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WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
Vandana et al.
World Journal of Pharmacy and Pharmaceutical Sciences
SJIF Impact Factor 2.786
Volume 3, Issue 8, 293-316.
Review Article
ISSN 2278 – 4357
MODERN TASTE CONCEALING TECHNIQUES IN
PHARMACEUTICALS: A REVIEW
Vandana Patil*, Vrushali Tambe, Bebee Pathare, Shashikant Dhole
Progressive education society’s Modern college of pharmacy (for ladies) Moshi, Pune412105, India
Article Received on
18 May 2014,
Revised on 16 June
2014,
Accepted on 09 July 2014
ABSTRACT
Taste is a critical factor in development of oral dosage form. Taste
masking is important for bitter drugs to improve the patient compliance
especially in the pediatric and geriatric populations. Two approaches
commonly used to overcome the bitter taste of drug are reduction of
*Correspondence for Author
Vandana Patil
drug solubility in the saliva and alteration of the ability of the drug to
Progressive education society’s
interact with taste receptors. These techniques not only mask the taste
Modern college of pharmacy
of drug, but also may enhance the bioavailability of dosage form. The
(for ladies) Moshi, Pune India
recent techniques of taste masking are inclusion complexation, use of
ion exchange resin, mass extrusion, and solid dispersions, coating
granulation, spray drying, microencapsulation, liposomes, emulsions and gel formation
effervescence. Evaluation of taste concealed formulation is done by panel testing,
measurement of frog taste nerve response, multichannel taste sensor and spectrophotometric
method.
Keywords: Taste, Taste bud and receptors, Taste masking, Methods, and Evaluation.
1.INTRODUCTION
Taste is an important factor in the development of an oral dosage form. Taste can be
categorized into five types viz. sweet, sour, salty, bitter, and umami or savory. Within hours
after birth the infants reject bitter taste and prefer sweet and umami taste. Taste buds
regenerate every two weeks. As with many of the senses, taste becomes altered as a function
of the aging process, which explains why most children find certain flavors to be too ‘strong’
when adults do not(1).
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Oral administration of bitter drugs with an acceptable degree of palatability is a key issue for
health care providers, especially for pediatric patients. To overcome this problem several
techniques are evolved to mask the bitter taste of drugs. These techniques not only serve to
mask the taste of a drug but also enhance the bioavailability of drug dosage forms. Various
methods
like
coating,
inclusion
complexes,
prodrug
approach,
microencapsulation,granulation, and adsorption, addition of flavors and sweeteners, ion
exchange resins are used for masking the taste of obnoxious drugs(1).
There is often correlation between the chemical structure of a compound and its taste. Low
molecular weight salts tend to taste salty where as high molecular weight salts tend toward
bitterness. Nitrogen containing compounds, such as alkaloids, tend to be quite bitter. Organic
compounds containing hydroxyl groups tend to become increasingly sweet as number of OH
group increase. Receptor mechanism involves initial depolarization at apical receptor site,
which causes local action potential in receptor cell. This in turn causes synaptic activation of
the primary sensory neuron (1).
2.Ideal properties for taste masking process (2)
Any taste masking process should exhibit following properties:
1.It should require minimum number of excipients for an optimum formulation.
2.It should have not any adverse effect on drug bioavailability.
3.It should involve least number of equipment’s and processing steps.
4.It should be carried out at room temperature.
5.Require excipients that are economical and easily available.
6.Least manufacturing cost.
7.Rapid and easy to prepare.
8.Require excipients that have high margin of safety.
3.Taste masking techniques
To achieve the goal of taste abatement of bitter or unpleasant taste of drug, various
techniques are reported. These are as follows:
3.1 Addition of flavoring and sweetening agents
3.2 Microencapsulation
3.3 Ion-exchange
3.4 Inclusion complexation
3.5 Granulation
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3.6 Adsorption
3.7 Prodrug approach
3.8 Bitterness inhibitor
3.9 Multiple emulsion technique
3.10 Gel formation
3.11 Miscellaneous
3.12 Hot melt coating
3.1 Taste masking with flavors and sweeteners
Masking of bitter taste by use of sweeteners is the simple approach. But this approach is not
very successful for highly bitter drugs. Sweeteners and flavors are generally being used along
with other taste masking techniques to improve the efficiency of this technique. Cooling
effect of certain flavoringagents aids in reducing perception of bitterness.There are a wide
range of alternative sweeteners in the market today. Table 1 presents a compilation of the
most common artificial and natural sweeteners used in pharmaceutical products and their
relative sweetness levels. Synthetic sweeteners such as aspartame and sucralose are
commonly used in most taste masked products. Recently, sweeteners of plant origin such as
stevia and glycyrrhizin have emerged as a viable alternative to the artificial sweeteners (3).
