Composites Part B 89 (2016) 60e66

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Composites Part B
journal homepage: www.elsevier.com/locate/compositesb

Novel nutraceutical Myricetin composite of enhanced dissolution

obtained by co-crystallization with acetamide
M. Mureşan-Pop a, L.B. Chiriac b, F. Martin c, S. Simon a, b, *
a
Babeş-Bolyai University, Institute of Interdisciplinary Research in Bio-Nano-Sciences, 400084 Cluj-Napoca, Romania
b
Babeş-Bolyai University, Faculty of Physics, National Magnetic Resonance Center, 400084 Cluj-Napoca, Romania
c
National Institute for Research and Development of Isotopic and Molecular Technologies, 400293 Cluj-Napoca, Romania

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

Article history: In order to improve the physicochemical properties and solubility of the nutraceutical compound
Received 19 August 2015 Myricetin, we investigated its propensity to form co-crystals with acetamide. A novel co-crystal was
Received in revised form obtained by solvent drop grinding of Myricetin and acetamide. The co-crystal formation was evidenced
21 October 2015
by X-ray powder diffraction, thermal analysis and spectroscopic techniques (FT-IR, 1H MAS NMR). Sta-
Accepted 4 November 2015
Available online 30 November 2015
bility study on exposure to elevated temperature and relative high humidity indicated that the co-crystal
change to Myricetin form within 8 weeks. On the other hand, solubility and dissolution measurements
showed a 4 times increase in the dissolution rate of the co-crystal in water compared to Myricetin. Our
Keywords:
A. Nano-structures
study shows that the co-crystal of Myricetin with acetamide could be a candidate for developing solid
B. Microstructures oral dosage formulations of enhanced bioavailability.
D. Physical methods of analysis © 2015 Elsevier Ltd. All rights reserved.
E. Assembly

1. Introduction ability to obtain salt forms of Myricetin was evidenced in relation

The flavonoid Myricetin 3,5,7-Trihydroxy-2-(3,4,5-
trihydroxyphenyl)-4-chromenone is a nutraceutical compound
with antioxidant properties, that is found in a large variety of
berries [1e3]. The biological properties of natural antioxidants
such as anticarcinogenicity, antimutagenicity, antiallergenicity,
and antiageing activity are well recognized and reported [1,3e6].
The major drawbacks of many of these natural compounds are the
low water solubility and bioavailability, which are strongly
limiting their development as active pharmaceutical ingredients.
Myricetin is considered a nutritional supplement that increases
energy level and vitality of the body. In scientific terms, attention
is directed to the poor solubility and stability of Myricetin in
water, which restricts its application as an antioxidant and
functional supplement in hydrophilic food. Moreover, the prob-
lem is also present in the pharmaceutical field because of the
difficulty to complete formulation [2,7]. In most studies the
* Corresponding author. Babeş-Bolyai University, Institute of Interdisciplinary
Research in Bio-Nano-Sciences, 400084 Cluj-Napoca, Romania. Tel.: þ40 264
405300; fax: þ40 264 591906.
E-mail address: simons@phys.ubbcluj.ro (S. Simon).
to possible solubility improvement. Literature revealed poly-
morphic forms and co-crystals of Myricetin obtained with
different coformers [8,9] or inclusion complexes [10]. Acetamide
is among the pharmaceutically acceptable coformers, as well as
nicotinamide, acetic acid, 4-hydroxy-benzoic acid and saccharin
[11]. Nevertheless, a risk could be always considered, e.g., even
though acetamide is not classified for carcinogenicity in humans,
and the animal studies have not reported any significant devel-
opmental effects from exposure to acetamide, however some
animal studies reported liver tumors from oral exposure to
acetamide [12,13].
The co-crystals offer the advantage of obtaining solid forms of
active pharmaceutical ingredients with improved chemical and
physical properties, without compromising their bioactivity, and
also provide the ability to combine multiple medications, two or
more active ingredients, into a crystal lattice [14e18]. The forma-
tion of a pharmaceutical co-crystal may yield a composite that has
favorable characteristics concerning bioavailability, dissolution,
shelf life, etc. [19].
Co-crystallization via solvent drop grinding is an alternative to
the traditional method of solution crystallization applied to modify
the physicochemical properties of pharmaceutical compounds
[20,21].

