Enhancing the hygroscopic stability of S-oxiracetam via pharmaceutical cocrystals

Article abstract of DOI:10.1021/cg300757k

Four cocrystals of (S-ox)(ga) (1), (RS-ox)(ga) (2), (S-ox)(pa) (3), and (RS-ox)(pa) (4) were prepared (S-ox = S-oxiracetam, RS-ox = racemic oxiracetam, ga = gallic acid, pa = 3,4-dihydroxybenzoic acid), and their structures were determined by single X-ray diffraction. In 1/2, two ga molecules link two S-ox/RS-ox molecules through intermolecular hydrogen bonds with a new R ²₂(9) synthon to form a tetramer, the tetramers are further linked by intertetramer hydrogen bonds to generate a 2D sheet, and the adjacent 2D sheets are connected by intersheet hydrogen bonds to form the 3D structure of 1/2. In 3/4, the ox molecules form a 1D helical chain through intermolecular hydrogen bonds, and the helical chains are further linked by pa molecules through intermolecular hydrogen bonds to form a 2D sheet. The results of hygroscopic stability experiments indicate that the hygroscopic stability of S-ox is much enhanced after the formation of cocrystal 1.

Full text of DOI:10.1021/cg300757k

Article
pubs.acs.org/crystal
Enhancing the Hygroscopic Stability of S‑Oxiracetam via
Pharmaceutical Cocrystals
Zi-Zhou Wang,† Jia-Mei Chen,*,‡ 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
S
* Supporting Information
ABSTRACT: Four cocrystals of (S-ox)(ga) (1), (RS-ox)(ga)
(2), (S-ox)(pa) (3), and (RS-ox)(pa) (4) were prepared (S-ox
= S-oxiracetam, RS-ox = racemic oxiracetam, ga = gallic acid,
pa = 3,4-dihydroxybenzoic acid), and their structures were
determined by single X-ray diffraction. In 1/2, two ga
molecules link two S-ox/RS-ox molecules through intermolecular hydrogen bonds with a new R2 (9) synthon to form a
2
tetramer, the tetramers are further linked by intertetramer hydrogen bonds to generate a 2D sheet, and the adjacent 2D sheets
are connected by intersheet hydrogen bonds to form the 3D structure of 1/2. In 3/4, the ox molecules form a 1D helical chain
through intermolecular hydrogen bonds, and the helical chains are further linked by pa molecules through intermolecular
hydrogen bonds to form a 2D sheet. The results of hygroscopic stability experiments indicate that the hygroscopic stability of S-
ox is much enhanced after the formation of cocrystal 1.
ox)(ga), (S-ox)(pa), and (RS-ox)(pa) were synthesized (ga =
gallic acid, pa = 3,4-dihydroxybenzoic acid,14 see Scheme 1),
and their structures and hygroscopic stability were investigated.
INTRODUCTION
■
During the past decades, chiral drugs have been playing a
significant role in the pharmaceutical industry. By the year of
2002, chiral drugs with a single enantiomer dosage form share
39% of the world market,1 and the number is increasing year by
year. According to the guidance of development of new chiral
drugs,2 single enantiomers of new drugs are encouraged to be
developed, and a single enantiomer for a certain drug can be
marketed under a different name to its racemic mixture.
The nootropic drug oxiracetam (4-hydroxy-2-oxo-1-pyrroli-
dine acetamide, ox) was first synthesized by Smith Kline
Beecham Company in 1974.3 It is a racemic compound
comprised of S-ox and R-ox (see Scheme 1). The structure of
racemic oxiracetam (RS-ox) has been reported,4 while the
structure of its single enantiomer (S-ox or R-ox) has not been
reported so far. It has been reported that S-ox has better
performance than RS-ox in treatment of cognition dysfunction.5
However, we found that S-ox is heavily hygroscopic and
deliquesces to a liquid within 3 days at 87% RH and 25 °C,
while RS-ox is stable under the same conditions, and this is in
accordance with Wallach’s rule,6−12 which states that a racemic
crystal is expected to have a higher density than its chiral
counterpart, resulting in a more efficient packing and higher
overall stability.13 Recently, Jones et al.7 first found that the
hygroscopic stabilities of chiral and racemic cocrystals also
follow a trend of Wallach’s rule: that is, the racemic cocrystal
appears to be more stable than its chiral counterpart. However,
their results are based only on two sets of cocrystals, and it
needs more examples to confirm this assumption.
