Innovative chiral resolution using enantiospecific co-crystallization in solution

Article abstract of DOI:10.1021/cg300307z

A large number of active pharmaceutical ingredients (API) are chiral. Most of them are synthesized as racemic mixtures, and a chiral resolution step is introduced somewhere along the production process. In this study, we have used the specific hydrogen bonding interactions present in co-crystals to develop a new resolution technique. As these interactions are strongly direction dependent, we highlighted that an enantiopure API only forms a co-crystal with one of two enantiomers of a chiral co-crystal former (or co-former). Unlike salts, a diastereomeric pair cannot be obtained. This enantiospecific behavior of co-crystal candidates suggests that a racemic mixture of this candidate can be resolved through a co-crystallization in solution, which hitherto has not been observed yet. As a study system, we chose (RS)-2-(2-oxopyrrolidin-1-yl) butanamide, as the S-enantiomer is an API and no viable salts of this compound have been identified. The only known resolution technique for this compound is, therefore, based on chiral chromatography. Because of enantiospecific interactions with an S-mandelic acid coformer, we were able to selectively co-crystallize the S-enantiomer in acetonitrile. This enantiospecific co-crystallization in solution has been thermodynamically verified, by construction of ternary phase diagrams at different temperatures. Initial results not only validate our innovative resolution technique through co-crystallization but also furthermore already showed high efficiency, as 70% of the S-enantiomer could be separated from the racemic mixture in a single co-crystallization step.

Full text of DOI:10.1021/cg300307z

Communication
pubs.acs.org/crystal
Innovative Chiral Resolution Using Enantiospecific Co-Crystallization
in Solution
Geraldine Springuel and Tom Leyssens*
́
́
Institute of Condensed Matter and Nanosciences, Universite Catholique de Louvain, Louvain-La-Neuve, Belgium
S
* Supporting Information
ABSTRACT: A large number of active pharmaceutical ingre-
dients (API) are chiral. Most of them are synthesized as racemic
mixtures, and a chiral resolution step is introduced somewhere
along the production process. In this study, we have used the
specific hydrogen bonding interactions present in co-crystals to
develop a new resolution technique. As these interactions are
strongly direction dependent, we highlighted that an enantiopure
API only forms a co-crystal with one of two enantiomers of a
chiral co-crystal former (or co-former). Unlike salts, a
diastereomeric pair cannot be obtained. This enantiospecific
behavior of co-crystal candidates suggests that a racemic mixture
of this candidate can be resolved through a co-crystallization in solution, which hitherto has not been observed yet. As a study
system, we chose (RS)-2-(2-oxopyrrolidin-1-yl)butanamide, as the S-enantiomer is an API and no viable salts of this compound
have been identified. The only known resolution technique for this compound is, therefore, based on chiral chromatography.
Because of enantiospecific interactions with an S-mandelic acid coformer, we were able to selectively co-crystallize the S-
enantiomer in acetonitrile. This enantiospecific co-crystallization in solution has been thermodynamically verified, by
construction of ternary phase diagrams at different temperatures. Initial results not only validate our innovative resolution
technique through co-crystallization but also furthermore already showed high efficiency, as 70% of the S-enantiomer could be
separated from the racemic mixture in a single co-crystallization step.
dentification of enantiospecific co-crystal formation between
two chiral compounds led to the development of an
through chiral chromatography, is used for an important
number of compounds and seems to be the only viable
technique for those compounds that do not or not easily form
salts.12
I
innovative chiral resolution technique, using an enantiospecific
co-crystallization in solution. Unlike classical chiral resolution,
the chiral resolving agent only co-crystallizes with one of the
two enantiomers, leading to a novel technique that allows
obtaining high yields in a single crystallization step and that
furthermore can be extended to the series of compounds that
do not or not easily form salts.
Here we introduce an innovative type of chiral resolution
through enantiospecific co-crystallization in solution. This
technique has the advantage of being economically and
environmentally more interesting compared to chromatography
and can furthermore be applied to compounds that do not or
not easily form salts. To show the potential of this technique,
we decided to use a model pharmaceutical compound which
does not easily form salts and which up to now required chiral
chromatography for effective resolution. The optimization of
the final process is not discussed here and will be described
elsewhere.
In this study, 2-(2-oxopyrrolidin-1-yl)butanamide (1) was
chosen as model pharmaceutical compound. This compound
shows two polymorphic forms with form I being the most
stable one.13−17 The S enantiomer of this compound, S-1,
shows nootropic activity and is marketed under the name
levetiracetam, as an anticonvulsant used to treat epilepsy.18,19
The R-enantiomer, R-1, does not show any biological effect.20
Chiral resolution is common practice in the biomedical and
pharmaceutical industry given the large number of chiral drug
candidates.1,2 In most cases, only one enantiomer shows
biological activity,3 while the other has either no physiological
effects or in the worst case scenarios shows undesirable or even
toxic effects.4 Separation of both enantiomers is, therefore, a
crucial step in the production process, either to ensure a higher
activity for a reduced dosage or to avoid unwanted side effects.
