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International Journal of Pharmaceutics 465 (2014) 239254

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

journa l homepage: www.e lsev ier .com/ locate / i jpharm

eview

aste-masking assessment of solid oral dosage formsA critical review

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

r t i c l e i n f o

rticle history:eceived 17 August 2013eceived in revised form5 December 2013ccepted 16 January 2014vailable online 6 February 2014

eywords:uman taste panelV spectroscopylectronic taste sensing systemample pretreatmentamplingtandardized protocols

hemical compounds studied in this article:cetaminophen (PubChem CID: 1983)iclofenac (PubChem CID: 3033)

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 efficacy are diverse. Taste-masking has gained in importance since the EU legislation on medicines for children came into force in2007, and taste-masking attributes are often required by regulatory authorities. However, standardizedguidance 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 themouth.Methodologicallimitations and problems regarding timepoint of evaluation, sampling or sample pretreatment are hardlyever addressed. This critical review aims to evaluate and discuss published strategies in this context.

2014 Elsevier B.V. All rights reserved.iclofenac sodium (PubChem CID:018304)oxycycline (PubChem CID: 54671203)etformin hydrochloride (PubChem CID:4219)heophylline (PubChem CID: 2153)

uinine sulphate (PubChem CID: 13119)

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2402. In vivo evaluation of taste-masking. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240

2.1. Panelists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2402.2. Administration and influence of pretreatment of drug formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2432.3. Time points of taste assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2432.4. Taste assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244

3. In vitro evaluation of taste-masking efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2453.1. Determination of taste-masking properties by UV spectroscopy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245

3.1.1. Dissolution step . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2453.1.2. Sampling procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2493.1.3. Analytical assessment and data evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2493.2. Determination of taste-masking properties by electronic taste sen3.2.1. Commercially available electronic taste sensing systems3.2.2. Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Corresponding author. Tel.: +49 211 8114225; fax: +49 211 8114251.E-mail addresses: [email protected] (M. Pein), [email protected] (M. Preis), Caro

378-5173/$ see front matter 2014 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.ijpharm.2014.01.036sing systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249

[email protected] (C. Eckert), [email protected] (F.E. Kiene).

dx.doi.org/10.1016/j.ijpharm.2014.01.036http://www.sciencedirect.com/science/journal/03785173http://www.elsevier.com/locate/ijpharmhttp://crossmark.crossref.org/dialog/?doi=10.1016/j.ijpharm.2014.01.036&domain=pdfmailto:[email protected]:[email protected]:[email protected]:[email protected]/10.1016/j.ijpharm.2014.01.036

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

3.2.3. Dissolution step . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2503.2.4. Sampling procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2513.2.5. Analytical assessment and data evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251

4. Correlation of in vivo and in vitro taste assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2525. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252

. . . . . .

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. Introduction

For drug therapy adherence and patient convenience, taste-asking of unpleasant tasting active pharmaceutical ingredients

APIs) is desirable. Many research and developing groups spendremendous effort on developing taste-masked formulations,hereof several approaches have been derived (Momin, 2012).ne taste-masking approach is to construct physical barriers asealized in coated tablets or granules. As tablets are intended toemain shortly in the oral cavity, a coating layer can shield thenpleasant taste of the API from the taste buds in the oral cavityntil the tablet has been completely swallowed (Malik et al., 2011;akano et al., 2013). Other common approaches are based on theddition of sweeteners, ion exchange resins (Fu Lu et al., 1991) oryclodextrins (Mady et al., 2010; Preis et al., 2012; Suthar and Patel,011). As a substance needs to be dissolved for perception by theeceptors located in taste buds on the human tongue, a lower sol-bility is tantamount to a less bad taste. Therefore, pH modifiersonverting a substance into its less soluble or even insoluble formre also used to achieve taste-masking effects (Ogata et al., 2012).ith regard to the chemical stability of drug substances, consid-

ration of the effects of mixing corresponding drug formulationsith food or beverages is important. For example, some antibioticsre sensitive to a decreased pH (e.g. azithromycin) like present inpple sauce, or to multivalent cations (e.g. tetracycline) presentn milk products. Nevertheless, this approach enables a simpli-ed administration to children and elderly patients (Sadrieh et al.,005), because these groups often face problems in swallowingolid dosage forms. Moreover, increased viscosity of a drug formu-ation might help to achieve a taste-masking effect by inhibitingrug diffusion to the taste receptors.Masking unpleasant tasting APIs is doubtlessly desirable, if they

re incorporated in solid oral dosage forms, which potentiallyelease the API within the oral cavity. This is even intended forrodispersible soliddosage forms (EuropeanPharmacopoeia, 2008;ood and Drug Administration, 2008). Standardized testing proto-ols and specification limits are provided by the pharmacopoeiauch as adequate disintegration times (Ph. Eur.: 3min Europeanharmacopoeia, 2008, FDA: 30 s (Food and Drug Administration,008)), but criteria for disintegration are not useful to judge abouthe taste-masking efficacy. Drug release specifications might beeasibly adapted for the assessment of taste-masking effects. Buthile, for example, immediate release dosage forms require a drugelease of 80% within the first 45min, such specifications are notrovided for the drug release of orodispersible solid dosage forms.ased on some taste-masking approaches, a delayed release behav-or ariseswithin the firstminutes of dissolution testing (Cerea et al.,004). According to a former FIP/AAPS guideline, a drug releasef 10% within the first 5min of dissolution indicates a success-ul taste-masking (Siewert et al., 2003). However, this arbitraryhreshold is highly dependent on the human perception thresh-ld of each individual drug substance and dissolution methods asuch are not applicable to judge about taste-masking effects based

n the addition of sweeteners or flavors.So far, human taste panels are often used for the assessment

f taste-masking properties, e.g. in Refs. (Bhoyar et al., 2011b;ilurzo et al., 2011; Douroumis et al., 2011; Fukui-Soubou et al.,. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252

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 ethi-cal and toxicological concerns, conducting human taste panels isquestionable, if the drugs of interest are still in the early stage ofdevelopment. On the contrary, analytical methods offer safe andobjective results. Thus, spectroscopic drug dissolution analysis andelectronic tongue measurements are often applied to assess theefficiency of taste-masking effects. Using UV spectroscopy, eitherthe dissolution profile of a sample is evaluated or the amount ofreleased drug after a predefined dissolution time is determined. Ininvestigations with electronic taste sensing systems (e-tongues),taste-masking effects are treated by univariate and/or multivariatemethods (Guhmann et al., 2012; Hoang Thi et al., 2012; Tokuyamaet al., 2009; Woertz et al., 2011b; Zheng and Keeney, 2006).