EXPERIMENTAL SECTION
■
General Remarks. S-ox and RS-ox were provided by Sichuan
Industrial Institute of Antibiotics. All of the coformers were purchased
from Aladdin Reagent Corporation. The solvents were commercially
available and used without further purification. Elemental analyses
were determined using an Elementar Vario EL elemental analyzer. The
IR spectra were recorded in the 4000 to 400 cm−1 region using KBr
pellets and a Thermo Scientific AVATAR330 FT-IR spectrometer.
Differential scanning calorimetry (DSC) was carried out on a Netzsch
STA 409PC instrument in N2 atmosphere. X-ray powder diffraction
(XRPD) patterns were obtained on a Bruker D8 Advance with Cu Kα
radiation (40 kV, 40 mA).
(S-ox)(ga), 1. A mixture of S-ox (0.158 g, 1 mmol) and ga (0.170 g,
1 mmol) was dissolved in 3 mL of methanol in a sealed flask, and
stirred at room temperature for 5 h. The resulting solution was
filtrated and evaporated slowly at room temperature. After about one
week, colorless prism-shaped crystals of 1 were isolated by filtration,
washed with diethyl ether, and dried under vacuum. Yield: 0.30 g, 91%.
Anal. Calcd for C13H16N2O8: C, 47.56; H, 4.91; N, 8.53. Found: C,
47.32; H, 5.12; N, 9.00%. IR data (KBr, cm−1) 3754 vs, 3195 s, 2980
m, 2375 w, 1686 s, 1659 s, 1604 m, 1495 w, 1451 m, 1396 m, 1349 w,
1285 s, 1248 m, 1077 w, 939 m, 863 w, 763 w, 706 w, 612 m, 457 w.
(RS-ox)(ga), 2. A mixture of RS-ox (0.158 g, 1 mmol) and ga
(0.170 g, 1 mmol) was stirred in 10 mL of ethanol in a sealed flask for
24 h, and the solution was filtrated and evaporated slowly at room
temperature. After about 2 weeks, colorless prism-shaped crystals of 2
In order to enhance the hygroscopic stability of S-ox and to
see whether the stability of their chiral and racemic cocrystals
follows the Wallach’s rule, four cocrystals of (S-ox)(ga), (RS-
Received: June 2, 2012
Revised: July 24, 2012
Published: August 7, 2012
© 2012 American Chemical Society
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Article
Scheme 1. Structures of Oxiracetam and Coformers
Table 1. Crystallographic Data and Details of Refinements for 1−4
1
2
3
4
formula
formula weight
crystal system
space group
a (Å)
C13H16N2O8
328.28
C13H16N2O8
328.28
C13H16N2O7
312.28
C13H16N2O7
312.28
monoclinic
P21
monoclinic
P21/c
monoclinic
C2
monoclinic
P21/c
12.4602(1)
8.8777(1)
12.7309(1)
103.0525(1)
1371.88(2)
4
12.6137(10)
8.9398(7)
12.5452(8)
103.580(7)
1375.10(18)
4
22.2113(6)
6.0673(2)
11.2292(3)
112.595(3)
1397.12(7)
4
10.7048(3)
6.2392(2)
21.4529(8)
107.200(3)
1368.75(8)
4
b (Å)
c (Å)
β (deg)
V (Å3)
Z
Dc (g·cm−3
T (K)
)
1.589
1.586
1.485
1.515
100
100
100
100
F(000)
688
688
656
656
crystal size (mm3)
0.3 × 0.3 × 0.1
1.154
0.2 × 0.2 × 0.1
1.151
0.4 × 0.2 × 0.2
1.046
0.2 × 0.1 × 0.1
1.068
μ (mm−1
)
Rint
0.0283
0.0511
0.0453
0.0310
0.0383
0.1049
5134
a
R1 [I > 2σ(I)]
0.0349
0.0526
0.0472
a
wR2[all data]
0.0954
0.1332
0.1258
reflns collected
Φmax (deg)
24843
5457
19455
71.82
64.99
72.72
69.98
unique reflns
observed reflns
GOF
5278
2259
2748
2516
5070
1893
2562
2066
1.039
1.051
1.050
1.080
Hooft parameter
0.13(8)
0.16(5)
a
2
2
2
R1 = ∑∥Fo| − |Fc∥/∑|Fo|. wR2 = [∑[w(Fo − Fc2)2]/∑w(Fo )2]1/2, w = 1/[σ2(Fo)2 + (aP)2 + bP], where P = [(Fo ) + 2Fc2]/3.
