Improving the solubility of agomelatine via cocrystals

Article abstract of DOI:10.1021/cg201423q

Four cocrystals of agomelatine with urea (1), glycolic acid (2), isonicotinamide (3), and methyl4-hydroxybenzoate (4) in 1:1 stoichiometry were successfully synthesized via six kinds of synthons. The structures of 1-4 were determined by the single crystal X-ray diffraction, in which 1-3 form two-dimensional hydrogen bonded frameworks between agomelatine and coformers, while 4 displays a one-dimensional chain structure. The results of differential scanning calorimetry measurements indicate that the melting points of 1-3 are between those of agomelatine and coformers, while the melting point of 4 is below those of agomelatine and coformer. After the formations of cocrystals, the solubility of agomelatine is much improved, and the solubility values of 1-4 in phosphate buffer of pH 6.8 are approximately 2.2, 2.9, 4.7, and 3.5 times as large as that of agomelatine Form II, and 1.6, 2.1, 3.4, and 2.5 times as large as that of agomelatine Form I. The solids of 1-4 can keep their crystalline forms in phosphate buffer of pH 6.8 for 3.5, 2.0, 6.0, and 15.0 h, respectively.

Full text of DOI:10.1021/cg201423q

Article
pubs.acs.org/crystal
Improving the Solubility of Agomelatine via Cocrystals
Yan Yan,† Jia-Mei Chen,*,‡ Na Geng,§ and Tong-Bu Lu*,†,‡
†MOE Key Laboratory of Bioinorganic and Synthetic Chemistry/State Key Laboratory of Optoelectronic Materials and
Technologies/School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China
‡School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China
§School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China
S
* Supporting Information
ABSTRACT: Four cocrystals of agomelatine with urea
(1), glycolic acid (2), isonicotinamide (3), and methyl
4-hydroxybenzoate (4) in 1:1 stoichiometry were successfully
synthesized via six kinds of synthons. The structures of 1−4
were determined by the single crystal X-ray diffraction, in
which 1−3 form two-dimensional hydrogen bonded frame-
works between agomelatine and coformers, while 4 displays a
one-dimensional chain structure. The results of differential
scanning calorimetry measurements indicate that the melting
points of 1−3 are between those of agomelatine and coformers, while the melting point of 4 is below those of agomelatine and
coformer. After the formations of cocrystals, the solubility of agomelatine is much improved, and the solubility values of 1−4 in
phosphate buffer of pH 6.8 are approximately 2.2, 2.9, 4.7, and 3.5 times as large as that of agomelatine Form II, and 1.6, 2.1, 3.4,
and 2.5 times as large as that of agomelatine Form I. The solids of 1−4 can keep their crystalline forms in phosphate buffer of pH
6.8 for 3.5, 2.0, 6.0, and 15.0 h, respectively.
Scheme 1. Structures of Agomelatine and Coformers (a−d)
INTRODUCTION
■
More than 70% of 1655 chemical pharmaceuticals are solid-
state in the United States Pharmacopoeia (29th ed.), suggesting
that the solid pharmaceutical forms screening is crucially
important. The solid pharmaceutical forms include polymorphs,
hydrates, salts, amorphous solids, solvates, and cocrystals.1,2
Pharmaceutical cocrystals were defined as structurally homoge-
neous crystalline materials that are constructed from at least
two neutral molecules containing an active pharmaceutical
ingredient (API) and other solid components (coformers) with
a well-defined stoichiometry,3,4 in which APIs and coformers
are not sustained by the covalent forces but by hydrogen-bond,
halogen-bond, π···π, and other noncovalent interactions.5−14
The cocrystallization of an API with coformers profoundly
affects its physical properties such as the melting point, stability,
hygroscopicity, solubility, dissolution rate, and bioavailabil-
ity.15−19 Like other solid forms, cocrystals possess intellectual
property issues and can be protected by legal issues that confer
cocrystals with unique commercial advantages and wide devel-
opment space.20
Agomelatine (Scheme 1), under a trade name Valdoxan or
Melitor, is an antidepressant for the treatment of major
depressive disorder. It has been reported that agomelatine has a
reduced level of sexual side effects as well as discontinuation
effects compared to some other antidepressants.21,22 Further-
more, agomelatine has positive effects on sleep.23 However,
agomelatine has poor solubility in water (1.1 mg/mL),24 so
different solid pharmaceutical forms of agomelatine including poly-
morphs and solvates were screened to increase its solubility.25−31
Up to now, six polymorphic forms of agomelatine (Forms I−
VI) have been reported,25−30 while their solubility has not
been investigated. In our previous study,31 two agomelatine
cocrystals with acetic acid and ethylene glycol were synthesized
and structurally characterized. The results of solubility
measurements indicate that the solubility values of two
cocrystals are approximately twice as large as that of
agomelatine Form II. However, these two cocrystals are not
stable in water, and agomelatine-acetic acid and agomelatine-
ethylene glycol solvate are easy to transform to Form I and
Form III respectively in water. In order to obtain cocrystals
with higher aqueous solubility and stability, more cocrystals of
agomelatine with coformers were screened in this study.
