups dealing with the assessment of tastemasking properties (Albertini et al., 2004; Bora et al., 2008; Patel
and Vavia, 2008; Sharma et al., 2012). These working groups offered
ve to seven different concentrations of the drug substance to the
volunteers, who assigned the samples to predened statements
about bitterness or palatability (Tables 13). To enhance comparability of the panelist statements, Albertini et al. and Suzuki et al.
additionally trained the panelists after the threshold determination
by assigning a dened score to given sample solutions (Albertini
et al., 2004; Suzuki et al., 2003).

243

Not
palatable
Slightly
palatable
Average

M. Pein et al. / International Journal of Pharmaceutics 465 (2014) 239254

244

M. Pein et al. / International Journal of Pharmaceutics 465 (2014) 239254

Fig. 1. Schematic release behavior of four model drug formulations in the mouth. The pretreatment procedures of Shah and Mashru (2008b) and Albertini et al. (2004)) are
related to signicantly different drug releases.

an important role regarding the results. Thus, in the following, literature based time points are subdivided into those with and those
without pretreatment.
Where the drug formulation is directly placed onto the tongue
of the panelist, the rst time point of assessment was mostly set
immediately after administration (Bhoyar et al., 2011a,b; Guffon
et al., 2012) or at predened time points: 10 s (Kasliwal and Negi,
2011; Makwana et al., 2010; Sharma and Chopra, 2012; Singh et al.,
2012), 15 s (Cilurzo et al., 2011), 20 s (Sharma et al., 2012), or 30 s
(Tokuyama et al., 2009). Some authors predened the rst time
point of assessment after the disintegration of the tablet without giving any further information regarding the time (Bhasin and
Ghosh, 2012; Douroumis et al., 2011; Liew et al., 2012; Mady et al.,
2010). As this parameter is individually perceived by each panelist,
the results lack comparability. Suzuki et al. investigated the taste
of a chewable tablet 10 s after 10 chews (Suzuki et al., 2003).
Following Albertini et al., taste-masking effects were evaluated
after 3 min of dissolution. The resulting dispersion was ltered and
the corresponding solution assessed over 5 s by the volunteers.
The duration of the ltration was not specied. Sha and Mashru
evaluated the taste impression after 15 s of pre-dissolution and an
assessment by the volunteers after retaining the dispersion for 30 s
into their mouths. As no ltration step was described before the
administration, the dissolution process could be expected to proceed also after the 15 s of pre-dissolution. However, Fig. 2 displays
the concentrations that were expected after another 30 s of further
dissolution in the panelists mouth.

In addition to the assessment of the taste-masking, Sadrieh et al.

also evaluated the aftertaste of their formulations (Sadrieh et al.,
2005). The panelists were therefore asked to report about the sensation one minute after swallowing the samples.
To dene reliable time points for the taste assessment, information is needed about the residence time of drug formulations in the
oral cavity. In a study from (Beck et al., 2005) children with attention decit hyperactivity disorder (ADHD) and autistic disorder
(AD) have been taught to swallow tablets. A successful swallowing
was dened, if the residence time did not exceed 30 s (Beck et al.,
2005). As this is a challenging case, 30 s are proposed as upper limit
of tablet residence time in the human mouth and thus, as time point
for the taste (masking) assessment.
2.4. Taste assessment
Scores or scales are the most popular ways to rate the taste of
formulations. Most scales use numeric systems (Table 2), while a
few use other scoring systems (Table 3). However, some scoring
systems assign low numbers to tasteless or pleasant tasting formulations and high numbers to a very unpleasant taste, while others
are correlated vice versa (Table 2). To enable correct inter-study
evaluation, the scales should at least be orientated comparably
(Davies and Tuleu, 2008).
The visual analog scale (VAS) offers an alternative way to analyze
taste perception (Nakano et al., 2013; Turner, 2009). The non-scaled
VAS has a dened length, mostly 100 mm, a starting point labeled

Table 3
Scoring systems for human taste panels using other score scales than numbers.

Scoring

(Sharma and Chopra,

2012)

(Singh et al., 2012)

(Suzuki et al., 2003)

(Tan et al., 2012)

(Tokuyama et al., 2009)

++ Taste-masked with
bitter after taste

No taste-masking
0 slightly masked

Taste of the chewable

tablets is compared
with 10 different
concentrations of
quinine sulphate,
labeled with numbers
of 110

Opportunity to
distinguish between no
bitterness, slight
bitterness (but
acceptable) and strong
bitterness
(unacceptable)

Bitterness and sweetness scores (not

labeled) according to training solutions:

+++ Complete
taste-masking

+ Complete
taste-masked

Quinine HCl:
1: 0.0029 mM
2: 0.012 mM
3: 0.031 mM
4: 0.078 mM
5: 0.2 mM

Sucrose:
1: 29.24 mM
2: 97.72 mM
3: 187.1 mM
4: 409.4 mM
5: 994.1 mM

M. Pein et al. / International Journal of Pharmaceutics 465 (2014) 239254

245

Fig. 2. Schematic release behavior of four model drug formulations in the mouth. The samples of Shah and Mashru (2008b) were dispersed over 15 s (dashed line) and
provided over 30 s as suspensions (indicated by the arrow, ending with the bold line). Albertini et al. provided ltered samples after a dissolution time of 3 min (Albertini
et al., 2004). The time, children with ADHD and AD could be taught to swallow a tablet was 30 s (Beck et al., 2005).