In contrast to the well-established pharmaceutical techniquesto obtain taste-masked formulations, taste assessment lacks pre-cise description. This imbalance is due to the lacking definition oftaste-masking and missing standard evaluation tests and specifi-cations. Although some reviews have dealt with the assessment oftaste-masking effects in recent years (Anand et al., 2007; Datrangeet al., 2012; Sagar et al., 2012; Shet and Vaidya, 2013), the criticalaspects coming along with the according evaluation of solid oraldosage forms are rarely discussed (Gittings et al., 2014; Woertzet al., 2011a).

As the application of analytical methods for taste-maskingassessment gained importance, since the EU legislation onmedicines for children came into force in 2007 (Breitkreutz, 2008;European Union, 2006), this review assembles and critically dis-cusses recent approaches of assessing taste-masking propertiesof solid oral dosage forms (granules, microspheres, pellets, tablesand film formulations). Manuscripts have been considered, if theassessment was performed with human taste panels (definedas in vivo evaluation) and/or UV spectroscopy and/or electronictongue measurements (defined as in vitro measurements). UVspectroscopy measurements comprise in this context on-line andin-line UV-monitoring of the drug dissolution aswell as off-line UVdetection or highperformance liquid chromatography (HPLC)mea-surements after sampling. Electronic tongue measurements haveonly been considered, if they were carried out with at least one ofthe commercially available instruments (Insent or Astree).

2. In vivo evaluation of taste-masking

Although there are standardized protocols for taste evalua-tion (DIN10959, 1998; DIN10961, 1996; DIN10969, 2001; ISO3972,1991), so far no standardized protocol exists for the evaluation oftaste-masking. Rather, the protocols described in literature differin their procedures, particularly with regard to the panelists, theadministration of the drug formulation and the time point(s) toassess the taste-masking effects (Table 1).

2.1. PanelistsAs summarized in Table 1, investigated studies have been con-ductedwith 430healthy adult humanvolunteers. If the ages of thegender-mixedpanelistswere reported, they varied between18 and

M.Pein

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241

Table 1In 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 specified, ODF: orodispersiblefilm, ODT: orodispersible tablet, SRT: sustained release tablets, TM: taste-masking).

API Dosage form Taste-maskingstrategy

Panelists Perceptionthreshold(mg/ml)

Panelisttraining

Dose of the sample(in mg API)

Administration ofthe solid oraldosage form

Time point ofevaluation

Taste-maskingassessment procedure(see also Tables 2 and 3)

Ref.

Aceclofenac ODT HPCD:APIcomplexes includingneotame(sweetener), orange& peppermint flavor

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

n.s. n.s. 100 One tablet placedonto the tongue

Immediately afteradministrationand at severalintervals for 5min

Time intensity methodfollowed by bitternessscores

(Kasliwal andNegi, 2011)

Acetaminophen Granules Application ofdifferent granulationprocesses


1.08 Yes 22.5 As solution(granulesdissolved over3min)

After the solutionwas held for 5 s inthe mouth

Scoring of pure APIsolution against solutionof the formulation (3mindissolved)

(Albertini et al.,2004)

Tablets Addition of WitepsolH-15 or cacao, cocoabutter, sucrose, cocoapowder andBenecoat BMI-40


242M.Pein


aceutics465

(2014)239254

Table 1 (Continued)


Panelists Perceptionthreshold(mg/ml)

Panelisttraining

Dose of the sample(in mg API)

Administration ofthe solid oraldosage form

Time point ofevaluation

Taste-maskingassessment procedure(see also Tables 2 and 3)

Ref.

Famotidine ODT Addition ofcarboxymethyl--CDand sulfobuthyether--CD

No.: 8age:2327ysex: n.s.

n.s. Yes 20 One tablet placedonto the tongue

Afterdisintegration ofthe tablet

Bitterness scores (Mady et al.,2010)

ODT Addition ofsweetener(aspartame), originaland generic products


n.s. Yes 10 One tablet placedonto the tongue

30 s afteradministration

Sweetness and bitternessscoring

(Tokuyamaet al., 2009)

LevocetirizineHCl

Granules,MDT

Addition ofion-exchange resintulsion-335


n.s. n.s. 5 One tablet placedonto the tongue


Bitterness level:++/+++

(Sharma andChopra, 2012)

Metformin HCl SRT Addition ofcation-exchangeresins indion 244,254 and 264


n.s. n.s. 300 n.s. 10min (seconds?)afteradministration(taste was alsoevaluated at1050 min(seconds?) afterrejecting thetablet)

Scores drug resincomplex against puredrug

(Bhoyar et al.,2011b)

Ofloxacin Microspheresfor ODT

Addition of Eudragit

E100No.: 5age: n.s.sex: male

n.s. n.s. n.s. n.s. n.s. Bitterness scores (Malik et al.,2011)

Ondansetron HCl Microspheres Spray drying withEudragit E100,addition of Chitosanand MethocelE15 LV

No.: 7age:2128ysex: 4m/3f

0.075 n.s. 0.006 As solution (1ml) 30 s afteradministration ofthe solutions

Y: recognition of bittertasteN: no perception of bittertaste

(Bora et al.,2008)

ODT Addition ofion-exchange resinindion 204

No.: 10age:1822ysex: n.s.

n.s. n.s. 8 Granules placedonto the tongue

10, 30, 60, 90, 120and 150 s afteradministration

Bitterness scores (Makwanaet al., 2010)

MDT Addition ofion-exchange resinindion 204,sweetening agentaspartame andflavoring agents(peppermint, vanilla)


n.s. n.s. 8 Granules placedonto the tongue


n.s. (Prajapati et al.,2010)

Piogliazone HCl ODT Coating of coregranules withEudragit EPO,addition ofaspartame and NaCl

No.: 29age:22.30.9 ysex:13m/16f

n.s. n.s. 30 n.s. Immediately afteradministrationand afterdisintegrating

VAS scoring mouth feel,bitterness, sweetness,saltiness, astringency,sourness, overallpalatability

(Nakano et al.,2013)

Pyridostigminebromide

Dispersibletablet

Addition of -CD andflavor

No.: 18age: n.s.sex: 9m/9f

n.s. n.s. 30 As dispersion(one tabletdispersed in10ml water)


Bitterness rating (Tan et al.,2012)

