AAPS PharmSciTech (2023) 24:67

https://doi.org/10.1208/s12249-023-02520-z

REVIEW ARTICLE

Advancements in Modified-release Oral Drug Delivery - Delivery

throughout the Gastro-intestinal Tract

An Overview of Taste‑Masking Technologies: Approaches, Application,

and Assessment Methods
Shuqin Hu1,2 · Xiaoxuan Liu2 · Shuangshuang Zhang1 · Danyi Quan1

Received: 22 September 2022 / Accepted: 24 January 2023 / Published online: 14 February 2023
© The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists 2023

Abstract
It is well-known that plenty of active pharmaceutical ingredients (API) inherently possess an unpleasant taste, which influ-
ences the acceptance of patients, especially children. Therefore, manufacturing taste-masked dosage forms has attracted a lot
of attention. This review describes in detail the taste-masking technologies based on the difference in the taste transmission
mechanism which is currently available. In particular, the review highlights the application of various methods, with a special
focus on how to screen the appropriate masking technology according to the properties of API. Subsequently, we overviewed
how to assess taste-masking efficacy, guiding researchers to rationally design taste-masking formulations.

Keywords oral drug delivery · pediatric · taste-masking application · taste-masking assessment methods · taste-masking
technologies

Introduction the contents of the investigation of pediatric drug product

development plan measures specified in the pediatric regula-
Taste-masking techniques have drawn a great deal of atten- tions (EMA 2008) [5]. For these reasons, the review aims
tion in the pharmaceutical industry because an objectionable to evaluate and discuss approaches for improving the taste
taste of medications would reduce patient acceptance [1, 2]. of medicine.
The number of articles published on the Web of Science on
the topic of taste-masking increased by nearly 80% in the last
decade compared to the previous decade, especially for the Taste Transmission Mechanism
topic of cyclodextrins, ion exchange resins, solid dispersion,
and nanoemulsion (Fig. 1). Although there are diverse avail- Before we discuss these taste-masking techniques, it is
able taste-masking methods, none can meet the requirements noteworthy to perceive the pathways of taste transmission
of all the types of drugs, which creates a challenge in choosing in humans. According to research, human taste buds can
the appropriate technology for different kinds of API [3, 4]. recognize varied compounds but can only distinguish five
However, some regulatory authorities have continually primary tastes: sour, umami, salty, sweet, and bitter. Each
updated relative policies and guidelines about taste-masking basic sense of taste has a specific channel that recognizes
methods, especially for the pediatric population. For exam- the transmission of taste signals [6–8]. Sweet, umami, and
ple, taste-masking or palatability assessments were listed in bitterness trigger G protein-coupled receptors (GPCRs)
[9, 10]. Simultaneously, salty and sour transmit taste sig-
* Danyi Quan nals through the ionic pathway; the salty taste could trig-
[email protected] ger ENaC; however, this taste transmission has not been
1 extensively studied [6, 7, 11]. If sharing the same type of
Institute of Advanced Drug Delivery Technology, No.10
Xinghuo Avenue Jiangbei New Area, Nanjing 210032, channel, one taste would affect another taste’s perception,
People’s Republic of China which could be applied in taste-masking. For instance, in
2
China Pharmaceutical University, No. 639 Longmian comparison to acid agents, sweeteners are more suitable
Avenue, Nanjing 211198, People’s Republic of China for masking bitterness.

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Fig. 1  The articles published between 2003 and 2022 are searched on to taste-masking and flavoring agents). The number of articles on dif-
the Web of Science every 5 years with the following qualifier: (a) the ferent flavor-masking technologies in different periods is summarized.
literature type is paper, non-review paper; (b) the research direction is The results show that solid dispersion is the technology with the larg-
pharmacy; and (c) the topics contain taste-masking and different fla- est number of published papers in the past 5 years, followed by ion
vor-masking technologies (for example, the first data topic is limited exchange resin and taste correction agent, and prodrug is the lowest

Taste‑Masking Technology flavoring agents can be classified in a variety of ways.