with no taste and an endpoint labeled with strong taste. The

advantage of this scale is its applicability to rate different types
of taste attributes like bitterness, sweetness, saltiness, astringency
and sourness, but also to describe the mouth feel (e.g. roughness,
grittiness) or the overall palatability (Nakano et al., 2013). Moreover, this scale can be used for children of six years and older
(Davies and Tuleu, 2008). For younger children ( 3 years), Davies
and Tuleu reported about facial hedonic scales as applicable scoring
systems (Davies and Tuleu, 2008). The absence of further descriptors leads, however, to a lower level of comparability between the
results of different panelists compared to other scaling systems. The
labeled magnitude scale (LMS) is another scoring system, which
was introduced by Green et al. for human taste studies (Green
et al., 1993,1996). This scale is labeled with the verbal descriptors
barely detectable, weak, moderate, strong, very strong and
strongest imaginable. The non-linear, quasi logarithmic spacing
between the descriptors supports the process of human perception, which is based on the WeberFechner law (Pfaffmann et al.,
1971; Pfaffmann, 1959). By specifying xed responses and the
ranges in between, the scale enables direct comparison between
the results of different panelists. Similar to the VAS, the LMS can be
used to describe different types of perception. But while the VAS
is more suitable for smaller perceptual ranges, LMS is suitable for
the description of highly divergent samples regarding their taste
intensity due to its broad scaling.
3. In vitro evaluation of taste-masking efcacy
When performing an in vitro evaluation of taste-masked solid
oral dosage forms, three basic steps have to be conducted independently of the applied analytical technique: dissolution, sample
withdrawal and analytical evaluation. To prove the applicability of
the chosen analytical method, a calibration with the pure active
pharmaceutical ingredient dissolved in the dissolution medium
should be performed. Nevertheless, calibration procedures and
results are rarely described in literature (Table 4) and the aforementioned three basic steps have been conducted in multiple ways.
3.1. Determination of taste-masking properties by UV
spectroscopy
The rational use of UV spectroscopy to determine taste-masking
effects is based on two assumptions: a substance needs to be

dissolved to cause an unpleasant taste, and in most cases the

unpleasant taste of the drug formulation is related to the included
API. This leads to a worsening taste sensation with increased
amount of released API. However, if one or more excipients contribute to the unpleasant taste, analytical determination of the API
concentration is insufcient. To determine the released API concentration, in-line, on-line or off-line methods have been applied in
literature. For a successful in-line assessment, a ber-optic UV sensing system was used by (Guffon et al., 2012). On-line measurements
have been conducted using a modied USP4 ow through dissolution method (Albertini et al., 2004). Off-line taken samples were
analyzed using a spectrophotometer (Bora et al., 2008; Kayumba
et al., 2007; Malik et al., 2011; Shiino et al., 2010; Vaassen et al.,
2012) or via HPLC connected with an UV detector (Cerea et al.,
2004; Guhmann et al., 2012; Hoang Thi et al., 2012; Tokuyama et al.,
2009). Regardless of the method, prerequisites for a successful analytical measurement are drug concentrations within the validity of
the Lambert-Beer-law, a sufcient selectivity, degassed dissolution
media and, regarding the off-line methods, an adequate sampling
sequence and procedure.
Most critical on the basis of UV measurements is the assumed
absolute correlation of released drug with the taste. Although the
amount of dissolved drug can be correlated with the taste, the inuence of excipients and not dissolved particles that do not inuence
spectral absorption measurements is disregarded. On the basis of
the instrumental approach, the tube-based lag time has to be considered for on-line approaches to specify a reliable lag time based
on a delayed release.

3.1.1. Dissolution step

Regarding determination of drug dissolution over time, differences in temperature, volume and media were described in
literature, which has also very recently been mentioned by (Gittings
et al., 2014). If the temperature of the dissolution medium has
been dened, it was set to 37 C 0.5 C. Water or phosphate buffer
as simulated saliva were used as media in most cases. However,
the pH value of the buffers varied between 5.5 and 7.4 (Table 3).
This range comprises the increasing saliva pH of 112 months old
children (pH 5.77.0), while a pH of 7.5 is well correlated with the
saliva pH of children >14 years and adults (Hermes, 2012). It was
reported that the investigated samples were mixed, shaken and/or
stirred in the dissolution media; if dened, the stirring speed varied
from 25 rpm up to 100 rpm. Some authors developed dissolution

246
Table 4
In vitro evaluation of taste-masking (a.i.: additional information, API: active pharmaceutical ingredient, CD: cyclodextrin, IVIVC: correlation with human threshold data, n.s.: not specied, m: dissolution medium, ODF: orodispersible
lm, ODT: orodispersible tablet, SSF: simulated saliva uid, T: temperature in C, V: volume in ml).
Dosage form

Taste-masking
strategy

In vitro
assessment
tool

Calibration
procedure

Taste-masking
criteria

IVIVC

Dissolution
settings

Sample
(pre)treatment

Drug dose

Sampling
timepoint

Ref.

