Does chirality influence the tendency toward cocrystal formation?

Article abstract of DOI:10.1021/cg500181t

We performed a systematic cocrystal search for the enantiopure and racemic version of a selected active pharmaceutical ingredient, expecting that a coformer giving a cocrystal with a single enantiomer will also interact with the racemic mixture since they present identical functional groups prone to cocrystallization. We identified several novel cocrystals of levetiracetam and its racemic equivalent, etiracetam, using a wide variety of nonchiral coformers. Fourteen novel cocrystals of the enantiopure compound were obtained, whereas 18 of the racemic compound were identified. Out of these, 13 share a common coformer. A structural analysis indicates that in most cases the strongest hydrogen bonding interactions occur both in the enantiopure, as well as the racemic cocrystal, whereas van der Waals interactions, or less strong secondary hydrogen bonding interactions, lead to a differentiation of the final structure. On the basis of our work, we suggest an approach that could lead to a more optimal cocrystal screening of an enantiopure compound, especially when a limited amount of this compound is available. Starting with a screen of the racemic compound, the set of possible coformers for the enantiopure screen can be limited to those yielding a positive hit in the former screen. Doing so, our example shows an increase in efficiency from 10% to 72%.

Full text of DOI:10.1021/cg500181t

Article
pubs.acs.org/crystal
Does Chirality Influence the Tendency toward Cocrystal Formation?
Fanny George,† Nikolay Tumanov,† Bernadette Norberg,‡ Koen Robeyns,† Yaroslav Filinchuk,†
Johan Wouters,‡ and Tom Leyssens*,†
†Institute of Condensed Matter and Nanosciences, Universite
́
catholique de Louvain, 1348 Louvain-la-Neuve, Belgium
‡Unite
de Chimie Physique, Theorique Et Structurale, University of Namur, Namur, Belgium
́ ́
S
* Supporting Information
ABSTRACT: We performed a systematic cocrystal search for
the enantiopure and racemic version of a selected active
pharmaceutical ingredient, expecting that a coformer giving a
cocrystal with a single enantiomer will also interact with the
racemic mixture since they present identical functional groups
prone to cocrystallization. We identified several novel cocrystals
of levetiracetam and its racemic equivalent, etiracetam, using a
wide variety of nonchiral coformers. Fourteen novel cocrystals
of the enantiopure compound were obtained, whereas 18 of the
racemic compound were identified. Out of these, 13 share a common coformer. A structural analysis indicates that in most cases the
strongest hydrogen bonding interactions occur both in the enantiopure, as well as the racemic cocrystal, whereas van der Waals
interactions, or less strong secondary hydrogen bonding interactions, lead to a differentiation of the final structure. On the basis of
our work, we suggest an approach that could lead to a more optimal cocrystal screening of an enantiopure compound, especially
when a limited amount of this compound is available. Starting with a screen of the racemic compound, the set of possible coformers
for the enantiopure screen can be limited to those yielding a positive hit in the former screen. Doing so, our example shows an
increase in efficiency from 10% to 72%.
INTRODUCTION
■
One of the goals of a crystallization process is to obtain a
pure form, especially when working with active pharmaceutical
ingredients (APIs).1 Different forms of these latter may be
accessible, among them polymorphs of the pure compound,2,3
salts,4,5 hydrates,6,7 and cocrystals.8−10 Forms may differ sig-
nificantly from one another in their physicochemical properties,
such as solubility or bioavailability,11,12 justifying the efforts toward
finding API forms with optimal properties without altering chem-
ical identity.13,14
Figure 1. Chemical structures of etiracetam (left) and levetiracetam
(right).
A multitude of drug substances are marketed as salts, but for
some APIs, especially ones without ionizable groups, no viable
salts can be isolated. In this case, formation of cocrystals is an
interesting alternative.15−18 In the context of this work, co-
crystals are considered as solids that are crystalline single phase
materials composed of two or more different molecular and/or
ionic compounds, called coformers, generally in a stoichiometric
ratio, with components being solid under ambient conditions.
They are therefore neither solvates nor salts.19
Identifying appropriate coformers able to cocrystallize with a
given API may be time-consuming (trial and error process) and
compound consuming, which is particularly an issue at the early
stages of drug research. Consequently, attempts are made to
predict matching coformers for a given compound, to improve
cocrystal screening efficiency. Within this context, Springuel
et al. showed that molecules presenting relatively similar chem-
ical structures have an increased likelihood to form cocrystals
with the same coformers.20 In this contribution, we use a
similar approach, investigating whether or not the likelihood
of forming a cocrystal between an enantiopure API and a
coformer is increased when this coformer was already shown to
be effective toward the racemic compound. For salts, this does
not seem surprising, as salt formation is mainly governed by
pKa differences between base and acid. Hence an acid (or base)
interacting with a given enantiopure API is also expected
to interact with the racemic API. For cocrystals, this is
less straightforward, as these compounds mostly depend on
hydrogen-bonding interactions, which are directional in nature.
In a recent contribution,21 cocrystals were shown to behave
differently with respect to salts when both components are
chiral; whereas for salts, formation of a diastereomeric pair
Received: February 3, 2014
Revised: April 25, 2014
Published: May 5, 2014
© 2014 American Chemical Society
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Table 1. Overview of Etiracetam and Levetiracetam Cocrystals
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Table 1. continued
---
*
a
b
c
No cocrystal. Cocrystal identified, structure not yet determined. Cocrystal confirmed by slurrying experiment. Solvate found. Cocrystal
confirmed by binary melting phase diagram.
seems to be the general rule, cocrystal systems are mostly
enantiospecific.
while a structural comparison was carried out to compare the
hydrogen-bonded network topology of enantiopure and
racemic cocrystals, using crystal structures obtained from single
crystal diffraction or synchrotron powder diffraction data.
