Ionic Cocrystals of Etiracetam and Levetiracetam: The Importance of Chirality for Ionic Cocrystals

Article abstract of DOI:10.1021/acs.cgd.9b00136

A striking variety of anhydrous and hydrated ionic cocrystals (ICCs) of the enantiopure antiepileptic drug (AED) levetiracetam and of its racemic intermediate etiracetam with the pharmaceutically acceptable salts CaCl₂ and MgCl₂ was synthesized and structurally characterized. The difference in the interaction of enantiopure and racemic compounds of interest with the inorganic salts was investigated. Variable-temperature X-ray powder diffraction (VT-XRPD) and calorimetric analyses (TGA and DSC) of all obtained ICCs showed a significant improvement in thermal stability with respect to pure racetams.

Full text of DOI:10.1021/acs.cgd.9b00136

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Article
Ionic cocrystals of etiracetam and levetiracetam:
the importance of chirality for ionic cocrystals
Lixing Song, Oleksii Shemchuk, Koen Robeyns, Dario Braga, Fabrizia Grepioni, and Tom Leyssens
Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.9b00136 • Publication Date (Web): 04 Mar 2019
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Page 1 of 11
Crystal Growth & Design
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Ionic cocrystals of etiracetam and levetiracetam: the importance of
chirality for ionic cocrystals
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0
†
‡
†
‡
‡*
Lixing Song, Oleksii Shemchuk, Koen Robeyns, Dario Braga, Fabrizia Grepioni, Tom
Leyssens
†
*
†Institute of Condensed Matter and Nanosciences, Université catholique de Louvain, Place Louis Pasteur 1, 1348
Louvain-la-Neuve, Belgium;
‡
Dipartimento di Chimica “Giacomo Ciamician”, Università di Bologna, Via Selmi 2, 40126 Bologna, Italy
ABSTRACT: A striking variety of anhydrous and hydrated ionic cocrystals (ICCs) of the enantiopure anti-epileptic drug
AED) levetiracetam and of its racemic intermediate etiracetam with the pharmaceutically acceptable salts CaCl and MgCl
2
was synthesized and structurally characterized. The difference in the interaction of enantiopure and racemic compounds
of interest with the inorganic salts was investigated. Variable temperature X-ray powder diffraction (VT XRPD) and
calorimetric analyses (TGA and DSC) of all obtained ICCs showed a significant improvement in thermal stability with
respect to pure racetams.
(
2
community.6,
11-18
Cocrystals in general, and ICCs in
INTRODUCTION
particular, are of enormous interest for the pharmaceutical
industry, since they can provide an alternative route to
new pharmaceutical formulations compared to
conventional salts. Particularly, the formation of cocrystals
can be of use if the API of interest has no ionizable
moieties, such as the compounds discussed in this work. In
the absence of ionizable groups and consequent salt
formation, molecular cohesion is usually enhanced in
molecular cocrystals by hydrogen and/or halogen bonds
and π-π stacking, whereas coulombic forces (ion-ion and
ion-dipole) are also at work and dominant in ICCs. Besides
their possible effect on the physicochemical properties of
Epilepsy is a prevailing chronic neurological disorder or
a group of disorders characterized by unprompted seizures
which tend to recur. More than 50 million people
worldwide are affected by this condition. Levetiracetam
(S)-2-(2-oxopyrrolidin-1-yl)butanamide, Fig. 1) is the
active pharmaceutical ingredient (API) of KEPPRA , an
anti-epileptic drug (AED) commercialized by UCB
Pharma. Levetiracetam is one of the most recent AEDs that
1
2
(
®
has been approved by Food and Drug Administration in
3
1
999.
O
O
1
9
the API, cocrystals have potential implications on
intellectual property issues.
NH2
NH2
20
N
N
O
O
Cocrystallization of chiral molecules has been
extensively studied by our groups, and has proven to be a
useful approach for the chiral resolution of racemic
mixtures. We showed that the application of (S)-mandelic
acid as a coformer allows to resolve a racemic solution of
Levetiracetam
(LEV)
Etiracetam
(ETI)
Fig. 1. The chemical structure of Levetiracetam and
21-22
etiracetam,
via selective formation of cocrystals with
Etiracetam
the S-enantiomer – the enantiomer which possesses anti-
epileptic activity. Although this approach resembles the
conventional method of chiral resolution by salt
formation, cocrystals between the coformer (S)-mandelic
acid and the opposite enantiomer (R-etiracetam with S-
mandelic acid) could not be obtained, once more
highlighting the differences of cocrystals with respect to
salts.