Acetaminophen

Granules

Application of
different
granulation
processes

UV
spectroscopy
(243 nm)

n.s.

Drug release of
pure API > tastemasked
formulation

n.s.

3 min

(Albertini
et al., 2004)

Wax matrix
containing
Eudragit EPO

UV
spectroscopy
(243 nm)

n.s.

API released after

10 min at pH
6.5 < threshold
conc. (35 g/ml)

Yes

200 mg

Each 5 min.

(Shiino et al.,
2010)

Powder

Addition of
caseinate and
lecithin

e-tongue
(Astree,
sensors JB, BA,
BB, HA, ZZ, CA,
GA)

n.s.

n.s.

n.s.

n.s.

(Hoang Thi
et al., 2012)

HPLC/UV
(243 nm)

n.s.

Based on
Euclidean
distances of the
placebo
formulations to
the drug
formulations
API released after
2 min < threshold
conc. according
to (Albertini
et al., 2004;
Shiino et al.,
2010)
Drug release of
the pure API is
compared to
drug release of
taste-masked
granules
Based on
Euclidean
distances of the
placebo
formulations to
the drug
formulations
Based on
Euclidean
distances of the
placebo
formulations to
the drug
formulations

Dissolution in
paddle apparatus
according to
USP24; on-line
sampling
(12.5 ml/min)
Dissolution in
paddle apparatus
according to
Japanese
Pharmacopoeia;
sample ltration
(0.45 m) before
off-line detection
n.s.

22.5 mg

Mold disks

V: 900
m: buffer
pH: 6.8
T: 37
a.i.: paddle
speed 50 rpm
V: 900
m:
phosphate
buffer
pH: 6.5
T: 37.0 0.5
a.i.: paddle
speed 50 rpm
V: n.s.
M: water
pH: n.s.
T: n.s.

Yes

V: 1 ml/min
m:
phosphate
buffer
pH: 7.4
T: 37

10 mg

2 min (4, 6, 8,
10, 15, 20, 25,
30 min)

n.s.

V: 10
m: SSF
pH: 6.8
T: n.s.

60 mg

5 min

(Huda and
Toshniwal,
2013)

n.s.

V: n.s.
m:
isopropylic
alcohol 80%
pH: n.s.
T: n.s.

Sample is placed in
a tube, dissolution
medium is
continuously
owing over the
sample, fractions
are kept
Dissolution of
granules; sample
ltration
(Whatman lter
paper) before
off-line detection
n.s.

n.s.

n.s.

(Bhasin and
Ghosh, 2012)

n.s.

V: n.s.
m: n.s.
pH: n.s.
T: n.s.

Dissolution of one
ODF

13.4 mg

After complete
dissolution

(Cilurzo et al.,
2011)

Atomoxetin
hydrochloride

Granules

Addition of
Eudragit EPO
and avors

HPLC/UV
(269 nm)

n.s.

Atorvastatin

ODT

Coating with
Eudragit EPO

e-tongue
(Astree,
sensors ZZ, AB,
GA, BB, CA, DA
and JE)

n.s.

Diclofenac
(sodium salt)

ODF

Addition of
sucralose,
saccharine,
xylitol, mint,
licorice and
soft fruit avor

e-tongue
(Insent SA402B,
bitterness
sensors C00,
AC0, AN0)

Yes

M. Pein et al. / International Journal of Pharmaceutics 465 (2014) 239254

API

Diclofenac
sodium (DSS),
potassium
(DPS), free acid
(DFA)

ODTs, granules

Coating with
Eudragit EPO

In mg/100 ml
DFA: 0.55
DSS: 313
DPS: 1001000

Based on
Euclidean
distances of the
placebo
formulations to
the drug
formulations

n.s.

V: 100
m: puried
water
pH: n.s.
T: n.s.

HPLC/UV
(254 nm)

n.s.

Drug release
after 3 min of the
taste-masked
formulations < drug
release of nontaste-masked
drug
formulations

n.s.

V: 50
m: SSF
pH: 7.4
T: 37 0.5
a.i.: 50 rpm
paddle speed

Based on
Euclidean
distances of the
placebo
formulations to
the drug
formulations
Based on
Euclidean
distances for
released drug
amount after 30 s
+ correlation
with bitterness
score from
human panel
Released amount
of famotidine
after 30 s

yes

V: 100
m: masking
agent
pH: n.s.
T: RT

Yes

V: 100
m: water
pH: n.s.
T: 37 0.5
a.i.: 25 rpm
paddle speed

Doxycycline,
ciprooxacin
HCl, potassium
chloride

Tablets

Mixing with
masking agents

e-tongue
(Astree,
sensors JB, BA,
BB, HA, ZZ, CA,
GA)

n.s.

Famotidine

ODT

Addition of
sweetener
(aspartame),
original and
generic
products

e-tongue
(Astree,
sensors ZZ, BA,
BB, CA, GA, HA
and JB)

n.s.

HPLC/UV
(254 nm:
famotidine,
250 nm:
aspartame)

n.s.

e-tongue
(Insent, sensors
C00, AE1, AC0,
AN0).

n.s.

