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PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY

Vol. 7, No. 4, pp. 491503, 2002

RESEARCH ARTICLE

Solid-State Characterization
of Fluconazole
Khouloud A. Alkhamis,* Aiman A. Obaidat, and
Adi F. Nuseirat
Faculty of Pharmacy, Jordan University of Science and Technology,
Irbid, Jordan

ABSTRACT
Two polymorphs and three solvates of fluconazole were isolated and characterized
by x-ray powder diffractometry, IR spectroscopy, differential scanning calorimetry
(DSC), thermogravimetry, and their dissolution rates. The different forms were
prepared by crystallization of the original powder in different solvents at different
cooling rates. X-ray diffraction patterns of the five solid modifications exhibited
substantial differences in both the intensity and position of the peaks. FTIR spectra
of the five different solid-state modifications also exhibited differences in the peaks
positions and intensities. DSC thermogram of anhydrate form I showed a single
melting point at 139.28C. Anhydrate form II showed two endothermic peaks at 136.5
and 139.28C and one exothermic peak in between. The DSC thermogram of acetone
1/4 solvate exhibited two endothermic peaks at 75.5 and 139.28C. Benzene 1/7
solvate exhibited two endothermic peaks at 131.5 and 138.88C. Hydrate E exhibited
two endothermic peaks at 102.7 and 139.28C. The DSC thermogram of anhydrate
form II showed that this form is sensitive to the application of a mechanical force.
The solubility study showed that anhydrate form II and acetone 1/4 solvate have
higher solubilities than anhydrate form I while benzene 1/7 solvate and
monohydrate have lower solubilities than anhydrate form I. The intrinsic
dissolution study confirmed these results.
Key Words: Dissolution; Fluconazole; Polymorphism; Polymorphs; Solubility;
Solvates

*Corresponding author. Fax: 11-962-2-7095019; E-mail: khou@just.edu.jo

491
DOI: 10.1081/PDT-120015052
Copyright q 2002 by Marcel Dekker, Inc.

1083-7450 (Print); 1097-9867 (Online)

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492

Alkhamis, Obaidat, and Nuseirat

INTRODUCTION
Fluconazole, 2-(2,4-difluorophenyl)-1,3-bis (1H-124triazol-1-yl)-propan-2-ol, is a potent and broad-spectrum
antifungal agent. Fluconazole is used clinically to treat
superficial Candida infections and esophageal Candida,
for acute therapy of disseminated Candida, for systemic
therapy of blastomycosis and histoplasmosis, for
dermatophytic fungal infections, and for prophylaxis in
neutropenic patients.[1,2] Fluconazole combines high oral
efficacy with water solubility.[3]
The first report of polymorphism in fluconazole was
the observation reported by Gu and Jiang[4] in 1995 that
fluconazole appears in two distinct crystalline forms.
These forms were characterized using x-ray diffraction
pattern, thermal analysis, and FT-Raman spectroscopy.
Samples of these two polymorphs (A and B) were
obtained from two different manufacturers. The stability
of these two forms and the possibility that fluconazole
might appear in other forms or solvates were not investigated. The analytical profile[5] reported the existence of
three polymorphic forms of fluconazole and a monohydrate. These forms were identified utilizing x-ray
powder diffractometry (XRPD) and dissolution rates. Lo
et al.[6] also obtained a monohydrate of fluconazole and
reported its x-ray diffraction pattern and infrared
spectrum. MacSweeney[7] also prepared several polymorphs and solvates of fluconazole, including a
monohydrate.
The purposes of the present study were: (a) to
characterize further the previously reported crystalline
fluconazole forms, and (b) to crystallize the material
from various solvent systems in an attempt to isolate new
polymorphs and solvates with rapid dissolution rates that
might be stable in solid state for a reasonable period.
MATERIALS AND METHODS
Preparation of Polymorphs
Anhydrate form I is the original form that was
obtained from Hikma Pharmaceutical Company (lot no.
3462195, Amman, Jordan), and Advanced Pharmaceutical Industries Company (lot no. F109010, Amman,
Jordan). This form was also obtained by dissolving a
suitable amount of fluconazole in propan-2-ol under
constant stirring (with the aid of heat). The solution was
filtered into a previously warmed conical flask through
filter paper. The filtered solution was cooled at room
temperature. Crystals appeared within 48 hr from
preparation, were filtered and dried in vacuo at room