Received: October 27, 2011
Revised: March 5, 2012
Published: March 28, 2012
© 2012 American Chemical Society
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As the structure of agomelatine contains one 2° amide group,
possible hydrogen bonding synthons containing 2° amide
group are shown in Scheme 2. The Cambridge Structural
The pKa values of agomelatine and four coformers a−d are
9.50, 0.18, 3.83, 10.61, and 8.4, respectively.32 The coformers
urea, isonicotinamide, and methyl 4-hydroxybenzoate are
pharmaceutically acceptable, in which urea and methyl
4-hydroxybenzoate are approved by the Food and Drug
Administration (FDA) as safe for internal administration,33
and isonicotinamide is an API. In addition, glycolic acid is also a
low-level toxic material with rat oral LD50 of 1950 mg/kg.32c
Thus, cocrystals 1−4 can be regarded as safe for oral dosage.
Scheme 2. Possible Hydrogen Bonding Synthons of
Agomelatine with Coformers
EXPERIMENTAL SECTION
■
Materials and General Methods. Agomelatine Form II was
purchased from Nantong Chemical Co. Ltd. Urea, glycolic acid,
isonicotinamide, and methyl 4-hydroxybenzoate were purchased from
Aladdin reagent Inc. All of the other chemicals and solvents were
commercially available and used as received. Elemental analyses were
determined using Elementar Vario EL elemental analyzer. Differential
scanning calorimetry (DSC) was recorded on a Netzsch STA 409PC
instrument and aluminum sample pans in nitrogen atmosphere, with a
heating rate of 10 °C/min. The infrared spectra were recorded in the
4000 to 400 cm−1 region using KBr pellets and a Bruker EQUINOX
55 spectrometer. X-ray powder diffraction (XRPD) patterns were
obtained on a Bruker D8 Advance with Cu Kα radiation (40 kV,
40 mA).
Database (CSD) survey reveals that there are 6961 crystal
structures that contain at least one 2° amide group, among
which 851 (12%) entries exhibit the supramolecular homo-
synthon I. Analysis of the remaining amide containing
compounds reveals that they are involved in supramolecular
heterosynthons with different complementary functional
groups such as carboxyl acid, ester, alcohol, etc. There are
1150 entries that contain both 2° amide and carboxyl acid
containing moieties. 381 (33%) of these entries exhibit synthon
II, whereas only 216 (19%) exhibit synthon III. The CSD
contains 893 crystal structures with both 2° amide and ester
moieties, and 108 entries (12%) exhibit heterosynthon IV.
Moreover, 2° amide-alcohol heterosynthons V and VI occur in
260 (16%) and 551 (33%) of the 1646 crystal structures that
contain both functional groups. The above survey indicates
synthons I−VI (Scheme 2) can be used for the constructions of
cocrystals of agomelatine. Therefore, a series of coformers that
may form synthons I−VI with agomelatine were selected to
cocrystallize with agomelatine, and four cocrystals of
agomelatine with urea (1), glycolic acid (2), isonicotinamide
(3), and methyl 4-hydroxybenzoate (4) were successfully
obtained, and their structures, solubility, and stability of 1−4
were investigated.
Agomelatine Form I. A methanol solution (3 mL) of agomelatine
Form II (100 mg) was added dropwise to 30 mL of water. The
precipitate formed was filtered off and dried in air. Yield, 99%. Anal.
Calcd for C15H17NO2: C, 74.05; H, 7.04; N, 5.76%. Found: C, 74.14;
H, 6.97; N, 5.84%. XRPD data, 2theta/°: 9.84, 12.4, 13.31, 15.14,
15.98, 16.62, 17.95, 18.88, 20.49, 20.99, 23.07, 23.44, 24.28, 25.1,
26.02, 26.82, 27.51.