Nicotine
hydrogen
tartrate salt

ODF

Addition of
avors

Based on
Euclidean
distances of the
placebo
formulations to
the drug
formulations,
compared also
with standard
bitter substance
quinine
hydrochloride

Yes

n.s.

V: n.s.
m: water
pH: n.s.
T: n.s.

20 units of each
ODT were
dispersed in
100 mL of puried
water; sample
ltration (0.22 m
Whatman lter), if
necessary
Dissolution of
232.5 mg
diclofenac
(equivalent free
acid) in 50 mL of
SSF (comparable to
one dose per 5 mL);
sample ltration
(0.22 m Whatman
lter) before
off-line detection
Mixing of drug
(formulation) with
masking matrix

Dissolution of 10
ODTs (=100 mg
API); sample
ltration under low
pressure

Dissolution of 10
ODTs (=100 mg
API); sample
ltration (0.45 m
pore size
membrane) before
off-line detection
Dissolution of
0.15% (w/v) drug
equivalent

23.25 mg

3 min

(Guhmann
et al., 2012)

3 min
(Sampling at
0.55 min)

100 mg (doxy)
500 mg (cipro)
130 mg (KI)

n.s.

(Sadrieh
et al., 2005)

10 mg

10 s, 20 s, 30 s
and 60 s

(Tokuyama
et al., 2009)

1.5 mg

n.s.

(Cilurzo et al.,
2010)

M. Pein et al. / International Journal of Pharmaceutics 465 (2014) 239254

e-tongue
(Insent
TS5000Z,
sensors AC0,
AN0, CT0, AE1,
C00, AAE, CA0)

247

248

Table 4 (Continued)
Dosage form

Taste-masking
strategy

In vitro
assessment
tool

Calibration
procedure

Taste-masking
criteria

IVIVC

Dissolution
settings

Sample
(pre)treatment

Drug dose

Sampling
timepoint

Ref.

NXP 1210

Lipid based
pellets

Lipids as
taste-masking
agents

UV
spectroscopy
(295 nm)

n.s.

< 5% drug release

within 2 min

n.s.

Dissolution in USP
33 paddle
apparatus 2

50% drug load

Drug release
after 2 min,
dissolution
measured
in-line

(Vaassen
et al., 2012)

Ooxacin

Microspheres

Addition of
Eudragit E100

UV
spectroscopy
(294 nm)

n.s.

n.s.

n.s.

Dissolution of
microspheres;
sample ltration
before off-line
detection

100 mg

5 min

(Malik et al.,
2011)

Ondansetron
HCl

Microspheres

UV
spectroscopy
(310 nm)

n.s.

Drug release after

5 min < human
threshold

Yes

Stirring and
dissolution under
stirring; ltration
before off-line
detection

8 mg

5 min

(Bora et al.,
2008)

Theophylline

Tablet

Spray drying
with Eudragit
E100, addition
of chitosan and
Methocel E15
LV
Coating with
Eudragit EPO

V: 900
m: KH2 PO4
buffer
pH: 7.5
T: 37
a.i.: 75 rpm
paddle speed
V: 25
m:
phosphate
buffer
pH: 6.8
T: n.s.
V: 25
m: buffer
pH: 6.8
T: n.s.

HPLC/UV
(291 nm)

1100 mg/L
(R2 = 0.998)

Onset of drug
release is delayed

n.s.

V: 900
m: buffer
pH: 5.5, 6
T: 37 0.5
a.i.: 50 rpm
paddle speed

n.s.

15 min

(Cerea et al.,
2004)

Quinine sulfate

Pellets

e-tongue
(Astree,
sensors BD, EB,
JA, JG, KA, OA,
OB), bitterness
score as a
function of
time
UV
spectroscopy
(235 nm)

n.s.

Bitterness
prediction
module

V: 100
m: water
pH: n.s.
T: n.s.

Dissolution in USP
26 paddle
apparatus 2;
sample ltration
(0.45 m nylon
lter) before
off-line detection
Dissolution;
sample ltration

100 mg

One
sample/min
over 5 min
bitterness
score as a
function of
time

(Kayumba
et al., 2007)

V: 900
m: water
pH: n.s.
T: 37 0.5
a.i.: 100 rpm,
rotation
speed of the
basket
V: n.s.
m: water
T: 37,
a.i.: 100 rpm
paddle speed

Sodium
phenylbutyrate

Granules

Coating with
Eudragit EPO

Coating,
composition:
n.s.

e-tongue
(Insent
TS5000Z,
sensors AC0,
AN0, CT0, AE1,
C00, AAE, CA0)

Fiber optical
UV probe
(Ocean optics)

n.s.

Drug
release < 9 mg/l
quinine (Suzuki
et al., 2003)

Yes

Log-linear
relation
between sensor
signal and drug
concentration
between
3001000 mg/ml
API
n.s.

Based on
Euclidean
distances of the
placebo
formulations to
the drug
formulations

n.s.

To provide a lag
time in the initial
dissolution phase
in contrast to the
licensed product

n.s.

