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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
492
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
493
494
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
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
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
496
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.
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.
498
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
3155.2
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.
500
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.
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 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
502
Figure 7.
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 .
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
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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