Etiracetam is encountered as a racemic intermediate in
the synthesis of levetiracetam. The racemic compound
contains, besides the active S-enantiomer (levetiracetam)
of pharmaceutical interest, R-etiracetam, which does not
exert the desired biological properties.4
cocrystals5-10
Ionic
(ICCs) are multicomponent
crystalline solid forms composed of neutral organic
molecules and salts in a defined stoichiometric ratio. Due
to their potentially more effective capacity to alter in a
desired way the physicochemical properties of interest
e.g. solubility, intrinsic dissolution rate, bioavailability,
morphology, hygroscopicity and thermal stability), ICCs
are increasingly attracting the attention of the scientific
Quite unexpectedly, ICCs formation has been found to
offer an additional tool for chiral resolution, as recently
discovered for the ionic cocrystals of alkali and alkaline
earth halides with the amino acids DL-histidine
DL-proline. The use of lithium halides results in a marked
2
3-24
(
and
25
+
preference for Li to selectively link the amino acids of only
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Crystal Growth & Design
Page 2 of 11
one chirality, with formation either of conglomerates or of
racemic crystals constituted of homochiral chains.
equilibrium. Then samples were filtered over sintered
glass, followed by XRPD analysis of the solid phases. The
results are shown in Table 1.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
22-23
Recently we showed for the first time that, in the
cocrystallization of levetiracetam and etiracetam with
Liquid assisted grinding (LAG). Powder samples can
be obtained mechanochemically through LAG of different
stoichiometric mixtures of LEV or ETI and CaCl or MgCl
2 2
with the addition of 10 μL of methanol. The sample was
ground in a RETSCH Mixer Mill MM 400 for 90 min with
a beating frequency of 30 Hz. The results are shown in
ZnCl
switch between
conglomerate.
2
, the stoichiometry ratio could be used to reversibly
racemic compound and
a
a
26
In this paper we take the ICC approach further, and
cocrystallize both enantiopure and racemic etiracetam
with inorganic salts accepted by the pharmacopoeia, i.e.
4 2 2
Table 1. ETI ·MgCl ·4H O was obtained by LAG of ETI and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MgCl (2 to 1) for 60 minutes in a Retsch MM200 ball
2
2 2
CaCl and MgCl . Taking into account the relatively low
miller, operated at a frequency of 25 Hz, in the presence of
a few drops of methanol.
melting points of the pure racetams (116 °C and 119 °C for
the enantiopure and the racemic compounds,
27
respectively), it was expected that, upon cocrystallization
Hot stage microscopy (HSM). Single crystals of
with the inorganic salts, thermal stability enhancement
could be achieved. This assumption was supported by our
previous study28 of ICCs of brivaracetam and seletracetam
with calcium and magnesium chlorides. In the present case
we also wanted to explore the behavior of racemic vs.
enantiopure pharmaceuticals in ICCs of alkaline earth with
respect to that observed with alkali metal salts, with a
particular focus on the thermal stability of the compounds
in the solid state.
2
ETI ·MgCl
2
·2H
2
O
were obtained using HSM. The
measurements were carried out using a Linkam TMS94
device connected to a Linkam LTS350 platinum plate. The
powder of ETI ·MgCl ·6H O was put in fomblin. The
2 2 2
sample was heated up to 110 °C and kept at this
temperature for 30 minutes. The sample was then slowly
cooled down (5 °C /min) to room temperature and the
obtained crystals were analyzed.
Single crystal X-ray diffraction (SCXRD). Data
collection was carried out in an Oxford X’Calibur S CCD
diffractometer equipped with a graphite monochromator
(Mo-Kα radiation, λ = 0.71073 Å) at room temperature and
a MAR345 using monochromated MoKα radiation (λ =
0.71073 Å) (Xenocs Fox3D mirror) produced by a Rigaku
UltraX18S rotating anode at room temperature.
Refinement details are listed in Table 2. All non-hydrogen
atoms were refined anisotropically. HNH and part of the
HOH atoms were located from difference Fourier maps and
refined. HCH and the remaining HOH atoms were added in
calculated positions and refined riding on their respective
EXPERIMENTAL SECTION
Materials.