Currently, two common industrially applied techniques for
the separation of two enantiomers are diastereomeric salt
formation3−8 and chiral chromatography.9−11 The first is a
relatively less costly process but can only be successfully applied
when the compound of interest can easily be converted into a
salt. In this case, addition of an enantiopure resolving agent
leads to the formation of two distinct diastereomeric salts,
which show dissimilar physical properties, allowing a chiral
resolution through crystallization. Albeit being relatively
expensive, the second technique, enantiomeric resolution
Received: March 2, 2012
Revised: June 11, 2012
Published: June 13, 2012
© 2012 American Chemical Society
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Although efforts have been made toward an enantiopure
synthesis,21 the enantiopure compound is still commonly
obtained from a racemic mixture, resolved using chiral
chromatography. Classical chiral resolution through crystal-
lization cannot be used as an alternative, as the compound does
not easily form salts.
In a recent paper, however, we found levetiracetam to show a
high efficiency toward co-crystal formation.22 Pharmaceutical
co-crystals are alternative crystalline solid forms comprising at
least two components  an API and a co-former (or co-crystal
former)  that are solid under ambient conditions. As no
proton transfer occurs between both components, co-crystals
are clearly different from salts and most often rely on a highly
directional intermolecular hydrogen bonding pattern for their
formation.23,24 Over the past decade, the main crystal
engineering efforts focused on the development of alternative
pharmaceutical solid forms allowing to improve physicochem-
ical properties of a drug, without altering its initial biological
functionality.25−29
The enantioselectivity behavior of the co-crystallization was
already reported for the formation of co-crystal30 and salt co-
crystal products.31 These contributions led to the suggestion
that co-crystallization could be used to obtain alternate chiral
resolution of racemic compounds but which until now has not
been observed yet. Up to now, only a chiral enrichment in
solution due to the formation of a co-crystal solid solution was
observed.32 Here we introduce a concrete example of chiral
resolution from a racemic mixture via an enantiospecific co-
crystallization in solution.
In our work, we showed that S-1 effectively co-crystallizes
with either S-mandelic acid, S-2, or S-tartaric acid, leading in
both cases to a 1:1 co-crystal.22 Astonishingly, S-1 does not
form a co-crystal with R-mandelic acid, R-2, nor with R-tartaric
acid, implying that unlike salts, a diasteriomeric pair of co-
crystals cannot be obtained (Scheme 1). This difference in
single eutectic point shown in the S-1−R-2 system confirms the
nonexistence of a co-crystal under standard conditions (Figure
1b). Similar diagrams are obtained for the S-1 and R/S-tartaric
acid systems and are available in the Supporting Information.
These diagrams are obtained from differential scanning
calorimetry (DSC) measurements on a series of mixtures of
S-1 and coformer under different proportions.
If S-1 selectively co-crystallizes with S-2, obviously the R
enantiomer, R-1, will selectively co-crystallize with R-2. On the
basis of this assumption, addition of S-2 to a racemic solution of
RS-1 could, under specific conditions, lead to an effective co-
crystallization of the LSMA co-crystal, hence allowing for the
recovery of the biologically active enantiomer through
enantiospecific co-crystallization. In this work, acetonitrile was
chosen as crystallization solvent, as this latter is a good solvent
for both components. Three components S-1, R-1, and S-2 are
initially dissolved in the solvent. In total, the system therefore
involves five variables: the three components, the solvent, and
the temperature. As our present goal is to develop a novel chiral
resolution through enantiospecific co-crystallization and not to
optimize such a process, we have decided, for simplicity
reasons, to fix the temperature and the molar percentage of
solvent. The system reduces to a three-variable system, which
can be represented in a ternary phase diagram such as the
hypothetical diagram presented in Figure 2. In an isothermal
plane, each top of the triangle corresponds to a suspension of
the pure compound in the appointed molar percentage of
solvent. The middle of the lower base represents a suspension
of the racemic compound in the solvent. The ternary phase
diagram graphically shows which solid phase is thermodynami-
cally stable in suspension for a given total composition.
Depending on the total composition, a solid−liquid suspension
will lead either to a pure solid phase or a mixture of solid phases
as presented in Figure 2. A change in temperature induces a
shift of the thermal stability zones, as indicated by the red
curves in Figure 2.
