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Physicochemical properties and thermal stability of quercetin hydrates in the

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DOI: 10.1016/j.tca.2012.04.015

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Thermochimica Acta 539 (2012) 109–114

Contents lists available at SciVerse ScienceDirect

Thermochimica Acta
journal homepage: www.elsevier.com/locate/tca

Physicochemical properties and thermal stability of quercetin hydrates in the

solid state
G.S. Borghetti a,∗ , J.P. Carini a , S.B. Honorato b , A.P. Ayala b , J.C.F. Moreira c , V.L. Bassani a
a
Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Av. Ipiranga 2752, CEP 90.610-000, Porto Alegre,
RS, Brazil
b
Departamento de Física, Universidade Federal do Ceará, Caixa Postal 6030, CEP 60.455-970, Fortaleza, CE, Brazil
c
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2600, CEP 90035-003, Porto Alegre, RS, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: In the present work three samples of quercetin raw materials (QCTa, QCTb and QCTc), purchased from
Received 21 December 2011 different Brazilian suppliers, were characterized employing scanning electron microscopy, Raman spec-
Received in revised form 10 April 2012 troscopy, simultaneous thermogravimetry and infrared spectroscopy, differential scanning calorimetry,
Accepted 13 April 2012
and variable temperature-powder X-ray diffraction, in order to know their physicochemical properties,
Available online 21 April 2012
specially the thermal stability in solid state. The results demonstrated that the raw materials of quercetin
analyzed present distinct crystalline structures, ascribed to the different degree of hydration of their crys-
Keywords:
tal lattice. The thermal stability of these quercetin raw materials in the solid state was highly dependent
Hydrates
Physicochemical properties
on their degree of hydration, where QCTa (quercetin dihydrate) was thermodynamically more stable than
Quercetin the other two samples.
Solid state © 2012 Elsevier B.V. All rights reserved.
Thermal stability

1. Introduction Quercetin (3,3 ,4 ,5,7-pentahydroxy-flavone) is one of the most

common dietary flavonoids (Fig. 1). Its biological properties have
Hydrates are crystalline forms containing either stoichiomet- been intensively investigated, which are very often related to
ric or non-stoichiometric amounts of water into the crystal lattice. its antioxidant activity [5]. In Brazil, quercetin raw materials are
They are also called pseudopolymorphs [1]. The solubility and the commercially available as quercetin dihydrate (C15 H10 O7 ·2H2 O).
stability of hydrates can differ significantly. These differences are However, the occurrence of quercetin raw materials from different
ascribed to variations in their crystalline structure [2]. suppliers in the Brazilian market presenting different crystalline
The physical stability of hydrates in the solid state is highly structures has been found by preliminary studies of our group
dependent on the environmental conditions. During processing or [6]. In the same way, the existence of dihydrate and anhydrous
storage, crystalline compounds are often exposed to water, mois- forms of quercetin has been reported by Olejniczak and Potrze-
ture and temperature changes and, thus, may be converted to other bowski [7]. The authors mentioned that the presence of hydration
crystalline form [1]. The hydration and dehydration, which refers to water molecules into the crystal lattice of the flavonoid has great
the transition between anhydrates and hydrates or between lower influence on its molecular geometry. In other words, the hydro-
and higher hydrates, may lead to the formation of a more or less gen bonding pattern differs according to the crystalline form of
stable form, an amorphous form or a mixture of crystalline forms. quercetin. For the dihydrate form, intermolecular hydrogen bonds
The phase transitions resulting from hydration or dehydration are occur between hydration water molecules and hydroxyl groups
often accompanied by changes in the physicochemical properties of of C3 , C4 and C7. For the anhydrous form, the hydroxyl group
bioactive substances. The effects of such transitions may have great of C3 is involved in the formation of an intramolecular hydro-
practical importance, especially for insoluble molecules in water, gen bond with the hydroxyl group of C4 and, thus, its solubility
such as quercetin [3], because they can affect their bioavailability in water is also reduced. The presence of hydroxyl groups in
[4]. C3 and C4 positions of the B ring, as well as a hydroxyl
group in C3 position of the C ring in conjunction with a C2 C3
double bond, is also related to the high antioxidant activity of
quercetin [8].
∗ Corresponding author at: Faculdade de Farmácia, Universidade Federal do Rio
Despite the knowledge concerning the occurrence of quercetin
Grande do Sul, Av. Ipiranga 2752, CEP 90.610-000, Porto Alegre, RS, Brazil.
Tel.: +55 51 3308 3004; fax: +55 51 3308 5437. raw materials presenting different crystalline structures in the
E-mail address: [email protected] (G.S. Borghetti). Brazilian market, there is a lack of information about the degree

0040-6031/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.tca.2012.04.015
 Author's personal copy

110 G.S. Borghetti et al. / Thermochimica Acta 539 (2012) 109–114

step of 0.02◦ 2, step exposure time of 3 s, heating rate of 5 ◦ C min−1

over the angle range of 3–32◦ 2, from room temperature (20 ◦ C)
up to 270 ◦ C.