S-2-(2-oxopyrrolidin-1-yl)butanamide
(levetiracetam) was purchased from Xiamen Top Health
Biochem Tech. Co., Ltd. (RS)-2-(2-oxopyrrolidin-1-
yl)butanamide (etiracetam) was prepared by racemization
of S-2-(2-oxopyrrolidin-1-yl)butanamide. 10
S-2-(2-oxopyrrolidin-1-yl)butanamide together with
g
of
a
catalytic amount (0.05 eq.) of MeONa were added to 10 mL
of methanol. The solution was kept under reflux and
continuous stirring for 24 h, then cooled to room
temperature. The compound crystallizes spontaneously.
After filtration, the compound was washed twice with
methanol and used as such.22 All other reagents were
purchased from Sigma and used without purification.
29
C and O atoms. SHELX-2014 was used for all structure
2
solutions and refinements on F .
X-ray powder diffraction (XRPD) and variable-
temperature X-ray powder diffraction (VT-XRPD). X-
ray powder diffraction data were collected with a
Solution experiments. All samples were prepared by
dissolution of the starting materials API:MX
2
(API=LEV or
PANalytical X’Pert Pro and on a Siemens D5000
ETI and MX = CaCl or MgCl ) in 1:1, 2:1 and 4:1
2
2
2
diffractometer equipped with a Cu X-ray source operating
at 40 KV and 40 mA and the secondary monochromator
allowing to select the Kα radiation of Cu (λ = 1.5418 Å). A
scanning range of 2θ values from 5° to 50° at a scan rate of
stoichiometric ratios in ethanol, methanol or water; the
solution was left to evaporate at room temperature. In
some cases single crystals were directly obtained from
solution; in other cases the slow evaporation brought
about the formation of oils, and single crystals were
obtained from these oils, left standing in the air at ambient
conditions for 1 to 10 days. The results are shown in Table
-1
0.6° min was applied. VT-XRPD diffractograms were
collected in the 5-50° 2θ range on a PANalytical X'Pert PRO
automated diffractometer, equipped with an X'Celerator
detector and an Anton Paar TTK 450 system for
measurements at controlled temperature. Data were
collected in the open air in Bragg-Brentano geometry,
using Cu-Kα radiation without a monochromator. Thermal
programs were selected on the basis of TGA results.
1
.
Slurry experiments. All slurry experiments were
performed by stirring aqueous suspensions of the starting
materials in 1:1, 2:1 and 4:1 stoichiometric ratios of API:MX
The total mass of starting materials was 100 mg. The
amount of water was set at 80 μL for the CaCl
experiments, and at 60 μL for the MgCl experiments. The
2
.
Differential scanning calorimetry (DSC). DSC
measurements were performed on a TA DSC2500 with
Tzero technology calibrated with indium under 50 mL/min
continuous nitrogen flow. Samples were prepared in
aluminium Tzero pans with punctured hermetic lid. The
2
2
suspensions were seeded with starting materials and
corresponding cocrystals and stirred at 25 °C over 48 h to
make sure that the system reached thermodynamic
2
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Page 3 of 11
Crystal Growth & Design
markedly dependent on the nature of the salt. For this
temperature profile applied starts at 30 °C and increases up
to 220 °C with a rate of 2 °C /min.
Thermogravimetric analysis
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5
6
reason the peculiarities of the interaction of the
investigated racetams with each inorganic salt will be
discussed in detail, to attempt a rationale for this variety.
(TGA).
TGA
measurements were performed on a Mettler Toledo TGA
e
/
SDTA851 using an alumina crucible. The heating profile
Cocrystals of levetiracetam and etiracetam with
CaCl2. Cocrystallization of calcium chloride with racemic
mixture ETI and LEV appeared to be quite straightforward.
In both cases only one crystalline form of ICC was
detected, regardless of the solvent or the method applied
applied starts at 25 ° C and goes up to 300 °C with a rate of
°C /min under continuous nitrogen flow of 50.0 mL/min.