To investigate how chiral APIs respond in cocrystallization
toward nonchiral coformers, we performed an experimental
cocrystal screen on an enantiopure and racemic version of a
pharmaceutically active compound that does not form a salt. As
a model compound we chose levetiracetam (LEVI), a nootropic
drug used as an anticonvulsant in the treatment of epilepsy.22,23
LEVI is the biologically active enantiomeric form of (RS)-2-(2-
oxopyrrolidin-1-yl) butanamide, also called etiracetam (ETI)
(Figure 1). Of the former, only one solid form is reported,24
while for the racemic compound two enantiotropically related
polymorphs and one hydrate have been studied extensively.25−29
Previous work showed LEVI to be a potent candidate for
cocrystal formation.20,30 In the current contribution, cocrystals
of LEVI and ETI were identified using solvent drop grinding.
X-ray powder diffraction (XRPD) was used to detect cocrystals,
EXPERIMENTAL SECTION
■
Starting Materials. S-2-(2-Oxopyrrolidin-1-yl)butanamide (leve-
tiracetam, LEVI) was purchased from Xiamen Top Health Biochem
Tech. Co., Ltd. 4-Nitrobenzoic acid (4NBA); adipic acid; oxalic acid
(OXA); and acetoacetamide were purchased from Acros Organics.
1,3,5-Benzenetricarboxylic acid; 2,2-dimethylsuccinic acid (DMSA);
5-hydroxylisophthalic acid; oxaloacetic acid; methyl 3,4,5-trihydrox-
ybenzoate; and 4,4-bipyridine were purchased from Alfa Aesar. 3-
Methylbutanamide was purchased from Maybridge. 1H-Pyrazole-3,5-
dicarboxylic acid monohydrate; 2,4-dihydroxybenzoic acid (DHBA);
3-nitrobenzoic acid (3NBA); 5-nitroisophtalic acid; anthranilamide;
and 4-chlorobenzaldehyde were purchased from Sigma-Aldrich.
Citraconic acid and gallic acid ethyl ester were purchased from TCI.
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These materials were used as received, without further purifica-
tion. (RS)-2-(2-Oxopyrrolidin-1-yl)butanamide (etiracetam, ETI) was
prepared by racemization of S-2-(2-oxopyrrolidin-1-yl)butanamide.
Ten grams of S-2-(2-oxopyrrolidin-1-yl)butanamide together with a
catalytic amount (0.05 equiv) of MeONa was added to 10 mL of
MeOH. The solution was kept at reflux under continuous stirring for
24 h and then cooled to room temperature. The compound crystallizes
spontaneously. After filtration, the compound was washed twice with
MeOH. The recovered compound was used as such.
Cocrystal Screen. Cocrystals were synthesized by solvent-drop
grinding of equimolar mixtures of LEVI or ETI and a suitable co-
former, with addition of 10 μL of methanol. Samples were ground in a
RETSCH Mixer Mill MM 400 for 90 min with a beating frequency of
30 Hz. The resulting powders were characterized using XRPD.
Comparison of the resulting diffraction pattern with the diffraction
patterns of the pure phases was used to indicate cocrystal formation.
All possible known forms of the pure phases were considered, to avoid
confusing cocrystal formation with other phase transformations (e.g.,
solvate formation polymorphism).
When mixtures resulted in formation of an amorphous phase, neat
(dry) grinding was performed instead. For all cocrystals identified,
attempts were made to obtain a single crystal sufficiently large for
structural XRD analysis.
X-ray Powder Diffraction (XRPD). X-ray diffraction measure-
ments were performed on a Siemens D5000 diffractometer equipped
with a Cu X-ray source operating at 40 kV and 40 mA and a secondary
monochromator allowing selection of the Kα radiation of Cu (λ =
1.5418 Å). A scanning range of 2θ values from 2° to 72° at a scan rate
of 0.6° min−1 was applied.
Synchrotron Radiation Powder X-ray Diffraction. Data for
LEVI−DHBA and LEVI−DMSA cocrystals were collected at the
MS-X04SA beamline at the Swiss Light Source (PSI, Switzerland)
using a 1D microstrip detector MYTHEN II. The wavelength was
0.775045 Å. Wavelength and zero-shift were calibrated using a NIST
640d Si standard sample. Patterns were indexed using FOX.31 Le Bail
fit was done using FOX31 and Fullprof32 programs. Space group for
each pattern was suggested taking into account analysis of systematic
absences and considering that space groups have to be chiral due to
presence of a chiral API molecule in the unit cell. The structure was
solved by global optimization in direct space using the FOX
program.31 Molecular model of LEVI,24 DMSA,33 and DHBA (using
the corresponding fragment in ETI−DHBA cocrystal structure) were
imported from structural models determined from single-crystal
diffraction. Constraints for interatomic distances and angles were
introduced: rigid group restraints were created to keep proper
geometry of planar rings, amide, and carboxylic acid groups. Antibump
restraints were not applied. Position, orientation, and conformation of
molecules were optimized. In average, one out of 10 trials leads to a
reasonable solution, so 200−300 runs were performed to find the
optimal solution. At the final stages of solution, torsion angle restraints
were applied to hydrogen atoms involved in hydrogen bonding to
achieve a reasonable geometry for the hydrogen bonds. The final
refinement was done by the Rietveld method using the Fullprof
suite,32 keeping the orientation of the molecules fixed. Unit cell
parameters, coordinates of two separate molecules, scale factor, and
overall temperature factor were refined. The background was
described by linear interpolation between selected points determined
from Le Bail fit. The final discrepancy factors are RI = 12.37%, Rp =
1.33%, Rwp = 1.53%, Rcp = 17.03%, and Rcwp = 18.22% for the LEVI−
DHBA cocrystal and RI = 8.75%, Rp = 1.25%, Rwp= 1.55%, Rcp
=
16.91%, and Rcwp = 17.37% for the LEVI−DMSA cocrystal. Their
refinement profiles are shown in the Supporting Information.
