Thermal characterization of the solid state and raw material fluconazole by thermal analysis and pyrolysis coupled to GC/MS

Article abstract of DOI:10.1007/s10973-009-0473-x

This article had studied the thermal characterization of the raw material and different fluconazole crystals, obtained through recrystallization with different solvents using thermoanalytical techniques (TG, DTA, DSC-50, DSC Photovisual, DSC-60) and Pyr-GC/MS. The results confirmed that the fluconazole volatilizes without decomposition until 250 °C. Pyr-GC/MS showed hexachlorobenzene like impurities in fluconazole raw material.

Full text of DOI:10.1007/s10973-009-0473-x

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J Therm Anal Calorim (2010) 100:289–293
DOI 10.1007/s10973-009-0473-x
Thermal characterization of the solid state and raw material
fluconazole by thermal analysis and pyrolysis coupled to GC/MS
Elisana Afonso Moura Æ Lidiane Pinto Correia Æ
´
´
ˆ
´
Marcia Ferraz Pinto Æ Jose Valdilanio Virgulino Procopio Æ
´
Fabio Santos de Souza Æ Rui Oliveira Macedo
Received: 1 June 2009 / Accepted: 4 September 2009 / Published online: 18 September 2009
´
´
Ó Akademiai Kiado, Budapest, Hungary 2009
Abstract This article had studied the thermal character-
ization of the raw material and different fluconazole crys-
tals, obtained through recrystallization with different
solvents using thermoanalytical techniques (TG, DTA,
DSC-50, DSC Photovisual, DSC-60) and Pyr-GC/MS. The
results confirmed that the fluconazole volatilizes without
decomposition until 250 °C. Pyr-GC/MS showed hexa-
chlorobenzene like impurities in fluconazole raw material.
as an analytical method capable of producing fast and
reproducible results [2–16].
This study aims at the thermal characterization of the raw
material and crystals fluconazole, obtained through the
recrystallization of three different solvents (acetone, meth-
anol, and chloroform), using the thermal techniques (TG,
DTA, DSC-50, DSC Photovisual, DSC-60) and the pyro-
lysis coupled to the gas chromatography interfaced to
spectrometry of mass (Pyr-GC/MS), to determine the kinetic
parameters of thermal stability and degradation products.
Keywords Thermal analysis Á Pyrolysis Á Fluconazole
Introduction
Experimental
The fluconazole (FLU) is an antifungal drug, derived from
the triazole, with a wide action range [1]. There are many
applications of thermal analysis in the pharmaceutical
industry, for example, for identification, characterization of
active and inactive ingredients, routine analysis, quality
control, stability study, and polymorphism. It comes about
Materials
Fluconazole (A) obtained from China, and crystals (B), (C)
and (D) were obtained from raw material fluconazole
recrystallization with different solvents such as methanol,
acetone and chloroform.
It was weighed 100.0 mg of fluconazole raw material
and solubilized in methanol, acetone, and chloroform
separately; after solubilization, few quantities of raw
material fluconazole was added in the solutions to obtain
saturated solutions. The saturated fluconazole solutions
were kept in refrigeration for 24 h. The crystals were
obtained from solvents for filtration and vacuum drying.