There are two kinds of flavorings, artificial flavorings and
According to the taste transmission mechanism, taste- natural flavorings, which are identified by their source.
masking approaches were mainly classified into two types Some researchers disclosed that frequent consumption
depending on the taste transmission mechanism. The of artificial flavorings might increase the risk of vascular
first type involves blocking taste transmission pathways, events and obesity [12, 13]; thus, it should be prudent to
including flavoring agents and bitter inhibitors. Based on apply artificial flavorings. Meanwhile, the flavoring agents
a paper by Temussi PA, adding flavors would help to avoid are routinely divided into sweeteners, acidic flavors, and
the bitter taste of medicine by competing with the drugs aromatic agents based on their taste. For example, sucra-
to stimulate taste receptor cells (TRCs) [9]. The second lose and aspartame are regarded as sweeteners. However,
type involves preventing the release of the unacceptable there may exist some differences in the special taste for
tasting drug in the oral cavity, through the utilization of each flavoring, e.g., saccharin sodium would taste of metal
cyclodextrins, ion exchange resins, solid dispersions, or bitterness after the initial sweetness [14, 15].
polymer coating, prodrug, microcapsules, liposomes, and From the pharmaceutical industry’s point of view, add-
nanoemulsion. The following presents an overview and the ing flavors is a very attractive method because of its inher-
current status of taste-masking technologies. ently enjoyable taste. Several key elements in the use of the
method should be discussed. Firstly, adding the number of
flavoring agents to medication formulations reduces but can-
Blocking Taste Transmission Pathways not eliminate the bitterness of drugs. Hence, it is generally
used in conjunction with other taste-masking technology.
Flavoring Agents According to a study by Aladdin Alayoubi et al., the combi-
nation of ion exchange resins with sucralose, maple flavor,
Flavors are referred to as a sort of excipient that inherently and grape flavor could leave no undesirable taste of clinda-
possesses a pleasant taste and odor. They are incredibly mycin HCl [16]. Yangjie Wei et al. disclosed that HP-β-CD
important for improving patient compliance in oral for- (1:1) with 0.09% saccharin sodium has been considered the
mulations, which are widely used in post-market products best selection to mask the bitter taste of lidocaine hydro-
(Table I). chloride [17].
There are numerous flavor agents in practical appli- Secondly, the synergistic effect of a specific sugar com-
cation, such as sucralose, aspartame, mannitol, saccha- bination should be the main consideration, so the sort and
rin sodium, and citric acid. Under different principles, ratio of flavorings should be filtrated on a case-by-case basis

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AAPS PharmSciTech (2023) 24:67 Page 3 of 15 67

Table I  Summary of Commercially Available Products with Flavoring Agents

Trade name API Flavor agents Dosage form Marketing authoriza- Date of sale
tion holder

Nurtec Rimegepant sulfate Menthol, menthone, menthyl Orally disintegrat- Biohaven Ireland 2020–02-27
acetate, sucralose, vanillin ing tablet
Evekeo Amphetamine sulfate Anhydrous citric acid, malic Arbor Pharms LLC 2019–01-30
acid, sucralose
Qmiiz Meloxicam Anhydrous citric acid, aspartame, Tersera 2018–10-19
orange flavor
Vyvanse Lisdexamfetamine Mannitol, sucralose, artificial Oral chewable Takeda Pharms USA 2017–01-28
dimesylate strawberry flavor tablet
Xeljanz Tofacitinib citrate Grape flavor (natural), sucralose, Oral solution Pfizer 2020–09-25
and xylitol
Qdolo Tramadol hydrochloride Citric acid, grape flavor, sucra- Athena 2020–09-01
lose
Evrysdi Risdiplam Isomalt, mannitol, strawberry Genentech Inc 2020–08-07
flavor, sucralose
Fintepla Fenfluramine hydro- Cherry flavor, citric acid, sucra- Zogenix Inc 2020–06-25
chloride lose
Elyxyb Celecoxib Acesulfame potassium, banana Bdsi 2020–05-05
flavor, bubble gum flavor, pep-
permint flavor, sucralose
Ozobax Baclofen Citric acid anhydrous, natural Metacel Pharms LLC 2019–09-18
grape flavor, sodium citrate
dihydrate, sucralose
Gloperba Colchicine Artificial cherry flavor, anhy- Romeg 2019–01-30
drous citric acid, sucralose
Epidiolex Cannabidiol Strawberry flavor, sucralose Gw Res Ltd 2018–06-25
Prexxartan Valsartan Grape flavor, sodium citrate Carmel Biosciences 2017–12-19
dihydrate, sucralose
Xatmep Methotrexate sodium Sodium citrate, citric acid, Azurity 2017–04-25
sucralose
Xyzal Allergy 24 h Levocetirizine dihydro- Saccharin sodium Sanofi 2017–01-31
chloride
Xarelto Rivaroxaban Anhydrous citric acid, mannitol, Oral suspension Janssen Pharms 2021–12-20
sucralose, sweet and creamy
flavor
Noxafil Powdermix Kit Posaconazole Artificial cherry flavor, citric Msd Merck Co 2021–05-31
acid, sodium citrate dihydrate
Dificid Fidaxomicin Citric acid, mixed berry flavor, Cubist Pharms LLC 2020–01-24
sodium citrate, sucralose
Katerzia Amlodipine benzoate Citric acid, sodium citrate, Azurity 2019–07-08
sucralose
Tiglutik Kit Riluzole Saccharin sodium Italfarmaco Spa 2018–09-05
Diacomit Stiripentol Aspartame, sorbito Biocodex Sa 2018–08-20
Macrilen Macimorelin Acetate Saccharin sodium Novo 2017–12-20
Carospir Spironolactone Citric acid anhydrous, sodium Cmp Dev LLC 2017–08-04
citrate dihydrate, saccharin
sodium, banana flavor
Emflaza Deflazacort Sorbitol Ptc Therap 2017–02-09