3. Results and discussion

The combination of several experimental techniques has been

employed for characterizing hydrates in the solid state. Pow-
Fig. 1. Chemical structure of quercetin.
der X-ray diffraction, one of the most reliable techniques for the
identification of crystalline structures, cannot easily differentiate
between true polymorphs and pseudopolymorphs. In cases where
of hydration of their crystal lattice as well as its influence on
single crystals of sufficient quality for structural determination are
the physicochemical properties and the thermal stability of the
difficult to obtain, pseudopolymorphism can be identified by ther-
flavonoid. For this reason, the objective of the present work
mogravimetric analysis or by Raman spectroscopy. The combined
was to characterize three samples of quercetin presenting dif-
use of thermogravimetry and infrared spectroscopy permits the
ferent crystalline structures, purchased from different suppliers,
identification of the solvent incorporated into the crystal lattice.
employing scanning electron microscopy, Raman spectroscopy,
On the other hand, Raman spectroscopy is especially important
differential scanning calorimetry, simultaneous thermogravimetry
because it detects low energy vibrations of atoms caused by differ-
and infrared spectroscopy, and variable temperature-powder X-ray
ences in crystal lattice packing. Additionally, the functional groups
diffraction, in order to know their physicochemical properties and,
involved in hydrogen bonds can display shifts of varying degrees
specially, their thermal stability in the solid state.
[9–12].

2. Experimental
3.1. Scanning electron microscopy
2.1. Materials
The photomicrographs revealed by SEM (Fig. 2) show that the
Three samples of pharmaceutical grade quercetin (QCT) were particle size order of quercetin samples is QCTb > QCTa > QCTc.
analyzed as supplied, without purification or recrystallization. These results can explain, at least partially, the lower solubility in
QCTa, QCTb and QCTc were purchased from Deg (São Paulo, Brazil), water, at 37 ◦ C, of QCTb (2.6 ␮g mL−1 ) when compared with the
Galena (São Paulo, Brazil) and SPFarma (São Paulo, Brazil), respec- other samples (3.7 ␮g mL−1 for QCTa and 6.5 ␮g mL−1 for QCTc)
tively. [13]. However, it is difficult to determine if these differences in
the particle size and morphology are caused by the pseudopoly-
2.2. Scanning electron microscopy (SEM) morphism or by changes in the crystal growth conditions, such
as degree of supersaturation, nature of the crystallization solvent,
The photomicrographs were taken at a voltage of 10 kV and a speed of solution agitation, rate of cooling, or presence of impurities
magnification of 3000× using a Jeol JSM 6060 microscope (Tokyo, [10].
Japan). The samples were fixed on brass stubs using a double-sided
adhesive tape and vacuum-coated with a thin layer of gold. 3.2. Fourier transform–Raman spectroscopy

