医薬品相互作用研究

Vol.45, No. 1（2021）

9（9）医薬品相互作用研究
一
般論
文

45（1） 9-17 （2021）

Characterization of Orally Disintegrating Tablets Containing Fluconazole
Prepared at a Hospital Pharmacy
Mari MATSUMOTOa,b）, Katsuma ARAIc）, Sachie HAYAKAWAb）, Katsuhiko SAWAKAMId）,
Kentaro SAWAKAMId）, Shigenari SHIDAc）, Yukio NOHARAc）, Kenji SUMIYAa,c）,
Kazuko MURATAa,c）, Yoshiko TAKEUCHIe）, Hirofumi TAKEUCHIe）, Ryo MURATAa,c*）
Graduate School of Science and Engineering, Iryo Sosei Universityb）
Department of Pharmacy, Iwaki Yumoto Hospitalc）
Faculty of Pharmacy, Iryo Sosei Universityd）Sawakami Pharmacye）Laboratory of Advanced Pharmaceutical Process Engineering, Gifu Pharmaceutical Universitya）（Received May 20, 2020; Revised September 18, 2020; Accepted October 4, 2020）
Abstract
Orally disintegrating tablets（ODTs）, which dissolve rapidly in the oral cavity, can be taken with or without a small
amount of water, making them a useful dosage form that helps patients who have difficulty in swallowing and improvescompliance. As a preliminarily experiment for hospital preparation of ODTs, in this study, we prepared fluconazole（FLCZ;
C13H12F2N6O）ODTs and evaluated usefulness of the formulation. The ODTs were prepared using lactose and mannitol as
excipients. Hardness was the highest for ODTs prepared using lactose and mannitol in a 2:1 ratio. Water-wetting time
was delayed for these ODTs. The water absorption ratio was the highest for ODTs prepared using mannitol alone andapproximately 25% for those prepared using other formulations. The addition of FLCZ to the excipients with lactose
and mannitol, mixed in a 2:1 ratio, decreased the hardness and extended disintegration time. Water-wetting time was
longer than for lactose ODTs but remained within the allowable range. In addition, the content and dissolution ratio were
determined. The masking efficiency of taste was evaluated using an electronic gustatory system. Additionally, ODT crosssection was observed under a scanning electron microscope, and the FLCZ distribution was observed from the mapping
image of elemental fluorine in FLCZ identified using energy-dispersive X-ray spectrometry. The results of this study
suggest that ODTs that disintegrate rapidly can be prepared at a hospital pharmacy without the need for manufacturing
equipment for tableting.
Keywords : fluconazole, orally disintegrating tablets, scanning electron microscope, hospital preparation

Introduction

Oral administration is the most common route of

drug administration. However, tablets and capsules

form that helps patients who have difficulty inswallowing and improves compliance 1,2）.

ODTs need to disintegrate quickly and have good

are not always easy to take, especially for patientsstrength. Tablets with both quick disintegrationdisease and for pediatric patients with undevelopedby preparing tablets with high porosity, adjustingwith decreased swallowing function due to aging or

ability and good strength have been developed

swallowing function. Orally disintegrating tablets

the amount of the disintegrant or binder added,

be taken with or without a small amount of water

these ODTs are manufactured using manufacturing（ODTs）and orally disintegrating films（ODFs）canbecause they dissolve or disintegrate rapidly inthe oral cavity. Therefore, they are a useful dosage〒970-8551 福島県いわき市中央台飯野5-5-1a, c）
5-5-1 Iino, Chuo-dai, Iwaki, Fukushima 970-8551, Japanb）
6 Daiyama, Jobanyumotomachi, Iwaki, Fukushima 972-8321, Japand）
3-6-5 Shimokubo, Misawa, Aomori 033-0023, Japane）
5-6-1 Mitahora -higashi, Gifu-city, Gifu 502-8585, Japan*Ryo Murata
E-mail: r-murata@isu.ac.jp, Tel: 0246-29-5432 FAX: 0246-29-5432

and devising a formulation design 3–7） . Generally,equipment. In contrast, a simple method of

preparing ODTs at a hospital pharmacy without10（10）

医薬品相互作用研究

Vol.45, No. 1（2021）

manufacturing equipment was reported 8,9） . Theyw a t e r a b s o r p t i o n t e s t s . M o r e o ve r, t h e t a b l e t s’in a refrigerator to prepare porous tablets.