temperature (RT), and then the crystals were stored in

amber glass bottles and kept in a desiccator over silica
pellets at RT.
Anhydrate form II crystals were obtained by
dissolving fluconazole in dichloromethane under constant stirring (with the aid of heat). The solution was
filtered into a previously warmed conical flask through
filter paper. The filtered solution was cooled at RT.
Crystals appeared within 6 hr from preparation, were
filtered and dried in vacuo at RT, and then the crystals
were stored in amber glass bottles and kept in a
desiccator over silica pellets at RT.
Crystals of acetone 1/4 solvate were obtained by
dissolving fluconazole in acetone under constant stirring
(with the aid of heat). The solution was filtered to remove
all nuclei, and then the filtered solution was cooled at RT.
After 48 hr, the resulted crystals were harvested by
filtration and dried in vacuo at RT. The resulted crystals
were stored in amber glass bottles and kept in a
desiccator over silica pellets at RT.
Crystals of benzene 1/7 solvate were obtained by
dissolving fluconazole in benzene under constant stirring
(with the aid of heat). The solution was filtered to remove
all nuclei, and then the filtered solution was cooled in a
refrigerator at 48C. After 48 hr, the resulted crystals were
harvested by filtration and dried in vacuo at RT. The
resulted crystals were stored in amber glass bottles and
kept in a desiccator over silica pellets at RT.
Crystals of monohydrate were obtained by dissolving
fluconazole in deionized water under constant stirring
(with the aid of heat). The solution was filtered to remove
all nuclei, and then the filtered solution was cooled at RT.
After 48 hr, the resulted crystals were harvested by
filtration and dried in vacuo at RT. The resulted crystals
were stored in amber glass bottles and kept in a
desiccator over silica pellets at RT.
The amorphous form was obtained by dissolving
fluconazole in chloroform under constant stirring (with
the aid of heat). The solution was filtered to remove all
nuclei, and then the filtered solution was cooled in a
freezer at 2 208C. After 6 hr, the products were removed
by filtration and dried in vacuo at RT. The resulted
product was stored in amber glass bottles and kept in a
desiccator over silica pellets at RT.
DSC
The thermograms of the different crystal forms were
recorded on a Shimadzu DSC-50 differential scanning
calorimeter (Shimadzu Corporation, Tokyo, Japan)
equipped with Shimadzu software. A heating rate of

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Solid-State Characterization of Fluconazole

108C/min was employed and a nitrogen purge was used.

The temperature axis was calibrated using ultrapure
indium (99.9999%). The sample size was in the range
3 9 mg. A crimped pan was used for the samples of all
modifications.
TGA
Thermogravimetric analysis was carried out using a
Shimadzu TGA-50 equipped with Shimadzu software
(Shimadzu Corporation, Tokyo, Japan). A heating rate of
108C/min was employed and a nitrogen purge was used.
The sample size was in the range 3 9 mg.
X-Ray Diffractometry
The x-ray patterns were collected on a PW 1729
Philips diffractometer using Cu Ka radiation, 35 kV,
20 mA. The samples were mounted on a slide and
exposed to x-ray beam. Samples were scanned from 5 to
358 2u. The speed of the detector was 50 sec/2u. All the
samples were run at room temperature.
FTIR
Infrared spectra were obtained on a Nicolet Avatar 5.1
ESP 360 Spectrometer IR System using Nicolet Omnic
software (Nicolet Instrument Corporation, Wisconsin).
The samples were analyzed using a diffuse reflectance
cell without any prior sample preparation other than
physically mixing the fluconazole with potassium
bromide.
Intrinsic Dissolution Rate
Tablets containing 300 mg of fluconazole were
prepared using a manual tablet press (Sepac 15,011) at
10 ton. The tablets obtained were transferred to a
Plexiglass holder and mounted in a water-jacketed
dissolution apparatus, equipped with a synchronous
motor operating at 120 rpm. A constant surface tablet
was exposed to 500 mL of water at 258C. The samples
were analyzed using a spectrophotometer equipped with
a photodiode array detector (Multispec-1501, Shimadzu
Corporation, Tokyo, Japan). This device contains a
sipper unit, which takes few milliliters of the solution
every 5 min and returns it back to the solution. Each
experiment was repeated two times. Prior to mounting
the compressed tablets in the holder for the dissolution
study, a scraping was obtained from the protected side of
the pellet. The differential scanning calorimetry (DSC)