2
RESULTS AND DISCUSSION
(
Scheme 1). Single crystals for the LEV and ETI ICCs could
be obtained both from solution and from the melt, and
were characterized as hydrates of formula
LEV ·CaCl ·2H O and ETI ·CaCl ·2H O. Regardless of the
The reactivity of both levetiracetam and etiracetam (in
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
the following LEV and ETI, respectively) with calcium and
magnesium chlorides was investigated by three different
methods, namely liquid assisted grinding (LAG, also called
2
2
2
2
2
2
30
application of different stoichiometric ratios, we always
got the same ICC, along with the excess of unreacted
starting material. The racemic and the enantiopure ICCs
are quasi-isostructural (Table 2 and Fig. 2) due to the
position of the chiral center in ETI molecule not directly
involved in the crystal packing, which will be discussed in
detail.
kneading ), slurry, and solvent slow evaporation of
undersaturated solutions. The latter method inevitably led
to the formation of viscous oils, irrespective of the solvent
used (water, methanol or ethanol) from which solids
precipitated in a period ranging from 1 to 10 days. The
solids were identified as ICCs. Liquid assisted grinding was
performed with methanol as solvent, while water was
utilized for the slurry experiments. Different
stoichiometric ratios were employed to check for all the
possible cocrystal forms and to determine the most stable
forms. The main results are listed in Table 1. Stoichiometric
3
1
2 2
excess of CaCl or MgCl was never detected in X-ray
powder diffraction patterns, as these salts are deliquescent
and contribute only to the background.
Table 1. ICCs obtained by reacting etiracetam (ETI) and
2 2
levetiracetam (LEV) with CaCl and MgCl .
ICC method
LEV:CaCl
1:1, 2:1, 4:1
2
2 2 2
LEV ·CaCl ·2H
O LAG, sl, sol
ETI:CaCl
:1, 2:1, 4:1
2
2 2 2
ETI ·CaCl ·2H
O LAG, sl, sol
1
LEV:MgCl
:1, 2:1, 4:1*
2
LEV
2
·MgCl
2
·2H
2
O LAG, sl, sol
Scheme 1. ICCs of LEV and ETI with CaCl2.
1
LAG, sl, sol
ETI
ETI
ETI
2
·MgCl
·MgCl
·MgCl
2
·6H
·6H
·2H
2
O
2
O
2 2
In both hydrated ICCs LEV ·CaCl ·2H
2
O
and
ETI:MgCl
2
sl
4
2
ETI ·CaCl ·2H O an octahedral coordination is observed
2
2
2
1:1
HSM
2
2
2
O
around the metal cation (Fig. 2a), comprising the oxygens
of 4 different molecules of LEV (2 oxygens of amide group
and two of pyrrolidinone) and two water molecules. Each
LAG
ETI
ETI
4
·MgCl
·MgCl
2
·4H
2
O
2
ETI:MgCl
2
2
O sl, sol
4
2
·6H
2+
LEV interacts in turn with a second Ca ion through its
2:1
amide and pyrrolidinone groups, resulting in a 2:1
stoichiometry and a 2D-layered structures (Fig. 2b).
Parallel layers (Fig. 2c) are connected to each other via
hydrogen bonds between chlorides and amide NH groups
2
or water molecules (Tables S1 and S2). It is noteworthy that
the calcium complexation is enantioselective in the
racemic crystal of ETI
the crystal is composed of distinct chains of R-ETI and S-
ETI (LEV), as observed in crystalline LEV ·CaCl ·2H O.
Superposition of the R-ETI layer onto LEV layer reveals
that the overall layer conformation is kept and that the
ETI:MgCl
O LAG, sol
4 2 2
ETI ·MgCl ·6H
4:1
*
no results from solution
LAG = liquid assisted grinding; sl = slurry; sol = evaporation
from solution; HSM = hot stage microscopy
2 2 2
·CaCl ·2H O. Fig. 2c right shows how
Table 1 shows a surprising difference in behavior
depending on the nature of the inorganic salt used. The
number of accessible forms, the nature of the racemate, the
stoichiometry and the hydration of the final ICCs are all
2
2
2
3
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Crystal Growth & Design
molecules are able to adapt themselves to the local change alkaline earth halides.
Page 4 of 11
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
in chirality (Fig. SI-1). This packing choice is reminiscent
of what systematically observed on crystals of the amino
23-24
25
acids DL-histidine
and DL-proline with alkali and
Table 2. Crystal data and details of measurements for the hydrated ICCS of LEV and ETI with CaCl
2
2
and MgCl .