were isolated by filtration, washed with diethyl ether, and dried under
vacuum. Yield: 0.32 g, 96%. Anal. Calcd for C13H16N2O8: C, 47.56; H,
4.91; N, 8.53. Found: C, 47.61; H, 4.93; N, 8.51%. IR data (KBr,
cm−1) 3377 vs, 3207 s, 2949 m, 2511 m, 1663 s, 1659 s, 1606 m, 1491
m, 1454 m, 1393 m, 1343 w, 1284 s, 1254 m, 1194 m, 1131 w, 1077 w,
939 m, 867 w, 770 w, 705 w, 607 m, 447 w.
(S-ox)(pa), 3. This compound was prepared by a similar procedure
to that of 1 except using pa instead of ga. Yield: 0.28 g, 90%. Anal.
Calcd for C13H16N2O7: C, 50.00; H, 5.16; N, 8.97. Found: C, 49.60;
H, 5.14; N, 9.04%. IR data (KBr, cm−1) 3417 vs, 3198 s, 2942 m, 1668
s, 1638 s, 1609 m, 1493 w, 1453 m, 1398 m, 1343 s, 1255 s, 1255 s,
1076 w, 1040 s, 971 w, 942 m, 870 w, 797 w, 715 m, 618 m, 444 w.
(RS-ox)(pa), 4. This compound was prepared by a similar
procedure to that of 2 except using pa instead of ga. Yield: 0.27 g,
88%. Anal. Calcd for C13H16N2O7: C, 50.00; H, 5.16; N, 8.97%.
Found: C, 50.00; H, 5.39; N, 8.92. IR data (KBr, cm−1) 3407 vs, 3299
s, 3212 s, 2934 m, 1669 s, 1640 s, 1607 s, 1491 w, 1445 s, 1403 m,
1341 s, 1241 s, 1030 s, 972 w, 943 m, 873 w, 777 w, 715 m, 615 m, 449
w.
CrysAlis PRO. All the structures were solved using direct methods to
yield the positions of all non-hydrogen atoms, which were refined first
isotropically and then anisotropically. The hydroxy group of RS-ox in 2
is disordered and was treated with half-occupancies of H and O atoms.
All 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. All
calculations were performed using the SHELXTL system of computer
programs.15 The crystallographic data are summarized in Table 1, and
the selected H-bond distances and angles are listed in Table S1
(Supporting Information).
Hygroscopic Tests. The hygroscopic tests were performed in a
Memert climate chamber at 25 °C, and the relative humidity (RH)
conditions were achieved within sealed desiccators containing the
saturated salt solutions of K2CO3, NaCl, KCl, and K2SO4 for 43, 75,
85, and 98% RH values, respectively.16−20 Each sample was sieved
using standard mesh sieves to provide sample with approximate
particle size ranges of 68−150 μm, and was examined by XRPD after
the hygroscopic test.
Cocrystals 1−4 can also be obtained by solvent-drop grinding of
equimolar amounts of oxiracetam and corresponding coformers with
ethanol.
Single Crystal X-ray Diffraction. Single crystal data for 1−4 were
collected at 100 K on an Agilent Xcalubur Nova CCD diffractometer
with graphite monochromated Cu Kα radiation (λ = 1.54178 Å). Cell
refinements and data reduction were applied using the program of
RESULTS AND DISCUSSION
■
Crystal Structures. Compound 1 crystallizes in P21 chiral
space group with a Hooft parameter of 0.13(8), indicating the
absolute configuration of S-ox can be identified. As shown in
Figure 1a, the asymmetric unit of 1 contains two S-ox and two
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Figure 2. Structures of the (a) tetramer, (b) 2D sheet, and (c) 3D
framework in 2 (the purple and green represent two different layers).
Symmetry codes: (A) 2 − x, 3 − y, 1 − z.
Figure 1. Structures of the (a) tetramer, (b) 2D sheet, and (c) 3D
framework in 1 (the purple and green represent two different layers).