V: n.s.
m: water
T: 37,
a.i.: 100 rpm
paddle speed

Dissolution
according to USP
Method 1applying
an automated
dissolution tester

Dissolution
according to
European
Pharmacopoeia

Dissolution
according to
European
Pharmacopoeia;
in-line detection

0, 5, 10, 15, 20,

30, 40, 50, 60,
90, 120 s

940 mg (per g
granules, if the
drug load is
comparable
with the drug
load of the
licensed
product)

Sampling after
2, 5, 30 min

One sample per

0.2 s over a
period of 3 min

(Guffon et al.,
2012)

M. Pein et al. / International Journal of Pharmaceutics 465 (2014) 239254

API

M. Pein et al. / International Journal of Pharmaceutics 465 (2014) 239254

249

methods according to realistic conditions regarding the volume of

saliva in the oral cavity (Bora et al., 2008; Guhmann et al., 2012;
Preis et al., 2012; Shukla et al., 2009; Sona and Muthulingam,
2011), but only (Hoang Thi et al., 2012) and (Preis et al., 2012)
referred also to a ow rate of the human saliva of 1 ml/min.
If the volume of saliva in the mouth of patients should be imitated for taste-masking evaluation, samples have to be dissolved in
real volumetric conditions considering a residual saliva amount of
12 ml in the oral cavity (Dodds et al., 2005; Lagerlf and Dawes,
1984; Siqueira and Nicolau, 2002; Watanabe and Dawes, 1990).
However, dissolution procedures have also been carried out in volumes up to 900 ml according to pharmacopoieal setup (Albertini
et al., 2004; Cerea et al., 2004; Kayumba et al., 2007; Shiino et al.,
2010; Singh et al., 2012; Sona and Muthulingam, 2011). Accordingly, the resulting kinetics do not match with the realistic situation
in the mouth. But seen from the opposite perspective, the drug concentration in the patients mouth might be inappropriate to match
decisive factors for the analytical dissolution evaluation (sink conditions and the LambertBeer rule for linearity).
To display real conditions in the mouth, the force exerted by the
tongue and the real temperature in the mouth as well as the osmolality of the saliva should also be considered. Realistic conditions
to enable the development more reliable taste-masking determination methods are listed in Table 5.

(Shiino et al., 2010), but did not explain this choice. Apart from
this approach, which was in both cases only based on one concentration and time point, the success of a taste-masking has also
been discussed on the basis of the dissolution prole (Cerea et al.,
2004; Guffon et al., 2012). A delayed initial drug release was therein
dened as desirable lag-time or delayed onset. In this context, Guffon et al. reported about an initial lag-time of 10 s before the slow
progressive drug release started (Guffon et al., 2012).
Regarding the drug releases shown in Fig. 4, formulation 4 would
achieve a successful taste-masking for 8 s, while formulation 1
would be dened as taste-masked for 84 s, if the human perception
threshold concentration of the model drug were equivalent to a 10%
drug release according to (Siewert et al., 2003). None of the formulations would have been dened as taste-masked by Bora et al. or
Shiino et al., but evaluating the formulations by Guffon et al., initial
lag-times of >10 s could be proven for formulations 13. The availability of these data on the one hand and the comparability of the
threshold concentrations on the other hand are the main disadvantages of the method that compares the human perception threshold
with the released amount of drug. While for several drugs no perception threshold could be found in literature, for acetaminophen
(paracetamol) e.g., at least two different threshold concentrations
were described: 0.35 mg/ml in phosphate buffer pH 5.8 (Sharma
et al., 2012) and 1.08 mg/ml in water (Albertini et al., 2004).

3.1.2. Sampling procedure

The sampling procedures in literature differed in choice of time
points and sampling frequency. One would expect comparable
periods for the in vitro evaluation and the in vivo evaluation.
However, most off-line performed experiments started after dissolution times of 15 min (Table 4), whereas the in vivo evaluation
took place after seconds (Section 2.1, Table 1). But a drug release
after 5 min can hardly be a decisive factor to specify reliable tastemasking effects. Long dissolution times obviously offer a safety
margin; but at the expense of receiving a bitter error as a result and
bioavailability problems. Starting the analytical evaluation directly
after a few seconds is more reliable (Garsuch and Breitkreutz, 2009;
Guffon et al., 2012; Kayumba et al., 2007; Tokuyama et al., 2009),
as highlighted in Fig. 3: Within the rst minute, formulations 3 and
4 have already released around 80% of the contained drug.
If the dissolution was evaluated using off-line UV measurement,
often only one sample had been drawn (Table 4). In contrast, in-line
(Guffon et al., 2012) and on-line experiments (Albertini et al., 2004;
Hoang Thi et al., 2012) offered a continuous observation of the dissolution prole, but it must be considered that peak broadening
and a delayed detection may occur due to the tubes of an on line
dissolution set up (Garsuch and Breitkreutz, 2009).