Table 1: List of commonly used sweeteners and their relative sweetness
Sweetening
agent
Aspartame
Acesulfame
potassium
Glycyrrhizin
Mannitol
Saccharin
Relative
sweetness
200
137-200
Comments
Solubility
Less stable in solution
Bitter in higher concentration
Slightly soluble in ethanol
Slightly soluble in ethanol
50
0.60
450
Moderately expensive
Negative heat of solution
Unpleasant after taste
Sucrose
Stevia
Sucralose
1(standard)
300
600
Most commonly used
Artificial sweetener
Synergistic sweetening effect
Soluble in water and alcohol
Soluble in alkali
Rapidly soluble in dilute
ammonium solution
Soluble in water
Soluble in water and ethanol
Freely soluble in water,
ethanol and methanol
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Table 2: Classification of flavoring agents(4)
Type
Natural
Artificial
Natural and artificial
Example
Peppermint
Vanilla
Strawberry
Comments
Less stable
Highly stable
Effective at low concentration
3.2 Taste masking by microencapsulation
It is important to understand that only soluble portion of the drug can generate the sensation
of taste and it is possible, or even likely, that coating the active drug with a properly selected
polymer film can reduce its solubility in saliva and thus taste could be masked. Coating the
drug particles creates a physical barrier between the drug and the taste buds and the taste of
active could be masked.
Microencapsulation is a process by which very tiny droplets or particles of liquid or solid
material are surrounded or coated with a film or polymeric material to mask the taste of bitter
drugs as well as to achieve better bioavailability. Coating agents employed in
microencapsulation are gelatin, povidone, HPMC, ethyl cellulose, carnauba wax,
acrylatesand shellac. In this method, bitter drugs are first encapsulated to give free flowing
microcapsules which are then blended with excipients and compressed into tablets.Coating
the active drug with a properly selected polymer film can reduce its solubility and taste could
be masked.
Advantages
 Taste masking can be achieved with the desirable fast or controlled drug release.
 Bitter liquids may be coated to convert them to solid particles.
 The coated bitter particles can adapt to a wide variety of dosage forms and product
applications.
 The goal of microencapsulation may be accomplished by any of the following techniques.
In literature first four techniques of microencapsulation have been reported for taste masking
purposes, as shown Table 3.
1. Air suspension coating
The air suspension coating process can appropriately be described as an upward moving,
expanded, fluidized bed in central portion of the coating chamber coupled with a downwardmoving, more condensed fluidized bed on the periphery of the column.Three types of air
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suspension coaters are available, namely, top spray coater, wurster bottom spray coater and
tangential spray coater.
2. Coacervation- phase separation
Coacervation-phase separation involves following three steps.
A) Formation of three immiscible chemical phases- The first step of coacervation phase
separation involves the formation of three immiscible chemical phases: a liquid vehicle
phase, a coating material phase and a core material phase. The three phases are formed by
dispersing the core material in a solution of coating polymer, the vehicle phase is used as a
solvent for polymer. The coating material phase consists of a polymer in aliquid phase, is
formed by using one of the of phase separation- coacervation method, that is by changing the
temperature of the polymer solution, by adding a solution, or by inducing a polymer- polymer
interaction.
B) Core material phase –The process consists of depositing the liquid polymer coating upon
the core material. This is accomplished by controlled, physical mixing of the coating material
and the core material in the manufacturing vehicle. Deposition of the liquid polymer coating
around the core material occurs if the polymer is absorbed at the interface formed between
the core material and the liquid vehicle phase, and this adsorption phenomenon is a
prerequisite to the effective coating.
C) Coating material phase- The process involves the rigidizing the coating, usually by
thermal, cross-linking or desolvation techniques, to form self-sustaining microcapsule.
3. Spray drying and spray congealing
Spray drying and spray congealing processes are similar in that both involve dispersing the
core material in a liquefied coating substance and spraying or introducing the core coating
mixture into some environmental condition, whereby, relatively rapid solidification (and
formation) of the coating is affected. The principal difference between the two methods is the
means by which coating solidification is accomplished. Coating solidification in the case of
spray drying is effected by rapid evaporation of a solvent in which the coating material is
dissolved. Coating solidification in spray congealing methods, however, is accomplished by
thermally congealing a molten coating material or by solidifying a dissolved coating by
introducing the coating - core material mixture into a non-solvent. Removal of the non-
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solvent or solvent from the coated product is then accomplished by sorption, extraction, or
evaporation techniques.