taste evaluation was performed using an electronic

used lactose as an excipient for ODTs and dried it
Mannitol, which is a sug ar alcohol, is w idelyused as an excipient because it is chemicallyinert to drug substances and other excipientsand has low hygroscopicity

10）. It is also used as

an excipient for ODTs because of its excellent

solubility, sweetness, and good palatability.

As a preliminarily experiment for hospital

preparation of ODTs, in this study, we attempted

content and dissolution ratio were assessed, andgustatory system. For further characterization of
the tablets, an ODT cross-section was observed

under a scanning electron microscope（SEM）andusing energy-dispersive X-ray spectroscopy（EDS）,
the distribution of FLCZ in ODTs was confirmed

by mapping image of elemental fluorine in the
structure formulation of FLCZ.

to prepare ODTs w ith rapid disinteg rat ion andMaterials and Methods

using mannitol and lactose. Fluconazole （FLCZ;

FLCZ was obtained from LKT. Labs. （St. Paul,

suitable strength based on a formulation study

C 13H 12F 2N 6O ）w a s u s e d a s t h e d r u g s u b s t a n c e .

F LC Z i s a s y n t h e t i c a n t i f u n g a l a g e n t f r o m t h etriazole group

11）. The resultant tablets werecharacterized by hardness, disinteg rat ion, andMaterials

MN）, powdered lactose and Diflucan ® capsule

50 mg from Pfizer（Tokyo, Japan）, and d-mannitol
from B Food Science（Aichi, Japan）.

Table 1. ODT formulations

Formulation code
Ingredient（%）

A

B

C

D

E

Lactose

100

75

67

50

-

Mannitol

-

25

33

50

100

ODT, orally disintegrating tablet.

1. Preparation

Methods

ODTs were prepared using lactose and mannitol

as excipients, as described previously by Sumiya
et al

8）

. Table 1 shows the mixing ratio of lactose

and mannitol. To prepare FLCZ ODTs, first, FLCZ

2. Hardness test

A hardness test was performed using a TH-

203MP tablet hardness tester （Toyama Sangyo,

Osaka, Japan）.

3. Evaluation of disintegration time

A disintegration test was performed using an NT-

and the excipients were mixed, and then the mixed

40H disintegration tester（Toyama Sangyo）withmass ratio of 2:1. The suspension was filled in a

4. Water absorption

powder and purified water were suspended in asyringe and was dispensed into molds（300 mg/

water at 37°C as the immersion fluid.

Water absorption was evaluated by measuringmold）, dried in a refrigerator for 96 h, and finallywett ing t ime and water absorpt ion rat ios w ith

such that one tablet contained 25 mg of FLCZ.

filter paper（5A, diameter: 9 cm）was placed on ataken out of the molds. FLCZ ODTs were prepared,reference to a previously reported method 12,13） . A

医薬品相互作用研究

Vol.45, No. 1（2021）

11（11）

Petri dish（diameter: 10 cm）and wetted with 2 mL

8. Morphological observations

placed at the center of the filter paper, and theJ S M - 6 0 1 0 L A S E M （ J E O L , To k y o , J a p a n ） a t a nof water tinted with red food color. An ODT wastime required for complete wetting was measured

by visual observation of color change of the

ODT. Water absorption ratio, R, was determinedaccording to the following equation:
R = 100（W a – W b）/ W bwhere W b and W a are the weight before and after

water absorption, respectively.
5. FLCZ content measurement

F LC Z O D Ts w e r e d i s s o l ve d i n w a t e r a t r o o mtemperature. The FLCZ concentration in thesolution was evaluated by high-performanceliquid chromatography（HPLC）. Reversed-phase

chromatography was performed using the LaChrom
Elite System（Hitachi, Tokyo, Japan）. The HPLC