LEV
2
·CaCl
2
ETI
2
·CaCl
2
LEV ·MgCl ·
ETI ·MgCl ·
ETI ·MgCl ·
ETI ·MgCl ·
2
2
2
2
2
2
4
2
·
2
2H O
2
·2H O
2
2H O
6H
2
O
2
2H O
2
6H O
(
C
8
H
2
14
N
·2H
2
O
2
)
2
(C
· CaCl2·2H
487.43
8
H
14
N
2
2
)
2
(C
· MgCl
471.66
8
H
14
N
·2H
2
2
)
2
(C
· MgCl
543.73
8
H
14
N
·6H
2
2
)
2
(C
· MgCl
471.66
8
H
14
N
·4H
2
2
)
2
(C
· MgCl
884.17
8
H
14
N
·6H
2
2
)
4
Formula
/g mol-1
·
CaCl
2
O
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
M
r
487.43
Crystal system
Space group
a /Å
Monoclinic
C2
Monoclinic
C2/c
Monoclinic
C2
Triclinic
P-1
Monoclinic
C2/c
Triclinic
P-1
14.8240(13)
10.8951(9)
16.3589(16)
90
14.0692(9)
10.8625(5)
17.1740(10)
90
14.0812(5)
10.7596(4)
16.1135(6)
90
8.0745(7)
8.6611(10)
10.4496(12)
81.505(10)
80.533(8)
77.491(9)
698.93(13)
0.5
13.7487(19)
10.5711(11)
17.042(2)
90
9.0093(8)
10.8861(11)
14.1818(14)
111.917(10)
90.833(8)
111.912(9)
1177.9(2)
0.5
b /Å
c /Å
α / °

/ °
108.273(10)
90
109.330(6)
90
106.817(4)
90
111.873(16)
90
γ / °
V /Å3
2508.9(4)
1
2476.7(2)
0.5
2336.92(16)
1
2298.5(5)
0.5
Z’
Z
4
4
4
1
4
1
d
calc /mg.cm-3
1.290
1.307
1.339
1.292
1.363
1.246

/mm-1
-range /°
Refls measd
0.498
0.504
0.343
0.305
0.348
0.216

3.24-29.18
3.68-29.46
2.93-26.02
3.88-26.28
4.05-19.92
3.64-29.58
6235/4463
1.098
5524/ 2871
1.076
8200/4319
1.028
5610/3188
0.964
4209/2032
0.949
9537/5423
1.037
/
unique
GoF
R
1
(obsd)
I>2(I)]
wR (all)
0
.067
0.063
0.038
0.065
0.081
0.069
[
2
0.119
0.158
0.1069
0.196
0.263
0.204
Fig. 2. a) Coordination around the Ca2+ cation in crystalline
LEV ·CaCl ·2H O and ETI ·CaCl ·2H O. b) A single 2D-layer of
ions, coordinated water and racetam molecules
extending in the ab-plane in crystalline LEV ·CaCl ·2H O and
ETI ·CaCl ·2H O; c) parallel 2D-layers projected down the b-
2
2+
2
2
2
2
2
Ca
2
2
2
2
2
2
axis in both ICCs. In addition to the strong coulombic
component, hydrogen bonds (not shown for clarity) are at
work between the chloride ions and the NH
groups/water molecules. Water oxygens in blue; grey and
orange spheres for ETI ·CaCl ·2H O refer to racetams with
opposite chirality; HCH atoms omitted for clarity.
2
(amide)
2
2
2
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2 2 2
Fig. 5. VT-XRPD for ETI ·CaCl ·2H O
2 2 2
Fig. 3. VT-XRPD for LEV ·CaCl ·2H O measured at different
temperatures showing the transition to a high temperature
form above 240 °C.
2 2 2
Fig. 6. TGA of ETI •CaCl •2H O
2 2 2
Fig. 4. TGA of LEV •CaCl •2H O
The thermal behavior of ETI
is similar to that of LEV ·CaCl ·2H
the XRPD pattern of ETI ·CaCl ·2H
2
2
·CaCl
O. At room temperature
O corresponds to the
2 2
·2H O (Fig. 5 and 6)
2
2
2
To study the thermal stability of the ICCs, VT-XRPD
studies were performed. At room temperature, the XRPD
2
2
simulated pattern obtained from single crystal data.