Agomelatine Form III. Form III was prepared according to the
patent method.26 Yield, 98%. Anal. Calcd for C15H17NO2: C, 74.05; H,
7.04; N, 5.76%. Found: C, 73.98; H, 7.15; N, 5.68%. XRPD data, 2θ/°:
10.15, 12.93, 16.27, 17.38, 17.84, 18.55, 19.20, 19.89, 20.32, 21.15,
23.33, 23.84, 24.52, 24.88, 25.07, 26.27, 26.86, 27.97, 29.51.
Agomelatine Urea Cocrystal (1:1), 1. A mixture of equimolar
agomelatine (50 mg) and urea (12 mg) was melted at 120 °C for
20 min, and then dissolved in 3 mL of butanone. The solution was
evaporated slowly at room temperature to get colorless column-shaped
Table 1. Crystallographic Data for 1−4
1
2
3
4
formula
C16H21N3O3
303.36
C17H21NO5
C21H23N3O3
365.42
C23H25NO5
395.44
formula weight
crystal system
space group
a, Å
319.35
monoclinic
P21/n
monoclinic
P21/c
orthorhombic
P212121
triclinic
P1
̅
9.8643(2)
9.1412(2)
18.1501(4)
90
13.3924(4)
7.1702(2)
18.0080(5)
90
7.9754(1)
8.9243(2)
27.7850(4)
90
9.4475(13)
b, Å
11.1603(17)
11.2471(16)
94.415(12)
103.739
c, Å
α, deg
β, deg
103.470(2)
90
111.240(3)
90
90
γ, deg
V, Å3
90
109.702
1591.60(6)
4
1611.77(8)
4
1977.59(6)
4
1068.4(3)
2
Z
Dc/g·cm−3
F(000)
1.266
1.316
1.227
1.229
648
680
776
420
crystal size/mm
rang of indices
Rint
0.20 × 0.15 × 0.10
−11,10; −10,10; −20,20
0.0245
0.20 × 0.10 × 0.05
−16,15; −8,8; −21,15
0.0302
0.20 × 0.20 × 0.05
−9,9; −10,10; −33,23
0.0272
0.20 × 0.10 × 0.05
−11,11; −13,13; −13,13
0.0506
GOF
1.086
1.042
1.077
1.036
R1 [I > 2σ(I)]
wR2 [all data]
0.0304
0.0384
0.0449
0.0607
0.0852
0.1039
0.1424
0.1982
a
2
2
2
R1 = Σ∥ Fo| − | Fc∥/Σ| Fo|. wR2 = [Σ[w(Fo − Fc2)2]/Σw(Fo )2]1/2, w = 1/[σ2 (Fo)2 + (aP)2 + bP], where P = [(Fo ) + 2Fc2]/3.
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Table 2. Hydrogen Bonding Distances and Angles for 1−4
D−H···A
D···A (Å)
D−H···A (deg)
a
1
N3−H5N···O1#1
N2−H2N···O3#2
N2#3−H2N#3···O3
N1#4−H1N#4···O3
N2−H3N···O2
3.0613(16)
2.8994(15)
2.8994(15)
2.8616(13)
2.8828(15)
158.9(16)
173.8(15)
173.8(15)
177.0(15)
162.3(15)
b
2
N1#1−H1N#1···O5
O3−H3···O1
2.8850(18)
2.5745(15)
2.8606(17)
2.8606(17)
174.4(18)
160.7
O5−H5···O4#2
O5#3−H5#3···O4
148.3
148.3
c
3
N3−H1···O3
2.830(3)
2.966(3)
2.886(4)
175(3)
177.1
156.4
N2−H2A···N1#1
N2−H2B···O1#2
d
4
O3−H3A···O2#1
N1−H1N···O4
2.654(3)
2.984(3)
159.3
165(3)
a
Symmetry codes: #1 −x + 2, −y − 1, −z + 2; #2 −x + 1, −y − 1, z +
b
2; #3 −x + 1, −y − 1, −z + 2; #4 x, y − 1, z. #1 x, −y − 1/2, z + 1/2;
c
#2 x − 1, −y + 1, −z − 2; #3 x − 1, −y + 1, −z − 2. #1 x + 1, y, z; #2
d
x, y − 1, z. #1 x, y − 1, z.
crystals of 1. Yield: 59 mg, 96%. Anal. Calcd for C16H21N3O3: C,
63.35; H, 6.98; N, 13.85%. Found: C, 63.46; H, 6.97; N, 13.92%.
