hon p.1 [100%]YAKUGAKU ZASSHI 130(12) 1737―1742 (2010)  2010 The Pharmaceutical Society of Japan

1737―Regular Article―

Preparation and Evaluation of Taste Masked Orally Disintegrating Tabletswith Granules Made by the Wet Granulation Method
Yayoi KAWANO,,a Akihiko ITO,b Masanaho SASATSU,aYoshiharu MACHIDA,a and Hiraku ONISHIa
aDepartment of Drug Delivery Research, Hoshi University, 2441 Ebara, Shinagawa-ku,

Tokyo 1428501, Japan, and bDepartment of Medicinal Therapy Research, Meiji
Pharmaceutical University, 25221 Noshio, Kiyose, Tokyo 2048588, Japan(Received April 17, 2010; Accepted September 16, 2010; Published online September 21, 2010)
Using furosemide (FU) as a model drug, we examined the wet granulation method as a way to improve the taste
masking and physical characteristics of orally disintegrating tablets (ODTs). In the wet granulation method, yogurt
powder (YO) was used as a corrective and maltitol (MA) was used as a binding agent. The taste masked FU tablets wereprepared using the direct compression method. Microcrystalline cellulose (AvicelPH-302) and mannitol were added as
excipients at a mixing ratio of 1/1 by weight. Based on the results of sensory test on taste, the prepared granules markedly improved the taste of FU, and a su‹cient masking eŠect was obtained at the YO/FU ratio of 1 or more. Furthermore,
it was found that the masking eŠect achieved by YO granules made with the wet granulation method was similar to or
better than that produced by the granules made with dry granulation method. All types of tablets displayed su‹cient
hardness (over 3.5×10－2 kN), and rapidly disintegrating tablets were obtained with YO granules produced at a mixing
ratio of FU/YO＝1/1, which disintegrated within 20 s. Disintegration time lengthened as the mixing ratio of YO to FU
increased. In the mixing ratio of FU/YO＝1/1, the hardness of tablets with granules made by the wet granulation
method exceeded that of tablets with granules made by the dry granulation method, with minimal diŠerences in disintegration time. The hardness and disintegration time of the tablets with granules made by the wet granulation method
could be controlled by varying the compression force. In conclusion, YO was found to be a useful additive for masking
unpleasant tastes. FU ODTs with improved taste, rapid disintegration and greater hardness could be prepared with YOcontaining granules made by the wet granulation method using MA as a binding agent.
Key words―orally disintegrating tablet; wet granulation method; maltitol; yogurt powder; taste masking

INTRODUCTION
As the practice of medicine advances, the apparent
needs of patients change. In drug therapy, for example, it has become essential to improve patients' quality of life (QOL) and rates of treatment compliance.
Although various dosage forms are used in drug therapy, oral dosage forms such as tablets, capsules, powders, granules and liquids are in wide use. In particular, tablets may be the most convenient dosage form
for patients over a broad age range,1) because they
can be easily handled and transported, and remain
stable for a prolonged period.2) Oral dosage forms
are not ideal for all patients, however, since many elderly patients often have di‹culty swallowing tablets
as well as capsules.
Therefore, it is desirable to develop a dosage form
that can be easily used by elderly patients. Starting ine-mail: y.kawano＠pha.twmu.ac.jp

the late 1980s, orally disintegrating tablets (ODTs)
were developed as an easily ingestible dosage form forpatients with swallowing disorders, including elderly
persons. ODTs are now widely used in clinical practice. Since ODTs rapidly disintegrate in saliva or in asmall volume of water, elderly, infantile, and dialysis
patients with restricted water intake can easily ingest
them. They have been produced by various methods,
including drying after ˆlling the pockets of a blister
package with a drug dispersion,3,4) drying after lowpressure compression of wet powder and / or
granules,57) compression of dry powder and/or
granules,810) and shaping by direct compression after
mixing excipients with the drug.11) One problem with
ODTs is that, unlike conventional tablets, they allow
patients to taste the drug. Because an unpleasant orbitter taste of the drug often leads to patients' noncompliance and reduction of QOL, taste masking isnecessary in designing ODTs.
Several taste-masking options are available, includ-hon p.2 [100%]1738