Surface water is lost up to 80 °C (when the sample is left
for prolonged periods at 80 °C, cooled to 25 °C under
nitrogen flow and reheated, one no longer observes the
endotherms related to the evaporation of the surface
water, Fig. SI-8 and SI-9). The dehydration process starts
above 140 °C (Fig. 5), and corresponds to the loss of two
water molecules (7.3% aligns with the theoretical loss of
pattern of LEV
pattern obtained from single crystal data. Upon heating
LEV ·CaCl ·2H O a number of events are observed. The
2 2 2
·CaCl ·2H O corresponds to the simulated
2
2
2
TGA trace shows a steady weight loss (Fig. 4) up to 80 °C,
which can easily be attributed to adsorbed surface water,
an observable for all ICCs discussed and due to the
hygroscopicity of the obtained ICCs. Between 90 °C and 130
°C a loss of 6.6% in weight corresponds to the loss of the 2
equivalents of water of the dihydrate (theoretical weight
loss =7.5% ), as also confirmed by VT-XRPD (Fig. 3). This
anhydrous form remains stable up to 240 °C, temperature
at which a transformation to a second anhydrous form
occurs, followed by degradation. If the heating is stopped
right before degradation occurs, and the sample is cooled
7.5%). The dihydrate of the racemic compound thus has a
higher thermal stability compared to that of the
enantiopure compound. No further changes in the crystal
phase of the anhydrate are observed up to its degradation
occurring at 230 °C. If the anhydrate is cooled to room
temperature, the initial dihydrate ICC is again obtained.
Cocrystals
of
levetiracetam
with
MgCl2.
back to room temperature, the initial LEV
again obtained.
2 2
·CaCl ·2H
2
O is
Cocrystallization of LEV with MgCl led to the formation of
2
LEV ·MgCl ·2H O, which is isomorphous with the CaCl
2
2
2
2
2
analogue (Table 2). As in the case of the ICC with CaCl ,
only one stoichiometry was observed, irrespective of the
starting stoichiometric ratio, solvent used and method
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Page 6 of 11
employed to obtain the cocrystals (Scheme 2). The thermal
behavior (Fig. 7 and 8) parallels the one observed for
LEV ·CaCl ·2H O, with surface water removal up to 100 °C
and a single dehydration process observed at ca. 150 °C
(experimental weight loss by TGA=8.6% ; theoretical
weight loss =7.6%); the anhydrate phase thus obtained
remains stable up to 240 °C. If the dehydration process is
followed via HSM, melting is observed for the anhydrous
phase at 240 °C, and recrystallization of the melt under
ambient conditions yields the dihydrated ICC
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
2
2
2 2 2
LEV ·MgCl ·2H O.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 2. ICCs of LEV and ETI with MgCl
put when the forms were only observed in VT XRPD. There is
an interconversion between ETI ·MgCl ·6H and
ETI ·MgCl ·6H O using LAG and by addition of the
appropriate amount of reactant.
2
. Grey boxes are
2
2
2
O
4
2
2
2
:1 system - the ICC ETI
Reaction of ETI with MgCl in 1:1 stoichiometry, with the
intent of obtaining ETI ·MgCl ·2H O, i.e. the CaCl
2
2 2 2
·MgCl ·nH O (n = 2, 6).
2
2
2
2
analogue, yielded an oil, which in a matter of a few days
crystallized into the hexa-hydrated ICC of formula
2+
2
ETI ·MgCl
2 2
·6H O
(Fig. 9). The Mg
cation is
hexacoordinated by two pyrrolidinone oxygens - belonging
to ETI R and S enantiomers - and by four water molecules,
thus forming a 0D complex instead of the 1D chains
encountered in the previously discussed ICCs. The amido
groups are hydrogen bonded to the chloride anions and to
2 2 2
Fig. 7. VT-XRPD for LEV ·MgCl ·2H O
2
water molecules via the -NH and -C=O moieties,
respectively (Table S4).
2 2 2
Fig. 8. TGA of LEV •MgCl •2H O
Cocrystals
of
etiracetam
with
MgCl
2
.
Cocrystallization of racemic mixture ETI with MgCl
2
leads
2 2 2
Fig. 9. 0D-complexes in crystalline ICCs Eti ·MgCl ·6H O.