Sodiumphenylbutyrate

Granulestablet

Coating,composition: n.s.


n.s. n.s. Tablet: 500granules:940

n.s. Immediately afteradministration,0.5 and 2h afteringestion

Information onacceptability, bitterness,saltiness, sweetness

(Guffon et al.,2012)

Sumatriptansuccinate

Granules Addition of Eudragit

E100, -CD andsweetener


n.s. n.s. Drug contentvaried dependingon TM strategy

Granules placedon posteriorlobe of tongue


Taste-masking andgrittiness evaluation

(Singh et al.,2012)

l of Pharmaceutics 465 (2014) 239254 243

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9 years (Bhoyar et al., 2011a,b; Mady et al., 2010; Maniruzzamant al., 2012; Sadrieh et al., 2005; Shah andMashru, 2008b). The tastempression of humans differs based on their nationality, eatingabits and age (Breitkreutz and Boos, 2007). Thus, missing infor-ation about the compositions and age structures of the groupf panelists reduces the significance of the results. Taste-maskingffects aremoreover desired to improve the compliance of patients,ho are not limited to the described panelists gender and agingtructures. Especially transferring the results of human (adult)aste panels to the taste impression of children can be accompa-ied with a significant falsification, as their taste impression variesremendous over age (Mennella and Beauchamp, 2008). To ensureeliability and comparability of panel results, two working stepshouldbecarriedoutbeforedetermining taste-maskingproperties:hreshold determination and training of the panelists. The humanerception threshold is the lowest concentration of a substance, auman still perceives. Also called bitterness value, its determina-ion is defined in detail in the (European Pharmacopoeia, 2008).imilar procedures were described and conducted very detailedy some working groups dealing with the assessment of taste-asking properties (Albertini et al., 2004; Bora et al., 2008; PatelndVavia, 2008; Sharmaet al., 2012). Theseworking groups offeredve to seven different concentrations of the drug substance to theolunteers, who assigned the samples to predefined statementsbout bitterness or palatability (Tables 13). To enhance compa-ability of the panelist statements, Albertini et al. and Suzuki et al.dditionally trained thepanelists after the threshold determinationy assigning a defined score to given sample solutions (Albertinit al., 2004; Suzuki et al., 2003).

.2. Administration and influence of pretreatment of drugormulations

Themost commonway to administer drug formulations to pan-lists is the one that depicts reality most accurately: placing therug formulation directly onto the tongue (Table 1). In contrary,ome authors administered a prepared solution or suspension.dministrationof dissolvedor disperseddrug formulations leads toefined concentrations of unpleasant tastingAPI offered to thepan-lists. However, an increasing taste sensation over time is expectedhen the drug formulation is placed directly onto the tongue. Pre-

reatment (dissolution/dispersion) times couldoffer safetymarginsor evaluating taste-masking effects, if theywere defined to be a lit-le longer than the timeneeded to swallowa solid oral dosage form.ut on the contrary, the prognoses of the taste-masking efficacyorsen, if the pretreatment times were too long.Although the pretreatment (dissolution/dispersion) time obvi-

usly influences the gustatoric sensation (especially of orodis-ersibledrug formulations), detailed informationwasonlygivenbyAlbertini et al., 2004) and (Shah andMashru, 2008b): while Alber-ini et al. described a dissolution time over a period of 3min (180 s)ollowed by a filtration of the sample, Sha and Mashru adminis-ered 1ml suspension prepared by dispersing equivalents of 1 grimaquine for 15 s in water. For the taste-masking evaluation ofhe four different drug formulations displayed in Fig. 1, these tworetreatment procedures would cause significant differences.But although the pH and viscosity of the human saliva have a

reat impact on the dissolution behavior and change with age andood intake (Pfaffe et al., 2011), detailed information are lackingoncerning taste-masking evaluation in the perused literature.

.3. Time points of taste assessmentAs described in Section 2.2, drug formulations have been admin-steredwith andwithout initial pretreatment for the taste-maskingvaluation. And as displayed in Fig. 1, the pretreatment time plays Ta

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ig. 1. Schematic release behavior of four model drug formulations in the mouth. Telated to significantly different drug releases.

n important role regarding the results. Thus, in the following, lit-rature based time points are subdivided into thosewith and thoseithout pretreatment.Where the drug formulation is directly placed onto the tongue

f the panelist, the first time point of assessment was mostly setimmediately after administration (Bhoyar et al., 2011a,b; Guffont al., 2012) or at predefined time points: 10 s (Kasliwal and Negi,011;Makwana et al., 2010; Sharma and Chopra, 2012; Singh et al.,012), 15 s (Cilurzo et al., 2011), 20 s (Sharma et al., 2012), or 30 sTokuyama et al., 2009). Some authors predefined the first timeoint of assessment after the disintegration of the tablet with-ut giving any further information regarding the time (Bhasin andhosh, 2012; Douroumis et al., 2011; Liew et al., 2012; Mady et al.,010). As this parameter is individually perceived by each panelist,he results lack comparability. Suzuki et al. investigated the tastef a chewable tablet 10 s after 10 chews (Suzuki et al., 2003).Following Albertini et al., taste-masking effects were evaluated

fter 3min of dissolution. The resulting dispersion was filtered andhe corresponding solution assessed over 5 s by the volunteers.he duration of the filtration was not specified. Sha and Mashruvaluated the taste impression after 15 s of pre-dissolution and anssessment by the volunteers after retaining the dispersion for 30 snto their mouths. As no filtration step was described before the

dministration, the dissolution process could be expected to pro-eed also after the 15 s of pre-dissolution. However, Fig. 2 displayshe concentrations that were expected after another 30 s of furtherissolution in the panelists mouth.

able 3coring systems for human taste panels using other score scales than numbers.

(Sharma and Chopra,2012)

(Singh et al., 2012) (Suzuki et al., 200

Scoring ++ Taste-masked withbitter after taste

No taste-masking0 slightly masked

Taste of the chewatablets is comparewith 10 differentconcentrations ofquinine sulphate,labeled with numof 110

+++ Completetaste-masking

+ Completetaste-maskedetreatment procedures of Shah and Mashru (2008b) and Albertini et al. (2004)) are

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 sen-sation one minute after swallowing the samples.

To define reliable time points for the taste assessment, informa-tion is needed about the residence time of drug formulations in theoral cavity. In a study from (Beck et al., 2005) children with atten-tion deficit hyperactivity disorder (ADHD) and autistic disorder(AD) have been taught to swallow tablets. A successful swallowingwas defined, 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 limitof tablet residence time in thehumanmouth and thus, as timepointfor the taste (masking) assessment.