3.2. Determination of taste-masking properties by electronic

taste sensing systems

3.1.3. Analytical assessment and data evaluation

Taste-masking approaches like coating or complexation aim to
delay the release of the unpleasant tasting API during dissolution
progress in the mouth. A success is assumed, if less API is released
from the taste-masked drug formulation compared to the pure API
or a comparable drug formulation without taste-masking characteristics. In literature, two different approaches are described to
prove this by means of UV spectroscopy. First, the concentration
of the released drug after predened dissolution times (Section
3.1.2) is compared for taste-masked and non-taste-masked drug
formulations using UV spectroscopy or HPLC/UV. The results based
on this method are even more of value, if the released concentration is compared to the human threshold. For example Bora et al.
published that the released concentration of ondansetron after a
dissolution time of 5 min was below the human perception threshold determined with a human taste panel (Bora et al., 2008). Shiino
et al. dened a drug release below the human threshold within
the rst 10 min of dissolution as successful taste-masking criteria

3.2.1. Commercially available electronic taste sensing systems

The commercially available electronic taste sensing systems are
supplied by Insent (Atsugi-Shi, Japan) and AlphaMOS (Toulouse,
France). Based on their measurement principle, they are sensitive
to different ionic molecules (Woertz et al., 2011a). The sensors
of Insent are dedicated to the human taste attributes saltiness,
sourness, sweetness, umami and bitterness. Additionally, there is
one sensor that is sensitive for astringency. When measuring the
sample, the change of membrane potential is registered. After a
short washing procedure, the potential is measured in the standard solution to obtain the so called aftertaste or CPA value (change
of membrane potential caused by absorption). The CPA value is a
measure for the lipophilic character of the analyzed substancethe
more lipophilic it is, the more it will be absorbed into the membrane and the higher will be the resulting CPA value. This value is
discussed to correspond with the human perception of bitter and
astringent (drug) substances (Kobayashi et al., 2010).
The underlying sensor technology of the Astree electronic taste
sensing system (AlphaMOS, France) is based on chemical eld effector transistor technology. The supplier provides different sensor
sets of seven sensors for pharmaceutical application, food application and one for validating bitterness intensity of new chemical
entities. Contrary to the Insent system, the sensors are not associated to taste attributes, but measure cross-selective. A detailed
overview on the set ups and measurement procedures of the Insent
and Astree electronic taste sensing systems are given elsewhere
(Pein et al., 2013; Woertz et al., 2010a, 2011a).
3.2.2. Rationale
The rational use of electronic taste sensing systems to determine
taste-masking effects is based on their non-specic multi sensor
approach, which enables one to measure the activity of molecules
within a drug formulation. Together with the ability of their sensors
to bind or interact with different chemical structures, they allow
one to assume an overall impression rather than only to determine
the concentration of the API. Best results for the determination of
taste-masking properties can be expected, if a (log-linear) dependency between concentrations of the unpleasant tasting API and

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M. Pein et al. / International Journal of Pharmaceutics 465 (2014) 239254

Table 5
Realistic properties related to conditions in the human mouth.
Saliva

Tongue

Characteristics

Residual volume

Flow rate

Osmolality

Values

12 ml

0.51 ml/min

50100 mosmol/kg

Literature

(Dodds et al., 2005;

Lagerlf and Dawes, 1984;
Siqueira and Nicolau, 2002;
Watanabe and Dawes,
1990)

(Lagerlf and
Dawes, 1984;
Zwier et al.,
2013)

(Dibdin et al., 1986;

Hermes, 2012)

pH depending
on age
5.77.5

Buffer capacity

Temperature

Force

6.1 mol/l

3536 C

(Hermes, 2012)

(Zwier et al.,
2013)

(Olsen, 2006)

0.135 N
(Hermes, 2012)

Fig. 3. Typical in vitro sampling frequencies indicated by the dashed lines (1, 2, 3 min) in comparison to the typical in vivo evaluation time of 30 s.

the sensor signal exists. Based on the potentiometric measurement

principle this is most likely for charged molecules. Differences in
sensor signals can then be expected to be based on lower API concentrations due to a successful taste-masking. An inclusion of an
API in cyclodextrins as described by Ono et al., could therefore be
correlated with a bitterness reduction (Ono et al., 2011).
It should be remarked at this point that a successful calibration procedure using the API of interest is not substitutable by
the operational qualication procedures of the suppliers (conditioning, calibration and diagnostic (AlphaMOS), sensor check
(Insent)), which should be performed before sample measurement. These procedures only prove if the sensors comply with
the basic requirements of the suppliers by providing information

about the stability of the sensors as well as their discriminating

power.
3.2.3. Dissolution step
Measuring one individual sample takes at least the time period
the sensors need to equilibrate: AlphaMOS recommends evaluating
only the mean value of the last 20 s of a measurement, which takes
120 s in total. Using the Insent, one measurement takes 30 s (Woertz
et al., 2011a). Moreover, e-tongue sensors are sensitive to changes
in temperature and lose their performance in solutions of higher
temperatures. The dissolution step has therefore to be carried out
before the e-tongue measurement. Consequently, taste-masking
effects can only be evaluated off-line.

Fig. 4. In vitro dissolution proles of four model formulations combined with the in vivo human perception threshold.