4. Solvent evaporation
The processes are carried out in a liquid manufacturing vehicle. The microcapsule coating is
dissolved in a volatile solvent, which is immiscible with the liquid manufacturing vehicle
phase. A core material to be microencapsulated is dissolved or dispersed in the coating
polymer solution. With agitation, the core coating material mixture is dispersed in the liquid
manufacturing vehicle phase to obtain the appropriate size microcapsule. The mixture is then
heated (if necessary) to evaporate the solvent for the polymer. In the case in which the core
material is dispersed in the polymer solution, polymer shrinks around the core. In the case in
which core material is dissolved in the coating polymer solution, a matrix - type microcapsule
is formed. Once all the solvent for the polymer is evaporated, the liquid vehicle temperature
is reduced to ambient temperature (if required) with continued agitation. At this stage, the
microcapsules can be used in suspension form, coated on to substrates or isolated as powders.
5. Multiorifice- Centrifugal process
Processing variables include the rotational speed of the cylinder, the flow rate of the core and
coating materials, the concentration and viscosity of the coating material, and the viscosity
and surface tension of the core material. The Multiorifice- centrifugal process is capable of
microencapsulating liquids and solids of varied size ranges, with diverse coating materials.
6. Pan coating
The pan coating process, widely used in the pharmaceutical industry, is among the oldest
industrial procedures for forming small, coated particles or tablets. The particles are tumbled
in a pan or other device while the coating material is applied slowly. The problem of bitter
and obnoxious taste of drug in pediatric and geriatric formulations is a challenge to the
pharmacist. In order to ensure patient compliance bitterness masking becomes essential.
Molecule interacts with taste receptor on the tongue to give bitter, sweet or other taste
sensation, when they dissolve in saliva.
7. Interfacial polymerization
The methods involve the reaction of monomeric units located at the interface existing
between a core material substance and a continuous phase in which the core material is
dispersed. The continuous or core material supporting phase is usually a liquid or gas, and the
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polymerization reaction occurs at a liquid-liquid, liquid-gas, solid-liquid, or solid-gas
interface(5).
Table 3: Examples of Taste concealed bitter drugs by microencapsulation
Sr.no Drug
Technique
1
Wurster
fluid Croscarmellose
bed coating
Eudragit
RL
30D,RS3OD
Eudragit
NE30D/RL30D, HPMC
Eudragit E100, cellulose
acetate
Acetaminophen
Caffeine/cimetidine
Ciprofloxacin
Levofloxacin
2
3
3
4
5
6
Sildenafil citrate
Chlorpheneramine
maleate
Dextromethorphan
Hydro bromide
Acetaminophen
Coating agent
Top spray fluid Eudragit NE30D,
bed coating
E-100
Ethyl cellulose
PVP-K30
Tangential spray Eudragit
E-100,
fluid bed coating Cellulose acetate
Theophylline
Eudragit NE30D, guar
gum
Ampicillin trihydrate Spray drying
Sodium CMC
Nizatidine
Eudragit E-100
Roxithromycin
Eudragit RS100/RL100
Clarithromycin
Spray
Glycerylmonostearate,
congealing
Eudragit E100
Chloroquine
Coacervation
Eudragit RS100
diphosphate
phase
Separation
Metronidazole
Solvent
Eudragit E, Fattibase
Evaporation
Dosage form
Ref.
Dispersible
tablet
Chewable
tablet
Oily
suspension
sachets
Suspension
Mouth melt
tablet
6
7
8
9
10
11
Chewable
tablet
Dry
suspension
Powders
Sprinkles
suspension
Powders
12
Powders
18
Dry
suspension
19
13
14
15
16
17
3.3 Taste masking using ion exchange resin
Ion exchange resins are synthetic inert organic polymers consisting of a hydrocarbon network
to which ionisable groups are attached. They have ability to exchange their labile ions for
ions present in the solution with which they are in contact.The most frequently employed
polymeric network used is a copolymer of styrene and divinyl benzene (DVB). Apart from
this other polymers such as those of acrylic and Methacrylic acid cross linked with DVB and
containing appropriate functional groups, have been used as ion exchange drug carriers (20,
21). Four major types of ion exchange resins are available which are summarized in Table 4
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Table 4: Examples of Common Ion exchange resin
Sr.no
Type
1
Strong
cation
2
Weak
cation
3
Strong
anion
Weak
anion
4
Exchange
species
-SO3H
Polymer
backbone
Polystyrene
DVB
Commercial resins
-SO3Na
Sodium
polystyrene
Meth acrylic
acid DVB
Tulsion T-344, Amberlite IPR 69,
Indion 254
Amberlite IRC50, Indion204, kyron-T- 23
104, Kyron-T-114, Tulsion-T-335
Tulsion T-339, Indion 234, kyron-T-134
Amberlite IR400, Indion 454
24
-COOH
-COO-K+
N+R3
N+R2
Polystyrene
DVB
Polystyrene
DVB
Amberlite IR 120, Dowex
Indion244, kayron-T-154
Amberlite IR 48, Dowex 2
Ref.