http://dx.doi.org/10.1016/j.compositesb.2015.11.024
1359-8368/© 2015 Elsevier Ltd. All rights reserved.
 M. Mureşan-Pop et al. / Composites Part B 89 (2016) 60e66
The purpose of present study was to investigate the possibility
to improve the dissolution rate of Myricetin (Myr) by co-
crystallization with Acetamide (AcAm).
2. Materials and methods
Myricetin was supplied by TeraCrystal SRL Romania and acet-
amide was acquired from Merck.
2.1. Preparation of co-crystals, Cc
A new co-crystal was synthesized by applying the solvent drop
grinding method. Myricetin (30 mg, 0.094 mmol) and acetamide
(5.567 mg, 0.094 mmol) were co-ground in a 1:1 stoichiometric
amount together with ethanol drops (two drops, c.a. 50 mL), up to
resulting a dry powder. Samples were ground in a Retsch Ocillating
Mixer MILL MM400, for 60 min (2  30 min with 5 min cooling
periods) at a rate of 30 Hz, in a stainless steel grinding jar with two
5 mm stainless steel grinding balls.
2.2. X-ray powder diffraction
X-ray diffraction patterns were obtained on a Shimatzu XRD-
6000 Diffractometer, equipped with a CuKa source
(l ¼ 1.54056 Å) radiation, operating at 40 kV source and 30 mA
intensity. All data were collected at room temperature; each sample
was scanned between 3 and 40 in 2q scan range, with a step size of
0.02 , a scan speed of 2 /min. The samples were ground in an agate
mortar in order to control crystals size and to minimize the pref-
erential orientations effects.
2.3. Morphological analysis
The particles morphology was studied with Motic optical mi-
croscope using the 40 objective and the images were captured
with a digital camera.
2.4. Thermal and thermogravimetric analysis
Thermal analysis (DSC) was performed on a Shimadzu DSC-60
differential scanning calorimeter (Shimadzu Corporation, Japan),
TA60 2.10 software was used for data acquisition and analysis.
Samples of 3e10 mg were weighted and placed in aluminum
closed pans, and heating was applied at 10  C min1, from room
temperature up to 400  C under flowing nitrogen flux of 70 mL/
min.
Thermogravimetric analysis (TGA) was carried out with a
simultaneous Shimadzu DTA/DTG-60H apparatus (Shimadzu Cor-
poration, Japan). Alumina open crucibles and a-alumina powder as
reference material were used and for data collection and analysis,
the Shimadzu TA60 2.10 software was used. The sample weights
were in the range of 5e10 mg, heating was operated under nitrogen
flow of 70 mL/min using an alumina sample cell (2, 5.8  2.5 mm2).
Heating was in a range of 20e400  C at the rate of 10  C min1 up to
decomposition.
2.5. Infrared absorption spectroscopy
Infrared absorption spectra were obtained using a JASCO 6200
Fourier Transform-Infrared Spectrometer (Jasco Inc., MD, USA), and
Spectra Manager software was used for data collection. Each
spectrum was recorded in the 400e4000 cm1 spectral domain
with a resolution of 2 cm1 and 256 scans. A background spectrum
of the potassium bromide pellet was recorded under the same
instrumental conditions and subtracted from each sample
61
spectrum. Each sample in pellet was prepared with approximately
1 mg of solid sample mixed with 150 mg of dry, pure spectral po-
tassium bromide powder. Data analysis was performed using Jasco
Spectra analysis software.
2.6. Solid state 1H MAS NMR spectroscopy
Solid state Magic Angle Spinning (MAS) Nuclear Magnetic
Resonance (NMR) analysis was performed on Bruker Avance III
spectrometer, operated at 14.1 T magnetic field. One-dimensional
1
H NMR spectra were recorded at 600.13 MHz Larmor frequency,
using a triple resonance (H/C/N) Efree 3.2 mm MAS probehead. 1D
1
H MAS NMR spectra were recorded employing a single pulse (SP)
sequence with low flip angle (5 ) and 32 scans were accumulated
with a recycled delay of 3 s while rotor sample holder was spun at
16 kHz. All spectra were referenced to tetramethylsilane (TMS) as
0.0 ppm.
2.7. Powder dissolution studies
All experiments were carried out using a mDISS ProfilerTM
apparatus (pION Inc., MA, USA) to assess the dissolution rate and
the apparent solubility of Myricetin and its co-crystal with acet-
amide. The system consists of an integrated diode array spectro-
photometer connected to a fiber optic UV probe located directly in
the reaction vessel and measures the concentration as a function of
time, without filtering the solution. Measurement of dissolution
kinetics and equilibrium solubility was determined spectrophoto-
metrically at 255e280 nm and the concentrations of samples were
calculated by means of a standard curve. Experiments were per-
formed in triplicate for both Myricetin and co-crystals of Myricetin
with acetamide. 1e4 mg of sample was suspended in 10 mL
deionized water (pH 6.6), and the resulting mixture was stirred at
25  C and 400 rpm.
2.8. Storage stability
For storage stability tests at elevated temperature and relative
high humidity, a Memmert Humidity Chamber was used. The sta-
bility of all samples was monitored after storage at 40  C and 75%
RH for up to eight weeks.
3. Results and discussion
Molecular structure of Myricetin (C15H10O8, MW ¼ 318.21 g/mol)
and acetamide (C2H5NO, MW ¼ 59.067) are shown in Scheme 1.
Myricetin, acetamide and the co-crystal thereof were charac-
terized by X-ray powder diffraction (XRPD), thermal analysis (DSC/
Scheme 1. Molecular structure of Myricetin and acetamide.
62 M. Mureşan-Pop et al. / Composites Part B 89 (2016) 60e66