Compound 3 crystallizes in the C2 chiral space group with a
Hooft parameter of 0.16(5), indicating the absolute config-
uration of S-ox can be identified. The asymmetric unit of 3
consists of one S-ox and one pa molecules. As shown in Figure
3a, the S-ox molecules in 3 are linked by intermolecular O−
ga molecules, and two ga molecules link two S-ox molecules
through four O−H···O and two N−H···O intermolecular
hydrogen bonds to form a tetramer, in which the R2 (9)
2
synthon constructed by amide and two phenol hydroxy groups
has not been reported before. In the tetramer, there are π···π
stacking interactions between two ga molecules, with the
centroid···centroid distance of 3.721 Å. The tetramers are
further linked by O−H···O intertetramer hydrogen bonds to
generate a 2D sheet (Figure 1b). The 2D adjacent sheets are
connected by intersheet hydrogen bonds in a crossover packing
fashion to form the 3D structure of 1 (Figure 1c).
Compound 2 crystallizes in a monoclinic P21/c space group.
As shown in Figure 2a, the asymmetric unit of 2 consists of one
disordered ox (S-ox or R-ox) molecule and one ga molecule.
Similar to the structure of 1, two ga molecules in 2 link two
disordered RS-ox molecules through four O−H···O and two
Figure 3. (a) Side view of a 1D hydrogen bonded left-handed helical
chain of (S-ox)n in 3. (b) The 2D sheets with the same chirality packed
along the b-axis.
N−H···O intermolecular hydrogen bonds with a R2 (9)
2
synthon to form a tetramer (Figure 2a), and there are also
existing weak π···π stacking interactions between two ga
molecules, with the centroid···centroid distance of 3.714 Å.
Similar to the case of 1, the tetramers in 2 are also linked by
O−H···O intertetramer hydrogen bonds to generate a 2D sheet
(Figure 2b), and the adjacent 2D sheets are further connected
by O−H···O and N−H···O intersheet hydrogen bonds to form
the 3D structure of 2. It is interesting to note that the density of
2 (1.586 g·cm−3) is close to that of 1 (1.589 g·cm−3), due to the
similar structures of 1 and 2.
H···O and N−H···O hydrogen bonds to form a 1D left-handed
helical chain of (S-ox)n. The left-handed helical chains are then
connected by pa molecules through intermolecular O−H···O
and N−H···O hydrogen bonds to generate a 2D homochiral
sheet (Figure 3b), and all the 2D homochiral sheets are packed
along the b axis to form the 3D structure of 3 (Figure 3b).
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Crystal Growth & Design
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a
The asymmetric unit of 4 contains one ox and one pa
molecules. It is interesting to note that all S-ox molecules in 4
are linked by intermolecular O−H···O and N−H···O hydrogen
bonds to form a 1D left-handed helical chain, while all the R-ox
molecules are linked by similar intermolecular O−H···O and
N−H···O hydrogen bonds to form a 1D right-handed helical
chain (Figure 4), further confirming the rule we found that
Table 2. Hygroscopic Test for APIs and Cocrystals at 25 °C
sample
RH
1 day 3 days 7 days 14 days 28 days 8 weeks
S-ox
43%
75%
87%
98%
43%
75%
87%
98%
43%
75%
87%
98%
43%
75%
87%
98%
43%
75%
87%
98%
43%
75%
87%
98%
√
√
√
×
√
√
×
√
√
×
√
√
×
√
√
×
√
√
×
×
×
×
×
×
RS-ox
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
×
√
√
√
×
√
√
√
×
√
√
√
×
√
√
√
×
1
2
3
4
√
√
√
√
√
√
√
√
√
√
√
×
√
√
√
√
√
√
√
√
√
√
×
√
√
√
√
√
√
√
√
√
√
×
√
√
√
√
√
√
√
√
√
√
×
√
√
√
√
√
√
√
√
√
√
×
Figure 4. 2D sheets containing the left-handed and right-handed
helical chains alternately packed along the b-axis in 4.
×
×
×
×
√
√
√
√
√
√
√
√
√
√
√
×
√
√
√
×
√
√
√
×
there is a correlation between the chirality of building blocks
and the helicity of 1D chains.21 All the 1D left-handed helical
chains are connected by pa molecules through intermolecular
O−H···O and N−H···O hydrogen bonds to generate a 2D
homochiral sheet (Figure 4), while all the 1D right-handed
helical chains are connected by pa molecules through similar
intermolecular O−H···O and N−H···O hydrogen bonds to
generate a 2D homochiral sheet with opposite chirality (Figure
4). The above 2D sheets containing the left- and right-handed
helical chains are alternately packed along the b axis to generate
a racemic compound of 4, which crystallizes in a centrosym-
metric space group P21/c.