Vol. 130 (2010)

ing sensory masking by adding correctives, chemicalmasking by means of chemical modiˆcations such as
the preparation of prodrugs and inclusion compounds of drugs, masking by coating the drug surface, and physical masking using a matrix or by inhibiting oral drug dissolution through adsorption toadditives.12) The sensory masking method, being simple and inexpensive, is usually the ˆrst choice.
Sweeteners and other ‰avors used for sensory masking include sugars and sugar alcohols such as sucrose,
xylitol, maltose, sorbitol and mannitol, as well as aromatic substances such as cocoa, green tea, coŠee,
vanilla, apple and strawberry.13,14)
We focused on the development of taste masked
ODTs by sensory masking because that is a simple
method. In a previous study,15) we attempted to prepare the masked taste granules by the dry granulation
method using furosemide (FU) as a model drug andmaltitol (MA) and yogurt powder (YO) as correctives. As the results, it was suggested that YO withsourness is more useful than MA with sweetness inmasking the taste of FU and that the taste masked
ODTs can be prepared with the YO-containing
granules.15) However, further improvement wasnecessary for taste masking and hardness of tablets.
In this study, we prepared and evaluated the ODTs
using YO-containing granules made by the wet granulation method.

Japan) were used as ˆllers for tablet preparation.
Magnesium stearate (Mg-St; Kozakai PharmaceuticalCo., Ltd., Tokyo, Japan) was used as a lubricant. Allother reagents used were of analytical grade.
Preparation of Granules
According to the formulation shown in Tables 1 and 2, YO was mixed
with FU to mask its taste at ratios of 1/1, 2/1 and 3/1
by weight, and granules were prepared by means of
the wet granulation method using 1030％ (w/v) MA
aqueous solution as a binder. The aqueous binder solution amounts were 5％ (v/w) of granules. The
C for 24 h, and the granules
granules were dried at 60°
that passed through a 20-mesh sieve but remained on
a 22-mesh sieve were used in this study. The obtained
granules were checked for their apparent density, calculated as the ratio of weight to the apparent volume(Table 1).
Sensory Test on Taste
A sensory test on taste of
all granule preparations was performed using 6
healthy adult volunteers (5 males and 1 female, with amean age of 33.3 years). This test was done according
to the Declaration of Helsinki. Namely, prior to thetasting, the volunteers were informed precisely about

Table 1. Formulation and Apparent Density of YO-containing Granules Prepared by Means of the Wet Granulation Using MA as a Binding AgentApp. density
MA aqueous(g/ml)
solution conc.(％)

MATERIALS AND METHODS

GranulesMixing ratio

Materials
Furosemide (FU; Sigma Co., Ltd.,South Croydon, Australia) was used as a model drug.
For granule preparation, yogurt powder (YO; T.
Hasegawa Co., Ltd., Tokyo, Japan) was used as acorrective. Maltitol (MA; Towa Chemical Industry
Co., Ltd., Osaka, Japan) was used as a binding
agent. Microcrystalline cellulose (Avicel PH302,
Asahi Chemical Co., Ltd., Tokyo, Japan) and mannitol (Towa Chemical Industry Co., Ltd., Osaka,

Y1-10M
Y1-20M
Y1-30M

FU/YO(1/1)

10
20
30

0.385
0.333
0.281

Y2-10M
Y2-20M
Y2-30M

FU/YO(1/2)

10
20
30

0.417
0.455
0.453

Y3-10M
Y3-20M
Y3-30M

FU/YO(1/3)

10
20
30

0.524
0.389
0.468

Table 2.
Formulation
Granules：FU/YO (mg)Mannitol (mg)
Microcrystalline cellulose (mg)
Total (mg)Formulation of Tablets Prepared from YO-containing Granules
Y1