Using XRPD data, it is nearly impossible to differentiate cocrystals
from salts. However, in the context of this work, we used a compound
that does not form salts. This resolves all issues concerning the
position of the hydrogen atoms.
Single Crystals. Single crystals were grown by slow evaporation
from an equimolar solution of starting materials or by cooling of the
corresponding supersaturated solution in suitable solvents. Different
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Figure 2. (a) Etiracetam and 2,2-dimethylsuccinic acid form an amide-carboxylic acid heterosynthon [R22(8)] ring motif and (b) a [C22(11)] infinite
chain motif in ETI−DMSA cocrystal.
Figure 3. (a) One molecule of DMSA (green) is linked to four molecules of LEVI through four H-bonds in LEVI−DMSA cocrystal. LEVI−DMSA
cocrystal shows (b) a [C22(11)] infinite chain motif and (c) an infinite chain with [C22(8)] motif.
solvents were used to increase the probability of identifying single
crystals large enough for analysis.
atoms implicated in H-bonds were localized in the Fourier difference
maps.
Single Crystal X-ray Diffraction. Single crystal X-ray diffraction
was performed on a Gemini Ultra R system (4-circle kappa platform,
Ruby CCD detector) using Cu Kα radiation (λ = 1.54056 Å). Cell
parameters were estimated from a pre-experiment run and full data
sets collected at room temperature. The structures were solved by
direct methods with the SHELXS-97 program and then refined on |F|2
using SHELXL-97 software.34 Non-hydrogen atoms were anisotropi-
cally refined, and the hydrogen atoms (not implicated in H-bonds) in
the riding mode with isotropic temperature factors were fixed at 1.2 times
U(eq) of the parent atoms (1.5 times for methyl groups). Hydrogen
RESULTS
■
Hydrogen bonding is the main driving force behind cocrystal
formation. As most of the typical cocrystal synthons are not
affected by chirality, one could expect that a coformer yielding a
cocrystal with a given chiral compound would also interact with
its racemic version, as similar hydrogen bonding synthons are
expected. However, in the case of cocrystals between two chiral
partners,21 it was shown that the van der Waals or π−π stacking
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Figure 4. (a) The ETI−DHBA cocrystal shows an amide−amide homosynthon [R22(8)] between the noncyclic amides of two ETI and a [R46(24)]
ring motif and (b) a dimer motif links ETI to DHBA.
interactions could be as important as the hydrogen bonding
interactions and influence cocrystal stability.
To investigate the propensity toward cocrystal formation
between a nonchiral partner and enantiopure or racemic com-
pound respectively, we performed a cocrystal screen for both
ETI (racemic) and LEVI (enantiopure) with a set of 152 achiral
coformers. These latter were selected to have at least one
alcohol, aldehyde, amide, amine, or carboxylic acid function. In
total, 14 novel cocrystals of LEVI were identified, which gives a
success rate for cocrystal formation of about 10%. A similar
number of cocrystals was also encountered for the racemic ETI
compound, yielding a total of 18 novel cocrystals (Table 1).
Strikingly, out of these, 13 involve a common coformer.
Although a negative test through grinding does not
necessarily imply the cocrystal phase does not exist, solvent-
drop grinding has been shown to be an efficient method for a
Figure 5. Stacking of three layers in ETI−DHBA cocrystal, showing
fast and effective detection of the majority of cocrystals.35 It is
however possible that some of the coformers that were ex-
cluded in the initial screen do lead to cocrystal formation under
different conditions (e.g., solvent screening, supercritical fluid
crystallization, etc.). Similarly, in some cases stoichiometrically
diverse cocrystals can exist. In the context of this work, we were
not concerned with identifying all possible cocrystal forms
between two given compounds. However, when it was evident
that grinding of an equimolar mixture led to excess amount of
one of the two components, different stoichiometries were
tested (e.g., 1:2 mixing was done for 3NBA and 4NBA as this
ratio led to full conversion according to XRPD analysis).
Out of the 32 novel cocrystals identified in this work, 15 have
been structurally characterized, either through single crystal
analysis or through XRPD structure determination. A pairwise
comparison of enantiopure and racemic cocrystals can yield
insight into the question, whether or not similar synthons are
observed in both cases.
infinite chain motifs [C22(12)] along the c axis and π stacking of
molecules of DHBA acid in the bc plane.
ETI−DMSA, ETI−OXA, ETI−3NBA, and ETI−4NBA
cocrystals were synthesized by slow evaporation at room temper-
ature of an equimolar, undersaturated solution of both coformers.
ETI−DHBA, LEVI−OXA, LEVI−3NBA, and LEVI−4NBA were
obtained by cooling crystallization to 3 °C. Finally, structures of
LEVI−DMSA and LEVI−DHBA cocrystals were determined from
synchrotron powder diffraction data.
Etiracetam−2,2-Dimethylsuccinic Acid (1:1) (ETI−
DMSA). The ETI−DMSA cocrystal crystallizes from acetoni-
trile in the monoclinic space group P21/c. The asymmetric unit
contains one molecule of ETI and one molecule of DMSA.