Water molecules marked in blue; HCH atoms omitted for
clarity.
to a more complex solid state landscape, with the outcome
being dependent on reaction and stoichiometric
conditions (scheme 2). Different stoichiometries are
2 2 2
obtained, namely ETI ·MgCl ·6H O (2:1 system) and
Upon heating, three subsequent transitions occur. A
first transition occurs at around 70 °C, a second at 100 °C
and a third at 130 °C. TGA trace and VT-XRPD patterns
ETI ·MgCl ·6H O (4:1 system), and the cocrystals are
4
2
2
hexahydrates, contrary to the dihydrates observed for all
other cases. Thermal dehydration processes will lead to
intermediate hydrate phases, as will be discussed below.
(
Fig. 10 and 11) confirm that each step corresponds to the
loss of two water molecules (21.6% total weight loss,
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Crystal Growth & Design
theoretical loss of 6 water molecules = 19.9%). Degradation
occurs starting from 250 °C. Based on this analysis, it can
be inferred that a hexa-hydrate, a tetra-hydrate, a di-
hydrate and an anhydrate phase to exist for the 2:1
cocrystal.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Fig. 12. ETI
axis.
2 2 2
·MgCl ·2H O. View down the crystallographic b-
In addition to the hexahydrate ETI
single crystals of the di-hydrated ETI ·MgCl
also be obtained, as the product of recrystallization of
2
·MgCl
2 2
·6H O ICC,
2
2
·2H
2
O could
2
Fig. 10. VT XRPD for Eti ·MgCl
2 2
·6H O.
ETI ·MgCl ·6H O from the melt in a Hot Stage Microscopy
2
2
2
experiment, in a similar approach to the one employed to
produce single crystals of LEV ·CaCl ·2H O from the melt
SI-Hot Stage Microscopy experiment). The obtained
crystals were analyzed and shown to be isomorphous with
the calcium analogue ETI ·CaCl ·2H O (Fig. 12). On the
basis of the crystal structure of the hexahydrate and the
dihydrate, we can conclude that the three successive water
losses of the hexahydrate upon heating correspond to the
loss of the water molecules not bound to the Mg cation,
followed by the loss of two of the four Mg bound water
molecules, and finally to the last two Mg bound water
molecules of the dihydrate.
2
2
2
(
2
2
2
2+
2+
2+
4
:1 system - the ICCs ETI
Cocrystallization from water of ETI with MgCl
in a 4:1 stoichiometric ratio, yielded the hexahydrate ICC
ETI ·MgCl ·6H O (Fig 13).
4
2
·MgCl ·nH
2
O (n=4,6)
2
, this time
4
2
2
2 2 2
Fig. 11. TGA of ETI •MgCl •6H O
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Fig. 13. ETI
4 2 2
·MgCl ·6H O. a) View along crystallographic a-axis. b) CO⋯NH hydrogen bonds among ETI molecules involved in
2+
the magnesium coordination. c) 1D chains by ETI molecules uncoordinated to Mg cations. Water molecules are marked in blue,
2+
2+
Mg cations are marked in orange, the carbon atoms of ETI molecules which are not involved into coordination with Mg are
marked in violet, hydrogens are omitted for clarity and dash lines are hydrogen bonds.
As for the 2:1 cocrystal, an octahedral coordination is
observed around the Mg cation with 2 molecules of ETI
(both R and S enantiomers) and 4 water molecules forming
a 0D complex. In the 4:1 cocrystal ETI
the oxygens of pyrrolidinone are involved in the
coordination with Mg , whereas the amide groups of ETI
form CO⋯NH hydrogen bonds (Fig. 13b). One peculiarity
of this structure is the presence of layers of ETI (R and S
enantiomers) uncoordinated to Mg cations. These ETI
molecules form 1D chains via hydrogen bonds with water
2+
4 2 2
·MgCl ·6H O only
2+
2+
2+
molecules coordinated to Mg (Fig. 13c). These chains are
held together via hydrogen bonds between amide groups
-
-
and via NH
2
---Cl and HOH---Cl hydrogen bonds (Table
S6). The ETI
4
·MgCl
·MgCl
O with one equivalent of MgCl2, indeed,
·6H O, whereas grinding of this latter
with 2 equivalents of ETI leads to ETI ·MgCl ·6H O.