Agomelatine Glycolic Acid Cocrystal (1:1), 2. To a mixture of
equimolar agomelatine (50 mg) and glycolic acid (16 mg) was added
2 mL of acetonitrile, and the resulting solution was refluxed for 2 h,
cooled to room temperature, and then evaporated slowly to get
colorless block-shaped crystals of 2. Yield: 61 mg, 93%. Anal. Calcd for
C17H21NO5: C, 63.94; H, 6.63; N, 4.39%. Found: C, 64.23; H, 6.53; N,
4.22%.
Figure 1. The structure of 1D chain (a) and 2D sheet (b) in 1.
melted at 135 °C, cooled to room temperature, and then dissolved in
2 mL of tetrahydrofuran and evaporated slowly. After about one week,
colorless block-shaped crystals of 3 were obtained. Yield: 74 mg, 98%.
Agomelatine Isonicotinamide Cocrystal (1:1), 3. A mixture of
equimolar agomelatine (50 mg) and isonicotinamide (25 mg) was
Figure 2. (a) The structure of glycolic acid dimer in 2. (b) Side view and (c) top view of the 2D sheet containing 1D right-handed and left-handed
helical chains. (d) The 3D structure of 2.
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Figure 4. The structures of 1D chain (a) and the 3D framework
(b) in 4.
using the program of CrysAlis PRO. The structures were solved by the
direct methods using the SHELX-97 program34 and refined by the full-
matrix least-squares method on F2. All non-hydrogen atoms were
refined with anisotropic displacement parameters. The hydrogen
atoms were placed in calculated positions with fixed isotropic thermal
parameters and included in the structure factor calculations in the final
stage of full-matrix least-squares refinement. Crystallographic data and
details of refinements of 1−4 are listed in Table 1, and the hydrogen
bonding distances and angles are given in Table 2.
Powder Dissolution Experiments. The absorbance values for
Forms I−III and cocrystals 1−4 in phosphate buffer of pH 6.8
at different times were detected by a Cary 50 UV spectrophotometry
at 230 nm, where all the coformers have no absorption at this
wavelength, and the concentrations of Forms I−III and cocrystals 1−4
were calculated by means of a standard curve (ε = 1.72 × 104 M−1).
The solids of Form I−III and 1−4 were milled to powder and sieved
using standard mesh sieves to provide sample with approximate
particle size ranges of 75−150 μm. In a typical experiment, 50 mL of
phosphate buffer (pH 6.8) was added to a flask containing 200 mg of
sample, and the resulting mixture was stirred at 25 °C and 500 rpm.
The solution was withdrawn from the flask at regular intervals and
filtered through a 0.22 μm nylon filter. A 10 μm portion of the filtered
aliquot was diluted to 1.0 mL with phosphate buffer (pH 6.8) and was
measured with UV/vis spectrophotometry. After 2.5 h experiments,
the undissolved solids were filtered and dried under a vacuum, and
analyzed by powder X-ray diffraction (PXRD).
Figure 3. The structures of 1D chain (a), 2D sheet (b), and 3D
framework (c) in 3 (the green and pink color are isonicotinamide and
naphthalene groups of agomelatine, respectively).
Anal. Calcd for C21H23N3O3: C, 69.02; H, 6.34; N, 11.50%. Found: C,
69.18; H, 6.57; N, 11.30%.
Agomelatine Methyl 4-Hydroxybenzoate Cocrystal (1:1), 4.
A mixture of equimolar agomelatine (50 mg) and methyl 4-
hydroxybenzoate (31 mg) were melted at 110 °C and then cooled
to room temperature and dissolved in 1 mL of acetonitrile. The
solution was allowed to evaporate slowly to get colorless column-
shaped crystals of 4. Yield: 80 mg, 98%. Anal. Calcd for C23H25NO5:
C, 69.86; H, 6.37; N, 3.54%. Found: C, 69.99; H, 6.20; N, 3.73%.