50, 22
25
Mechanism of binding of ion exchange resin with drugs:
Insoluble ion exchange resins may be supplied in case of cation exchangers as sodium,
potassium or ammonium salts and of anion exchangers usually as the chloride. It is frequently
necessary to convert a resin completely from one ionic from to another. Charged drugs are
normally loaded on to ion exchange resins by two methods viz, column method and batch
method (26,27).
Column method
Highly concentrated drug solution is passed through the column containing resins. Maximum
efficiency is best obtained by the column method.
Batch method
In this method the drug solution is agitated with a quantity of resin until equilibrium is
attained.
The reaction involved during complexation of drug with resin may be indicated as follows
(28).
Re-COO-H⁺ +Basic drug⁺⟶Re-COO-Drug⁺+ H⁺
Re-N⁺(CH3)3Cl¯ + Acidic drug¯ ⟶ Re-N⁺(CH3)3 Drug¯ + Cl¯
Upon ingestion, drugs are most likely eluted from cation exchange resins by H+, Na+ or K+
ions and from anion exchange resins by Cl-, as these ions are most plentiful available in
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gastrointestinal secretions. Typical reactions involved in the gastrointestinal fluids may be
envisaged as follows:
In the stomach
Re-COO-Drug+ +HCl ⟶ Re-COOH + Drug Hydrochloride
Re-N(CH3)+3 Drug- + HCl ⟶ Re-N(CH3) 3 Cl + Acidic drug
In the intestine
Re-COO-Drug + + NaCl⟶ Re-COONa + Drug Hydrochloride
Re-N(CH3) + 3 Drug- + NaCl ⟶ Re-N+(CH3) 3 Cl + Sodium salt of drug
Exchange capacity
The exchange capacity of an ion exchange resin refers to the number of ionic sites per unit
weight or volume (meq/gram or meq/ml).
Sulfonic acid resin derived from polystyrene matrix have lower exchange capacities, about 4
meq/gm, than carboxylic acid resin derived from acrylic acid polymer, about 10 meq/gm,
because of bulkier ionic substituents of sulfonic acid resin and polystyrene matrix(26).
Weak acid cation exchange resins have a pKa value of about 6, so that at pH 4 or above their
exchange capacity tends to increase. Ionization of weak acid cation exchange resin occurs to
an appreciable extent only in alkaline solution, i.e., in their salt form. This is reported that
their exchange capacity is very low below pH 7 and moderately constant values at pH about
9.
Ion exchange resins are used in drug formulation to stabilize the sensitive components (29),
forsustain release of the drug (30-34), and for taste masking. Interaction of amine drugs with
polycarboxylic acid ion exchange resinindicated that these resins may be quite useful in taste
coverage.Thesestudies indicated that saliva, with an average pH of 6.7 and a cation
concentration of 40meq/1, would only elute a limited percentage of drug from adsorbates.
However rapid elution would occur as soon as the adsorbates is exposed to the low pH of the
stomach. The particle coating of polycarboxylic acid ion exchange resin adsorbates can also
be considered as a method for achieving taste coverage (35-39).
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Taste masking of bitter drugs using in strong acid cation exchangers
Sulphonation
In sulphonation reaction the polystyrene beads contacted at high temperature with
concentrated sulphuric acid. The product is a polystyrene sulphonate, which is a strong acid.
The hydrogen and sodium forms of strong acid resins are highly dissociated and exchange the
Na+ and H+ are exchange over the entire pH range. The exchange capacity of strong acid
resins is independent of solution pH. These resins would be used in the hydrogen form for
complete deionization they are used in the sodium form for water softening. After exhaustion,
the resin is converted back to the hydrogen form with a sodium chloride solution (40).
Examples of drugs masked using ion exchange resins are given in table 5and 6.