An amide−carboxylic acid heterosynthon, described in graph
set notation as [R22(8)],36 is formed between the noncyclic
amide of ETI and the carboxylic acid function in position 4 of
DMSA (Figure 2a). In addition, the carboxylic acid function
in position 1 links two molecules of ETI through a [C22(11)]
hydrogen-bonded infinite chain motif: the acid function of
DMSA acts as an acceptor of the second proton of the non-
cyclic amide function (the one not included in the ring motif
mentioned above) and as a donor to the cyclic carbonyl function
of ETI. This chain propagates along the c-axis (Figure 2b).
Crystal Structure Analysis. The structural analysis below
focuses on the five coformers for which a cocrystal was found
for both ETI and LEVI, allowing a comparison of the number
and types of H bonding patterns formed in a pair of cocrystals.
Crystallographic parameters for those 10 cocrystals are
displayed in Table 2.
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Figure 6. (a) An infinite chain motif [C22(12)] and a dimer motif links LEVI to DHBA acid in LEVI−DHBA cocrystal and (b) another dimer motif
joins two LEVI (one pink, one green).
On the whole, the ETI−DMSA cocrystal exhibits a layered
stacking, all the hydrogen bonds being located inside each layer.
Secondary interactions hold the layers together due to the pres-
ence of the ethyl groups of ETI molecules and the carbonated
chains of DMSA oriented outward from the layer planes.
Levetiracetam−2,2-Dimethylsuccinic acid (1:1) (LEVI−
DMSA). Structure of the LEVI−DMSA cocrystal was deter-
mined from synchrotron powder diffraction data in the mono-
clinic space group P21. The asymmetric unit contains one
molecule of LEVI and one molecule of DMSA.
One molecule of DMSA is linked to four molecules of LEVI
through four H-bonds, two with each carboxylic acid function.
The carboxylic acid in position 1 has the carbonyl group bound
to a hydrogen of the noncyclic amide of a first molecule of
LEVI, while the hydroxyl is connected to the cyclic carbonyl
function of a second molecule of LEVI (Figure 3a), leading to a
similar [C22(11)] hydrogen-bonding infinite chain motif as
observed for the racemic ETI−DMSA cocrystal (Figure 3b). In
this first cocrystal comparison, similar motifs can hence be en-
countered between enantiopure and racemic cocrystals. In turn
the carboxylic acid group in position 4 accepts a H-bond from
the noncylic amide of a third LEVI molecule while donating
one to the noncyclic amide carbonyl group of a fourth LEVI
molecule, creating a second infinite chain motif [C22(8)], along
the a-axis (Figure 3c). In contrast with the racemic ETI−DMSA
cocrystal, no amide-carboxylic acid heterosynthon [R22(8)] is
observed, implying that not all hydrogen bonding patterns are
comparable in both cases.
Figure 7. Stacking of three layers in LEVI−DHBA cocrystal, showing
infinite chain motifs along the b axis.
An amide−amide homosynthon [R22(8)] is formed between
the noncyclic amides of two ETI molecules (Figure 4 a). A
ETI···DHBA dimer motif is also observed, based on a hydrogen
bond between the DHBA hydroxyl group (in position 4) and
the cyclic oxygen of ETI (Figure 4 b).
Here again, a [C22(12)] infinite chain motif is observed. This
motif is formed through a first hydrogen bond donated by
the DHBA carboxylic acid function to the oxygen atom of the
noncyclic amide. The second hydrogen bond joins the non-
cyclic ETI amide with the DHBA hydroxyl group in position 4
(Figure 5).
Overall, molecules of LEVI and DMSA are also organized in
layers, which stack along the c axis.
Etiracetam−2,4-Dihydroxybenzoic Acid (1:1) (ETI−
DHBA). The ETI−DHBA cocrystal crystallized from acetoni-
trile and belongs to the monoclinic space group P21/n. One
molecule of ETI and one molecule of DHBA occupy the
asymmetric unit.
Each DHBA molecule is locked in a near planar conforma-
tion through the formation of an intramolecular H-bond be-
tween the carboxylic acid’s carbonyl group and the hydrogen of
the nearest hydroxyl group (in position 2).
A final structural element of interest is the π stacking of
DHBA molecules along the c axis, with each successive mole-
cule rotated by 180 °C. Consequently, two consecutive infinite
chains link through a [R46(24)] ring motif (Figure 4a). In this
motif, there are an uneven number of hydrogen acceptors and
donors as the ETI oxygen atom of the noncylic amide is involved
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Figure 8. (a) An amide-carboxylic acid heterosynthon [R22(8)] is formed between ETI and OXA and a [R44(14)] ring motif links two ETI with two
OXA, in ETI−OXA cocrystal. (b) One [R44(14)] ring motif (green) is linked to four identical ones (blue and pink) through hydrogen bonds.
in two different hydrogen bonds. On the whole, a close stacking of
layers along the c axis is observed, held together by hydrophobic
interactions, due to the presence of nonpolar groups oriented
outward.
shows an infinite chain motif [C22(12)] although constructed
from slightly different hydrogen bonds. A first hydrogen bond is
formed between the donating DHBA carboxylic acid function
and the LEVI noncyclic amide carbonyl function, while a
second hydrogen bond joins the LEVI noncyclic amide to the
DHBA oxygen of the hydroxyl in position 4 (Figure 6a). This
chain allows the growth of the network along the b axis and
shows alternating LEVI and DHBA molecules.