Fig. 1. XRPD patterns of a new co-crystal compared with its starting materials.

TGA), Fourier transform infrared (FT-IR) and 1H MAS NMR spec-

troscopy. Physical stability testing and dissolution rate measure-
ments were also carried out.

3.1. X-ray powder diffraction analysis

The X-ray powder diffraction (XRPD) patterns of Myr and AcAm

starting materials (Fig. 1) evidence distinct diffraction lines for the
two crystalline compounds. The Myr diffractogram contains the
main features recorded from myricetin samples of other prove-
nances [8,9]. The XRPD pattern of the solid material obtained by co-
crystallization process Cc, shows the appearance of several new
peaks at distinguishable 2q positions, and disappearance of the
characteristic reflections of Myr. This points out that a novel solid
form Cc, likely a co-crystal of Myricetin with acetamide was formed.
Fig. 3. DSC/TGA analysis from a Myr (a) and Cc (b).
The width of the diffraction lines indicates nanometric crystallites.
The crystallites size determined with Scherrer equation is about
20 nm both for components and their co-crystal form. crystals are formed from hundreds of nanocrystallites, according to
Particles morphology was studied by optical microscopy. A rod crystallites size estimated from XRPD data.
shape is evidenced for both Myricetin (Myr) and its co-crystal with
acetamide (Cc), but larger particle size are observed for Myr 3.2. Thermal analysis
compared to Cc (Fig. 2). The size of Myricetin crystals is between 5
and 50 mm, while that of Myricetin co-crystals with acetamide is Thermal behavior of the solid forms was investigated by DSD/
about 3e5 mm. These images allow roughly calculate that the TGA analysis and the results were compared with previous studies

Fig. 2. Optical micrographs of Myricetin (a) and its co-crystal with acetamide (b).
 M. Mureşan-Pop et al. / Composites Part B 89 (2016) 60e66 63

Fig. 4. DSC curves from Myr, AcAm, and CC.

[7,8,22,23]. DSC/TGA analysis of Myr compound (Fig. 3a) revealed

two endothermic peaks with onset temperatures at 61  C,
DH ¼ 13.68 J/g and at 84  C, DH ¼ 14.96 J/g, associated to
dehydration of the compound, with weight mass loss of 3.283%
and 3.041%. A third and a fourth endothermic signal with onset
temperatures at 312  C, DH ¼ 26.35 J/g, and 322  C,
DH ¼ 22.92 J/g can be attributed to the melting and decomposi-
tion processes, events accompanied by a weight mass loss
of 2.142% and 3.283% respectively. The final event is exothermic
with an onset temperature at 349  C, DH ¼ 37.56 J/g and 363  C,
DH ¼ 18.64 J/g, and corresponds to decomposition of compound.
DSC/TGA curves of the co-crystal Cc (Fig. 3b) show a different Fig. 6. 1H MAS NMR resonance spectra of Myr and AcAm starting compounds, and Cc.
thermal behavior compared to Myr and AcAm, with significant The expected spectrum of equal molar mixture of Myr and AcAm was added for
change in the endothermic events. The first endothermic event comparison.
with onset temperature at 148  C and DH ¼ 193.11 J/g corre-
sponds to non-hydrated character of Cc. The second signal with
onset temperature at 302  C and DH ¼ 49.49 J/g evidences the thermal events evidenced in DSC runs can be easier observed
melting of the Myr enclosed in the new co-crystal formed with relative to each other in Fig. 4.
AcAm, and its stability up to ca. 348  C, DH ¼ 33.99 J/g. The final
exothermic signal with onset temperature at 351  C, DH ¼ 47.10 J/g 3.3. FT-IR analysis
reveals the decomposition of the new co-crystal. TGA analysis of
the co-crystal (Fig. 3b) evidences four plateaus with onset tem- FTIR spectra of co-crystals, pure Myricetin and acetamide
peratures similar to DSC and total weight loss of 35.839%. The coformer are different (Fig. 5) and indicate Myricetin and acet-
amide coformer interaction.