E. A. Moura Á L. P. Correia (&) Á M. F. Pinto Á
´
J. V. V. Procopio Á R. O. Macedo
Pharmaceutical Sciences Department, Federal University of
´ ´
Pernambuco—UFPE, Artur de Sa Avenue, Cidade Universitaria,
740-521 Recife, PE, Brazil
e-mail: li.correia@gmail.com
E. A. Moura
e-mail: elisanamoura@yahoo.com.br
Thermal analysis
R. O. Macedo
e-mail: ruiomacedo@yahoo.com.br
The calorimetric curves of fluconazole raw material (A) and
crystals (B), (C), and (D) were recorded using a Shimadzu
Calorimeter, model DSC-50, calibrated with standard
indium under the same conditions as the samples were
measured. The DSC curves were recorded at a heating rate
F. S. de Souza Á R. O. Macedo
Unified Laboratories of Medicine Development and Assay—
LUDEM, Federal University of Parahyba—UFPB, Campos I,
58059-900 Joa
˜o Pessoa, PB, Brazil
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290
E. A. Moura et al.
of 2.0, 5.0, 10.0, 20.0, and 40.0 °C/min from room tem-
perature up to 250.0 °C in nitrogen (50.0 mL/min). It was
weighed about 2.0 mg of raw material and crystals fluco-
nazole. DSC photovisual data were recorded applying a
Shimadzu Calorimeter model DSC-50 coupled to a model
VCC-520 photovisual system connected to an Olympus
microscope and to a Sony camera in nitrogen (50.0 mL/min)
at a heating rate of 10.0 °C/min from room temperature up
to 250.0 °C. The DSC photovisual system was connected to
a computer using Assimetrix software. The pictures of the
samples were visualized and recorded at real time according
to their DSC curves observing the phase transition of the
samples. The DSC cooling/heating curves of the fluconaz-
ole and crystals were obtained after two cycles of sequential
heating and cooling [16], and recorded using a Shimadzu
calorimeter model DSC-60, coupled to a model EK90/SH
cooling system Peltier, in nitrogen (30.0 mL/min) at heating
rates of 5.0, 10.0 and 20.0 °C/min. The sample was heated
up to 160.0 °C, and held at this temperature for 3 min before
cooling to room temperature at the same heating rates. The
sample cooled to room temperature was reheated up to
160.0 °C under similar conditions. The DTA curves of fluco-
nazole (A) were recorded using a Shimadzu differential
thermal analyzer model DTA-50 in nitrogen (50.0 mL/min)
at a heating rates (10.0, 20.0 and 40.0 °C/min), up to the
temperature of 900.0 °C. The drug was characterized
through its typical transition phases, using a TASYS pro-
gram, from Shimadzu. Thermogravimetric curves were
recorded in a Shimadzu thermobalance model TGA-50H
apparatus calibrated with calcium oxalate monohydrate.
The dynamic and isotherm curves were obtained in nitro-
gen (50.0 mL/min) and synthetic air (20.0 mL/min). The
dynamic TG curves were recorded at a heating rate of
10.0, 20.0, and 40.0 °C/min from ambient up to 900.0 °C.
Isothermal curves were recorded at 155.0, 160.0, 165.0,
170.0, and 175.0 °C for 300 min. The sample mass was
5.0 0.5 mg. The kinetic parameters of decomposition
were calculated using the Arrhenius equation on the basis of
TG isothermal data [17]. The reaction order (n), frequency
factor (A), and activation energy (Ea) were determined
using the Ozawa model for the TG dynamic data in the
synthetic air atmosphere [6]. TG data were analyzed using
Tasys software from Shimadzu.
NBS library. The sample’s volume corresponds to a little
fluconazole crystal put in platinum crucible and introduced
to the pyrolyzer at the temperatures of 250.0, 500.0, and
750.0 °C, separately for each experiment.
Results and discussion
The DSC-50 curves of fluconazole raw material (A) and
crystals (B, C and D) were better characterized at a heating
rate of 2.0 °C min-1 (Fig. 1). The calorimetric curve of
the raw material fluconazole (A) showed an endothermic
peak corresponding to the melting point temperature at
138.4 °C. The calorimetric curves of the crystals B, C, and
D present different thermal behaviors. The crystals showed
two endothermic peaks in the melting point of the fluco-
nazole, for the crystal B in the temperatures of 136.7 and
138.6 °C, the crystal C showed endothermic peaks in the
temperatures of 135.1 and 138.9 °C and the crystal D
showed endothermic peaks of 136.0 and 138.5 °C, corre-
sponding to the presence of two polymorphs formed in the
process of recrystallization in different solvents.