Table 5:Taste masking of bitter drugs using in strong acid cation exchangers
Examples of drug
Product name
Matrix
Amphetamine
Buflomedil
Propranolol HCl,
dextroamphetamine
Erythromycin
stearate
Amberlite
IPR69
Tulsion 344
Styrene
DVB
Styrene
DVB
Styrene
DVB
Kyron-T-154
Functional
group
-SO3H
Standard
ionic form
Na+
Ref.
-SO3H
Na+
41
-SO3H
Na+
41
41
Weak acid cation exchangers
In a weak acid resin, the ionizable group is a carboxylic acid (COOH) as opposed to the
sulfonic acid group (SO3H) used in strong acid resins. These resins behave similarly to weak
organic acid.
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For the weak acid resin to react, it must be dissociated. Therefore, the H+ ion in the acid must
be taken away by an alkali. For instance, the following reaction is immediate and irreversible
R-COOH + Na+OH–
R-COO–Na+ + H+OH–
This is a neutralization reaction in which the product is water (hence the irreversibility).
Weak acid resins exhibit a much higher affinity for hydrogen ions than strong acid resins.
The degree of dissociation of a weak acid resin is strongly influenced by the solution pH.
Consequently, resin capacity depends in part of solution pH (44).
Table 6: Taste masking of bitter drugs using in weak acid cation exchangers
Examples of drug
Functional
Group
Standard
Ionic form
Exchange
Capacity
Ref.
Methacrylic
-COO¯
H⁺
10meq/kg
41
Amberlite
IPR88
Methacrylic
-COO¯
K⁺
Norfloxacin,
ofloxacin,
Roxithromycin
Tulsion 335
Methacrylic
-COO¯
H⁺
10meq/kg
42
Chloroquine
phosphate,
Quinine sulphate,
Ciprofloxacin,
Paracetamol
Tulsion 339
Methacrylic
-COO¯
K⁺
-
42
Cefuroxime axetil,
Cefpodoximeproxet
il, Norfloxacin
Kyron-T-104
Methacrylic
-COO¯
H⁺
-
43
ItoprideHCl,
Ofloxacin,
Tramadol HCl
Kayron-T114
Methacrylic
-COO¯
H⁺
-
43
Methacrylic
-COO¯
H⁺
10meq/kg
44
Crosslinked
polyacrylic
-COO¯
H⁺
10meq/kg
44
Crosslinked
polyacrylic
-COO¯
K⁺
-
44
Spiramycin,
Dimenhydrinate.
Paroxetine,
beta-lactam
antibiotics,
Product
name
(resin)
Amberlite
IPR64
Norfloxacin,ofloxac Indion 204
in,
Famotidine,roxithro
mycin,
Indion 214
Dicyclomine HCl,
azithromycin
Indion 234
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-
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Ciprofloxacin,
Choroquinephospha
te
Indion 294
Nicotine taste
masking
AmodiaquineHCl,
Chloroquine
phosphate
QuinineSulphate,
Ibuprofen
Roxithromycin,
Cefaclor
Dextromethorphan,
Cloxacillin sodium,
Erythromycin
estolate,
Ciprofloxacin HCl,
Erdosteine,
Indion 464
crosslinked
Polymethacrylic -COO¯
crosslinked
Poly
-COO¯
methacrylic
-
Kayron-T134
Crosslinked
polyacrylic
-COO¯
K⁺
-
45
Doshion
P544
Methacrylic
-COO¯
H⁺
-
46
K⁺
9.5meq/g
44
H⁺
The process has disadvantagethat the resin can be fouled by some substances present in the
water (such as organic matter or Fe +++ ions).
But in general the advantages of the process (long life of resins, cheap maintenance etc.)
outweigh the disadvantages. In addition (47).
3.4 Inclusion complexation
Inclusioncomplexes are ‘host-guest’ relationship in which complexing agent actsas host and
cavity act as guest (48). The complexing agent is capable of masking bitter taste of drug by
either decreasing its oral solubility on ingestion or decreasing the amount of drug particles
exposed to taste buds, thereby reducing the perceptionof bitter taste. Vander wall forces are
mainly involved in inclusion complexes. B-cyclodextrin is most widely used complexing
agent for inclusioncomplex. It is sweet, non-toxic cyclic oligosaccharide obtained from
starch. Table 7 enlists examples of various drugs taste masked by inclusion complexation.
Table7: Examples of drugs taste masked by inclusion complexes
Drug
Category
Complexing agent used
Ref.