during formulation development. In some cases, the bitter combined application of aspartame, saccharin sodium, ace-
taste of diclofenac acid oral films could be inhibited by pep- sulfame K, and isomaltose could mask the bitter taste of
permint flavorings, licorice flavorings, and trichiliocosm metformin [20].
mixtures [18]; the combination of granules and sour milk Thirdly, the acceptable daily intake (ADI) of sweeteners
powder could reduce the bitter taste of furosemide [19]; the is also worthy of attention. When preparing a formulation,

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if the limit is exceeded, there may be carcinogenic effects, temperature increment led to a decrease in the p-methoxy
elevated blood sugar, and other adverse reactions. This risk cinnamic acid inclusion complex's constant stability [40].
should be avoided, especially for pediatric patients [21, 22]. Several investigations have shown that cyclodextrins are
Meanwhile, in the pursuit of enjoyable mouthfeel, exces- an efficient tool to not only mask the taste but also enhance
sively palatable drugs could increase the compliance of the solubility in water for the drugs of BCS class II and
patient. Medication overdose and extraneous sweeteners IV [41]. Azathioprine, a water-insoluble API, improves
can cause physical harm to patients; these are things to be its solubility through the complex with cyclodextrin [42];
avoided, especially for children’s health [23, 24]. beta-cyclodextrin could improve the taste and solubility of
alpha-hydrocycholic and praziquantel [43, 44].
Bitterness Inhibitors Additionally, the stability constant of the drug/cyclodex-
trin complexation could assess the bitter masking efficiency
Ideally, a bitterness inhibitor would be universal for the major- as a reference [45–47]. Since the stability constant does not
ity of drugs to provide a pleasing mouthfeel via blocking the reach 100%, it is normal that a small amount of free drug
taste pathway [25]. Breslin has proposed that salt-type agents exists without complexing with cyclodextrin. The joint
had an inhibitory effect on bitter taste; as an example, sodium usage with other masking methods could suppress the bitter
acetate could potentially block bitter taste [26]. Ryusuke taste of the free drug to create a more pleasant taste. Besides,
Yoshida et al. demonstrated that endocannabinoids could cyclodextrins taste slightly sweet [48] and have a synergistic
improve sweet taste [27]. The research status of bitterness effect combining the application with sucrose [49].
suppressants was merely fit for a range of APIs with the same
features. In some cases, it has been found that chlorogenic acid Ion Exchange Resins
could relieve the bitterness of alkaline drugs in a dose-depend-
ent manner [28]. Probenecid has restrained the amargosa of Ion exchange resins are functional excipients, with a molecu-
salicylic acid by suppressing the bitter taste receptor [29]. lar weight exceeding 10,000 and a large internal cavity. They
Bitter inhibitors are currently limited for certain feature are being used in an ever-increasing way to mask the taste
drugs. If inhibitors that directly interdict a certain part of [50]. Studies have indicated that several medicines like clin-
the taste conduction channel could be researched, attention damycin hydrochloride, Fe (II), and clarithromycin could
should be paid to whether they would influence the taste of meet an acceptable level of taste through the complexing
normal foods [24]. Besides, Julie A Mennella et al. have veri- with ion exchange resin [51].
fied that the function of the same bitter inhibitors is signifi- Their taste-masking mechanism involves the drug entering
cantly dissimilar for patients in the different age groups [30]. the inner cavity of ion exchange resin to form a complexation,
and the complexation retains structural integrity in the neutral
oral environment, with minimal bitterness release. Under the
Preventing the Release of the Unacceptable Taste acidic environment in the stomach, the medicine was released
in the Oral Cavity from the complexation after being replaced by ­H+ [52].
There are a variety of ion exchange resins and marketed
Cyclodextrins (CD) drugs using ion exchange resins (Table II); thus, numerous
properties of ion exchange resins need to be investigated,
Cyclodextrin contains a hydrophobic hollow internal cav- including exchange capacity, cross-linking, ionization, par-
ity and hydrophilic external surface, with the advantage ticle size, and porosity. The exchange capacity could poten-
of high water solubility, non-toxicity, and high biological tially affect the performance of the drug resonates. In other
availability [31–33]. Based on “the rule of the likes dis- words, it is of value to elect a resin with adaptive capacity
solves each other,” cyclodextrin is appropriate for wrapping [50, 52]. Levamisole could be complexed with AmberLite
hydrophobic substances to avoid release in the buccal [34]. IRP-64, which is more suitable than AmberLite IRP-69 [53].
Fluconazole has achieved satisfactory taste after complexing Ion exchange resins are an excellent option for acidic and
with β-cyclodextrin and hydroxypropyl-β-cyclodextrin [35]. basic drugs. As an alternative, this is a question worthy of
The bitterness of propyl bromide and hydroxyphenyl has discussion about how to sort out ion exchange resins accord-
decreased by complexing with cyclodextrin [36]. ing to property of drugs. Firstly, the chemical structure of
The inclusion complexation would reach overall equi- the medicine helps determine whether to select a cation
librium, which could be presented as the stability constant exchange resin or anion exchange resin. For instance, ani-
of the drug/cyclodextrin complexes [37]. It is determined onic drugs like methylphenidate hydrochloride, betahistine
by multiple elements [38, 39], such as CDs type, solvent hydrochloride, and chlorpheniramine maleate were accept-
type, temperature, pH, reaction time, and the ratio of drug/ able for complexing with cation exchange resin to achieve
cyclodextrin complex. Dewi Isadiartuti et al. disclosed that taste-masking [54–56], whereas the basic drugs like rifampin