X-ray Powder Diffraction and DSC Analyses. XRPD
was used to check the phase purity of all the cocrystals. The
results indicate that the patterns of the samples prepared by the
solvent-drop grinding method fit well with those simulated
from the single crystal data (Figure S1), indicating pure phases
of cocrystals were obtained by the grinding method. The data
of DSC analyses show that the melting point of 1 (183.5 °C) is
very close to that of 2 (183.8 °C), while the melting point of 3
(134.6 °C) is much lower than that of 4 (143.4 °C) (Figure
S2). In addition, the melting points of cocrystals 1 (183.5 °C)
and 2 (183.8 °C) are between those of API (mpS‑ox = 139.0,
mpRS‑ox = 173.7 °C) and coformer (mpga = 250.2 °C), while the
melting points of cocrystals 3 and 4 are lower than those of API
and coformer (mppa = 200.8 °C).
Hygroscopic Stability. To check if the hygroscopic
stability of S-ox can be improved via cocrystals, the hygroscopic
stability of S-ox, RS-ox, and 1−4 was investigated, and the
results are shown in Table 2. From Table 2 it can be found that
the hygroscopic stability of 1 is much higher than that of S-ox,
indicating the hygroscopic stability of S-ox can indeed be
enhanced via cocrystals, and 1 is stable at all relative humidities
across all time points. In addition, the hygroscopic stability of 3
and 4 follows a trend of the Wallach’s rule, in which the density
of racemic 4 (1.515 g·cm−3) is higher than that of chiral 3
(1.485 g·cm−3) and 4 is more stable than 3. However, 1 and 2
do not follow the Wallach’s rule, as the density of racemic 2
(1.586 g·cm−3) is close to that of chiral 1 (1.589 g·cm−3), and 1
and 2 show similar hygroscopic stability under our hydroscopic
a
The symbol √ means that the crystalline compound was stable at
that condition and time point, and the symbol × means that the
compound deliquesced to a liquid at that condition and time point.
conditions. We also performed the XRPD measurements for
samples 1−4 after the hygroscopic stability test for 8 weeks (see
Table 2), and we found that the phases for all the samples
without deliquescing remain unchanged, indicating samples 1−
4 are stable and did not convert to drug and/or to conformer
before deliquescing (deliquescing means the sample becomes a
liquid). The overall hygroscopic stability trend is summarized as
1 ≈ 2 > 4 > RS-ox > 3 > S-ox. Gallic acid (ga) and 3,4-
dihydroxybenzoic acid (pa) can absorb moisture to form
hydrate at 87% and 98% RH, respectively. Obviously, the lower
hygroscopic stability of 3 and 4 is not caused by the
hygroscopicity of coformers. The highest stability of 1 and 2
mainly attributes to the introduction of additional hydrogen
bonding stabilization, as ga contains three hydroxyl groups,
while pa only contains two hydroxyl groups: one additional
hydroxyl group in ga can form more hydrogen bonds with S-ox
and RS-ox in 1 and 2 to generate 3D hydrogen bonded
frameworks, while 3 and 4 only form 2D sheets; thus, the
hygroscopic stability of 1 and 2 is higher than that of 3 and 4.
CONCLUSIONS
■
Four cocrystals of 1−4 were prepared by the methods of
solution evaporation and solvent-drop grinding, in which 1 and
2 form 3D hydrogen bonded frameworks with a new R2 (9)
2
synthon, while 3 and 4 exhibit 2D homochiral and racemic
sheets containing 1D helical chains. The results of hygroscopic
stability measurements indicate that the hygroscopic stability of
S-ox has been much enhanced after the formation of cocrystals
1. In addition, the hygroscopic stability of 3 and 4 follows a
trend of Wallach’s rule, while 1 and 2 do not follow a trend of
such rule. Cocrystals 1 and 2 are stable at all relative humidities
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Article
and for all time points we tested, due to their more extended
hydrogen bonded frameworks.
ASSOCIATED CONTENT
* Supporting Information
H-bond distances and angles, the XPRD patterns, DSC curves,
and CIF data for 1−4. This material is available free of charge
via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*Fax: +86-20-84112921. E-mail: chenjm37@mail.sysu.edu.cn;
lutongbu@mail.sysu.edu.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by 973 Program of China
(2012CB821705) and NSFC (Grant Nos. 91127002,
21101173, 21121061, and 20831005).
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