Chloroquine phosphate
Antimalarial
Tannic acid
49
Ibuprofen
NSAID
Hydroxypropyl B-cyclodextrin
50
Benexate hydrochloride
Antiulcer
B-cyclodextrin
51
Metronidazole benzoate
Anti-bacterial
ᵞ-cyclodextrin
52
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Hexitidine
Anti-bacterial
B-cyclodextrin
53
Zipeprol
Anti tussive
B-cyclodextrin
54
Levosulpiride
Anti-psychotic
B-cyclodextrin
55
Guaiacol
Anti diarrhetic
B-cyclodextrin
56
Dioscin
CVS disorders
B-cyclodextrin
57
Zinc acetate dehydrate
Recover
deficiency
zinc AnetholB-cyclodextrin 58
complex and saccharin
Cyclodextrins (CDs) have mainly been used as complexing agents to increase the aqueous
solubility of poorly water-soluble drugs and to increase their bioavailability and stability. In
addition, CDs have been used to reduce or prevent gastrointestinal or ocular irritation, reduce
or eliminate unpleasant smells or tastes, prevent drug or drug additive interactions, or even to
convert oils and liquid drugs into microcrystalline or amorphous powders.
3.5 Granulation
Granulation is a less expensive, rapid operation and an easy taste making technique. It is the
common processing step in the production of tablet dosage form. Some saliva insoluble
polymers are used as binding agent. Granules prepared from these polymers show less
solubility in saliva and thus taste could be masked. Granulations lower the effective surface
area of the bitter substance that come in contact with the tongue upon oral intake. Taste
masked granules, prepared from saliva insoluble polymer, can be formulated in various type
of tablet dosage form e.g. chewable tablet, rapidly disintegrating tabletetc.(59).
Liquids and low melting point waxes such as glycerol palmito stearate, glycerylbehenate and
hydrogenated caster oil are commonly used during the granulation to achieve the taste
masking (60,61).
Table 8: Examples of drugs taste masked by granulation technology are enlisted in table
Drug(s)
Granulating
Agent(s)
Percentage
excipients
Erythromycin
Alginic acid
Drug : polymer
Ratio of 2.5:1 to
50:1
Dextromethorphan
Cyclodextrin
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of Comments
Ref.
Taste masked granules, which 60
can be formulated as dry
syrup suspensions/
chewable
of
dispersible
tablets
Drug : polymer
Mixing of drug with
61
Ratio of between Cyclodextrin followed by
0.9:1 and 1:25
granulation;
without
complexation
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Microcrystalline
cellulose (MCC)
Calcium compound
Erythromycin
Norfloxacin
Ondansetron
Levofloxacin
Ratio of drug to A simpler and more effective
MCC is 70:30 to process compared to coating
90:10 w/w
Sugar alcohol
Alginic acid
Meth
acrylic acid ester
Polyacrillin
potassium
Castor oil, sugar alcohol
61
62
63
64
65
66
3.6 Adsorption
Adsorption of bitter tasting drug can be considered as the less saliva soluble versions of these
drugs. Adsorption involves preparing a solution of the drug and mixing it with an insoluble
powder that will adsorb the drug, removing the solvent, is dried and used in the preparation of
the final dosage form. Many substrates like veegum, bentonite, silica gel and silicates can be
used for the preparation of adsorbate of bitter drugs(67).
Table 9: Examples of drugs and adsorbent used in adsorption technique(68)
Drug
Ranitidine
Dextromethorphan hydrobromide
Trimethoprim
Loperamide
Phenyl propanolamine
Adsorbent
Magnesium trisilicate
Magnesium trisilicate
Magnesium aluminium silicate(veegum F)
Magnesium aluminium silicate(veegum F)
Magnesium aluminium silicate(veegum F)
3.7 Prodrug approach:
A prodrug is a medication that is administered in an inactive or less than fully active form,
and then it becomes converted to its active form through a normal metabolic process, such as
hydrolysis of an ester form of the drug.
Chemical modification, including prodrug design is an effective method for reducing
solubility, and improving taste. A prodrug is chemically modified inert drug precursor which
upon biotransformation liberates the pharmaceutically active parent compound. Bitterness of
a molecule may be due to the efficiency of the taste receptor substrate adsorption reaction,
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which is related to the molecular geometry of the substrate. If alteration of the parent
molecule occurs by derivative formation, the geometry is altered, affecting the adsorption
constant. Thus the magnitude of a bitter taste response or taste receptor-substrate adsorption
constant may be modified by changing the molecular configuration of the parent molecule.