2.4. Taste assessment

Scores or scales are the most popular ways to rate the taste offormulations. Most scales use numeric systems (Table 2), while afew use other scoring systems (Table 3). However, some scoringsystems assign low numbers to tasteless or pleasant tasting formu-lations and high numbers to a very unpleasant taste, while othersare correlated vice versa (Table 2). To enable correct inter-studyevaluation, the scales should at least be orientated comparably

(Davies and Tuleu, 2008).

Thevisual analog scale (VAS)offers analternativeway toanalyzetasteperception (Nakanoet al., 2013; Turner, 2009). Thenon-scaledVAS has a defined length, mostly 100mm, a starting point labeled

3) (Tan et al., 2012) (Tokuyama et al., 2009)

bled

bers

Opportunity todistinguish between nobitterness, slightbitterness (butacceptable) and strongbitterness(unacceptable)

Bitterness and sweetness scores (notlabeled) according to training solutions:

Quinine HCl:1: 0.0029mM2: 0.012mM3: 0.031mM4: 0.078mM5: 0.2mM

Sucrose:1: 29.24mM2: 97.72mM3: 187.1mM4: 409.4mM5: 994.1mM

M. Pein et al. / International Journal of Pharmaceutics 465 (2014) 239254 245

F . Thep ne). Ae let w

waoago(astrlwebt1rtuiti

3

opwtpsrm

3s

e

ig. 2. Schematic release behavior of four model drug formulations in the mouthrovided over 30 s as suspensions (indicated by the arrow, ending with the bold lit al., 2004). The time, children with ADHD and AD could be taught to swallow a tab

ith no taste and an endpoint labeled with strong taste. Thedvantage of this scale is its applicability to rate different typesf taste attributes like bitterness, sweetness, saltiness, astringencynd sourness, but also to describe the mouth feel (e.g. roughness,rittiness) or the overall palatability (Nakano et al., 2013). More-ver, this scale can be used for children of six years and olderDavies and Tuleu, 2008). For younger children ( 3 years), Daviesnd Tuleu reported about facial hedonic scales as applicable scoringystems (Davies and Tuleu, 2008). The absence of further descrip-ors leads, however, to a lower level of comparability between theesults of differentpanelists compared toother scaling systems. Theabeled magnitude scale (LMS) is another scoring system, whichas introduced by Green et al. for human taste studies (Greent al., 1993,1996). This scale is labeled with the verbal descriptorsbarely detectable, weak, moderate, strong, very strong andstrongest imaginable. The non-linear, quasi logarithmic spacingetween the descriptors supports the process of human percep-ion, which is based on the WeberFechner law (Pfaffmann et al.,971; Pfaffmann, 1959). By specifying fixed responses and theanges in between, the scale enables direct comparison betweenhe results of different panelists. Similar to the VAS, the LMS can besed to describe different types of perception. But while the VASs more suitable for smaller perceptual ranges, LMS is suitable forhe description of highly divergent samples regarding their tastentensity due to its broad scaling.

. In vitro evaluation of taste-masking efficacy

When performing an in vitro evaluation of taste-masked solidral dosage forms, three basic steps have to be conducted inde-endently of the applied analytical technique: dissolution, sampleithdrawal and analytical evaluation. To prove the applicability of

he chosen analytical method, a calibration with the pure activeharmaceutical ingredient dissolved in the dissolution mediumhould be performed. Nevertheless, calibration procedures andesults are rarely described in literature (Table 4) and the afore-entioned three basic steps havebeen conducted inmultipleways.

.1. Determination of taste-masking properties by UV

pectroscopy

The rational use of UV spectroscopy to determine taste-maskingffects is based on two assumptions: a substance needs to besamples of Shah and Mashru (2008b) were dispersed over 15 s (dashed line) andlbertini et al. provided filtered samples after a dissolution time of 3min (Albertinias 30 s (Beck et al., 2005).

dissolved to cause an unpleasant taste, and in most cases theunpleasant taste of the drug formulation is related to the includedAPI. This leads to a worsening taste sensation with increasedamount of released API. However, if one or more excipients con-tribute to the unpleasant taste, analytical determination of the APIconcentration is insufficient. To determine the released API con-centration, in-line, on-line or off-linemethods have been applied inliterature. For a successful in-line assessment, afiber-opticUVsens-ing systemwasusedby (Guffonet al., 2012). On-linemeasurementshave been conducted using a modified USP4 flow through dissolu-tion method (Albertini et al., 2004). Off-line taken samples wereanalyzed using a spectrophotometer (Bora et al., 2008; Kayumbaet 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;Guhmannet al., 2012;HoangThi et al., 2012; Tokuyamaet al.,2009). Regardless of themethod, prerequisites for a successful ana-lytical measurement are drug concentrations within the validity ofthe Lambert-Beer-law, a sufficient selectivity, degassed dissolutionmedia and, regarding the off-line methods, an adequate samplingsequence and procedure.

Most critical on the basis of UV measurements is the assumedabsolute correlation of released drug with the taste. Although theamount of dissolveddrug canbe correlatedwith the taste, the influ-ence of excipients and not dissolved particles that do not influencespectral absorption measurements is disregarded. On the basis ofthe instrumental approach, the tube-based lag time has to be con-sidered for on-line approaches to specify a reliable lag time basedon a delayed release.

3.1.1. Dissolution stepRegarding determination of drug dissolution over time, dif-

ferences in temperature, volume and media were described inliterature,whichhasalsovery recentlybeenmentionedby (Gittingset al., 2014). If the temperature of the dissolution medium hasbeen defined, it was set to 37 C0.5 C.Water or phosphate bufferas 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 oldchildren (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 wasreported that the investigated samples were mixed, shaken and/orstirred in the dissolutionmedia; if defined, the stirring speed variedfrom 25 rpm up to 100 rpm. Some authors developed dissolution

246M.Pein


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Table 4In vitro evaluationof taste-masking (a.i.: additional information,API: activepharmaceutical ingredient, CD: cyclodextrin, IVIVC: correlationwithhuman thresholddata, n.s.: not specified,m:dissolutionmedium,ODF: orodispersiblefilm, ODT: orodispersible tablet, SSF: simulated saliva fluid, T: temperature in C, V: volume in ml).


In vitroassessmenttool

Calibrationprocedure

Taste-maskingcriteria

IVIVC Dissolutionsettings

Sample(pre)treatment

Drug dose Samplingtimepoint

Ref.