M. Pein et al. / International Journal of Pharmaceutics 465 (2014) 239254

251

In most studies, (puried) water is described as dissolution

medium (Table 4). In contrast to this dissolution medium, imitating
the physiological behavior of saliva, also beverages and food matrices (e.g. pudding) as taste-masking matrices (Sadrieh et al., 2005)
or isopropylic alcohol (Bhasin and Ghosh, 2012) were used. While
the use of beverages and food matrices seems reasonable, there
is no rational explanation to use isopropylic alcohol. If described,
the temperature of the dissolution medium has been set to 37 C
(Guffon et al., 2012; Tokuyama et al., 2009). However, in most studies no detailed information on the temperature of the dissolution
medium was given, though the temperature has a likewise strong
impact on the dissolution itself. Another high impact factorthe
agitation of the dissolution mediumhas only been described by
few working groups (Table 4).
3.2.4. Sampling procedure
The most critical but likewise least described step is the
sampling procedure. Measuring samples with electronic tongues
requires sample volumes between 25 or 100 ml (Astree) and
2 40 ml (Insent) (Woertz et al., 2011a). These volumes cannot be
withdrawn and ltered as quickly and easily as small volumes. Still,
the samples have to be ltrated immediately. The ltration process
is required due to sensor robustness as particles could damage the
sensors. Additionally, ltration has to be performed immediately
after sampling to avoid ongoing dissolution.
Filtering 25 ml to 100 ml does not necessarily allow an immediate assessment, as this process can last up to 30 s depending on the
ltration setup. Additionally, accuracy and precision of the resulting data are likely to be falsied, because the needed high volume
requires an individual dissolution experiment for each time point
of assessment and each repetition. Regarding the taste-masking
assessment based on electronic tongue measurements, the sampling is the most critical parameter and should be performed by
applying vacuum ltration and lters with a dened pore size.
According to literature, at least some details on their sampling
procedure were provided by Tokuyama et al. (2009), Kayumba et al.
(2007) and Guhmann et al. (2012). Guhmann et al. described an
immediate removal of the particles after the pre-dened dissolution time of three minutes by microltration using a syringe tted
with a 0.22 m Whatman glass microber lter. Kayumba et al. ltered the samples after a specic time interval (15 min) through
a 0.45 m lter. In both cases, the time that was needed for the
ltration was not provided. Although one could assume a short ltration time, the only detail that was provided by Tokuyama et al.
was that the samples were ltered under reduced pressure.
3.2.5. Analytical assessment and data evaluation
Taste-masking properties are evaluated by comparing the
sensor signals of the taste-masked sample with the placebo formulation and the pure drug substance using univariate or mostly
multivariate statistics (Table 4). A successful calibration (Section
3.2) as performed by (Cilurzo et al., 2011), (Guhmann et al., 2012)
and (Guffon et al., 2012) served as the actual basis for univariate
data analysis and provided a detailed overview for each sensor
response (Guhmann et al., 2012). Fig. 5 displays such a successful calibration showing log-linear concentration dependent signals
for each sensor but sensor 4, whereby the sensor signals can either
increase or decrease depending on the composition of the sensor membrane. The log-linear ranges of the sensors are between
0.00550 mM (sensor 1) and 0.550 mM (sensor 3).
Regarding the e-tongue sensor response evaluation, multivariate data analysis (MVDA) is preferred. Most reliable information
can be assumed from those sensors showing a concentration
dependency for the investigated drug (Woertz et al., 2011a). For
multivariate evaluation, a software is required that summarizes
all sensor responses of the e-tongue and allows comparison of

Fig. 5. Calibration procedure of e-tongue sensors. Sensors 13 show concentration

dependent signals while sensor 4 lacks sensitivity.

Fig. 6. Schematic PCA map displaying sensor outputs of an electronic taste sensing
system in a two-dimensional graph; the information of the pure API are compared
with those of a drug-free formulation (placebo) and taste-masking approaches (formulation 1 and 2).

different formulations based on this complex information. A principal component analysis (PCA) aims to reduce the multidimensional
sensor information. The main information is then given in a two- or
three-dimensional graph, displaying the main discriminating factors as principal component 1 (PC1) on the x-axes, PC2 on the y-axes
and PC3 on the z-axes. In the schematic PCA map (Fig. 6), the API
represents the unpleasant taste, while the drug-free formulation
(placebo) displays the desired taste.
A pleasant taste for the drug formulation can be assumed, if
the distance to the placebo formulation is small or closely located.
Accordingly, an unsuccessful taste-masking approach is expected,
the closer the distance is towards the pure API. Euclidean distances
as the basis of each multivariate statistics can be calculated according to equation 2, where p and q represent the samples and n is the
number of variables used for the model in MVDA (Woertz et al.,
2010b).

d(p, q) =

n
i=1

(pi qi )2

The similarity between a reference sample and test samples

can be calculated using these Euclidean distances as proposed by
(Cilurzo et al., 2011). But although multivariate evaluation techniques like PCA are powerful tools to evaluate complex data, they
might produce erroneous results due to factors such as incorrect
classication (Goodner et al., 2001).
Based on the practical approach, benecial results can be
expected, if additionally each excipient is measured separately to
evaluate its effect on the electronic tongue signals. The amount of