Table 1
Chemical shift (d) of resonance signals from 1H MAS NMR spectra.

d (ppm)
AcAm Myr Cc Myr þ AcAm

e 11.2 11.9 11.1

e 9.4 8.7 9.4
-
7.9 7.9 7.9
7.5 e e 7.5
7.2 e e 7.2
6.8 e e 6.8
e 6.0 6.3 6.1
4.9 e e 4.9
4.5 e 4.6 4.5
3.9 e 3.5 3.9
3.5 e e 3.5
2.3 e 2.1 2.3
1.8 1.8 1.8
e e 1.1 e
Fig. 5. FT-IR spectra of AcAm, Myr and Cc.
64 M. Mureşan-Pop et al. / Composites Part B 89 (2016) 60e66
Fig. 7. Dissolution rate of Myr and Cc in deionized water.
Myricetin presents one carbonyl group and 6 phenolic hydroxyl
groups, and formation of the co-crystal with acetamide is likely
involving hydrogen bonding [24,25].
The IR spectrum of Myr is mostly similar to that of myricetin
used for pharmaceutical co-crystals generation with other
coformers [9]. It consists of characteristic peaks located at 3413 and
3289 cm1 due to presence of the OeH stretching frequency of the
hydrogen donating substituents (hydroxyl groups), attached to the
aromatic ring structures of flavonoids compound, at 1662 cm1 and
1602 cm1, corresponding to the eC]O stretching vibrations,
involved in intramolecular hydrogen bonding, at 1520 cm1 and
1469 cm1 attributed to the C]C stretching vibrations, of aromatic
groups, at 1328 cm1 and 1224 cm1, due to CeOeC vibrations, and
the band at 1025 cm1 corresponding to the CeH bending
vibrations.
The Cc spectrum shows distinct shifts in the hydroxyl and
carbonyl region of Myr, implying that the OeH and C]O groups in
Myr are likely involved in the formation of hydrogen bonds through
the co-crystallization process. The OeH stretching frequency of the
Cc is shifted to 3454 cm1 and 3366 cm1, respectively, compared
to the position in pure Myr. A new band appears at 3413 cm1, most
probably related to the presence of n(NeH) stretching vibration and
the intermolecular NeH$$$O interaction.
Fig. 8. XRDP patterns after storage in climate chamber for one week.
A large peak at 3197 cm1 is due to the n(OeH) stretching mode
of the OH group involved in the intermolecular OeH$$$O hydrogen
bonds. In the fingerprint 1700e1000 cm1 region the CeOH in-
plane bending vibrations of Myr are shifted to lower wave-
numbers in Cc spectrum (from 1328 to 1224 cm1 to 1316 and
1200 cm1, respectively), indicating the effect of co-crystallization
process. The comparison between the infrared spectra of the Cc
with those of the starting components denotes that a co-crystal of
Myr and AcAm is obtained. The spectral differences between Myr,
AcAm and Cc can be related to the occurrence of intermolecular
interactions between Myr and AcAm.
3.4. Solid state nuclear magnetic resonance analysis
1
H solid-state nuclear magnetic resonance spectra of the com-
ponents and their co-crystal (Fig. 6) show the existence of distinct
chemical environments of protons in Myr, AcAm and in the new co-
crystal Cc. The resonance lines at chemical shift of 4.6, 3.5 and
2.1 ppm are recorded in Cc spectrum and correspond to acetamide
moiety. These lines are shifted compared to the physical mixture
between Myr and Acetamide, thereby indicating co-crystal for-
mation. Flavonoid molecules present characteristic chemical shifts
related to their hydroxyl groups [26].
By comparison of co-crystal phase spectrum with that resulted
by simple addition of Myr and AcAm spectra, it is better evidenced
that in the new Cc phase the AcAm molecules are the most dis-
torted, being strongly affected the environments of the protons that
are giving the lines with 2 < d < 4 ppm in AcAm spectrum (Table 1).
The new peak arising at 1.1 ppm in Cc spectrum can be associated to
the protons that are involved in hydrogen bonds which are stabi-
lizing the new Cc, the same that are giving the infrared absorption
band at 3197 cm1 (Fig. 5, Cc).
3.5. Dissolution rate studies
In the dissolution experiment, the saturation solubility of Myr-
icetin was determined to be 16.90 mg/mL (Fig. 7). This value is
consistent with that reported in previous studies [2], namely a
solubility of Myricetin in pure water about 16.60 mg/mL at pH of
7.56, which increases with decreasing pH value of the liquid
medium.
Dissolution testing in deionized water for the co-crystal of
Myricetin with acetamide showed an increase to value of about
Fig. 9. DSC curve from Myr and Cc before and after storage in climate chamber for
eight weeks.
 M. Mureşan-Pop et al. / Composites Part B 89 (2016) 60e66
Table 2
Comparison of thermal analysis data for Myricetin and co-crystal of Myricetin with acetamide before and after stability testing.
Sample Tmax
Before storage in climate chamber
   