493

thermograms at 108C/min were obtained from the

scrapings in order to determine the changes that occurred
in the samples during the compression process. At the
end of the dissolution experiment, the surface of the
pellets exposed to the dissolution medium was sampled
and the DSC thermograms were obtained to determine
the changes that took place in the tablet during the
dissolution run.
Determination of Solubility
The solubilities of the polymorphs, solvates, and
hydrates in deionized water were determined at 258C. An
excess amount of the samples were added to 20 mL
screw-top bottles containing 10 mL water. One layer of
Teflon tape was placed over the top of each bottle to
prevent solution contact with the cap. The screw cap
bottle was then put on the bottle. The samples were
rotated (30 rpm) for a period of time in excess of that
required for equilibrium (24 hr). After equilibration, the
solutions were filtered rapidly through Teflon membranes, which were installed in stainless steel filter
holders. The filtered solutions were analyzed using
spectrophotometer equipped with a photodiode array
detector (Multispec-1501, Shimadzu, Japan).
RESULTS AND DISCUSSION
XRD
Since every polymorph produces its own characteristic powder pattern owing to the unique crystallography
of its structure, powder x-ray diffraction is clearly the
most powerful tool for a specification of the polymorphic
identity[8] of a compound. Therefore, the definitive
polymorph identification in this study should be based on
x-ray powder diffraction patterns. The x-ray diffraction
patterns of polymorphs, solvates, and the amorphous
form are shown in Fig. 1 while Table 1 shows the d
distances and the relative intensities (I/I0) of the observed
peaks in these patterns.
The x-ray diffraction patterns of the polymorphs and
solvates of fluconazole show substantial differences in
the position of the peaks, suggesting the existence of
different crystal forms. All samples show definite
diffraction peaks indicative of crystalline materials
except the amorphous form, which possesses no
distinguishable crystal lattice nor unit cell, and consequently has almost zero crystallinity.
The x-ray diffraction pattern of anhydrate form I
(Fig. 1A) resembles anhydrate form I that was

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494

Alkhamis, Obaidat, and Nuseirat

Figure 1. X-ray powder diffraction of fluconazole. Key: (A) anhydrate form I, (B) anhydrate form II, (C) acetone 1/4 solvate,
(D) Benzene 1/7 solvate, (E) monohydrate, and (F) amorphous.

described by Gu and Jiang.[4] However, the x-ray diffraction pattern of anhydrate form II (Fig. 1B)
shows substantial differences from anhydrate form II
that was described by the same investigators. The

difference suggests that these two forms are completely

different.
The x-ray diffraction pattern of the monohydrate
(Fig. 1E) resembles the monohydrate form that was

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Solid-State Characterization of Fluconazole

Table 1
X-Ray Powder Diffraction Data for Fluconazole
Anhydrate Form I
2u
10.2
15.3
16.35
16.75
20.25
20.7
21.3
22.2
23.05
25.25
25.85
29.5

Anhydrate Form II

Acetone 1/4 Solvate

Benzene 1/7 Solvate

Monohydrate

d-Distance

I/I0 (%)

2u

d-Distance

I/I0 (%)

2u

d-Distance

I/I0 (%)

2u

d-Distance

I/I0 (%)

2u

d-Distance

I/I0 (%)