Single Crystal X-ray Diffraction. Single-crystal X-ray diffraction
data for cocrystals 1−4 were collected on an Agilent Xcalubur Nova
CCD diffractometer with graphite monochromated Cu Kα radiation
(λ = 1.54178 Å). Cell refinement and data reduction were applied
RESULTS AND DISCUSSION
■
Crystal Structures. The asymmetric unit of 1 contains one
urea and one agomelatine molecule, in which the urea
molecules alternately link the agomelatine molecules through
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Figure 5. DSC curves for agomelatine Form II, coformers and cocrystals 1−4.
molecule forms five hydrogen bonds with adjacent urea and
agomelatine molecules, and each agomelatine molecule forms
three hydrogen bonds with adjacent three urea molecules
(Figure 1b).
The asymmetric unit of 2 contains one agomelatine and one
glycolic acid molecules. In 2, two glycolic acid molecules form a
dimer through two O(5)−H(5)···O(4)#2 and O(5)#3−H(5)
#3···O(4) hydrogen bonds (Figure 1a), with the O···O distance
of 2.861(2) Å. Along the ac plane, glycolic acid dimers
alternately link the agomelatine molecules through the
intermolecular hydrogen bonding interactions (synthons III
and VI) to generate a 2D sheet, which contains helical
chains with alternately right-handed and left-handed helicity
(Figure 2b), with the O(3)−H(3)···O(1) and N(1)#1−H(1N)
#1···O(5) hydrogen bonding distances of 2.575(2) and
2.885(2) Å, respectively. All the 2D sheets are packed along
the b axis via interlayer C−H···π interactions between the adja-
cent naphthalene groups of agomelatine molecules to generate
the 3D structure of 2 (Figure 2c), with a C−H···π distance of
3.604 Å.
Similar to 1, the isonicotinamide molecules in 3 alternately
link the agomelatine molecules through two N(2)−H-
(2B)···O(1)#2 and O(3)···H(1)−N(3) intermolecular hydro-
gen bonds (synthon I) to form a 1D chain along the b axis
(Figure 3a), with the N···O distances of 2.886(4) and 2.830(3)
Å, respectively. The 1D chains are further connected by the
interchain hydrogen bonds between the pyridine nitrogen atom
of isonicotinamide in one chain and the amine group of
isonicotinamide in the adjacent chain to generate a 2D sheet
(Figure 3b), with the N(2)−H(2A)···N(1)#1 distance of
Figure 6. Powder dissolution profiles for agomelatine Form I, Form II,
Form III, and 1−4 in phosphate buffer of pH 6.8.
two N(2)−H(3N)···O(2) and O(3)···H(1N)#4−N(1)#4
intermolecular hydrogen bonds (synthon I) to form a one-
dimensional (1D) chain along the b axis (Figure 1a), with
N···O distances of 2.883(2) and 2.862(1) Å, respectively. The
adjacent chains are further connected via three additional
interchain hydrogen bonds to generate a two-dimensional (2D)
sheet (Figure 1b), in which two hydrogen bonds form between
the adjacent two urea molecules (N(2)−H(2N)···O(3)#2 =
O(3)···H(2N)#3−N(2)#3 = 2.899(2) Å, synthon I), and the
third one forms between the urea N(3) atom within one chain
and the O(1) atom of agomelatine within another chain
(N(3)−H(5N)···O(1)#1 = 3.061(2) Å). In 1, each urea
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Figure 7. XRPD patterns for 1 (a), 2 (b), 3 (c), and 4 (d) before and after powder dissolution experiments in phosphate buffer of pH 6.8.
packed along the b axis to generate the 3D structure of 4
(Figure 4b).
DSC Analyses and Powder Dissolution. The DSC curves
of agomelatine Form II, coformers and cocrystals are shown in
Figure 5. It can be found that the melting points at 137, 92,
121, and 68 °C for 1−4, respectively, are different from those
of agomelatine Form II and corresponding coformers. It is
interesting to note that each melting point for 1−3 is between
those of agomelatine Form II and corresponding coformers,
while the melting point for 4 is lower than those of agomelatine
Form II and methyl 4-hydroxybenzoate (Figure 5). This can be
attributed to their different structures, as 1−3 form 2D
hydrogen bonding linked frameworks, while 4 only forms 1D
hydrogen bonding linked chains, and the weaker interchain
interactions in 4 lead to its lower melting point.