Y2

Y3

Y4

Y5

Y6

Y7

Y8

Y9

Y1-10M

Y1-20M

Y1-30M

Y2-10M

Y2-20M

Y2-30M

Y3-10M

Y3-20M

Y3-30M

20/20
80
80

20/20
80
80

20/20
80
80

20/40
70
70

20/40
70
70

20/40
70
70

20/60
60
60

20/60
60
60

20/60
60
60

200

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No. 12the purpose of the tasting and the pharmacologicalcharacteristics and possible adverse eŠects of FU.
They rinsed their mouths su‹ciently before and after
the tasting. FU powder and each sample were kept inthe volunteer's mouth for 30 s and then spat out. FU
powder tasted unpleasant for all the volunteers, andits taste was recognized as the score 1. When the unpleasant taste by FU was lost completely and only thetaste of FU was felt, the score was set to 5. The taste
score was set to the range of 15 based on the degreeof FU unpleasant taste in the manner as reported
previously.15,16) Namely, the scores were set as follows: 1 (distasteful, equivalent to FU powder taste),2 (slightly taste, FU taste remaining fairly), 3 (mean,
FU taste remaining to some extent), 4 (slightly tasty,
FU taste slightly remaining), 5 (tasty, FU taste iscompletely lost and only YO taste). The scores wereanalyzed using the Kruskal-Wallis test, in which ahigher score was considered to indicate a higher
masking eŠect, and p＜0.05 was regarded as signiˆcant.
Preparation of Tablets
An SSP-10A manualpress (Shimadzu Corp., Kyoto, Japan) was used to
produce tablets. Flat tablets with a diameter of 10
mm (200 mg/tablet) were prepared. These tablets
contained the granules along with mannitol andmicrocrystalline cellulose at a mixing ratio of mannitol to microcrystalline cellulose＝1/1, according to
the compositions shown in Table 2. A small amountof Mg-St was added as a lubricant.
Physical Characteristics of Tablets
Hardness
was measured in the diametral direction using a Monsanto hardness tester (Creve Coeur, MO, USA). Thismeasurement was performed on 6 tablets of each type
and the mean hardness for each type was calculated.
C
Tablet disintegration time was measured at 37°
using the JP 15th disintegration test apparatus (Toyama Sangyo Co., Ltd., Osaka, Japan), and deˆned as
the time taken for each tablet to completely disintegrate and disappear from the basket. Puriˆed water
was used as the test medium. This measurement was
performed on 6 tablets of each type and the mean disintegration time for each type was calculated.
Water absorption time of tablets was measured using methylene blue aqueous solution to ˆnd the disintegration mechanism of the tablets. Absorbent cotton
soaked with a 0.04％ aqueous solution of methylene
blue was placed in a dish. A tablet was placed ‰at on
the cotton, and the time required to change the color

1739

of the whole tablet to blue was measured as water absorption time. This measurement was performed on 6
tablets of each type and the mean water absorption
time for each type was calculated.
RESULTSThe Taste-masking EŠect of Granules
The
results of the granule sensory test on taste are shownin Table 3. In this test, the median score for granules
with YO ranged from 45. YO-containing granules
were given high scores regardless of the FU/YO mixing ratio and the concentration of MA solution. It
was found that high taste-masking eŠects could beachieved by adding a quantity of YO equal to or morethan that of FU.
Physical Characteristics of the Tablets
Hardness of Tablets
Initially, all tablets werepressed from granules prepared at a compression
pressure of 1 kN for 30 s. The hardness values ofthese tablets are shown in Fig. 1. The hardness ofeach tablet was 3.5×10－2 kN or greater, and was not
aŠected by the FU/YO mixing ratio.
In addition, we prepared Y1 tablet under varying
levels of compression force to investigate the in-Table 3.
GranulesMedianSensory Test (Taste) of Granules

Y1- Y1- Y1- Y2- Y2- Y2- Y3- Y3- Y310M 20M 30M 10M 20M 30M 10M 20M 30M
4

4.5

4.5

5

5

4.5

5

4.75

5

Minimum  
5 3
5 35 45 2
5 45 35
3 5 3 5 3Maximum
No signiˆcant among granules ( p＞0.05 ).

Fig. 1. Hardness of Tablets Prepared from YO-containing
GranulesCompression force: 1 kN. The length of each bar indicates the mean
±S.D. (n ＝6).

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Fig. 2. EŠect of Compression Force on Hardness of Tablets
Prepared from Y1-10M Granules

Vol. 130 (2010)

Fig. 4. EŠect of Compression Force on Disintegration Timeof Tablets Prepared from Y1-10M Granules
Each point represents the mean ±S.D. (n＝6).

Each point represents the mean ±S.D. (n＝6).

Fig. 3. Disintegration Time of Tablets Prepared from YOcontaining Granules

Fig. 5. Water Absorption Time of Tablets Prepared from
YO-containing Granules

Compression force: 1 kN. The length of each bar indicates the mean
±S.D. (n ＝6).

Compression force: 1 kN. The length of each bar indicates the mean
±S.D. (n＝6). Over 1800 sec.

‰uence of compression force on tablet hardness (Fig.
2). The hardness of Y1 tablet increased as the compression force rose.
Disintegration Time of Tablets
The disintegration times of the tablets prepared at a compression
force of 1 kN for 30 s are shown in Fig. 3. Y1, Y2 andY3 tablets prepared using the granules made at a FU/
YO mixing ratio of 1/1 disintegrated much more
rapidly, within 20 s. The disintegration time lengthened as the mixing ratio of YO to FU increased. Fromthese ˆndings, it was concluded that the tablets obtained using Y1 granules showed very short disintegration time (less than 20 s) and su‹cient hardness(greater than 3.5×10－2 kN). Moreover, the in‰uenceof compression force on the disintegration time of Y1
tablets was also investigated (Fig. 4). The disintegra-

tion times of Y1 tablets lengthened as compression
force increased.
Water Absorption Time of Tablets
The water
absorption time of the prepared tablets was measured
to study the diŠerence in disintegration time among
all the tablets. The water absorption times of thetablets prepared using granules at a compression
force of 1 kN for 30 s are shown in Fig. 5. The tablets
prepared from granules composed of FU and YO at a
mixing ratio of 1/1 showed the fastest water absorption. The water absorption time lengthened as the YO
content increased.
In addition, we also investigated the in‰uence ofcompression force on water absorption time in Y1
tablet. It was found that absorption time lengthened
as compression force rose (Fig. 6).