Acetaminophen Granules Application ofdifferentgranulationprocesses

UVspectroscopy(243nm)

n.s. Drug release ofpure API > taste-maskedformulation

n.s. V: 900m: bufferpH: 6.8T: 37a.i.: paddlespeed 50 rpm

Dissolution inpaddle apparatusaccording toUSP24; on-linesampling(12.5ml/min)

22.5mg 3min (Albertiniet al., 2004)

Mold disks Wax matrixcontainingEudragit EPO


n.s. API released after10min at pH6.5 < thresholdconc. (35g/ml)

Yes V: 900m:phosphatebufferpH: 6.5T: 37.00.5a.i.: paddlespeed 50 rpm

Dissolution inpaddle apparatusaccording toJapanesePharmacopoeia;sample filtration(0.45m) beforeoff-line detection

200mg Each 5min. (Shiino et al.,2010)

Powder Addition ofcaseinate andlecithin

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

n.s. Based onEuclideandistances of theplaceboformulations tothe drugformulations

n.s. V: n.s.M: waterpH: n.s.T: n.s.

n.s. n.s. n.s. (Hoang Thiet al., 2012)

HPLC/UV(243nm)

n.s. API released after2min< thresholdconc. accordingto (Albertiniet al., 2004;Shiino et al.,2010)

Yes V: 1ml/minm:phosphatebufferpH: 7.4T: 37

Sample is placed ina tube, dissolutionmedium iscontinuouslyflowing over thesample, fractionsare kept

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

Atomoxetinhydrochloride

Granules Addition ofEudragit EPOand flavors

HPLC/UV(269nm)

n.s. Drug release ofthe pure API iscompared todrug release oftaste-maskedgranules

n.s. V: 10m: SSFpH: 6.8T: n.s.

Dissolution ofgranules; samplefiltration(Whatman filterpaper) beforeoff-line detection

60mg 5min (Huda andToshniwal,2013)

Atorvastatin ODT Coating withEudragit EPO

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

n.s. Based onEuclideandistances of theplaceboformulations tothe drugformulations

n.s. V: n.s.m:isopropylicalcohol 80%pH: n.s.T: n.s.

n.s. n.s. n.s. (Bhasin andGhosh, 2012)

Diclofenac(sodium salt)

ODF Addition ofsucralose,saccharine,xylitol, mint,licorice andsoft fruit flavor

e-tongue(Insent SA402B,bitternesssensors C00,AC0, AN0)

Yes Based onEuclideandistances of theplaceboformulations tothe drugformulations

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

Dissolution of oneODF

13.4mg After completedissolution

(Cilurzo et al.,2011)

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247

Diclofenacsodium (DSS),potassium(DPS), free acid(DFA)

ODTs, granules Coating withEudragit EPO

e-tongue(InsentTS5000Z,sensors AC0,AN0, CT0, AE1,C00, AAE, CA0)

In mg/100mlDFA: 0.55DSS: 313DPS: 1001000

Based onEuclideandistances of theplaceboformulations tothe drugformulations

n.s. V: 100m: purifiedwaterpH: n.s.T: n.s.

20 units of eachODT weredispersed in100mL of purifiedwater; samplefiltration (0.22mWhatman filter), ifnecessary

23.25mg 3min (Guhmannet al., 2012)

HPLC/UV(254nm)

n.s. Drug releaseafter 3min of thetaste-maskedformula-tions

248M.Pein


aceutics465

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Table 4 (Continued)


In vitroassessmenttool

Calibrationprocedure

Taste-maskingcriteria

IVIVC Dissolutionsettings

Sample(pre)treatment

Drug dose Samplingtimepoint

Ref.

NXP 1210 Lipid basedpellets

Lipids astaste-maskingagents


n.s. < 5% drug releasewithin 2min

n.s. V: 900m: KH2PO4bufferpH: 7.5T: 37a.i.: 75 rpmpaddle speed

Dissolution in USP33 paddleapparatus 2

50% drug load Drug releaseafter 2min,dissolutionmeasuredin-line

(Vaassenet al., 2012)

Ofloxacin Microspheres Addition ofEudragit E100


n.s. n.s. n.s. V: 25m:phosphatebufferpH: 6.8T: n.s.

Dissolution ofmicrospheres;sample filtrationbefore off-linedetection

100mg 5min (Malik et al.,2011)

OndansetronHCl

Microspheres Spray dryingwith Eudragit

E100, additionof chitosan andMethocel E15LV


n.s. Drug release after5 min

l of Ph

msP2r

tr11Hue2iicdd

tltn

3

ppHstammbaGa4

o(Hsad

3

dpfotpo3fotpdoet

M. Pein et al. / International Journa

ethods according to realistic conditions regarding the volume ofaliva in the oral cavity (Bora et al., 2008; Guhmann et al., 2012;reis et al., 2012; Shukla et al., 2009; Sona and Muthulingam,011), but only (Hoang Thi et al., 2012) and (Preis et al., 2012)eferred also to a flow rate of the human saliva of 1ml/min.

If the volume of saliva in the mouth of patients should be imi-ated for taste-masking evaluation, samples have to be dissolved ineal volumetric conditions considering a residual saliva amount of2ml in the oral cavity (Dodds et al., 2005; Lagerlf and Dawes,984; Siqueira and Nicolau, 2002; Watanabe and Dawes, 1990).owever, dissolution procedures have also been carried out in vol-mes up to 900ml according to pharmacopoieal setup (Albertinit al., 2004; Cerea et al., 2004; Kayumba et al., 2007; Shiino et al.,010; Singh et al., 2012; Sona and Muthulingam, 2011). Accord-ngly, the resulting kinetics donotmatchwith the realistic situationn themouth. But seen from the opposite perspective, the drug con-entration in the patients mouth might be inappropriate to matchecisive factors for the analytical dissolution evaluation (sink con-itions and the LambertBeer rule for linearity).To display real conditions in themouth, the force exerted by the

ongue and the real temperature in themouth as well as the osmo-ality of the saliva should also be considered. Realistic conditionso enable the development more reliable taste-masking determi-ation methods are listed in Table 5.