Scheme 1. (Top) S-1 Co-Crystallizes with S-2, Leading to a
1:1 Co-Crystal (LSMA Co-Crystal). (Bottom) R-1 Does Not
Form a Co-Crystal with S-2
Experimental ternary phase diagrams have been obtained
through screening of different total compositions in acetonitrile
at a given temperature. A set of supersaturated solutions were
created by dissolving all solids at higher temperatures. All
solutions were then placed at the defined temperature and
seeded with a mixture of all possible solid states, that is, RS-1
form I, S-1, S-2, and the LSMA co-crystal. After two weeks, the
system was assumed to have reached equilibrium. For each
initial composition, the liquid phase was then analyzed using
both achiral and chiral high-performance liquid chromatog-
raphy (HPLC) to determine not only the solution concen-
tration but also the enantiomeric excess (ee). The isolated solid
phase was investigated using X-ray powder diffraction (XRPD),
which allows distinguishing between the different possible solid
forms.
The final aspect of ternary phase diagrams will depend on the
nature and amount of solvent, as well as the temperature.34
Under the conditions considered here, certain zones of the
hypothetical ternary diagram presented in Figure 2 do not
appear experimentally at 9 °C and −10 °C. The zones
appearing will depend on the amount of solvent, as well as the
temperature. The zone in which S-1 is the only stable form in
suspension (zone III)35 is not observed. Consequently, the
zones in which the co-crystal and the (RS)-1 phase are stable
become adjacent, thereby enclosing a zone in which their
mixture is stable in suspension, zone (II + IV), as shown in
Figure 3.
behavior is probably due to the presence of highly directional
hydrogen bonding patterns observed in co-crystals in contrast
to the less directional nature of ionic bonds in salts. This
fascinating behavior, already referred to by Thorey et al. in
2010,30 suggests again that a co-crystallization in solution can
be enantiospecific and could be used as a novel resolution tool.
To confirm the nonexistence of a diasteriomeric co-crystal pair,
melting phase diagrams, shown in Figure 1, were constructed
for the S-1−S-2 and S-1−R-2 pairs. As shown in Figure 1a, the
S-1−S-2 system shows two asymmetric eutectic temperatures, a
characteristic of a binary co-crystal melting diagram,33 while the
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Figure 1. (a) Binary melting phase diagrams of S-1 and S-2 exhibit two asymmetric eutectic points indicating co-crystal formation. (b) Binary
melting phase diagrams of S-1 and R-2 exhibit a single eutectic melting point indicating the absence of co-crystal formation. Liquidius (black square)
and eutectic melting temperatures (gray diamond) are shown. Black lines and dashed gray lines are fitted through experimental data.
For the separation of S-1 from a racemic mixture using
enantiospecific co-crystallization, two conditions need to be
satisfied. First, the chosen conditions of crystallization (nature
and amount of solvent, and temperature) need to allow co-
crystal formation. Furthermore, the zone (II) (or alternatively
(I + II))35 needs to cross the racemic composition line (red-
dotted line in Figure 3), as is the case here.
To establish the efficiency of our novel resolution technique,
four initial racemic mixtures were selected along the racemic
composition line. These points (denoted A, B, C, and D in
Figure 3) were considered at 9 °C, 3 °C, and −10 °C. The
initial composition, as well as the final composition of all
phases, is shown in Table 1. At 9 °C, only one condition (point
C) led to an effective enantiospecific co-crystallization, with the
LSMA co-crystal being the only stable form in suspension
(zone II). The remaining solution becomes enriched in R-1 (ee
Figure 2. Hypothetical ternary phase diagram of an enantiospecific co-
= 7.92%), and 14.67% of the initial amount of S-1 can be
crystal system. The red curve shows the effect of a decrease in
recovered in the solid phase. No crystallization is observed for
temperature.
Table 1. Results of Enantiospecific Co-Crystallization in
Acetonitrile from an Initial Racemic Mixture of RS-1
initial
concentration
final solid state in
suspension (XRPD
analysis)
% S-1 recovered
in solid phase
(yield)
RS-1
S-2
% ee in
solution
mol % mol %
At 9 °C
A.
B.
C.
D.
39.6
41.5
42.7
45.7
60.4
58.5
57.3
54.3
0
0
0
0
LSMA
7.92
0
14.67
0
At 3 °C
LSMA
A.
B.
C.
D.
39.7
41.3
42.5
45.7
60.3
58.7
57.5
54.2
24.66
22.90
24.22
27.80
39.56
37.26
38.99
43.50
LSMA
LSMA
LSMA
Figure 3. Schematic ternary phase diagram of R-1/S-1/S-2 system in
acetonitrile, based on experimental results at −10 °C. The
experimental results used to create this phase diagram are given in
the Supporting Information.