Myr Endothermic events ~76 C; 95 C; 316 C; 336 C
Exothermic events ~360  C; 367  C
Cc Endothermic events ~175  C; 326  C; 348  C
Exothermic events ~356  C
40 mg/mL after 25 min, compared to 10 mg/mL in the case of Myr-
icetin. Also, the solubility of the co-crystal increases with time, up
to almost 70 mg/mL after 80 min, which indicates a better disso-
lution rate compared to that of pure Myricetin.
4. Stability testing
Experimental data from literature [2] showed that Myricetin
would be relatively stable at body temperature due to a lower
degradation rates, but is unstable at temperatures higher than
40  C. This aspect should be taken into account particularly when
high temperatures are required during manufacturing. On the other
hand, it is suggested to keep Myricetin medicines at low temper-
atures in order to prevent the degradation.
The stability of the solid forms was tested by storage of Myr and
Cc at increased temperature (40  C) and high humidity (75%RH) for
2 months in open containers in climate chamber.
XRPD patterns showed that co-crystal form obtained from
Myricetin with acetamide tends to turn into crystalline form like
Myricetin, after one week in climate chamber (Fig. 8).
DSC curves recorded from Myr and Cc evidence for co-crystal
different temperatures of the thermal events before and after
storage in climate chamber (Fig. 9) as well as the tendency of Cc to
revert to the form of Myricetin compound after eight week storage
in climate chamber.
Table 2 summarizes data regarding the thermal events occurred
during heating of Myr and Cc samples, in 23e400  C temperature
range, before and after storage in climate chamber for eight weeks.
The data reveal that by maintaining of co-crystal in the climate
chamber, at high temperature and humidity, it tends to turn to the
crystalline form of Myricetin.
Changes discussed above are also revealed by infrared spec-
troscopy. Fig. 10 displays the infrared absorption bands of Myr and
Cc after maintaining in climate chamber for eight weeks. The
Fig. 10. FT-IR spectra after storage in climate chamber for 8 weeks.
65
After storage in climate chamber
Endothermic events ~74  C; 92  C; 315  C; 336  C
Exothermic events ~361  C; 367  C
Endothermic events ~90  C; 312  C; 334  C
Exothermic events ~364  C
infrared data confirm the results obtained by thermal analysis and
XRPD, i.e. Myr remains unchanged, but Cc highly changes into Myr.
5. Conclusions
A novel co-crystal form of the nutraceutical compound Myr-
icetin with acetamide was obtained by solvent-drop grinding. The
co-crystal nature was characterized by complementary analytical
techniques such as X-ray diffraction, thermal analysis, FT-IR and
MAS-NMR and spectroscopic methods. The co-crystal has sub-
stantially higher aqueous solubility and dissolution rate than
Myricetin, it is thermally stable in solid state, but it transforms to
Myricetin like form on exposure to elevated temperature and
relative high humidity. FT-IR and MAS-NMR data show new
hydrogen bonding interactions. The results prove the potential of
this novel co-crystal to be developed in an oral formulation with
improved bioavailability compared to the low water-soluble Myr-
icetin. The development risk related to the poor stability of the co-
crystal at elevated temperature and relative high humidity could be
mitigated by a careful control of the storage conditions.
Acknowledgments
This work was possible due to the financial support of the
Sectorial Operational Program for Human Resources Development
2007e2013, co-financed by the European Social Fund, under the
project number POSDRU/159/1.5/S/132400 with the title “Young
successful researchers e professional development in an international
and interdisciplinary environment” and project POSDRU/159/1.5/S/
137750 e “Doctoral and postdoctoral programs e support for
increasing research competitiveness in the field of exact Sciences”.
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