2.3. Fourier transform–Raman spectroscopy The Raman spectra obtained for the three samples of quercetin
in the fingerprint region are presented in Fig. 3. It is possible to
The Raman spectra of the samples were recorded using a Bruker associate the spectrum obtained for QCTa with that previously
Vertex 70 FTIR/FT-Raman spectrometer (Ettlingen, Germany) reported by Cornard et al. [14] and Teslova et al. [15]. Its main
equipped with a Nd:YAG laser (1064 nm excitation line) and a features are ␯(C O) stretching (1660 cm−1 ), ␯(C2 C3) stretching
liquid-nitrogen cooled Ge detector. The analyses were performed at (1608 cm−1 ), and phenyl and benzo rings ␯(C C) stretchings (1590
room temperature, by accumulating 1024 scans over the frequency and 1549 cm−1 ). The group of bands between 1500 and 1300 cm−1
range from 2000 up to 100 cm−1 , and with a resolution of 4 cm−1 . cannot be described by a single internal coordinate, but it can be
associated with a set of mechanical coupled vibrations of ␯(C C)
2.4. Differential scanning calorimetry (DSC) and stretchings and in-plane ␦(CH) and ␦(C OH) bendings. Although it
thermogravimetry (TG) is not possible to associate a single band to the ␯(C2 C1 ) stretching,
contributions of interring bond are expected in this region.
Simultaneous DSC and TG experiments were performed using As it will be shown later by VTPXRD, QCTb seems to be a mix-
a Netzsch STA 409 PC/PG equipment (Selb, Germany) coupled to ture of different crystalline forms of the flavonoid. Thus, we will
a Bruker Tensor 27 Fourier Transformed infrared spectrometer focus our discussion in the comparison between QCTa and QCTc.
(Ettlingen, Germany). The analyses were performed from room The most remarkable differences observed in the Raman spectra of
temperature (20 ◦ C) up to 500 ◦ C, at 10 ◦ C min−1 , under nitrogen gas these samples are the shift of the ␯(C2 C3) stretching mode from
flow (60 mL min−1 ), by using crimped aluminum pans with a pin- 1608 cm−1 to 1616 cm−1 and the shift of the bands around 1439
hole in which approximately 5 mg of the samples were accurately and 1328 cm−1 , which are related to the ␯(C2 C1 ) stretching. A
weighed. similar effect was observed by Cornard et al. [16] when the Raman
lines of quercetin in the solid state and in solution were compared.
2.5. Variable temperature-powder X-ray diffraction (VTPXRD) The frequency variations observed can be ascribed to changes in
the molecular conformation induced by the crystal field and that
The diffractograms of the samples were recorded using a Rigaku are specially related to the relative orientation of the phenyl and
Rint 2000 equipment (Tokyo, Japan) under the following operating pyrone rings, showing that the conformational changes are mostly
conditions: Cu K␣ radiation ( = 1.5406 Å), reflection mode, voltage located around the C2 C1 bond. Quantum mechanical calculations
of 40 kV, current of 40 mA, scanning rate of 0.5◦ 2 min−1 , scanning lead to a nonplanar structure with a torsion angle of about 28◦ [16],
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G.S. Borghetti et al. / Thermochimica Acta 539 (2012) 109–114 111

whereas the value determined by X-ray diffraction in the crystalline

state is around 5.5◦ [17,18]. On the other hand, the bands related to
the phenyl and benzo rings stretchings (around 1590, 1549, 1400
and 1370 cm−1 ) remained unaltered.

3.3. Differential scanning calorimetry

The DSC curves obtained for the three samples of quercetin

exhibited two main endothermic events that have been previously
reported by other studies [7,19–22], as illustrated in Fig. 4. The
first one corresponds to the release of the solvent incorporated
into the crystal lattice. For QCTa and QCTb, it occurs at high tem-
peratures (approximately 105 ◦ C and 119 ◦ C, respectively), which
suggests that the solvent molecules are strongly held by the crys-
tal lattice. On the other hand, QCTc showed a broad endotherm
at low temperature (approximately 82 ◦ C), thus, this phenomenon
seems to involve low enthalpy. The second endothermic event is
related to the melting point and occurred at approximately 317 ◦ C
for QCTa, 323 ◦ C for QCTb, and 318 ◦ C for QCTc. An exothermic event
following melting was also observed for all samples and corre-
sponds to the degradation of quercetin (at approximately 340 ◦ C for
QCTa, 350 ◦ C for QCTb, and 345 ◦ C for QCTc). Additionally, a minor
endothermic event was observed for QCTb and QCTc at approxi-
mately 272 ◦ C and 231 ◦ C, respectively, suggesting the occurrence
of a solid–solid transition of the corresponding anhydrous forms.
This phenomenon was not observed for QCTa.

3.4. Simultaneous thermogravimetry and infrared spectroscopy

The TG curves obtained for the three samples of quercetin exhib-

ited a two-step weight loss within the same temperature range
observed in DSC analysis, as illustrated in Fig. 5. The simultane-
ous analysis by infrared spectroscopy allowed the identification of
the solvent incorporated into the crystal lattice of the samples. The
insets in the figure show the integrated intensity of the infrared
spectra of the released gases in the ␯(OH) and ␯(CO) stretching
regions of water and carbon dioxide, respectively. Therefore, the
first weight loss is clearly associated with a dehydration process,
since water vapor was the only gas released. In the second weight
loss (approximately 14.7%, 22.2% and 19.9% for QCTa, QCTb and
Fig. 2. Photomicrographs of quercetin samples: (a) QCTa, (b) QCTb, and (c) QCTc. QCTc, respectively) it can be observed the release of carbon dioxide,
characterizing a degradation process.
The thermogravimetric analysis confirmed that all samples of
quercetin characterized in this work are hydrates, excluding the
occurrence of solvates. However, these hydrates contain different
amounts of water into the crystal lattice, approximately 10.5% for
QCTa, 2.9% for QCTb and 5.1% for QCTc, which can explain their
distinct crystal structure (as it will be shown later by VTPXRD).