Although a lot of structural elements are once more similar
between racemic and enantiopure cocrystals, contrary to the
ETI−DHBA cocrystal, no homosynthon is found between the
noncyclic amides of two LEVI molecules. Instead a
supplementary hydrogen bond exists between the LEVI
noncyclic carbonyl group and the proton of the noncyclic
amide of a neighboring LEVI molecule (Figure 6b). As was the
case for the racemic cocrystal, the carbonyl of the noncyclic
amide is involved in two hydrogen bonds.
Levetiracetam−2,4-Dihydroxybenzoic acid (1:1)
(LEVI−DHBA). The LEVI−DHBA cocrystal was determined
ab initio from XRPD data and belongs to the orthorhombic
space group P212121. The same cocrystal was crystallized from
solution by Springuel et al.20 with almost identical structural
parameters, confirming the validity of our results originating
from synchrotron radiation data analysis. Four molecules of
LEVI and four molecules of DHBA occupy the unit cell.
As in the racemic ETI−DHBA cocrystal, each DHBA mol-
ecule is locked in a near planar conformation through the for-
mation of an intramolecular H-bond. Likewise, a similar dimer
motif connects the DHBA hydroxyl group in position 4 to the
LEVI cyclic amide (Figure 6a). Furthermore, the structure also
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Figure 9. (a) One layer in the ab plane and in (b) ac plane in ETI−OXA cocrystal.
On the whole, a close stacking of layers along the c axis can
be observed. In a given layer, there is no π stacking of mole-
cules of DHBA since those are slightly staggered along the a
axis. Each layer has a thickness of two molecules of DHBA or
LEVI, depending on the position along the b axis. Layers are
held together by secondary interactions, due to the presence of
the nonpolar parts of LEVI molecules oriented outward, facing
the DHBA aromatic cycles. Figure 7 shows the stacking of three
layers in the bc plane.
LEVI−OXA cocrystal parameters are almost identical to
those of the ETI−OXA cocrystal. Similar hydrogen bonding
motif and tridimensional patterns are observed (Figure 10).
Etiracetam−Oxalic Acid (1:1) (ETI−OXA). The ETI−
OXA cocrystal crystallizes in the monoclinic space group P21/c.
The asymmetric unit contains one molecule of ETI and one
molecule of OXA.
An amide-carboxylic acid heterosynthon [R22(8)] is formed
between the noncyclic amide of ETI and one of the OXA
carboxylic acid functions. In addition, the second hydrogen of
the ETI noncyclic amide acts as a hydrogen bond donor for the
second carboxylic acid function. These two interactions link
two ETI molecules with two OXA molecules forming a [R44(14)]
ring motif (Figure 8a).
Figure 10. An amide-carboxylic acid heterosynthon [R22(8)] is formed
between LEVI and OXA and a [R44(14)] ring motif links two LEVI
with two OXA in LEVI−OXA cocrystal.
This latter ring motif binds to four similar ring motifs through
a hydrogen bond between the ETI cyclic amide carbonyl group
and the OXA carboxylic acid hydroxyl function not participating in
the aforementioned heterosynthon (Figure 8b).
On the whole, the ETI−OXA structure is arranged in
separate layers stacked along the a-axis. Layers are once more
held together thanks to the hydrophobic groups of ETI
pointing outward. Figure 9, panels a and b show one layer in
the ab plane and in the ac plane, respectively.
Levetiracetam−Oxalic Acid (1:1) (LEVI−OXA). The
enantiopure LEVI−OXA cocrystal crystallizes from acetonitrile
in the monoclinic space group P21. The asymmetric unit
contains one molecule of LEVI and one molecule of OXA.
Etiracetam−3-Nitrobenzoic Acid (1:1) (ETI−3NBA).
The ETI−3NBA cocrystal, isolated from acetonitrile, was
solved in the triclinic space group P1. Two molecules of ETI
̅
and two molecules of 3NBA occupy the unit cell, forming a
tetramer.
In the unit cell, one observes the presence of an amide-
carboxylic acid [R22(8)] heterosynthon between the ETI non-
cyclic amide and the 3NBA carboxylic acid (Figure 11a).
Furthermore, two ETI molecules form an amide [R22(14)]
homosynthon ring motif: the cyclic carbonyl of one molecule
acts as an acceptor to the noncyclic NH of a second, resulting
in the folding of the tetramer into an S shape (Figure 11b).
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Figure 11. (a) The ETI−3NBA cocrystal exhibits an amide-carboxylic acid heterosynthon [R22(8)] between ETI and 3NBA and an amide
homosynthon of [R22(14)] ring motif between two ETI (b) An S-shape tetramer formed by two ETI and two 3NBA.
Figure 12. Stacking of tetramers (a) in the bc plane and (b) in staggered rows, in ETI−3NBA cocrystal.
Tetramers are stacked in staggered rows and are linked
to one another by weak hydrophobic interactions between the
phenyl and pyrrolidone groups directed outward (Figure 12).
Leviteracetam−3-Nitrobenzoic Acid (1:2) (LEVI−
3NBA). The LEVI−3NBA cocrystal was obtained by cooling
a saturated 1:2 solution (ratio suspected by XRPD) of coformers
in acetonitrile and solved in the orthorhombic space group P212121.
One molecule of LEVI and two molecules of 3NBA coexist in the
asymmetric unit.
The carboxylic acid functions of these two molecules of
3NBA are involved in different hydrogen bonding motifs with
one LEVI: as for the racemic version, a [R22(8)] heterosynthon
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Those two 4NBA molecules are involved in different kinds of
hydrogen bonds with the ETI: the carboxylic function of the
first forms a [R22(8)] heterosynthon with the noncylcic amide of
ETI while the second takes part in a zigzag [C22(16)] infinite
chain motif (Figure 14). In this motif, a first hydrogen bond is
formed between the noncyclic amide of ETI and the nitro
group of 4NBA, while a second hydrogen bond joins the ETI
cyclic amide carbonyl function to the acid of 4NBA.