.1.2. Sampling procedureThe sampling procedures in literature differed in choice of time

oints and sampling frequency. One would expect comparableeriods for the in vitro evaluation and the in vivo evaluation.owever, most off-line performed experiments started after dis-olution times of 15min (Table 4), whereas the in vivo evaluationook place after seconds (Section 2.1, Table 1). But a drug releasefter 5min can hardly be a decisive factor to specify reliable taste-asking effects. Long dissolution times obviously offer a safetyargin; but at the expense of receiving a bitter error as a result andioavailability problems. Starting the analytical evaluation directlyfter a few seconds ismore reliable (Garsuch andBreitkreutz, 2009;uffon et al., 2012; Kayumba et al., 2007; Tokuyama et al., 2009),s highlighted in Fig. 3:Within the first minute, formulations 3 andhave already released around 80% of the contained drug.If the dissolutionwas evaluated using off-line UVmeasurement,

ften only one sample had been drawn (Table 4). In contrast, in-lineGuffon et al., 2012) and on-line experiments (Albertini et al., 2004;oang Thi et al., 2012) offered a continuous observation of the dis-olution profile, but it must be considered that peak broadeningnd a delayed detection may occur due to the tubes of an on lineissolution set up (Garsuch and Breitkreutz, 2009).

.1.3. Analytical assessment and data evaluationTaste-masking approaches like coating or complexation aim to

elay the release of the unpleasant tasting API during dissolutionrogress in the mouth. A success is assumed, if less API is releasedrom the taste-masked drug formulation compared to the pure APIr a comparable drug formulation without taste-masking charac-eristics. In literature, two different approaches are described torove this by means of UV spectroscopy. First, the concentrationf the released drug after predefined dissolution times (Section.1.2) is compared for taste-masked and non-taste-masked drugormulations using UV spectroscopy or HPLC/UV. The results basedn this method are even more of value, if the released concentra-ion is compared to the human threshold. For example Bora et al.ublished that the released concentration of ondansetron after a

issolution time of 5minwas below the human perception thresh-ld determinedwith a human taste panel (Bora et al., 2008). Shiinot al. defined a drug release below the human threshold withinhe first 10min of dissolution as successful taste-masking criteriaarmaceutics 465 (2014) 239254 249

(Shiino et al., 2010), but did not explain this choice. Apart fromthis approach, which was in both cases only based on one con-centration and time point, the success of a taste-masking has alsobeen discussed on the basis of the dissolution profile (Cerea et al.,2004;Guffon et al., 2012). A delayed initial drug releasewas thereindefined as desirable lag-time or delayed onset. In this context, Guf-fon et al. reported about an initial lag-time of 10 s before the slowprogressive drug release started (Guffon et al., 2012).

Regarding thedrug releases shown inFig. 4, formulation4wouldachieve a successful taste-masking for 8 s, while formulation 1would be defined as taste-masked for 84 s, if the human perceptionthreshold concentrationof themodel drugwere equivalent to a10%drug release according to (Siewert et al., 2003). None of the formu-lations would have been defined as taste-masked by Bora et al. orShiino et al., but evaluating the formulations by Guffon et al., initiallag-times of >10 s could be proven for formulations 13. The avail-ability of these data on the one hand and the comparability of thethreshold concentrations on the other hand are themain disadvan-tages of themethod that compares thehumanperception thresholdwith the released amount of drug. While for several drugs no per-ception threshold could be found in literature, for acetaminophen(paracetamol) e.g., at least two different threshold concentrationswere described: 0.35mg/ml in phosphate buffer pH 5.8 (Sharmaet al., 2012) and 1.08mg/ml in water (Albertini et al., 2004).

3.2. Determination of taste-masking properties by electronictaste sensing systems

3.2.1. Commercially available electronic taste sensing systemsThe commercially available electronic taste sensing systems are

supplied by Insent (Atsugi-Shi, Japan) and AlphaMOS (Toulouse,France). Based on their measurement principle, they are sensitiveto different ionic molecules (Woertz et al., 2011a). The sensorsof Insent are dedicated to the human taste attributes saltiness,sourness, sweetness, umami and bitterness. Additionally, there isone sensor that is sensitive for astringency. When measuring thesample, the change of membrane potential is registered. After ashort washing procedure, the potential is measured in the stan-dard solution to obtain the so called aftertaste or CPA value (changeof membrane potential caused by absorption). The CPA value is ameasure for the lipophilic character of the analyzed substancethemore lipophilic it is, the more it will be absorbed into the mem-brane and the higher will be the resulting CPA value. This value isdiscussed to correspond with the human perception of bitter andastringent (drug) substances (Kobayashi et al., 2010).

Theunderlying sensor technologyof theAstreeelectronic tastesensing system(AlphaMOS, France) is basedonchemicalfieldeffec-tor transistor technology. The supplier provides different sensorsets of seven sensors for pharmaceutical application, food appli-cation and one for validating bitterness intensity of new chemicalentities. Contrary to the Insent system, the sensors are not asso-ciated to taste attributes, but measure cross-selective. A detailedoverview on the set ups andmeasurement procedures of the Insentand Astree electronic taste sensing systems are given elsewhere(Pein et al., 2013; Woertz et al., 2010a, 2011a).

3.2.2. RationaleThe rational useof electronic taste sensing systems todetermine

taste-masking effects is based on their non-specific multi sensorapproach, which enables one to measure the activity of moleculeswithin a drug formulation. Togetherwith the ability of their sensorsto bind or interact with different chemical structures, they allow

one to assume an overall impression rather than only to determinethe concentration of the API. Best results for the determination oftaste-masking properties can be expected, if a (log-linear) depen-dency between concentrations of the unpleasant tasting API and


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

Saliva Tongue

Characteristics Residual volume Flow rate Osmolality pH dependingon age

Buffer capacity Temperature Force

Values 12ml 0.51ml/min 50100mosmol/kg 5.77.5 6.1mol/l 3536 C 0.135N

Literature (Dodds et al., 2005;Lagerlf and Dawes, 1984;Siqueira and Nicolau, 2002;Watanabe and Dawes,1990)

(Lagerlf andDawes, 1984;Zwier et al.,2013)

(Dibdin et al., 1986;Hermes, 2012)

(Hermes, 2012) (Zwier et al.,2013)

(Olsen, 2006) (Hermes, 2012)

nes (1

tpscAc

ttt(mt

Fig. 3. Typical in vitro sampling frequencies indicated by the dashed li

he sensor signal exists. Based on the potentiometricmeasurementrinciple this is most likely for charged molecules. Differences inensor signals can then be expected to be based on lower API con-entrations due to a successful taste-masking. An inclusion of anPI in cyclodextrins as described by Ono et al., could therefore beorrelated with a bitterness reduction (Ono et al., 2011).