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M. Pein et al. / International Journal of Pharmaceutics 465 (2014) 239254

pure drug and of the excipients should be comparable to those in

the drug formulation being investigated.
4. Correlation of in vivo and in vitro taste assessments
Some authors correlated in vitro with in vivo results (Bora et al.,
2008; Hoang Thi et al., 2012; Kayumba et al., 2007; Sadrieh et al.,
2005; Shiino et al., 2010; Tokuyama et al., 2009). Results obtained
in comparative studies with electronic taste sensing systems disclosed an agreement between human panels and the in vitro results.
Tokuyama et al. for example conrmed that the logarithmically
transformed bitterness score of the conducted human taste panel
correlated well with increasing Euclidean distances obtained by
the sensor responses (Tokuyama et al., 2009). The scoring within
the taste panel was, however, a numerical one comprising numbers
from 1 (hardly bitter) to 5 (very bitter). Kayumba et al. used Astree
in combination with a statistical model dened as bitterness prediction tool (Kayumba et al., 2007). This evaluation tool correlates
instrumental sensor values with human sensory scores based on a
set of bitter reference compounds. Thus, by analyzing the e-tongue
samples with the bitterness prediction tool, they indirectly correlated them with the palatability ranking of the information of
human taste panels. The implemented bitterness score is based on
a numerical scale, providing 5 descriptors and 4 subdivisions per
descriptor (14: undetectable, 48: slightly bitter,. . . 1720: unacceptable). In their study, Kayumba et al. also observed the drug
dissolution prole by UV detection and compared the amount of
released drug with the human perception threshold of quinine sulphate given by Suzuki et al. (Suzuki et al., 2003) and Katsuragi
et al. (Katsuragi et al., 1997). Based on their results, they concluded
that the e-tongue data match better with the in vivo data than the
results of the UV detected drug dissolution (Kayumba et al., 2007).
However, details were neither provided about the drugs, which
have been utilized for the bitterness prediction module, nor about
panelists based information, such as composition and training procedure. Regarding the drug dissolution, the approach to correlate
instrumental analytical data with the human perception threshold was also performed by (Albertini et al., 2004; Bora et al., 2008;
Hoang Thi et al., 2012; Shiino et al., 2010) (Table 4).
Eckert et al. evaluated taste varying effects (Eckert et al., 2013).
Still, their results on the taste evaluation of multicomponent mixtures illustrated parts of the problem that have to be considered, if
in vivo and in vitro data are correlated. They revealed a higher selectivity and sensitivity of the analytical in vitro methods e-tongue
and HPLC/UV compared with the results based on a professional
human taste panel. The analytical methods detected minor differences regarding the composition of ingredients, while panelists
could only differentiate the most deviating samples (Eckert et al.,
2013). In addition to qualitative correlations, quantitative correlations also remained critical.
To judge about taste-masking success, in vivo data is still
required independent of the analytical method. But even if this
information is available, the reliability of the analytical results with
regard to the in vivo evaluation has to be proven. Therefore, it
should be veried that the analytical limit of quantitation of the
applied method is below the human perception threshold.
5. Conclusions
Drug formulations are ideally taste-masked, if they provide
a neutral taste or at least a taste perceived identically to the
placebo formulation. The most reliable method to determine
taste-masking properties by detecting taste as overall gustatoric
impression including smell, mouthfeel, visual appearance and
emotions, is performing a trained human taste panel. As it is

unlikely that the same number of panelists is available for each

study, a standardized training such as that described by (Albertini
et al., 2004; Suzuki et al., 2003) is needed. However, age and sex of
the panelists should be dened in each published study, especially
if the investigated drug formulations are assigned to a special
patients group like the elderly or children. To avoid falsied taste
masking assessment, authors recommend administration of the
drug formulations as such, without any pretreatment.
The assessment of taste-masking properties by human taste
panels for drugs in the early stage of development is without doubt
questionable, due to ethical and toxicological concerns. In contrast, analytical in vitro methods are safe and offer moreover the
advantage of objectied results. Bearing in mind the question of
reliability, a shift from one to the other methodology would be
desirable.
For the dissolution step of in vitro samples, real parameters in
the oral cavity such as volume, pH and osmolality of saliva as well
as the exerted tongue force should be considered, and have been
proposed in this review (Table 5). Future directions related with
this idea were also summarized by (Gittings et al., 2014). In-line
detection methods are strongly recommended over off-line detection methods, if the taste-masking approach is accompanied with a
delayed release of the drug. So far, this can only be realized with UV
detection. Electronic tongue sensors need improvement to ensure
short equilibration times and higher robustness towards temperature and particles, which is required for dissolution studies. For
off-line detection methods, 30 s is proposed as time point for the
rst sampling, as children with attention decit hyperactivity disorder and autistic disorder could be trained to swallow a tablet
within this time span (Beck et al., 2005). To improve the relevance
of the off-line result, at least one more sample should be taken after
one or two minutes of dissolution, imitating a longer swallowing
process. For appropriate e-tongue results, these samples should be
ltered immediately by applying a vacuum pump, as this handling
avoids ongoing dissolution.
Assuming that each critical aspect of the individual methods can
be overcome, still the correlation of the results based on in vitro
methods with those of a human taste panel remains challenging. A
higher selectivity and sensitivity of the analytical in vitro methods
e-tongue and HPLC/UV is expected compared with in vivo results.
Taste-masking can only be assumed, if the released amount of API
does not exceed the human perception threshold within the predened dissolution time. Therefore, it should be veried that the
analytical limit of quantitation of the applied method is below the
human perception threshold.
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