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Table II  Summary of Commercially Available Products with Ion Exchange Resins

Trade name API Adaptation disease Ion exchange resins Marketing author-
ization holder

Vesicare Ls Solifenacin succinate Muscarinic receptor antagonist Polacrilin Potassium Astellas

Tussionex Hydrocodone and chlorpheniramine Cough and upper respiratory symptoms Dowex ® 50 UCB Pharma
Ondansetron Ondansetron Nausea and vomiting Amberlite IRP-64 Barr Pharm
Novonorm Repaglinide Diabetes mellitus, type II Polacrilin Potassium Novo Nordisk A/S
Darvocetn 50 Acetaminophen; propoxyphene napsylate Symptoms of mild to moderate pain Amberlite Xanodyne Pharm
Tussicaps Chlorpheniramine and hydrocodone Upper respiratory combinations Amberlite IR 120 Hi-Tech Pharma

were fit for anionic exchange resin [57]. Secondly, sustained- Polymer Coating
release formulation can be prepared by microencapsulation or
coating of the resin complex. For example, amiloride hydro- Polymer coating was evidenced as a valuable strategy to
chloride is microencapsulated after complex formation with mask the taste [72]. Diclofenac granules decrease the appar-
ion exchange resin to achieve effective slow release [52, 58]. ent bitterness after coating with Eudragit ® E PO [73],
Eudragit® E 100 coating effectively masks the bitterness
Solid Dispersion (SD) of mirtazapine [74], and memantine hydrochloride coating
granules have achieved a pleasure taste [75].
Solid dispersion is a solid matrix in which the drug is amor- The coating film (Table III) is poorly soluble in the saliva
phously dispersed in the carrier and within the interaction medium, drug particles coated by these coating film could
existing between the drug and carrier [59]. In the mouth, the not dissolve in the oral cavity, and then the aim of taste-
carrier acts as a mask to prevent the medicine to trigger the masking has been achieved. Paracetamol (APAP) has been
taste buds. In the paper by Basheer Al-Kasmi et al., SD has coated by water-insoluble ethylcellulose polymers, thereby
achieved the desired effect in taste-masking [60]. having good palatability [76, 77].
As a mature technique for preparing solid dispersions, the Fluid-bed coating is the most extensively applied process
HME preparation method has been extensively used in the for polymer coating of highly effective and uniform disper-
pharmaceutical industry in that its high-throughput and eco- sion [82, 83]. Bitter drug substances, such as ondansetron
nomic value [61, 62]. Bees wax and cetyl alcohol achieves hydrochloride and bleomycin hydrochloride, were coated
a great masking of the bitterness when the coating amount with Eudragit® E PO to prepare orally disintegrating tablets
exceeds 5% w/w [63]. At a PMOL content of 30%, VA64 (ODT) with excellent taste [82, 84].
has made drugs appealing to patients [64]. When using coating technology, it is important to identify
Apart from taste-masking, solid dispersion could meet the the optimum coating film thickness of polymer which has
purpose of other specific applications through the rational the opposite effect on taste-masking and drug release [85].
selection of the polymer. If you would prefer to improve the In general, a higher molecular weight of polymers will lead
solubility and bioavailability of API, hydrophilic carriers like to a slower release of core materials. But when the particle
polyethylene glycol (PEG) could be selected. Artemether and size exceeds 250 µm, it would produce a gritty sensation
monoaminoglycyrrhizoylpentahydrate (GLY) solid disper- in the mouth, affecting the taste [86, 87], and the dissolu-
sion might inhibit bitterness and enhance the bioavailability tion rate could be influenced by the diameter of the coater
[65]. Acetaminophen and neomycin could form solid disper- [88–90]. Ulrike Stange et al. have confirmed that when the
sions to increase the solubility and stability [66]. ratio of naproxen sodium granules and Eudragit® E reached
If you aim to formulate enteric-soluble preparation, 1:1, the taste could be well-masked, and the release degree
selecting enteric-coated carriers such as cellulose acetate was the highest [76]. In addition, a diameter of the particles
hydrogen phthalate (CAP) for preparing solid dispersions larger than 100 mm is preferred to prevent particle cohesion
should be considered. Take erythromycin as an example, the during the coating process and to reduce the electrostatic
goal of suppressing the taste of bitterness and increasing the charges causing uneven coating [91].
dissolution rate in the intestinal tract has been achieved after
it was amorphously dispersed in the carriers [67]. Besides, it Other Taste‑Masking Technologies
is essential to investigate the stability of the solid dispersion
during long-term storage [68, 69]. It is also worth mention- Prodrug The design principle of prodrugs is to reduce the
ing that hot-melt extrusion is more suitable for thermally solubility of drugs in the oral cavity through several chemi-
stable drugs [70, 71]. cal modifications (such as esterification and amidation).