system comprised an L-2130 pump, an L-2300

column oven, a D-2500 integrator, and a L-2400

UV-VIS detector. HPLC analysis was performedon TSK GEL ODS-120H（4.6 × 150 mm, Tosoh,Tokyo, Japan） at 40 °C. The mobile phase wasODT cross-sections were observed under

acceleration voltage of 10 kV. Elemental analysis
was performed to confirm the distributionof elemental fluorine in FLCZ using EDS, and
FLCZ distribution was observed by mapping theelemental fluorine in FLCZ. The EDS spectra of thecontained elements were confirmed, and a tablet

without FLCZ and an FLCZ ODT were compared.
9. Statistical analysis

Data were expressed as mean

± standard

deviation, and statistical differences wereanalyzed using one-way analysis of variance,
followed by the Tukey–Kramer post hoc test for

multiple comparisons. All statistical analyses
were performed using Statcel 3 software （OMS
Publishing Inc., Saitama, Japan）. *P < 0.05 and**P < 0.01.

Results

The different tablet properties were changed

acetonitrile and water（1:4, v/v）with a flow rateby changing the type of filler in the formulation.

nm. A sample of 20 μL was injected into a column

test are shown in Fig. 1. Hardness of tablets wasof 1.1 mL/min, and detection wavelength of 260

using the Chromaster 5280 autosampler.
6. Evaluation of the dissolution test

A drug dissolution test was performed using an

The results of measurements of the hardness

lowest for ODTs prepared using only mannitol as
an excipient [mannitol ODTs（Man ODTs）]. While

the ODT prepared with lactose showed higher

NTR-6200AC dissolution tester（Toyama Sangyo）.

hardness than Man ODTs, hardness significantly

C, with a paddle stirring speed of 50 rpm. At time

lactose ratio. The highest hardness was observed

The test was performed in 900 mL of water at 37°

increased by formulating a suitable mannitol-to-intervals of 0.5, 1.5, 3, 5, 10, 20, 40, and 60 min,for ODTs prepared using both lactose and mannitol

filtered through a 0.45 μ m membrane filter（GLlactose and mannitol. The addition of FLCZ（active

released was measured using HPLC. HPLC analysis

hardness of the resultant tablet.

7. Taste evaluationin Fig. 2. The disintegration time decreased as

5 mL samples were withdrawn. The samples were

Science, Tokyo, Japan）, and the amount of FLCZ
conditions for FLCZ were as described before.

The taste was evaluated using an electronic

in a 2:1 ratio among the several formulations with

substance）, to the tablet formulation decreased

The results of the disintegration test are shown

the concentration of mannitol increased. The

gustatory system（ASTREE V5, Alpha M.O.S. Japan,

tablet w ith lactose and mannitol in a 1:1 rat io

dissolved in 30 mL of purified water, and 25 mL

shorter disintegration time than lactose tablet.

Tokyo, Japan）. A sample tablet was completelyof the prepared sample solution was used for themeasurement. Principal component analysis（PCA）

was performed using AlphaSoft V2020, Data points
from the samples were compared using calculated
Euclidean distances on the PCA map.

as well as a mannitol tablet showed significantly

The addition of FLCZ resulted in an increase in
disintegration time.

T h e w a t e r- w e t t i n g t i m e w a s d e l a y e d f o r t h etablets prepared with lactose and mannitol in a

2:1 ratio compared with those prepared with the12（12）

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Vol.45, No. 1（2021）

*
**

*

80

**

**

Hardness (N)

70
60

**

**

50
40
30
Fig. 2

20
10
0

A

B

C

D

E

C ＋ FLCZ

Fig. 1. Hardness evaluation of ODT（A）Lactose;（B–D）lactose and mannitol mixture in ratios of 3:1, 2:1, 1:1;（E）mannitol and（C + FLCZ）lactose-to-mannitol ratio of 2:1 with 25 mg
of FLCZ. Data are presented as mean ± standard deviation（n = 10）. *P < 0.05; **P < 0.01. ODT, orally disintegrating tablet; FLCZ, fluconazole.