8.67
5.79
5.42
5.29
4.38
4.29
4.17
4.00
3.86
3.53
3.45
3.03

49.51
25.98
58.64
90.87
100
50.98
50.98
41.43
35.53
43.19
64.68
62.29

7.8
13.75
15.45
17.25
18.35
19.15
19.85
22.5
23.95
25.75
27.85
29.05

11.33
6.44
5.74
5.14
4.84
4.64
4.47
3.95
3.72
3.46
3.20
3.07

67.78
38.2
100
37.12
82.56
72.46
43.44
52.56
58.47
62.79
45.96
52.25

8.25
9.45
12.95
15.65
19.7
20.05
23.4
25.75
27.75
28.30
29.80
30.45
30.90

10.47
9.36
6.84
5.66
4.51
4.43
3.80
3.46
3.21
3.15
3.00
2.94
2.89

18.8
30.92
25.02
43.09
24.44
28.53
100
69.28
26.24
44.49
26.53
23.37
21.76

9.25
17.5
18.4
23.5
27.7

9.56
5.06
4.82
3.79
3.22

100
4.47
58.2
5.9
18.94

8.2
9.4
15.75
16.15
18.7
20.05
30.95

10.78
9.41
5.63
5.49
4.75
4.43
2.89

8.97
100
75.95
6.01
5.28
8.35
9.39

495

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496

obtained by previous investigators.[5,7] However, it

shows substantial differences from the monohydrate
form that was described in the patent.[6]
IR Spectra
Each fluconazole form has been found to yield a
characteristic IR spectrum. As shown in Fig. 2 and in the
data collected in Table 2, the bands associated with
the triazole group, the 2,4-difluorobenzyl group, and the
propane backbone were found to be particularly sensitive
to structural differences.[4,9]
DSC Thermograms
The DSC thermograms of the different polymorphs
and solvates are shown in Fig. 3. This figure shows that
anhydrate form I exhibits only a single endothermic
peak, which corresponds to the melting of the crystals.
The melting point of anhydrate form I agrees with the
result obtained by previous investigators.[4] In contrast,
anhydrate form II is thermokinetically metastable during
the heating process. Heating rates of 10 and 18C/min
were employed in this study. The DSC thermogram of
anhydrate form II exhibits an endothermic peak
corresponding to the melting point of the anhydrate
form II, followed by an obvious exothermic peak and a
large endothermic peak corresponding to the melting of
anhydrate form I when 18C/min heating rate was used.
The exothermic peak corresponds to crystallization of the
unstable melt, which on further heating melts to give the
anhydrate form I. The anhydrate form II was heated
slowly from room temperature up to its melting point
(18C/min), and since no transition temperature was
observed, this might indicate that anhydrate form I and
anhydrate form II are monotropic. However, this could
not be confirmed using the heat of fusion rule of
Burger, which states that if the higher melting form has
the lower heat of fusion, the two forms are usually
enantiotropic; otherwise they are monotropic[10] since
the fusion peak of anhydrate form II is so near the fusion
peak of anhydrate form I that DSC cannot resolve them.
In addition, anhydrate form II exhibits polymorphic
transformation with time, as will be discussed later. The
melting point reported by previous investigators[4] for
anhydrate form II is 28C higher than that obtained in this
investigation. The results from the x-ray diffraction
patterns and the melting points indicate that these two
forms are completely different.
The DSC thermogram of fluconazole acetone 1/4
solvate is shown in Fig. 3C. Two endothermic peaks are

Alkhamis, Obaidat, and Nuseirat

seen at 75.53 and 139.188C. The first peak corresponds to

desolvation of the crystals while the second peak
corresponds to the melting point of the crystals and it
agrees with the melting point of anhydrate form I.
The DSC thermogram of fluconazole benzene 1/7
solvate is shown in Fig. 3D. Two endothermic peaks are
seen at 131.54 and 138.88C. The first peak corresponds to
desolvation of the crystal while the second peak
corresponds to the melting point of the crystals and it
agrees with the melting point of anhydrate form I.
The DSC thermogram of fluconazole monohydrate is
shown in Fig. 3E. Two endothermic peaks are seen at
102.71 and 139.208C. The first peak corresponds to
dehydration of the crystal, and the temperature agrees
with the boiling point of water. The second endothermic
peak corresponds to the melting point of the crystals.

TG Thermograms
The TG thermograms of the different polymorphic
transformations, obtained at 108C/min, are shown in
Fig. 4. Figure 4A and B shows that there is no weight loss
in the temperature range before melting occurs. This
indicates that the anhydrate forms I and II are not
solvates of fluconazole, and that the endothermic events
occurred during DSC are due to melting events of the
crystals and not due to solvent loss.
The TG thermogram of fluconazole acetone 1/4
solvate is shown in Fig. 4C. This figure shows 5.14%
weight loss in the temperature range 67.5 87.638C. The
weight loss occurred in a temperature range higher than
the boiling point of acetone. This indicates that the first
endothermic peak observed in the DSC thermogram of
fluconazole acetone 1/4 solvate is due to desolvation of
acetone, and not due to a polymorphic transition. Based
on the previously mentioned results, it was calculated
that one acetone molecule is bonded to four fluconazole
molecules.
The TG thermogram of fluconazole benzene 1/7
solvate is shown in Fig. 4D. This figure shows 3.82%
weight loss in the temperature range 128.86 139.338C.
The weight loss occurred in a temperature range higher
than the boiling point of benzene. This indicates that the
first endothermic peak observed in the DSC thermogram
of fluconazole benzene 1/7 solvate is due to desolvation
of benzene, and not due to a polymorphic transition.
Based on the information given about the molecular
weights of both benzene and fluconazole, and the percent
of weight loss, it is calculated that one benzene molecule
is bonded to seven fluconazole molecules.