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Table III  Commonly Used Characteristic Material Application References

Coating Film Examples
Water-insoluble Eudragit® RL 30D Cetirizine [28]
Ethylcellulose Lafutidine [78]
pH-sensitive release Eudragit® E Azithromycin [79]
Kollicoat Smartseal ®30 D Quinine sulfate [80]
chitosan Ondansetron [81]

Studies have demonstrated that propiverine hydrochloride encapsulation of poorly water-soluble drugs while meeting the
has good organoleptic properties via modified chemical needs of masking and improving bioavailability [108]. Gert et
structure to influence the solubility in the saliva [92]. Moreo- al. confirmed the encapsulation of nano-self-emulsifying drug
ver, the bitterness of province salicylate is more minor than delivery system with clavulanic prepared into oral liquid sys-
that of province hydrochloride [93]. tem agent [109], and Andriy Dashevskiy et al. demonstrated
that the bitterness of medicine could be effectively masked by
Microcapsules Microcapsules wrap the tiny particles or drop- encapsulating with Kollicoat ® Smartseal 30D [110].
lets of the API (capsule core) with a thin layer, or membrane, Additionally, the prodrug strategy noted whether the
of another material (capsule shell). Their sizes typically chemically modified drug could rapidly transform into the
range from several micrometers to hundreds of micrometers parent drug structure after entering the gastrointestinal tract
[94–97]. Several main factors including pH values, tempera- [111–113]. For liposome strategy, this is more suitable for
tures, particle sizes, and additives can strongly influence the lipophilic substances than for hydrophilic substances [114,
encapsulation efficiency of microcapsules [98]. The drug 115]. Despite this, the reverse is true for inverted lipid nano-
delivery system seems to be promising for improving the particles (RLBNs). Take atomoxetine hydrochloride as an
acceptance of the drug. For instance, cetirizine hydrochloride example, which is loaded by RLBNs and then dispersed
has been encapsulated by Eudragit® E PO to block the trans- into liquid formulations to create an acceptable taste [116].
mission of bitter taste [99]; diclofenac sodium could form a
microcapsule system with ethyl cellulose-toluene-petroleum
ether [100]; Eudragit® L 100: API = 1:4 microcapsule has
achieved significant bitter taste-masking effect [101]. Application