The extremely bitter antibiotics have been the focus of much work in reversible drug
modification(69).
Table10: Examples of antibiotics taste masked by this technique
Drug
Chloramphenicol
Clindamycin
Erythromycin
Lincomycin
Tetracycline
Category
Broad spectrum antibiotic
Linosamide antibiotic
Macrolide antibiotic
Lincosamide antibiotic
Broad spectrum antibiotic
Modification done
Palmitate or phosphate ester
Alkyl ester
Alkyl ester
Phosphate or alkyl ester
3,4,5-trimethoxy benzoate salts
Triamcinolone
Treatment of ulcerative colitis Diacetate ester
and skin disorder
Ref.
70
71
72
73
74
75
The prodrug approach can be used to increase or decrease the solubility of a drug depending
on its ultimate use. One disadvantage of making a less soluble prodrug (to mask taste) may
result in compromised bioavailability.There are numerous examples where solubility needs to
be increased. The prime examples involve drugs whose solubility is so low that a solution
dosage form for intravenous usage is not possible.
3.8 Bitterness inhibitor
The development of a specific universal inhibitor for bitter taste has been widely required in
the fields of taste physiology. One difficulty in discovery of universal inhibitor for bitter taste
is that a substance that inhibits bitterness of one compound will not influence the bitterness of
a second because many different classes of compound impart bitterness.
Bitter substances are commonly hydrophobic in nature hence lipoprotein (PA-LG) composed
of phophatidic acid and B-lacto globulin can mask the target sites for bitter substances on the
taste receptor membrane without affecting responses to salts, acids, sugars or sweet amino
acids.
Bitter taste of brucine, berberine, chloride, caffeine, denatonium benzoate, glycyl L-leucine,
L-phenylalanine, naringin, propranolol hydrochloride, quinine hydrochloride, strychnine
nitrate and theophylline have been suppressed by lipoprotein(76).
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3.9 Multiple emulsion technique
This is the novel technique used to mask the taste of bitter drugs. Multiple emulsions can be
prepared by dissolving drug in the inner aqueous phase of w/o/w emulsion under condition of
good shelf stability. So that release of drug through oil phase takes place in gastrointestinal
media (77).
The w/o/w or o/w/o type multiple emulsions are vesicular systems in which active ingredients
can be entrapped in internal phase. The entrapped substances can be transferred from internal
phase to external phase through the ‘membrane phase’. This phase controls the release of
drug from systems.
These system could be used for controlled – release delivery of pharmaceuticals. If the
system is stable enough for a reasonable shelf-life, the formulation could also mask the taste
of drug. Both w/o/w and o/w/o multiple emulsions of Chloroquine phosphate have been
prepared and reported to be partially effective in masking the bitter taste of drug (78).
The major problem as regards stability is the presence of two thermodynamically
unstableinterfaces. Two different emulsifiers are necessary for their stabilization, one with a
low HLB for the w/o interface and a second one with a high HLB for the o/w interface. There
are several approaches to overcome instability- and release-problems in double emulsions.
3.10 Gel formation
Water insoluble gelations on the surface of tabletcontaining bitter drug can be used for
tastemasking. Sodium alginate has the ability to causewater insoluble gelation in presence of
bivalentmetal ions. Tablets of amiprolose hydrochloridehave been taste masked by applying
an undercoatof sodium alginate and overcoat ofcalcium gluconate. In presence of saliva,
sodiumalginate reacts with bivalent calcium and form water insoluble gel and thus taste
masking achieved (79).
3.11Miscellaneous taste masking approaches
3.11.1 Use of by effervescent agents
Effervescent agents have been shown to be useful and advantageous for oral administration
of drugs and have been employed for use as taste masking agents for dosage forms that are
not dissolved in water prior to administration. A chewing gum composition of
bittermedicament was formulated to supply the medicament to oral cavity for local
application or for buccal absorption. It comprise a chewing base, an orally administrable
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medicament, a taste masking generator of carbon dioxide, and optionally a taste bud
desensitizing composition (e.g., oral anesthetic such as benzocaine) and other non-active
material such as sweeteners, flavoring components, and fillers (80). Recently, effervescent
tablets of fentanyl and prochlorperazine were developed to supply these drugs to the oral
cavity for buccal, sublingual, and gingival absorption. The formulations contain the drug in
combination with effervescent agent to promote their absorption in the oral cavity and to
mask their bitter taste. An additional pH adjusting substance was also included in fentanyl
formulation for further promotion for absorption (81).