3.5. Variable temperature-powder X-ray diffraction

The diffractograms obtained for the three quercetin hydrates at

room temperature (20 ◦ C) are illustrated in Fig. 7a and the main
diffraction peaks are summarized in Table 1. All of them exhibited
a series of sharp peaks, suggesting that the flavonoid exists as a
crystalline material. However, the differences observed in the peak
positions, which correspond to the periodic packing of molecules in
the solid state, suggest that the three samples of quercetin present
distinct crystalline structures. QCTa exhibited a diffraction pattern
characteristic of quercetin dihydrate [7,17,18,22–27]. QCTb pre-
sented some peaks at a diffraction angle coincident to that exhibited
by QCTa (10.7◦ , 12.3◦ , 13.4◦ , 14.0◦ , 24.2◦ , 26.4◦ , 27.3◦ and 29.5◦ 2),
Fig. 3. FT-Raman spectra of quercetin samples (QCTa, QCTb, and QCTc) in the fin- suggesting that this sample is very probably a mixture of quercetin
gerprint region.
dihydrate and other crystalline form of the flavonoid. On the other
hand, QCTc exhibited a diffraction pattern very different from that
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112 G.S. Borghetti et al. / Thermochimica Acta 539 (2012) 109–114

Fig. 4. Differential scanning calorimetry curves of quercetin samples (QCTa, QCTb and QCTc). The insets show a magnified region for better visualization.

Fig. 5. Thermogravimetry curves of quercetin samples (QCTa, QCTb and QCTc). The insets show the integrated intensity of characteristic bands of H2 O and CO2 observed in
the infrared spectra of the released gases.

Table 1
Main diffraction peaks obtained for quercetin samples (QCT) and their new crystalline forms by using variable temperature-powder X-ray diffraction ( = 1.5406 Å).

Quercetin samples Diffraction peaks (◦ 2)

Room temperature (20 ◦ C) Transition 1a (dehydration) Transition 2b (solid-solid)

QCTa 10.65; 12.34; 13.51; 14.07; 15.76; 7.47; 9.17; 10.77; 12.66; 14.36; 15.01; –
24.29; 26.52; 27.27; 29.54 16.71; 21.15; 25.86
QCTb 10.70; 12.34; 13.48; 14.02; 17.83; 11.79; 12.11; 12.44; 13.36; 13.75; 7.47; 9.24; 10.77; 12.94; 14.36; 15.01;
24.26; 26.41; 27.34; 28.20; 29.5 16.73; 17.77; 26.19; 28.04 16.71; 21.90; 25.92
QCTc 4.52; 8.86; 9.69; 13.00; 16.58; 21.86; 9.89; 10.72; 13.24; 17.71; 21.66; 24.31; 7.50; 9.30; 10.83; 13.03; 14.45; 15.21;
24.76; 25.94; 27.86 25.95; 27.57 16.71; 21.80; 25.86
a
Phase transition 1 occurred at 110 ◦ C for QCTa and QCTb and at 40 ◦ C for QCTc.
b
Phase transition 2 occurred at 270 ◦ C for QCTb and 250 ◦ C for QCTc.
 Author's personal copy

G.S. Borghetti et al. / Thermochimica Acta 539 (2012) 109–114 113

Fig. 6. Variable temperature-powder X-ray diffraction patterns of quercetin samples: (a) QCTa, (b) QCTb, and (c) QCTc.

presented by QCTa and QCTb and, thus, this sample seems to cor- corresponding anhydrous forms was different from that observed
respond to a third crystalline form of quercetin. for the original forms and different from each other (Table 1). In
After the characterization of their crystalline structures, the the same way, a second phase transition was observed for QCTb
thermal stability of the three quercetin hydrates was analyzed in (at 270 ◦ C) and QCTc (at 250 ◦ C), confirming the occurrence of a
the solid state by VTPXRD. The phase transition expected because of solid–solid transition of the corresponding anhydrous forms and
the molecular rearrangement during the dehydration of quercetin the above-mentioned thermal behavior by both samples. On the
was observed at 110 ◦ C for QCTa (Fig. 6a) and QCTb (Fig. 6b), and other hand, no phase transition was observed for QCTa on heat-
40 ◦ C for QCTc (Fig. 6c). The diffraction pattern obtained for the ing above 110 ◦ C. The resulting diffraction patterns at 270 ◦ C are

Fig. 7. Powder X-ray diffraction patterns of quercetin samples (QCTa, QCTb and QCTc) at (a) room temperature and (b) 270 ◦ C.
 Author's personal copy

114 G.S. Borghetti et al. / Thermochimica Acta 539 (2012) 109–114

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