Liposomes Liposomes have a special amphiphilic character. There are diverse taste-masking techniques, and each
They mostly form micelles or are organized as lipid bilayers method has a range of specific application situations, so
with the hydrophobic tails lined up against one another and the electing the appropriate flavor-masking technology is a
hydrophilic head group facing the water on both sides [102, highly challenging work for certain active pharmaceutical
103]. The technological strategies to achieve a taste-masking ingredients. Thus, we presented various taste-masked tech-
effect are highly suitable after wrapping the bitter medicine nologies for different types of active substances and sum-
with the spherical body [104]. Loratadine with obvious bitter- marized the selection rules based on the latest research.
ness could be masked by the encapsulation of liposomes [105].
Application in Oral Dosage Form
Nanoemulsion Nanoemulsions are thermodynamically
stable, isotropic, transparent, or translucent homogeneous Application in Oral Liquid Dosage Form
dispersion systems with particle sizes of 1 to 100 nm sponta-
neously formed by water, oil, surfactants, and cosurfactants, Oral liquid dosage forms include suspensions, solutions, and
which can avoid the transmission of adverse taste by encap- syrups that are available for oral administration, especially
sulating the drug into the internal phase. Crodamol GTCC, for populations with swallowing difficulties [117, 118]. Dur-
Glycerox 767HC, and Croduret 40 ss were applied for devel- ing formulation development, if you have failed to address
oping self-micro emulsifying formulations to achieve the the challenge of masking the taste of drugs, the preparation
effect of flavor-masking [106, 107]. would be tough to get the product to market, in that the drop-
lets of medicine are widely dispersed in liquids and easily in
The design of some drug delivery systems, including micro- contact with taste receptors in the mouth [119, 120].
capsules, liposomes, and nanoemulsions, could mask the taste According to the summary of papers and patents
and improve the bioavailability of drugs by manufacturing liq- (Table IV) of oral liquid preparations from 2017 to 2022,
uid dosage forms. Phospholipid liposomes were fitting for the the frequently utilized masking technologies include

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 Table IV  Summary of Oral Liquid Preparation in Papers and Patents from 2017 to 2022
Taste-masking technologies API Adaptation disease Ingredients Taste evaluation methods References

Flavoring agents Tranexamic acid Fibrinolytic hemorrhages Cherry-vanilla, peppermint, mint E-tongue sensors [123]
flavoring, and aspartame
Nucleoside and/or nucleotide Memory loss, dementia, and Cellulose, xanthan gum, geranium, Human volunteers [124]
reduced brain function alginate, galactomannans, and
mixture thereof
Atomoxetine Attention deficit hyperactivity Peppermint and orange flavors Human volunteers [125]
AAPS PharmSciTech (2023) 24:67

disorder
Bitterness inhibitors and (S)-N-(5-((R)-2-(2,5- Difluorophenyl)- Pain, inflammation, cancer, and Abelei®, FONA®, sucrose, - [126]
flavoring agents pyrrolidin-1-yl)-pyrazolo [1,5 a] certain infectious diseases sorbitol, sucrose, saccharines
pyrimidin-3-yl)-3-hydroxypyrroli- sucralose, thaumatin, and acesul-
dine-1-carboxamide fame K
Cyclodextrins Griseofulvin Dermatophyte and ringworm β-cyclodextrin E-tongue sensors [36]
infections
Praziquantel Infections caused by Schistosoma Sulfobutyl ether-β-cyclodextrin Animal testing [127]
worms
Polymer coating Berberine hydrochloride Diarrhea Mannitol E-E-E-E-E-tongue sensors, [128]
animal testing, and human
volunteers
Prodrug Hydroxychloroquine sulfate Uncomplicated malaria, lupus Ion-pairing agents E-tongue sensors [129]
erythematosus, and rheumatoid
arthritis
Microcapsules Cefpodoxime proxetil Bacterial infections Phytantriol E-tongue sensors [130]
Propranolol hydrochloride Hemangioma Eudragit® E PO E-tongue sensors [131]
Indinavir HIV Monoolein Human volunteers [132]
Liposomes Atomoxetine hydrochloride Attention deficit hyperactivity Liposome Human volunteers and in vitro [116]
disorder (ADHD) taste assessment
BER, quinine sulfate, gentiopicroside, - Amphiphilic block copolymers E-tongue sensors, animal testing, [133]
and matrine and human volunteers
Mefloquine Malaria prophylaxis 1,2-Stearoyl-sn-glglycerol- E-tongue sensors [108]
phosphocholine (DSPC) and
cholesterol
Nanoemulsions Ibuprofen Defervescence Oil phase: orange peel and corn E-tongue sensors, animal testing, [134]
oils (3:7, w/w) and ibuprofen and human volunteers
Efavirenz Burning mouth syndrome Campus PG8 NF, Cremophor E-tongue sensors and human [109]
RH40, and Transcutol HP were volunteers
selected as oil, surfactant, and
co-surfactant
Cyclodextrins and flavoring Cefixime Gastroenteritis and colitis without Sulfobutylether-β-cyclodextrin and Human volunteers [122]
agents specification of infectious agent histidine
Ion exchange resin and Quinine sulfate dihydrate, diclofenac - Kollicoat Smartseal 30D and ion Human volunteers [110]
polymer coating sodium exchange resin
Page 7 of 15 67