**
**

250

*

Time (s)

200

**

**

150
100
50
0

A

B

C

D

E

C ＋ FLCZ

Fig. 2. Disintegration evaluation of ODT（A）Lactose;（B–D）lactose and mannitol mixture in the ratios of 3:1, 2:1, and 1:1;（E）mannitol and（C + FLCZ）lactose-to-mannitol ratio of 2:1 with

25 mg of FLCZ. Data are presented as mean ± standard deviation（n = 10）. *P < 0.05; **P < 0.01. ODT, orally disintegrating tablet; FLCZ, fluconazole.

other formulations. Similarly, these tablets showed

and mannitol in a ratio of 2:1 resulted in a longer

was the highest for Man ODT and approximately

the time remained within the allowable range.

The addition of FLCZ to the excipient with lactose

five tablets. The drug content of each formulation

greater hardness（Fig. 3）. Water absorption ratio

25% for ODTs prepared with other formulations.

water absorption time than for lactose ODTs, but
The FLCZ content of the tablets was measured for

医薬品相互作用研究(a) Wetting time

13（13）

Fig. 3***16

Vol.45, No. 1（2021）

14

*
**
**

**

*

Time (s)

12
10
8
6
4
2
0

A

B

C

D

E

C + FLCZ

E

C + FLCZ(b)Water absorption ratio
**

*

**

35
30

(%)

25
20
15
10
5
0

A

B

C

D

Fig. 3. Wetting time and water absorption ratio of ODT（a）Wetting time and（b）Water absorption ratio.（A）Lactose;（B–D）lactose and mannitol mixture in the ratios of 3:1, 2:1, and 1:1;（E）mannitol and（C + FLCZ）lactose-to-mannitol ratio of 2:1 with 25 mg of FLCZ. Data are presented as mean ± standard deviation（n = 5）.
*P < 0.05; **P < 0.01. ODT, orally disintegrating tablet; FLCZ, fluconazole.

was ~99.5% ± 2.2% of the expected value. This

>80% of FLCZ eluted within 10 min after thewell dispersed during tablet preparation.

product Diflucan ® capsules, the FLCZ ODTs eluted

formulations are shown in Fig. 4. In FLCZ ODTs,

dissolut ion amount of FLCZ at 60 min was theresult confirmed that the suspended drug crystals
The drug dissolution profiles of FLCZ-containing

start of the test. Compared with the commercial

FLCZ （active substance） in a shorter time. The

14（14）

医薬品相互作用研究

Vol.45, No. 1（2021）

100

Dissolution rate (%)

80

60

40
: C＋
+ FLCZ
C
FLCZ

20

0

: Diflucan® capsule 50 mg
DiflucanCapsule 50mg

0

10

20

30

40

50

60

Time (min)Fig. 4. Dissolution profile of FLCZ formulations
Control experiment on dissolution rate performed using Diflucan® capsules（50 mg）. Data arepresented as mean ± standard deviation（n = 3）. FLCZ, fluconazole.

same between the two dosage forms.

with that of the control. The masking efficiency

active sample solutions containing FLCZ and

5 However, a
in a 2:1 rat io was 68.8% （Fig. Fig.
5）.

Euclidean distances were calculated betweenof lactose was 74.3% and lactose and mannitol

corresponding placebo solut ion. Controls were

statistical comparison of the results showed no

FLCZ and water. The masking effects on taste were

The SEM image of fracture surface of the tablets

used to describe the Euclidean distance between

calculated by comparing each Euclidean distancenoticeable differences.

is shown in Fig. 6. The FLCZ ODT spectrum

500

80

450

Euclidean distance

400

60

350

50

300
250

40

200

30

150

20

100

10

50

0

Euclidean distance
Masking efficiency (%)

Masking efficiency (%)

70

control
433
0

A
111
74.3

C
135
68.8

0

Fig. 5. Masking efficiency of excipient
Euclidean distance was calculated between the active sample solution containing FLCZ and the corresponding placebo sample
solution.（Control）FLCZ;（A）Lactose;（C）lactose–to-mannitol ratio of 2:1. ODT, orally disintegrating tablet; FLCZ, fluconazole.