VT-XRPD patterns and TGA trace (Fig. 14 and 15) show
the loss of two water molecules from ETI ·MgCl ·6H
between 80 °C and 100 °C (4.3% weight loss, theoretical
w%=4.1). Four further H O molecules are lost between 120
C and 160 °C (7.8% weight loss, theoretical w%=8.2). The
weight loss between 160-200 °C is caused by the loss of 2
2 2
·6H O ICC could thus be seen as a
“
cocrystal” of ETI
2
2
·6H O and ETI. Grinding of
2
4 2 2
Fig. 14. VT XRPD for Eti ·MgCl ·6H O.
ETI
4
·MgCl
·6H
2 2
leads to ETI
2
·MgCl
2
2
4
2
2
4
2
2
O
2
°
2+
equivalents of ETI, which are not coordinated to the Mg
cation (41.4% weight loss, theoretical w%=38.5). The
resulting ETI ·MgCl anhydrate form remains stable up to
45 °C.
2
2
2
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Crystal Growth & Design
noteworthy that ETI ·MgCl ·2H O, which is isostructural
Fig. 15. TGA of ETI
4
•MgCl
2
•6H
2
O
2
2
2
1
2
3
2 2 2
with ETI ·CaCl ·2H O, shows the same type of homochiral
preference for etiracetam molecules of the same chirality
(S-ETI and R-ETI) upon complexation with the Ca
cations.
Surprisingly, ETI
4
·MgCl
2
·4H
2
O was formed by MeOH
2
using a 2:1 stoichiometry, which was
2+
LAG of ETI with MgCl
shown by a comparison of the XRPD patterns of the
ground phase and the pattern of ETI ·MgCl ·6H O heated
to 100 °C (temperature at which 2 water molecules are lost)
Fig. 16). The thermal behavior above 100 °C of this ground
phase (Fig. SI-13) is found identical to that of
ETI ·MgCl ·6H O.
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
All cocrystals showed a significant increase in the
thermal stability of both LEV and ETI in the ICCs with
respect to the parent organic systems. All ICCs underwent
dehydration and showed thermal stability up to 240-260
4
2
2
(
°
C.
4
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ASSOCIATED CONTENT
Supporting Information. Supporting information files
are available free of charge via the Internet at
http://pubs.acs.org. Additional experimental data,
superimposition information, details of hydrogen bonds,
Experimental XRPD and DSC curves (PDF).
CCDC 1894095-1894100 contain the supplementary
crystallographic data for this paper. The data can be
obtained free of charge from The Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/structures. (or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB21EZ, UK; fax: (+44)1223-336-033; or e-mail:
deposit@ccdc.cam.ac.uk).
AUTHOR INFORMATION
Corresponding Author
Fig. 16. XRPD patterns of Eti
cyan line) and the MeOH LAG ground sample (black line).
4 2 2
·MgCl ·6H O heated to 100 °C
(
* E-mail: tom.leyssens@uclouvain.be;
fabrizia.grepioni@unibo.it.
Stability tests for ETI ICCs with MgCl
above, the combination of ETI and MgCl leads to multiple
hydrate forms. Slurry experiments (Table 1) performed at
25 °C show the hexahydrate forms ETI ·MgCl ·6H O and
ETI ·MgCl ·6H O to be the most stable phases in water at
25 °C.
2
. As shown
ORCID:
2
Lixing Song: 0000-0003-4874-3551
2
2
2
ACKNOWLEDGMENT
4
2
2
This work was supported by a STSM Grant from COST
Action CM1402 Crystallize. Lixing Song would like to thank
the China Scholarship Council (CSC) for financial support.
CONCLUSIONS
The interaction of enantiopure LEV and racemic ETI
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ETI ·CaCl ·2H O and LEV ·CaCl ·2H O which possess
2
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Ionic cocrystals of etiracetam and levetiracetam: the importance of
chirality for ionic cocrystals
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Lixing Song, Oleksii Shemchuk, Koen Robeyns, Dario Braga, Fabrizia Grepioni, Tom
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*
Leyssens
This work focuses on ionic cocrystallization of enantiopure LEV and racemic mixture ETI with inorganic salts
and MgCl . A diverse solid state landscape and chiral packing choice were demonstated and all the ionic cocrystals
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showed a significant increase in the thermal stability respect to the parent organic systems.
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