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Solid-State Characterization of Fluconazole

497

Figure 2. FTIR spectra of fluconazole. Key: (A) anhydrate form I, (B) anhydrate form II, (C) acetone 1/4 solvate, (D) benzene 1/7
solvate, and (E) monohydrate.

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498

Alkhamis, Obaidat, and Nuseirat

Table 2
Effect of Crystal Polymorphism on Selected Infrared Bands of Fluconazole
Wavenumber (cm21)

Anhydrate Form I
Triazole group
3121.1
1367.2
1253.4
1137.0
967.5
2,4-Difluorobenzyl group
3013.3
1620.2
1271.7
1074.6
Propane backbone
2961.6
1463.6,1452.1
1353.5
1116.2
1025.9
Solvent peaks

Anhydrate
Form II

Acetone 1/4
Solvate

Benzene 1/7
Solvate

Monohydrate

Assignment

3118.9
1367.6
1257.8
1140.8
970.7

1369.8
1249
1138.7
967.5

3118.6
1367.8
1252.8
1137.8
966.5

3115.4
1370.3
1249.1
1139.8
967.6

CH stretch
Ring stretch
Ring stretch
Ring breath
Ring bend

3104.4
1616.7
1275.6
1091.2

3062
1618.3
1276.3
1082.7

3018.4
1618.4
1272.7
1082.2

3019
1618.8
1275.8
1083.13

CH stretch
CvC stretch
CF stretch
CH deform

2965.1
1459,1445.4
1355.8
1121.3
1026.1

2956.6
1466.4,1458.7
1357.9
1111.9
1015

2963.4
1466.1,1451.5
1355.2
1116.2
1021

2955.9
1466.5,1445.1
1358.6
1111.7
1020.2

CH2 stretch
CH2 scissor
CH bend
CZC stretch
CZ(OH) stretch

3155.6,1557.9,
1474.1,1437.7,
833.4

The TG thermogram of fluconazole monohydrate is

shown in Fig. 4E. This figure shows 5.02% weight loss in
the temperature range 103.41 126.988C. The weight loss
occurred in the temperature range corresponding to the
boiling point of water. Based on the information given
about the molecular weights of both water and fluconazole, and the percent of weight loss, it is calculated that
one water molecule is bonded to one fluconazole
molecule.
Intrinsic Dissolution
The dissolution properties of different modifications
were studied by determining the intrinsic dissolution
rates[11] in distilled water at 258C. Discs of the
modifications were examined by DSC before the
dissolution study. No detectable transformation associated with compression was found in the discs of the
anhydrate form I or the solvates. However, the
compression of anhydrate form II brought about a
transformation to the most stable form (anhydrate form
I). This is shown in Fig. 5. This figure indicates that

3155.2

anhydrate form II is a metastable form, and that it

transforms upon compression to anhydrate form I. In
addition, no transformation in anhydrate form I or the
solvates was observed after the dissolution rate
determinations.
A comparison between the dissolution rates of
different modifications (except anhydrate form II) is
shown in Fig. 6. The dissolution rate constants and
the 95% confidence intervals are given in Table 3.
The results at the 95% confidence level indicates that the
dissolution rate constants are significantly different. The
dissolution rates were linear during the experiment
period. This also indicates that no change in the forms
occurred during the measurement period. The dissolution
rates were in the order amorphous . acetone 1/4
solvate . anhydrate form I . benzene 1/7 solvate .
monohydrate.
The dissolution rate constant of the amorphous
form was the highest. This result is expected, since the
amorphous form usually has rapid dissolution rate
and higher solubility than the crystalline[12] form.
The dissolution rate constant of the monohydrate was

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Solid-State Characterization of Fluconazole

499

Figure 3. DSC thermograms of fluconazole polymorphs and solvates. Key: (A) anhydrate form I, (B1) anhydrate form II 108C/min
heating rate, (B2) anhydrate form II 18C/min heating rate, (C) acetone 1/4 solvate, (D) benzene 1/7 solvate, and (E) monohydrate.