It should be remarked at this point that a successful calibra-ion procedure using the API of interest is not substitutable byhe operational qualification procedures of the suppliers (condi-

ioning, calibration and diagnostic (AlphaMOS), sensor checkInsent)), which should be performed before sample measure-ent. These procedures only prove if the sensors comply with

he basic requirements of the suppliers by providing information

Fig. 4. In vitro dissolution profiles of four model formulations, 2, 3min) in comparison to the typical in vivo evaluation time of 30 s.

about the stability of the sensors as well as their discriminatingpower.

3.2.3. Dissolution stepMeasuring one individual sample takes at least the time period

the sensors need to equilibrate: AlphaMOS recommends evaluatingonly the mean value of the last 20 s of a measurement, which takes120 s in total.Using the Insent, onemeasurement takes30 s (Woertzet al., 2011a). Moreover, e-tongue sensors are sensitive to changes

in temperature and lose their performance in solutions of highertemperatures. The dissolution step has therefore to be carried outbefore the e-tongue measurement. Consequently, taste-maskingeffects can only be evaluated off-line.

combined with the in vivo human perception threshold.

l of Pharmaceutics 465 (2014) 239254 251

mtcotit(imiaf

3

sr2wtisa

afiiroapa

p(twtafitw

3

smm3adrffis0

acdma

Fig. 5. Calibration procedure of e-tongue sensors. Sensors 13 show concentrationdependent signals while sensor 4 lacks sensitivity.

Fig. 6. Schematic PCA map displaying sensor outputs of an electronic taste sensingM. Pein et al. / International Journa

In most studies, (purified) water is described as dissolutionedium (Table 4). In contrast to this dissolutionmedium, imitating

he physiological behavior of saliva, also beverages and foodmatri-es (e.g. pudding) as taste-masking matrices (Sadrieh et al., 2005)r isopropylic alcohol (Bhasin and Ghosh, 2012) were used. Whilehe use of beverages and food matrices seems reasonable, theres no rational explanation to use isopropylic alcohol. If described,he temperature of the dissolution medium has been set to 37 CGuffon et al., 2012; Tokuyama et al., 2009). However, inmost stud-es no detailed information on the temperature of the dissolutionedium was given, though the temperature has a likewise strong

mpact on the dissolution itself. Another high impact factorthegitation of the dissolution mediumhas only been described byew working groups (Table 4).

.2.4. Sampling procedureThe most critical but likewise least described step is the

ampling procedure. Measuring samples with electronic tonguesequires sample volumes between 25 or 100ml (Astree) and40ml (Insent) (Woertz et al., 2011a). These volumes cannot beithdrawn and filtered as quickly and easily as small volumes. Still,

he samples have to be filtrated immediately. The filtration processs required due to sensor robustness as particles could damage theensors. Additionally, filtration has to be performed immediatelyfter sampling to avoid ongoing dissolution.Filtering 25ml to 100ml does not necessarily allow an immedi-

te assessment, as this process can last up to 30 s depending on theltration setup. Additionally, accuracy and precision of the result-ng data are likely to be falsified, because the needed high volumeequires an individual dissolution experiment for each time pointf assessment and each repetition. Regarding the taste-maskingssessment based on electronic tongue measurements, the sam-ling is the most critical parameter and should be performed bypplying vacuum filtration and filters with a defined pore size.According to literature, at least some details on their sampling

rocedurewere provided by Tokuyama et al. (2009), Kayumba et al.2007) and Guhmann et al. (2012). Guhmann et al. described animmediate removal of the particles after the pre-defined dissolu-ion time of three minutes by microfiltration using a syringe fittedith a 0.22mWhatman glass microfiber filter. Kayumba et al. fil-

ered the samples after a specific time interval (15min) through0.45m filter. In both cases, the time that was needed for theltration was not provided. Although one could assume a short fil-ration time, the only detail that was provided by Tokuyama et al.as that the samples were filtered under reduced pressure.

.2.5. Analytical assessment and data evaluationTaste-masking properties are evaluated by comparing the

ensor signals of the taste-masked sample with the placebo for-ulation and the pure drug substance using univariate or mostlyultivariate statistics (Table 4). A successful calibration (Section.2) as performed by (Cilurzo et al., 2011), (Guhmann et al., 2012)nd (Guffon et al., 2012) served as the actual basis for univariateata analysis and provided a detailed overview for each sensoresponse (Guhmann et al., 2012). Fig. 5 displays such a success-ul calibration showing log-linear concentration dependent signalsor each sensor but sensor 4, whereby the sensor signals can eitherncrease or decrease depending on the composition of the sen-or membrane. The log-linear ranges of the sensors are between.00550mM (sensor 1) and 0.550mM (sensor 3).Regarding the e-tongue sensor response evaluation, multivari-

te data analysis (MVDA) is preferred. Most reliable information

an be assumed from those sensors showing a concentrationependency for the investigated drug (Woertz et al., 2011a). Forultivariate evaluation, a software is required that summarizesll sensor responses of the e-tongue and allows comparison ofsystem in a two-dimensional graph; the information of the pure API are comparedwith those of a drug-free formulation (placebo) and taste-masking approaches (for-mulation 1 and 2).

different formulations based on this complex information. A princi-pal component analysis (PCA) aims to reduce themultidimensionalsensor information. Themain information is then given in a two- orthree-dimensional graph, displaying the main discriminating fac-tors asprincipal component 1 (PC1) on the x-axes, PC2on the y-axesand PC3 on the z-axes. In the schematic PCA map (Fig. 6), the APIrepresents the unpleasant taste, while the drug-free formulation(placebo) displays the desired taste.

A pleasant taste for the drug formulation can be assumed, ifthe 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 distancesas the basis of eachmultivariate statistics can be calculated accord-ing to equation 2, where p and q represent the samples and n is thenumber 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 samplescan be calculated using these Euclidean distances as proposed by(Cilurzo et al., 2011). But although multivariate evaluation tech-niques like PCA are powerful tools to evaluate complex data, theymight produce erroneous results due to factors such as incorrect

classification (Goodner et al., 2001).

Based on the practical approach, beneficial results can beexpected, if additionally each excipient is measured separately toevaluate its effect on the electronic tongue signals. The amount of

2 l of Ph

pt

4

22icTtcttfidissrhadcdrpetrHhpcioH

Stitahfc2t

rirsa

5

aptie

52 M. Pein et al. / International Journa

ure drug and of the excipients should be comparable to those inhe drug formulation being investigated.