Overall, these bonding patterns create thin layers, densely
stacked along the three directions.
Levetiracetam−4-Nitrobenzoic Acid (1:2) (LEVI−
4NBA). The LEVI−4NBA cocrystal was obtained by cooling
a saturated 1:1 solution of coformers in ethyl acetate and solved
in the triclinic space group P1. One molecule of LEVI and two
molecules of 4NBA coexist in the unit cell.
The carboxylic acid functions of these two molecules of NBA
are involved in different hydrogen bonding motifs with one
LEVI molecule. As for the racemic version, a [R22(8)] acid-
amide heterosynthon is observed for the carboxylic acid func-
tion of a first molecule, with the LEVI noncyclic amide. The se-
cond takes part in a zigzag [C22(11)] infinite chain motif different
from the one observed in the enantiopure version (Figure 15). In
this motif, the 4NBA accepts a H-bond from the LEVI noncyclic
amide and acts as a hydrogen bond donor to the LEVI cyclic
carbonyl; allowing the growth of the chain along the b-axis. The
nitro group is not involved in any hydrogen bond.
Figure 13. A [R22(8)] heterosynthon and a [R22(11)] ring motif are
formed by 3NBA and the two LEVI molecules in the asymmetric unit
cell of LEVI−3NBA cocrystal, resulting in a V-shaped trimer.
is observed for the carboxylic acid function of a first molecule,
while that of the second takes part in a [R22(11)] ring motif
(Figure 13) not observed in the enantiopure version. This motif
is formed by a proton of the LEVI noncyclic amide acting as a
H donor to the 3NBA carbonyl. The motif is completed by a
cyclic amide carbonyl group binding to the 3NBA acid proton.
These H bonding interactions result in the formation of a
V-shaped trimer.
Overall, those bonding patterns form thin layers, densely
stacked along the three directions, as in the ETI−4NBA
cocrystal.
Overall, trimers are held together by π stacking of 3NBA
molecules and hydrophobic interactions, leading to the final 3D
network.
Etiracetam−4-Nitrobenzoic Acid (1:2) (E4NBA). The
ETI−4NBA cocrystal was obtained by evaporation of a 1:1
solution of coformers in acetonitrile, and solved in the
monoclinic space group P21/c. One molecule of ETI and two
molecules of 4NBA coexist in the asymmetric unit.
DISCUSSION
■
In this contribution, we show that enantiopure and racemic
versions of a selected API, LEVI, have a tendency to form
cocrystals with identical nonchiral partners. This implies that
Figure 14. [R22(8)] acid-amide heterosynthon and the [C22(16)] infinite chain motif formed in the ETI−4NBA cocrystal.
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Crystal Growth & Design
Article
Figure 15. [R22(8)] acid−-amide heterosynthon and the [C22(11)] infinite chain motif present in the LEVI−4NBA cocrystal.
cocrystal screening of an enantiopure molecule can be performed
more effectively if the cocrystal screening of the racemic compound
has already been performed. In early stages of drug research, the
racemic compound is often more readily available, compared to
the enantiopure compound. At this stage, it thus seems more
interesting to perform an extended screen using the racemic
compound, followed by a reduced screen with the enantiopure
compound using the coformers that led to positive hits in the first
screen. Our results show that if 152 coformers are tested both on
the racemic as well as on the enantiopure compound, a comparable
success rate of about 10% (18/152 and 14/152 respectively) is
observed. On the other hand, if only the reduced set of 18
coformers which gave a positive hit during the racemic screen were
to be used for the enantiopure screen, a success rate of up to 72%
(13/18) is achieved. Although one out of the 14 enantiopure
cocrystals would not have been identified using this approach, 90%
less compound is required for the enantiopure cocrystal screen,
which can be a significant advantage, as well as a speed-up for
cocrystal studies in early stages of drug development.
This type of heterosynthon was already found in literature20 in
the LEVI−D-tartaric acid or S-methylsuccinic acid cocrystals.
Our structural results show a dense hydrogen bonding net-
work for all cocrystals. Surprisingly, each potential hydrogen
donor/acceptor group of LEVI or ETI (two carbonyls and two
hydrogens) is involved in hydrogen bonding patterns, contrary
to the pure ETI and leviteracetam structures. This increased
number of hydrogen bonds likely explains in part the pro-
pensity of this compound toward cocrystallization.
Preponderance of ETI cocrystals over LEVI stands a priori in
favor of the Wallach’s rule39 which states that crystals of
racemic molecules show higher densities than those of
enantiomeric forms, being thus more stable.40,41 This rule,
however, no longer holds when the number of hydrogen
bonds is important, as is the case here. Table 2 indeed shows
that for some coformers, the racemic form is denser while for
other coformers, the opposite is observed.
Another striking common element found in almost all
cocrystals studied in this contribution (with exception of 3NBA-
based cocrystals) is the formation of layered 3D networks, with
layers held together by hydrophobic interactions. This shows that,
although hydrogen bonding interactions are the main driving force
toward cocrystal formation, possible steric hindrance and
hydrophobic interactions (π−π and van der Waals) also need to
be taken into account when considering the overall structure.42−44
A structural investigation into five racemic-enantiopure
cocrystal pairs shows that, although not all structural elements are
identical, similarities with respect to hydrogen bonding synthons can
be found between the enantiopure and racemic cocrystals.