The images captured at room temperature in the DSC
photovisual show the drug and crystals without visible
alterations (Fig. 2). The following images correspond to
the melting process of the samples. For the sample A, it is
possible to observe the phase transition at the temperatures
138.5 and 139.6 °C, which occurs in a uniform manner in
all the sample extensions. The images captured for crystals
B, C, and D show two events at temperatures 138.3, 138.6,
and 138.2 °C, respectively: the melting process of the first
polymorphic form (less stable), and the polymorph form
more stable staying unaltered. In the figures captured at the
temperatures of 138.7, 138.9, and 138.5 °C were observed
the melting of the second form for the crystals B, C, and D,
respectively. The images confirm the presence of poly-
morphs forms visualized in the conventional DSC curves.
At the temperatures 220.3, 221.6, 220.1, and 225.4 °C for
DSC
mW
10.00
Fluconazole (A)
Fluconazole crystal (B)
Fluconazole crystal (C)
5.00
0.00
Pyrolysis—GC/MS
A pyrolyzer coupled to a Shimadzu gas phase chromato-
graph, model GCMS-QP5050A was used for the studies
of pyrolysis. The oven was programmed with the follow-
ing temperature 70.0 °C (initial) and at a heating rate of
10.0 °C/min up to 290.0 °C. The temperature of the ions
source was 300.0 °C. The identification of the compounds
was made comparing their mass spectra with the Wiley/
Fluconazole crystal (D)
200.00
–5.00
100.00
Temperature/°C
Fig. 1 Calorimetric curves of the fluconazole and its crystals at the
heating rate of 2.0 °C/min
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Thermal characterization of the solid state and raw material fluconazole
291
DSC
mW
10.00
First heating/cooling cycles
91,74°C
5.00
0.00
138,97°C
32,87°C
Second heating/cooling cycles
–5.00
138,74°C
139,56°C
150.00
–10.00
50.00
100.00
Temperature/°C
Fig. 3 DSC-cooling curves of the fluconazole A, in the heating/
cooling cycles, at a rate of 5.0 °C/min
Fig. 2 Images from the DSC-photovisual of the fluconazole A and its
crystals recrystallized in methanol, acetone, and chloroform (B, C,
and D) at the ambient temperature, onset, peak, and 250.0 °C
DTA
uV
FLU razão de 10°C/min
FLU razão de 20°C/min
FLU razão de 40°C/min
20.00
the samples A, B, C, and D respectively, it is seen a white
spot possibly from the crystallization of the samples. At the
temperature of 250.0 °C, it is observed a volatilization of
the samples studied.
0.00
The DSC-60 curves of fluconazole raw material and its
crystals B, C, and D showed to be better characterized at
the heating rate of 5.0 °C min-1. The data obtained for the
samples in the first heating cycle are similar to the ones
obtained in the DSC-50. The sample (A) showed an
endothermic peak typical of melting at a temperature of
138.9 °C. The samples B, C, and D showed two endo-
thermic peaks corresponding to the melting of two poly-
morphs forms at the temperatures (137.9 and 139.4 °C),
(137.8 and 139.9 °C), and (138.2 and 139.9 °C), respec-
tively. In the second heating cycle, the sample (A) showed
an endothermic peak at 32.8 °C corresponding to the glass
transition, followed by an exothermic peak at 91.7 °C
possibly from the crystallization, and two endothermic
peaks at the temperatures 138.7 and 139.5 °C (Fig. 3). The
characteristic of the two different crystalline forms melt-
ing, obtained after cooling of the fluconazole melting in the
first heating and cooling cycle [6]. For the crystals B, C,
and D in the second heating cycle the processes of glass
transition are evidenced at the temperatures 31.7, 36.2 and
34.1 °C, of crystallization at the temperatures 91.3, 94.7
and 95.7 °C, respectively, and two endothermic peak’s
characteristic of two crystalline forms melting processes
(similar to the first heating cycle), at the temperatures
(138.2 and 139.5 °C) for the crystal B, (137.9 and
138.0 °C) for the crystal C and (138.0 and 138.8 °C) for
the crystal D. In the first and second cooling cycles, no
thermal phenomena were observed in all the samples
studied.