医薬品相互作用研究

Backscattered electron image

Vol.45, No. 1（2021）

Elemental mapping image(Fluorine)

15（15）

Fig. 6

Qualitative analysis spectrum

A

300μm

C

300μm

E

300μm

C + FLCZ

300μm

Fig. 6. SEM observation of ODT fracture surface（A）Lactose;（C）lactose-to-mannitol ratio of 2:1;（E）mannitol; and lactose-to-mannitol ratio of 2:1 with 25 mg FLCZ（C + FLCZ）. SEM, scanning electron
microscope; ODT, orally disintegrating tablet; FLCZ, fluconazole.

16（16）

医薬品相互作用研究

confirmed the presence of fluorine in themolecular structure of FLCZ, whereas the fluorine

spectrum was not detected for the tablet without

FLCZ. In addition, the mapping image of fluorine

confirmed that FLCZ was uniformly distributed.

Vol.45, No. 1（2021）

rapidly. The time taken by Lac ODT until natural

disintegration without physical irritation in the oralcavity is approximately 100 sec. This timeframe isappropriate for a useful preparation 8）.

In addition, the elution of FLCZ from ODTs was

The morphological observation of the ODT cross-faster than that from capsules, possibly because

ODTs）and Man ODTs showed that Man ODTs have

F LC Z i s u n i f o r m l y d i s t r i b u t e d , a n d i t s r e l e a s emany Man ODTs were missing when removed from

dissolution rate.

s e c t i o n a n d c o m p a r i s o n o f l a c t o s e O D Ts （ L a clarger particles compared with Lac ODTs. In fact,

the molds.

Discussion

FLCZ is clinically used in capsules and dry

syrups in an oral dosage form. A previous study
prepared ODFs containing FLCZ and evaluatedtheir formulation properties 14） . ODF is a flexible

o f t h e g o o d s o l u b i l i t y o f m a n n i t o l . M o r e o ve r,
from the tablet surface leads to an increase in the
Euclidean distances between active samples andthe corresponding placebo sample were calculatedusing the electronic gustatory system to evaluate

the masking efficiency of the excipients. The

Euclidean distance represents taste similarityb e t w e e n t h e s a m p l e p a i r s 15,16）. T h e d i s t a n c e

between FLCZ and water was expressed as thethin-film formulation. When ODF disintegrates,

taste intensity of the drug. The masking efficiency

ingest ion. In this study, we prepared ODTs

Euclidean distances between the formulat ions.

dosage form. To improve the essential properties

the excipients. The excipient of the ODT prepared

the stickiness of the film base may be felt after

containing FLCZ to broaden the options of its oralby the fillers was evaluated by comparing theThis efficiency is attributed to the sweetness ofof ODTs prepared with the simple molding method

is expected to show a masking effect on the tasteof excipient used for tablets on their properties.

correlate w ith the actual bitterness score, andat a hospital pharmacy, we tested the effect of type

Man ODTs showed a better disintegration

property but lower hardness than Lac ODTs.

However, hardness increased by formulating

mannitol with lactose as a filler, and ODTs

prepared using lactose and mannitol in a 2:1 ratio
showed the highest hardness among the tablets

prepared in this study.

O D Ts p r e p a r e d w i t h m a n n i t o l a r e p r o b a b l yof FLCZ. However, Euclidean distance may notfurther study is warranted to examine humangustatory sensation.

Conclusions

As a preliminarily experiment for hospital

preparat ion of ODTs, we attempted to prepare

ODTs capable of rapid disintegration. The resultso f t h i s s t u d y s u g g e s t e d t h a t O D Ts w i t h q u i c kunable to withstand the pressure applied duringdisintegration ability can be prepared at a hospitallarge and their particle–particle bonding is weak.

equipment such as a tableting machine.

removal from molds because mannitol particles are

Therefore, when mannitol and lactose are mixed,
lactose enters the gaps between the mannitol

particles, increasing hardness. It also showed that

increasing hardness may affect the water wetting

time.

When FLCZ was added with lactose and mannitol

in a 2:1 ratio, hardness tended to decrease anddisintegration time tended to increased. However,pharmacy without the need for any manufacturing

Conflict of interest

The authors declare no conflicts of interest.

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