3.11.2 Rheological modification
Increasing the viscosity with rheological modifier such as gums orcarbohydrates can lower
the diffusion of bitter substances from the saliva to the taste buds. Acetaminophen suspension
wasformulated with xanthan gum (0.1‐0.2%) and microcrystalline cellulose (0.6‐1%) to
reduce bitter taste(82). The antidepressant drug mirtazapine is formulated as an aqueous
suspension using methionine (stabilizer) and maltitol (thickening agent). Maltitol is stable in
the acidic pH range of 2 to 3 and besides, it masks the unpleasant taste of the drug. It also
inhibitsthe undesirable local anesthetic effect of the drug(83).
3.11.3 Continuous multipurpose melt (CMT) Technology
The CMT method was developed for the continuous granulation and Coating of
pharmacologically active substances(84).
3.12 Hot melt coating
Polymer coating are widely used to provide drug protection, taste masking, coloration and
modified drug release. Typically, coating polymers must be diluted or dispersed in solvents
(water or organic) prior to coating and gliding agents are commonly added to prevent particle
sticking throughout processing. Lipid excipients present an attractive alternative to standard
polymer coatings as they only require melting before application directly onto the substrate.
Solvent evaporation is not required; consequently powders with very high specific surface
areas can be coated rapidly. A number of different lipid excipients can be used in coating and
choosing the appropriate excipient for the application requires an understanding of their
physic-chemical properties and its associated effect on drug release.
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4.Evaluation techniques
Tasteis a very subjective perception. Depending on individuals, the perceived taste may vary
to different degrees. Still, well controlled experimental set up, can accurately and
reproducibly measure taste thresholds. To quantitatively evaluate taste sensation, following
methods have been reported in literature
4.1 Panel testing (human subjects)
4.2Measurement of frog taste nerve responses.
4.3Multichannel taste sensor/ magic tongue
4.4Spectrophotometric evaluation/ D30’s value
4.1 Panel Testing
This method involves taste comparison between test and reference solutions by a group of
about 5‐10 human volunteers.Reference solutions vary in taste from tasteless to very
bitter.Numerical values are then assigned to these levels of bitterness. Subsequently, test
solution is tasted and rated on the same scale to assess its bitterness. This method is easy
accompanied with theaccuracy of human perception of taste against any other
gustatoryevaluation technique(85).
4.2 Measurement of Frog Taste Nerve Responses
In this method, adult bull frogs are anaesthetized intraperitoneallyand the glossopharyngeal
nerve is then located and dissected fromthe surrounding tissue and cut proximally. An
ac‐amplifier and anelectronic integrator are used to respectively amplify and integratethe
nerve impulses. The peak height of the integrated response isthen taken as the magnitude of
response.
Quinine sulphate formulations, tastes masked by PA‐LG (phosphatidic acid‐lactoglobulin)
combination have been reported to be evaluated by this technique(86).
4.3 Multichannel Taste Sensor / Magic tongue
This is an automated taste sensing device to detect the magnitude ofbitterness of a drug
substance. The device has a transducer which iscomposed of several kinds of lipid/polymer
membranes withdifferent characteristics that can detect taste in a manner similar tohuman
gustatory sensation. Taste response is transferred into apattern composed of electric signals of
membrane potentials of thereceptor part. Different response electric potential pattern
areobtained for substance producing different taste qualities (87).
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Recently, the technique has been applied, for the quantitativeevaluation of the bitternessof
some commercially available medicinescontaining quinine,diclofenac sodium, salicylic
acid,theophylline, caffeine and metronidazole(88).
4.4 Spectrophotometric Method
A known quantity of the taste‐masked formulation is mixed with 10ml of distilled water in 10
ml syringe by revolving the syringe,end toend, five times in 30 seconds.The test medium is
then filteredthrough a membrane filter, followed by spectrophotometricdetermination of the
concentration of the drug in the filtrate. If thisconcentration is below the threshold
concentration, it may beconcluded that the bitter taste would be masked in vivo.
Thistechnique has been applied to evaluate the taste masked granules ofsparfloxacin, with
threshold concentration being 100µg/ml (89).
CONCLUSION
Taste masking of bitter drug has paramount importance in pharmaceutical industry to gain
widespread marketability. Taste masking procedure should be rationally selected based on the
chemical structure of the drug, physicochemical properties, stability of the drug and
excipients and design of dosage form.In addition to the taste masking, these techniques may
also enhance the onset of action as well as bioavailability of drug. Ideal taste masking
procedure should notdecrease bioavailability and stability of the drug.
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