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cyclodextrin complexation, ion exchange resin, liposomes,

References microcapsules, and nanoemulsions. In some cases, cefix-
[135]

[136]

[137]
ime complexed with cyclodextrin and chloroquine diphos-
phate was coated by Eudragit® E 100, respectively, and
then developed into an oral suspension to have excellent
palatability [121, 122].
Taste evaluation methods

Application in Oral Solid Dosage Forms

Human volunteers

Human volunteers
E-tongue sensors

In recent years, oral fast-release solid dosage forms (such as

oral film, orally disintegrating tablet, and dispersible tablet)
have raised concerns in usage despite their advantages of
good stability, accurate dosing, easy manufacturing, small
packaging size, and easy handling by patients [138–140].
Eudragit® RS 100 and Pullulan
Amberlite IPR64, sorbitol, and

When the solid formulation disintegrates into small parti-

Eudragit® E PO and Sorbitan

cles, it inevitably dissolves in the saliva, thus triggering a

taste receptor. Consequently, palatability continues to be
the main obstacle to the development of oral solid systems.
Besides, it is significant for solid dosage forms to judge the
risk of subsequent processes. Taking a pressed tablet as an
Ingredients

sucrose

example, considering the quantity of compression hardness

is critical for the integrity of masking particles in that high
pressing power is more prone to causing the cracking of
particle/powder coating film [141, 142].
Based on the summary of papers and patents (Table V)
of oral solid formulations in 2017–2022, regular masking
techniques include cyclodextrin, ion exchange resin, solid
dispersion, and polymer coatings. Ibuprofen and meth-
Adaptation disease

Anti-inflammatory

acrylate copolymer were formulated into solid dispersion

and further prepared orally disintegrating tablets [121].
In addition, we should pay attention to the diameter of
Anemia

granules disintegrated which would affect the taste. For

HIV

oral films and orally disintegrating tablets, drug loading

is also a noteworthy issue [24].

How to Choose the Rational Method According

to API?

After detailing the application of each masking method, it

is vital to know how to filter an appropriate taste-masking
method conformed to drug properties (Fig. 2). First, we
Prednisone
Saquinavir

should measure the initial taste of API by investigating

Fe (II)

information or evaluative methods. Generally, the first

API

choice is to use flavoring agents to mask the taste.

After that, if the taste is still unacceptable, we should
Microcapsules and flavoring
Taste-masking technologies

Polymer coating and flavor-

survey the physical and chemical properties of API, which

Ion exchange resins and

is the key factor to influence the choice of flavor-masking

Table IV  (continued)

approach. For instance, if the drug is the ionic type with

flavoring agents

a large molecule structure, ion exchange resins are worth

ing agents

trying [56]; if it is a hydrophobic drug, cyclodextrin inclu-

agents

sion is applicable [41]; if it is a heat-stable drug, the hot-

melt extrusion method is worth recommending [71]; if

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 Table V  Summary of Oral Solid Preparation in Papers and Patents from 2017 to 2022
Taste-masking technologies API Adaptation disease Ingredients Taste evaluation methods References

Flavoring agents Ibuprofen Anti-inflammatory analgesic Gelatin - [143]

Diclofenac Anti-inflammatory analgesics Namely mint, licorice mint, and - [144]
sucralose
Amphotericin B Oropharyngeal candidiasis Sorbitol - [145]
Quetiapine fumarate The positive and negative symptoms of Artificial flavor, artificial grape flavor, - [146]
psychosis artificial mint flavor, ascorbic acid,
AAPS PharmSciTech (2023) 24:67