–20.00
–40.00
0.00
200.00
400.00
Temperature/°C
600.00
800.00
Fig. 4 Differential thermal analysis curves of the fluconazole A, at
the heating rates of 10.0, 20.0, and 40.0 °C/min
The DTA curves of the fluconazole (Fig. 4) proved that
the drug presented melting endothermic processes similar to
the DSC. At the rates of 10.0, 20.0, and 40.0 °C min-1, it is
possible to observe at the temperatures of 99.4 °C 0.31,
99.3 °C 0.07, 100.5 °C 0.45, respectively, an endo-
thermic peak typical of water loss. The endothermic peaks
of melting of FLU are observed at the rates of 10.0, 20.0,
and 40.0 °C min-1 at the temperatures of 138.5 °C 0.28,
138.8 °C 0.19, and 139.8 °C 0.82, respectively. It
was also possible to observe at the different heating rates, in
the temperature interval from 216.1 to 319.8 °C, an exo-
thermic peak followed by two endothermic peaks, possibly
due to the crystallization of the sample, following of vola-
tilization, confirming the white spot at the temperature
220.3 °C and the sample absence in the photovisual at the
temperature of 250.0 °C.
The dynamic thermogravimetric curves obtained in the
synthetic air atmosphere, at the heating rate of 10.0 °C/min,
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292
E. A. Moura et al.
TGA
mg
4.00
1
2
3
2.00
0.00
0.00
200.00
400.00
600.00
800.00
Fig. 5 Thermogravimetric dynamic of the fluconazole A, at the
heating rates of (1) 10.0, (2) 20.0, and (3) 40.0 °C/min
have shown that the fluconazole presents a mass loss
from 4.16 to 4.57% before the melting temperature at the
average initial temperature (Ti) in 65.8 °C ( 0.53) and
average final temperature (Tf) at 110.2 °C ( 0.40), corre-
sponding to the water loss of the sample [18]. The fol-
lowing phase corresponds to the mass loss of the FLU with
the average Ti at 240.4 °C ( 2.2) and Tf at 310.8 °C
( 1.87), with a mass loss from 94.02 to 94.32%. The
behavior of the fluconazole in the dynamic curves at
the heating rate of 20.0 and 40.0 °C shows to be similar in
the mass loss percentages. The temperature of the mass loss
is dislocated to higher temperatures with the increase of the
heating rate (Fig. 5).
Ozawa’s model, for the TG dynamic data, has been
employed in the kinetic studies to evaluate the kinetic
parameters, activation energy (Ea), frequency factor (A)
and reaction order (n). The data has evidenced a thermal
process with kinetic of zero order for the fluconazole, with
the values of Ea (95.83 KJ/mol 2.76), frequency factor
(2.831 9 108 min-1 0.57 9 108), in the decomposed
fraction a10. With the data from the TG isothermal curves,
the rate constants of mass loss were calculated, at the
analyzed temperatures, following the Arrhenius equation
considering the zero order of decomposition determined
by the Ozawa method. According to the coefficients of
correlation, the isothermal data confirm zero order of
decomposition (Table 1).
The degradation products corresponding to the phase of
mass loss of the fluconazole were identified through
pyrolysis coupled to GC–MS. The pyrogram obtained at
the temperature of 250.0 °C can be visualized in the Fig. 6,
where two peaks have been detected, the first correspond-
ing to the hexachlorobenzene and the second identified
as fluconazole, confirming that at the temperature of
240.0 °C, the mass loss observed in the thermogravimetric
curve (Fig. 5), does not correspond to the degradation of
the drug, but to the volatilization of the fluconazole in its
intact molecular form. The pyrograms were also obtained
at the temperatures of pyrolysis of 500.0 and 750.0 °C,
(Figs. 7 and 8, respectively), where the products of deg-
radation of the fluconazole were detected in the state of
123