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No. 121741

Fig. 6. EŠect of Compression Force on Water Absorption
Time of Tablets Prepared from Y1-10M Granules
Each point represents the mean ±S.D. (n＝6).

DISCUSSION
FU has an unpleasant taste, and we attempted toprepare ODTs using a sensory taste-masking technique. The taste masked granules were ˆrst preparedby the wet granulation method using YO and MA,
and then tablets were produced using these granules.
In order to produce taste-masked granules, YO wasadded to FU at various mixing ratios, and an MA solution was used as a binder. As a result of the sensory
test on taste, the median score for YO-containing
granules made by wet granulation method ranged
from 45 (Table 3). In our previous study, the median score of the mixture of FU and corn starch (1：1,
w/w) was 1, and that of YO-containing granules
made by dry granulation method ranged from 3
3.5.15,16) Therefore, it was indicated that the wet
granulation method was similar or better than to thedry granulation method for taste masking. The improvement may be because MA was used as binder inthis study. Further, the increase of amount of YO did
not aŠect taste score. It was found that a su‹cientmasking eŠect could be achieved by the addition of aquantity of YO equal to that of FU.
The hardness of tablets prepared using taste
masked granules was not aŠected by the ratio of FU
to YO. All types of tablets exhibited hardness of morethan 3.5×10－2 kN. The disintegration time lengthened with the increase in the concentration of YO.
The tablets prepared using granules at a FU/YO mixing ratio of 1/1, which showed a su‹cient masking
eŠect, could withstand a force over 3.5×10－2 kN,
and disintegrated rapidly (within 20 s). As reported

previously,15) the hardness and disintegration time oftablets prepared using granules made by the dry
granulation method were approximately 3.43×10－2
kN and 18.5 s, respectively. Based on those ˆndings,
the tablets by wet granulation appeared to show good
hardness and rapid disintegration ability, similar to or
better than the previously reported tablets by dry
granulation. The in‰uence of compression force on
the physical characteristics of the tablets in this study
was similar to that found for the dry granulation
method, namely, the hardness and disintegration timeof tablets could be controlled by altering the compression force.
From the water absorption properties of thetablets, it was suggested that water absorption rateshould be importantly related to the disintegration
rate of the tablets produced by the wet granulation
method as in the case of the tablets produced by thedry granulation method. When FU and YO were mixed in equal amounts, the disintegration time was correlated with water absorption time. Increase in theconcentration of YO lengthened water absorption
time of the tablets. It seems that the diŠerent solubility and binding abilities of YO aŠect the water absorption times of the resulting tablets. Also, addition of
microcrystalline cellulose and mannitol at a higher ratio might be one of the reasons for rapid water absorption in the tablets prepared using the Y1 granules.
Greater compression force raised hardness and water
absorption time probably due to the promotion of thecontact of components and lower porosity of thetablets, which are general phenomena.
CONCLUSION
Using FU, which has an unpleasant taste, as amodel drug, we produced and characterized taste
masked ODTs using the granules prepared by the wet
granulation method to ˆnd the adequate condition to
obtain better taste masked ODTs. The YO-containing
granules were clearly useful for masking the unpleasant taste of the FU. The taste masking was completed well for all the formulations, and the eŠect was
not so diŠerent among these formulations. When thetablets were produced by compression using microcrystalline cellulose and mannitol as excipients, thetablets made with the granules prepared at a FU/YO
mixing ratio of 1/1 exhibited excellent hardness andthe most rapid disintegration, though the hardness
and disintegration time depended on the compression

hon p.6 [100%]1742

Vol. 130 (2010)

force.
The moderate sourness based on YO appeared toact eŠectively for the masking of FU tastes. In addition, it was indicated that the addition ratio of YO to
FU did not have to be high for masking of the FU
tastes.
In summary, we have found that the wet granulation method using YO as a corrective and MA as abinding agent is useful for masking unpleasant tastesof FU, and that good taste masked ODTs with rapid
disintegration time and excellent hardness could be
prepared with the granules of the mixing ratio of FU/
YO＝1/1.
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