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500

Alkhamis, Obaidat, and Nuseirat

Figure 4. TGA thermograms of fluconazole polymorphs and solvates. Key: (A) anhydrate form I, (B) anhydrate form II, (C) acetone
1/4 solvate, (D) benzene 1/7 solvate, and (E) monohydrate.

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Solid-State Characterization of Fluconazole

501
Table 3
Dissolution Rate Constants of Fluconazole Polymorphs and
Solvates

Form
Anhydrate form I
Acetone 1/4 solvate
Benzene 1/7 solvate
Monohydrate
Amorphous

Figure 5. DSC thermogram of fluconazole anhydrate form II.

Key: (1) before compression, (2) after compression.

Figure 6.

Dissolution
Rate Constant
(mg/mL min)

95% Confidence
Interval

1.334
1.499
1.206
1.133
1.579

1.327 1.342
1.495 1.504
1.203 1.209
1.130 1.136
1.568 1.589

the lowest. This result was also expected, since the

monohydrate usually possesses a lower activity and
would be in a more stable state relative to the
anhydrous stable form.
The dissolution rate constant of acetone 1/4 solvate
was higher than anhydrate form I while the dissolution
rate constant of benzene 1/7 solvate was lower than
anhydrate form I. This could be due to the nature of the
acetone and benzene, and their strength of interaction
with fluconazole.
There is a substantial difference in the dissolution rate
results obtained in this study and those presented by Dash
and Elmquist.[5] The results presented indicate that the
dissolution rate constants are not significantly different
while the results of this study indicate that they are
significantly different.

Comparison of dissolution rates of fluconazole in distilled water at 258C.

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502

Figure 7.

Alkhamis, Obaidat, and Nuseirat

DSC thermograms of anhydrate form II after (1) 2 days, (2) 7 days, (3) 11 days, (4) 16 days, (5) 21 days, and (6) 30 days.

Solubilities
The solubilities of the different modifications in water
were also determined. The data are given in Table 4. The
solubilities were in the order amorphous . acetone 1/4
solvate . anhydrate form II . anhydrate form I .

benzene 1/7 solvate . monohydrate. The order of

solubilities agrees with the results obtained from the
intrinsic dissolution experiments. Although the solubility
of the metastable form (anhydrate form II) is higher than
anhydrate form I, it should not be considered as an
equilibrium value, since anhydrate form II is unstable

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Solid-State Characterization of Fluconazole

503

REFERENCES

Table 4
Solubility Data for Fluconazole Polymorphs and
Solvates in Water
Form
Anhydrate form I
Anhydrate form II
Acetone 1/4 solvate
Benzene 1/7 solvate
Monohydrate
Amorphous

Solubility
(mg/mL)

S.D.

4.29
4.6
5.18
3.77
3.56
5.2

0.08
0.14
0.11
0.06
0.08
0.10

and can be easily transformed to the most stable form

(anhydrate form I). However, this result still indicates
that the solubility of the metastable form is higher than
the stable one.
Polymorphic Transformation as a Function
of Time
The polymorphic transformation of anhydrate form II
as a function of time was also investigated. Figure 7
shows that anhydrate form II converts to the most stable
form (anhydrate form I) within less than a month at
ambient temperature and pressure. The key point of Fig. 7
is the rapid conversion of anhydrate form II to anhydrate
form I. This result indicates that anhydrate form II is not
stable enough to be used during ordinary manufacturing
processes.

1.

2.

3.

4.

5.

6.
7.

8.

9.

10.

ACKNOWLEDGMENTS
The authors are greatly indebted to Professor Keith
Guillory of the College of Pharmacy at the University of
Iowa for his constructive comments and suggestions as
well as for bringing to us quite a few critical references.
This work was supported by a grant from Jordan
University of Science and Technology, Irbid-Jordan
(Grant no. 50/2000).
Received January 5, 2002
Accepted May 18, 2002

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