ascorbyl palmitate, and aspartame

Cyclodextrins Captopril Hypertension β-cyclodextrin Human volunteers [147]
Catechin - β-cyclodextrin Human volunteers [148]
Ion exchange resins Clarithromycin Bacterial infections Indion® 234 - [53]
Betahistine hydrochloride Anti-vertigo Ion exchange resin E-tongue sensors [55]
Cetirizine hydrochloride Cold or allergy symptoms Ion exchange resins Human volunteers [149]
Solid dispersion Itraconazole Fungal infections of the fingernails or PVP/PVA, HPC, and Soluplus E-tongue sensors [150]
toenails
Isoniazid Tuberculosis Eudragit® E PO E-tongue sensors and animal [151]
testing
Macrocyclic compounds Hepatitis C virus (HCV) infection Poloxamer, polyvinylpyrrolidone, and - [152]
hydroxypropyl cellulose
Polymer coating Acetaminophen Ild to moderate pain, to treat moderate Ethylcellulose - [66]
to severe pain in conjunction with opi-
ates, or to reduce fever
Propranolol hydrochloride Hemangioma Eudragit® E PO E-tongue sensors [131]
Chlorphenamine maleate Antiallergic Kollicoat Smartseal 100P Human volunteers and animal [153]
testing
Sacubitril and valsartan Cardiovascular and renal diseases HPMC, PVP - [154]
Liposomes Mefloquine Malaria prophylaxis and treatment 1,2-stearoyl-sn-glycerol-3-phosphocho- E-tongue sensors [108]
line (DSPC) and cholesterol
Paracetamol Headache, muscle aches, arthritis, back- Cetyl alcohol, triple pressed stearic - [155]
ache, toothaches, colds, and fevers acid, and cetyl ester
Microcapsules Solid forms of a stimulator of NO related disorders Hydroxypropyl-methylcellulose, - [156]
soluble guanylate cyclase hydroxypropyl cellulose, glyceryl
monostearate, glyceryl stearate, and
wax
Polymer coating and solid Enrofloxacin Uncomplicated and complicated Double-coated by Stearic acid solid Animal testing [157]
dispersion infections(pig) dispersion and Chitosan-alginate
microparticle
Solid dispersion and flavor- Co-trimoxazole (SMX and Pneumocystis carinii pneumonia Sweetness and Eudragit ®E 100 Human volunteers [158]
ing agents TMP)
Microcapsules and flavor- Sucrose octaacetate - Stearic acid, pullulan, and Sucralose Human volunteers [159]
ing agents
Page 9 of 15 67

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67 Page 10 of 15 AAPS PharmSciTech (2023) 24:67

Fig. 2  An introduction to the idea of choosing a commonly used taste-masking method based on the nature of the API. For example, if the drug
is heat stable, you can try to prepare a solid dispersion with a suitable carrier by hot-melt extrusion for taste-masking purposes

it is a drug with the poor bioavailability, you can apply take animal testing as a taste assessment tool, it is crucial
the solid dispersion, cyclodextrin, ion exchange resin, to improve the reliability of the result through a pre-exper-
microcapsule, composite emulsion, or liposome [103]. In iment that measures the deviation ratio of taste evaluation
addition, it must be kept in mind that the addition of the trials between mice and human volunteers. In this case, an
flavoring agents could be used in conjunction with other enlarged sample could have the same effect.
methods to provide the desirable taste [16, 17].

Electronic Taste Sensing Systems (E‑Tongues)

Taste Assessment Methods The electronic tongue detects the diverse degree of taste and
subsequently presented response signals in precise numbers
Owing to the result of the taste assessment trial, it would based on a multi-sensor array [109]. The applied electronic
play a guiding role in screening the taste-masking technology tongue sensor can indicate a different association between the
and adjusting the manufacturing parameters. It is essential to physical and chemical properties of the applied medium and
describe in detail the widely used taste assessment apparatus the efficiency of masking the taste [134]. It has the advan-
and methodologies, containing animal testing, electronic taste tages of non-specificity, high sensitivity, and non-subjectivity.
sensing systems, and human volunteers [160]. We should focus on several parts. Firstly, the taste
evaluation consequence of electronic tongue is based on
abundant data. Secondly, it poses a challenge in response
Animal Testing to small differences in taste, such as after-bitter and per-
sistent bitter and bitter with hemp; thus, it prefers to adapt
It is well-known that animals have a “brief-access taste for preliminary exploration in the laboratory [165, 166].
aversion (BATA) model” just like humans [161]: they tend
to eat more of what they like and eat less of what they dis-
like. Albini Noor Jahan et al. have confirmed that rat and Human Volunteers
human volunteers would respond similarly in the face of
dainty and aversive tastes [162]. Thereby, we could use As we all know, the most accurate and standard evalua-
rats instead of humans to evaluate taste [163]. tion method is human volunteers’ taste assessment [167].
Another study shows that the solubility of drugs in rat However, they may not be the same among the evalua-
saliva was different from that in humans, so the animal tion results due to the influence of people’s health status,
trial was inadvisable [164]. Given the above, if we aim to diet, and aging [168], which should be considered in the

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experimental design. Deviations might be reduced after Conflict of Interest The authors declare no competing interests.
enlarging the sample or describing the taste in plenty of
detail. In addition, it should be noted that all human vol-
unteers would be informed and approved by the Scientific References
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critically for important intellectual content; Xiaoxuan Liu, substantial zen H. Development of a taste-masked oral suspension of clin-
contributions to the conception or design of the work; Shuangshuang damycin HCl using ion exchange resin Amberlite IRP 69 for use
Zhang, substantial contributions to the conception or design of the in pediatrics. Drug Dev Ind Pharm. 2016;42:1579–89.
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