In particular the amide-acid heterosynthon is commonly
encountered. In a CSD search, Steiner37 states that in 10% of
cocrystal structures containing an amide and a carboxylic acid
functional group, the [R22(8)] acid-amide heterosynthon is
present. Similarly, Vishweshwar et al.38 established that this
percentage increases to approximately 50% when the implied
amide is a primary amide. In our structures, this element is also
frequently encountered. ETI cocrystals display a [R22(8)] acid-
amide heterosynthon with all coformers but DHBA. For
this latter, a [R22(8)] amide homosynthon is found instead. In
leviteracetam cocrystals structures, these motifs are only pres-
ent in LEVI−OXA, LEVI−3NBA, and LEVI−4NBA cocrystals.
In the LEVI−DMSA cocrystal, the [R22(8)] heterosynthon is
replaced by a [C22(8)] heterosynthon formed between one
molecule of LEVI and two molecules of DMSA (or conversely).
CONCLUSION
■
In this article, we show that enantiopure and racemic versions
of a selected API tend to form cocrystals with identical non-
chiral coformers. Indeed, using 152 nonchiral coformers, we
identified 14 novel cocrystals of LEVI, an enantiopure com-
pound and 18 of ETI, its racemic version. Out of these, 13
share a common coformer. A structural investigation into five
racemic-enantiopure cocrystal pairs demonstrated that,
although not all structural elements are identical, they often
show similar hydrogen bonding synthons.
Hence, in early stages of drug research, when a racemic
compound is often more readily available than its enantiopure
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Article
(12) Liao, X.; Gautam, M.; Grill, A.; Zhu, H. J. J. Pharm. Sci. 2010, 99,
246−254.
counterpart, we suggest to perform an extended screen using
the racemic compound, followed by a focused screen with the
enantiopure one, using the coformers that led to positive hits in
the first screen. In our case, this two-step approach would allow
a success rate of 72% instead of 10%, would require 90% less
compound, and would significantly speed up cocrystal studies.
(13) Rasenack, N.; Muller, B. W. Int. J. Pharm. 2002, 245, 9−24.
̈
(14) Aaltonen, J.; Allesø, M.; Mirza, S.; Koradia, V.; Gordon, K. C.;
Rantanen, J. Eur. J. Pharm. Biopharm. 2009, 71, 23−37.
(15) Aakeroy, C. B.; Grommet, A. B.; Desper, J. Pharmaceutics 2011,
̈
3, 601−614.
(16) Thakuria, R.; Delori, A.; Jones, W.; Lipert, M. P.; Roy, L.;
Rodríguez-Hornedo, N. Int. J. Pharm. 2013, 453, 101−125.
(17) Tilborg, A.; Michaux, C.; Norberg, B.; Wouters, J. Eur. J. Med.
Chem. 2010, 45, 3511−3517.
ASSOCIATED CONTENT
■
S
* Supporting Information
Structures of the racemic enantiopure cocrystal pairs described
in this contribution have been deposited at the Cambridge
Crystallographic Data Centre and allocated the deposition
numbers 984565 for ETI−DMSA, 984566 for LEVI−DMSA,
984567 for ETI−DHBA, 984568 for LEVI−DHBA, 984569 for
ETI−3NBA, 984570 for LEVI−3NBA, 984571 for ETI−4NBA,
984572 for LEVI−4NBA, 984573 for ETI−OXA, 984574 for
LEVI−OXA. Additional images of these cocrystals and the
refinement profiles of LEVI−DMSA and LEVI−DHBA
cocrystals. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) Pharmaceutical Salts and Co-crystals; Wouters, J.; Quer
́ ́
e, L., Eds.;
Royal Society of Chemistry: Cambridge, UK, 2011.
(19) Aitipamula, S.; Banerjee, R.; Bansal, A. K.; Biradha, K.; Cheney,
M. L.; Choudhury, A. R.; Desiraju, G. R.; Dikundwar, A. G.; Dubey, R.;
Duggirala, N.; Ghogale, P. P.; Ghosh, S.; Goswami, P. K.; Goud, N. R.;
Jetti, R. R. K. R.; Karpinski, P.; Kaushik, P.; Kumar, D.; Kumar, V.;
Moulton, B.; Mukherjee, A.; Mukherjee, G.; Myerson, A. S.; Puri, V.;
Ramanan, A.; Rajamannar, T.; Reddy, C. M.; Rodriguez-Hornedo, N.;
Rogers, R. D.; Row, T. N. G.; Sanphui, P.; Shan, N.; Shete, G.; Singh,
A.; Sun, C. C.; Swift, J. A.; Thaimattam, R.; Thakur, T. S.; Kumar
Thaper, R.; Thomas, S. P.; Tothadi, S.; Vangala, V. R.; Variankaval, N.;
Vishweshwar, P.; Weyna, D. R.; Zaworotko, M. J. Cryst. Growth Des.
2012, 12, 2147−2152.
(20) Springuel, G.; Norberg, B.; Robeyns, K.; Wouters, J.; Leyssens,
T. Cryst. Growth Des. 2012, 12, 475−484.
(21) Springuel, G.; Robeyns, K.; Norberg, B.; Wouters, J.; Leyssens,
T. Cryst. Growth Des. 2014, submitted.
(22) Sekhon, B. S. ARS Pharm. 2009, 50, 99−117.
(23) Hurtado, B.; Koepp, M. J.; Sander, J. W.; Thompson, P. J.
Epilepsy Behav. 2006, 8, 588−592.
(24) Herman, C.; Vermylen, V.; Norberg, B.; Wouters, J.; Leyssens,
T. Acta Crystallogr. B. Struct. Sci. Cryst. Eng. Mater. 2013, 69, 371−378.
(25) Herman, C.; Haut, B.; Aerts, L.; Leyssens, T. Int. J. Pharm. 2012,
437, 156−161.