. Correlation of in vivo and in vitro taste assessments

Some authors correlated in vitro with in vivo results (Bora et al.,008; Hoang Thi et al., 2012; Kayumba et al., 2007; Sadrieh et al.,005; Shiino et al., 2010; Tokuyama et al., 2009). Results obtainedn comparative studies with electronic taste sensing systems dis-losedanagreementbetweenhumanpanels and the invitro results.okuyama et al. for example confirmed that the logarithmicallyransformed bitterness score of the conducted human taste panelorrelated well with increasing Euclidean distances obtained byhe sensor responses (Tokuyama et al., 2009). The scoring withinhe taste panelwas, however, a numerical one comprising numbersrom1 (hardly bitter) to 5 (very bitter). Kayumba et al. usedAstreen combination with a statistical model defined as bitterness pre-iction tool (Kayumba et al., 2007). This evaluation tool correlatesnstrumental sensor values with human sensory scores based on aet of bitter reference compounds. Thus, by analyzing the e-tongueamples with the bitterness prediction tool, they indirectly cor-elated them with the palatability ranking of the information ofuman taste panels. The implemented bitterness score is based onnumerical scale, providing 5 descriptors and 4 subdivisions perescriptor (14: undetectable, 48: slightly bitter,. . . 1720: unac-eptable). In their study, Kayumba et al. also observed the drugissolution profile by UV detection and compared the amount ofeleased drugwith the human perception threshold of quinine sul-hate given by Suzuki et al. (Suzuki et al., 2003) and Katsuragit al. (Katsuragi et al., 1997). Based on their results, they concludedhat the e-tongue data match better with the in vivo data than theesults of the UV detected drug dissolution (Kayumba et al., 2007).owever, details were neither provided about the drugs, whichave been utilized for the bitterness prediction module, nor aboutanelists based information, such as composition and training pro-edure. Regarding the drug dissolution, the approach to correlatenstrumental analytical data with the human perception thresh-ld was also performed by (Albertini et al., 2004; Bora et al., 2008;oang Thi et al., 2012; Shiino et al., 2010) (Table 4).Eckert et al. evaluated taste varying effects (Eckert et al., 2013).

till, their results on the taste evaluation of multicomponent mix-ures illustrated parts of the problem that have to be considered, ifn vivo and invitrodata are correlated. They revealed ahigher selec-ivity and sensitivity of the analytical in vitro methods e-tonguend HPLC/UV compared with the results based on a professionaluman taste panel. The analytical methods detected minor dif-erences regarding the composition of ingredients, while panelistsould only differentiate the most deviating samples (Eckert et al.,013). In addition to qualitative correlations, quantitative correla-ions also remained critical.

To judge about taste-masking success, in vivo data is stillequired independent of the analytical method. But even if thisnformation is available, the reliability of the analytical resultswithegard to the in vivo evaluation has to be proven. Therefore, ithould be verified that the analytical limit of quantitation of thepplied method is below the human perception threshold.

. Conclusions

Drug formulations are ideally taste-masked, if they provideneutral taste or at least a taste perceived identically to the

lacebo formulation. The most reliable method to determineaste-masking properties by detecting taste as overall gustatoricmpression including smell, mouthfeel, visual appearance andmotions, is performing a trained human taste panel. As it isarmaceutics 465 (2014) 239254

unlikely that the same number of panelists is available for eachstudy, a standardized training such as that described by (Albertiniet al., 2004; Suzuki et al., 2003) is needed. However, age and sex ofthe panelists should be defined in each published study, especiallyif the investigated drug formulations are assigned to a specialpatients group like the elderly or children. To avoid falsified tastemasking assessment, authors recommend administration of thedrug formulations as such, without any pretreatment.

The assessment of taste-masking properties by human tastepanels for drugs in the early stage of development is without doubtquestionable, due to ethical and toxicological concerns. In con-trast, analytical in vitro methods are safe and offer moreover theadvantage of objectified results. Bearing in mind the question ofreliability, a shift from one to the other methodology would bedesirable.

For the dissolution step of in vitro samples, real parameters inthe oral cavity such as volume, pH and osmolality of saliva as wellas the exerted tongue force should be considered, and have beenproposed in this review (Table 5). Future directions related withthis idea were also summarized by (Gittings et al., 2014). In-linedetection methods are strongly recommended over off-line detec-tionmethods, if the taste-masking approach is accompaniedwith adelayed release of the drug. So far, this can only be realizedwith UVdetection. Electronic tongue sensors need improvement to ensureshort equilibration times and higher robustness towards temper-ature and particles, which is required for dissolution studies. Foroff-line detection methods, 30 s is proposed as time point for thefirst sampling, as children with attention deficit hyperactivity dis-order and autistic disorder could be trained to swallow a tabletwithin this time span (Beck et al., 2005). To improve the relevanceof the off-line result, at least onemore sample should be taken afterone or two minutes of dissolution, imitating a longer swallowingprocess. For appropriate e-tongue results, these samples should befiltered immediately by applying a vacuum pump, as this handlingavoids ongoing dissolution.

Assuming that each critical aspect of the individualmethods canbe overcome, still the correlation of the results based on in vitromethods with those of a human taste panel remains challenging. Ahigher selectivity and sensitivity of the analytical in vitro methodse-tongue and HPLC/UV is expected compared with in vivo results.Taste-masking can only be assumed, if the released amount of APIdoes not exceed the human perception threshold within the pre-defined dissolution time. Therefore, it should be verified that theanalytical limit of quantitation of the applied method is below thehuman perception threshold.

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Taste-masking assessment of solid oral dosage forms-A critical review1 Introduction2 Inprotect protect unhbox voidb@x penalty @M {}vivo evaluation of taste-masking2.1 Panelists2.2 Administration and influence of pretreatment of drug formulations2.3 Time points of taste assessment2.4 Taste assessment

3 Inprotect protect unhbox voidb@x penalty @M {}vitro evaluation of taste-masking efficacy3.1 Determination of taste-masking properties by UV spectroscopy3.1.1 Dissolution step3.1.2 Sampling procedure3.1.3 Analytical assessment and data evaluation

3.2 Determination of taste-masking properties by electronic taste sensing systems3.2.1 Commercially available electronic taste sensing systems3.2.2 Rationale3.2.3 Dissolution step3.2.4 Sampling procedure3.2.5 Analytical assessment and data evaluation

4 Correlation of inprotect protect unhbox voidb@x penalty @M {}vivo and inprotect protect unhbox voidb@x penalty @M {}vitro taste assessments5 ConclusionsReferences

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