Figure 8. A correlation between the solubility of coformers and the
The results of XRPD measurements for 1−4 indicate that all
stability of cocrystals in phosphate buffer of pH 6.8.
the peaks displayed in the measured patterns closely match
those in the simulated patterns generated from the single-
crystal diffraction data (Figure S1, Supporting Information),
2.966(3) Å. The 2D sheets are linked by the C−H···π
interactions between the pyridine groups of isonicotinamide
indicating single phases of 1−4 are formed. Powder dissolution
molecules (green color), and the π···π interactions between the
profiles for agomelatine Forms I−III and 1−4 in phosphate
naphthalene groups of agomelatine molecules (pink color) to
buffer of pH 6.8 are shown in Figure 6. From Figure 6, it can be
form the 3D structure of 3 (Figure 3c), with the C−H···π and
π···π distances of 3.591 and 3.478 Å, respectively.
found that both the dissolution rate and solubility values of 1−
4 are larger than those of agomelatine Forms I−III, indicating
In 4, the agomelatine molecules are alternately connected by
the methyl 4-hydroxybenzoate molecules through two N(1)−
H(1N)···O(4) and O(3)−H(3A)···O(2)#1 intermolecular
hydrogen bonds (synthons IV and V) to form a 1D chain
along the b axis (Figure 4a), with the N···O distances of
2.984(3) and 2.654(3) Å, respectively. All the 1D chains are
the solubility of agomelatine can be indeed improved via
forming the cocrystals. The solubility values of 1−4 are
approximately 2.2, 2.9, 4.7, and 3.5 times as large as that of
Form II, and 1.6, 2.1, 3.4, and 2.5 times as large as that of
agomelatine Form I. After the dissolution experiments, the
undissolved solids were filtered and dried under a vacuum, and
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the results of XPRD analyses indicate only 2 transformed to
Form I, while 1, 3, and 4 remained unchanged. Indeed, the
solids of 1−4 can keep their crystalline forms in phosphate
buffer of 6.8 for 3.5, 2.0, 6.0, and 15.0 h, respectively (Figure 7),
and then 1, 2, and 4 transformed to Form I, while 3 trans-
formed to Form III. The above results indicate that both the
solubility and stabilities of 1−4 in phosphate buffer are better
than those of agomelatine with acetic acid and ethylene glycol
we reported before. It is interesting to note that the stabilities
of 1−4 in phosphate buffer are related to the solubility of
corresponding coformers (Figure 8), as the solubility values of
glycolic acid (b), urea (a), isonicotinamide (c), methyl 4-hydroxy-
benzoate (d), and agomelatine Form II in phosphate buffer of
pH 6.8 are 1786, 873, 163, 30, and 0.51 mg/mL, respectively,
and the stability of corresponding 2, 1, 3, and 4 is 2.0, 3.5, 6.0,
and 15.0 h in phosphate buffer of pH 6.8, respectively,
indicating the larger difference of solubility between the
agomelatine and coformer in a given cocrystal leads to the
lower stability of the cocrystal, as the coformer with larger
solubility in a cocrystal is easier to dissolve in water and leads to
the cocrystal decomposed more quickly in water.
(2009ZX09501-022), and China Postdoctoral Science Founda-
tion (Grant No. 20110490919).
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CONCLUSIONS
■
Six kinds of synthons were used to construct the cocrystals of
agomelatine, and four cocrystals of agomelatine with urea,
glycolic acid, isonicotinamide, and methyl 4-hydroxybenzoate
were obtained and determined by single crystal X-ray
diffraction, in which 1−3 form 2D hydrogen bonded
frameworks between agomelatine and coformers, while 4
displays a 1D chain structure. The melting points for 1−3
are between those of agomelatine Form II and corresponding
coformers, while the melting point for 4 is lower than those of
agomelatine Form II and coformer due to the weaker interchain
interactions in 4. The aqueous solubility of agomelatine is
increased after the formations of cocrystals 1−4, and 3 shows
the highest solubility value, indicating the solubility of
agomelatine can be improved via cocrystals. In addition, the
stability of 1−4 in phosphate buffer of 6.8 is better than that of
agomelatine cocrystals with acetic acid and ethylene glycol we
reported before, and the stability of cocrystals is contrary to the
solubility values of corresponding coformers. As solubility and
bioavailability are often related, we believe that the bioavail-
ability of agomelatine may also be increased after the formation
of cocrystals 1−4, and this study is ongoing in our lab.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The XPRD patterns and IR spectra for 1−4. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Fax: +86-20-84112921. E-mail: chenjm37@mail.sysu.edu.cn
(J.-M.C.); lutongbu@mail.sysu.edu.cn (T.-B.L.).
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by 973 Program of China
(2012CB821705), NSFC (20831005, 21101173, 91127002
and 21121061), the National Key Program of China
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