AUTHOR INFORMATION
■
Corresponding Author
*Tel: +32 10 47 2811. Fax: +32 10 47 27 07. E-mail: tom.
leyssens@uclouvain.be. Web: http://www.uclouvain.be/
leyssens-group.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(26) Herman, C.; Haut, B.; Douieb, S.; Larcy, A.; Vermylen, V.;
Leyssens, T. Org. Process Res. Dev. 2012, 16, 49−56.
(27) Herman, C.; Leyssens, T.; Debaste, F.; Haut, B. J. Cryst. Growth
2012, 342, 57−64.
(28) Herman, C.; Haut, B.; Halloin, V.; Vermylen, V.; Leyssens, T.
Org. Process Res. Dev. 2011, 15, 774−782.
(29) Herman, C.; Leyssens, T.; Vermylen, V.; Halloin, V.; Haut, B. J.
Chem. Thermodyn. 2011, 43.
The authors would like to thank the UCL, UNamur and FNRS
(PDR T009913F, T016913) for financial support. We acknowl-
edge the Fonds Speciaux de Recherche (UCL) for the incoming
́
postdoctoral fellowship cofunded by the Marie Curie actions of the
European Commission granted to N.T. The research leading to
these results has received funding from the European Community’s
Seventh Framework Programme (FP7/2007-2013) under Grant
Agreement No. 312284 (CALIPSO).
(30) Springuel, G.; Leyssens, T. Cryst. Growth Des. 2012, 12, 3374−
3378.
̌
(31) Favre-Nicolin, V.; Cerny, R. J. Appl. Crystallogr. 2002, 35, 734−
́
REFERENCES
■
743.
(32) Rodríguez-Carvajal, J. Phys. B Condens. Matter 1993, 192, 55−
(1) Billot, P.; Hosek, P.; Perrin, M.-A. Org. Process Res. Dev. 2013, 17,
505−511.
69.
(2) Bauer, J.; Spanton, S.; Henry, R. F.; Quick, J.; Dziki, W.; Porter,
W.; Morris, J. Pharm. Res. 2001, 18, 859−866.
̈
(33) Ozcan, Y.; Osmanoglu, S.; Ide, S. Anal. Sci. 2003, 19, 1221−
1222.
(3) Fabbiani, F. P. A.; Allan, D. R.; Parsons, S.; Pulham, C. R.
CrystEngComm 2005, 7, 179.
(34) Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112−122.
̌ ̌ ́
(35) Delori, A.; Friscic, T.; Jones, W. CrystEngComm 2012, 14, 2350.
(4) Kumar, V.; Malhotra, S. V. ACS Symp. Ser. 2010, 1038, 1−12.
(5) Neau, S. H. In Water-Insoluble Drug Formulation; Rong, L., Ed.;
CRC Press: Boca Raton, 2000; pp 405−425.
(36) Etter, M. C.; MacDonald, J. C.; Bernstein, J. Acta Crystallogr.,
Sect. B 1990, 46, 256−262.
(37) Steiner, T. Angew. Chemie Int. Ed. 2002, 41, 48−76.
(38) Vishweshwar, P.; McMahon, J. a; Bis, J. a; Zaworotko, M. J. J.
Pharm. Sci. 2006, 95, 499−516.
(6) Karki, S.; Friscic,
2007, 4, 347−354.
́
T.; Jones, W.; Motherwell, W. D. S. Mol. Pharm.
(7) Khankari, R. K.; Grant, D. J. W. Thermochim. Acta 1995, 248,
61−79.
(39) Wallach, O. Justus Liebig’s Ann. Chem. 1895, 286, 90−118.
́ ́ ́
(40) Friscic, T.; Fabian, L.; Burley, J. C.; Reid, D. G.; Duer, M. J.;
(8) Sanphui, P.; Kumar, S. S.; Nangia, A. Cryst. Growth Des. 2012, 12,
4588−4599.
Jones, W. Chem. Commun. (Cambridge) 2008, 1644−1646.
(41) Brock, C. P.; Schweizer, W. B.; Dunitz, J. D. J. Am. Chem. Soc.
1991, 113, 9811−9820.
(9) Viertelhaus, M.; Hilfiker, R.; Blatter, F.; Neuburger, M. Cryst.
Growth Des. 2009, 9, 2220−2228.
(42) Baures, P. W.; Rush, J. R.; Wiznycia, A. V.; Desper, J.; Helfrich,
B. A.; Beatty, A. M. Cryst. Growth Des. 2002, 2, 653−664.
(43) Takata, N.; Shiraki, K.; Takano, R.; Hayashi, Y.; Terada, K.
Cryst. Growth Des. 2008, 8, 3032−3037.
(10) Espinosa-Lara, J. C.; Guzman-Villanueva, D.; Arenas-García, J.
I.; Herrera-Ruiz, D.; Rivera-Islas, J.; Roman
́
-Bravo, P.; Morales-Rojas,
H.; Hopfl, H. Cryst. Growth Des. 2013, 13, 169−185.
̈
(11) Cheney, M. L.; Shan, N.; Healey, E. R.; Hanna, M.; Wojtas, L.;
Zaworotko, M. J.; Sava, V.; Song, S.; Sanchez-Ramos, J. R. Cryst.
Growth Des. 2010, 10, 394−405.
(44) Vishweshwar, P.; Nangia, A.; Lynch, V. M. Cryst. Growth Des.
2003, 3, 783−790.
2892
dx.doi.org/10.1021/cg500181t | Cryst. Growth Des. 2014, 14, 2880−2892