At −10 °C
LSMA
A.
B.
C.
D.
39.9
41.5
42.3
45.7
60.1
58.5
57.7
54.3
50.30
49.38
53.38
52.66
66.93
66.11
69.60
68.99
LSMA
LSMA
LSMA
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(2) Stinson, S; Chiral, C. Pharmaceuticals. Chem. Eng. News. 2001, 79
(40), 56−61.
the three remaining conditions (A, B, and D). For experiments
at 3 °C and −10 °C, all conditions led to the enantiospecific co-
crystallization of the LSMA co-crystal (zone II). As indicated
schematically in Figure 2, lowering of the crystallization
temperature is expected to lead to a more efficient resolution.
This is confirmed by the results shown Table 1, with the ee in
the remaining solution increasing up to 27.80% and 53.4% at
respectively 3 °C and −10 °C. Choosing these latter conditions,
69.60% of the initial amount of S-1 can be selectively recovered
in the solid phase.
These results not only demonstrate the feasibility of our
novel resolution technique but also show its potential strength,
as up to 70% yield was obtained in a single resolution step for a
compound, which cannot be separated using classical chiral
crystallization resolution techniques. Optimization of the
process conditions should allow increasing the yield even
further.
In this study a novel resolution technique was developed
using enantiospecific co-crystallization in solution. Unlike
classical chiral resolution using a pair of diasteriomeric salts,
the resolution technique developed here is enantiospecific, the
difference most likely being due to the highly directional nature
of the hydrogen bonding pattern in co-crystals. The added
chiral resolving agent specifically co-crystallizes with only one
of the two enantiomers of interest and is unable to form a co-
crystal with the other. This novel resolution technique is
particularly useful, as it leads to high effective yields in a single
resolution step and can furthermore be used for the series of
compounds that do not or not easily form salts, and which up
to now, required chiral chromatography for effective resolution.
(3) Lorenz, H.; Capla, F.; Polenske, D.; Elsner, M. P.; Seidel-
Morgenstern, A. Crystallization based separation of enantiomers
(review). J. Univ. Chem. Tech. Met. 2007, 42 (1), 5−16.
(4) Lyseng-Williamson, K. A. Levetiracetam: a review of its use in
epilepsy. Drugs 2011, 71 (4), 489−514.
́ ́ ́
(5) Fogassy, E.; Nogradi, M.; Kozma, D.; Egri, G.; Palovics, E.; Kiss,
V. Optical resolution methods. Org. Biomol. Chem. 2006, 4, 3011−
3030.
(6) Kumar, V.; Malhotra, S. V. Ionic liquids as pharmaceutical salts: a
historical perspective. ACS Symp. Ser. 2010, 1038, 1−12.
(7) Neau, S. H. Pharmaceutical salts. Water-Insoluble Drug
Formulation 2000, 405−425.
(8) Srinivas, N. R. Evaluation of experimental strategies for the
development of chiral chromatographic methods based on diaster-
eomer formation. Biomed. Chromatogr. 2004, 18 (4), 207−233.
(9) Chankvetadze, B. Recent trends in enantioseparation of chiral
drugs. In Molecular Biology in Medicinal Chemistry, Book Series: Methods
and Principles in Medicinal Chemistry; Dingermann, T., Steinhilber, D.,
Folkers, G., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: New York,
2004; Chapter 21, pp 181−210.
(10) Wu, J.; Liu, P.; Wang, Q.; Chen, H.; Gao, P.; Wang, L.; Zhang,
S. Investigation of enantiomeric separation of chiral drugs by CE using
Cu(II)−clindamycin complex as a novel chiral selector. Chromatogra-
phia 2011, 74, 789−797.
(11) Ward, T. J. Chiral separations. Anal. Chem. 2002, 74, 2863−
2872.
(12) Blaschke, G.; Chankvetadze, B. Resolution of Enantiomers of
Chiral Drugs. In New Trends in Synthetic Medicinal Chemistry, Book
Series: Methods and Principles in Medicinal Chemistry; Gualtieri, F., Eds.;
Wiley-VCH Verlag GmbH: New York, 2008; Chapter 6, pp139−173.
(13) Herman, C.; Leyssens, T.; Vermylen, V.; Halloin, V.; Haut, B.
Towards an accurate and precise determination of the solid-solid
transition temperature of enantropic systems. J. Chem. Thermodyn.
2011, 43 (5), 677−682.
ASSOCIATED CONTENT
■
S
* Supporting Information
(14) Herman, C.; Haut, B.; Halloin, V.; Vermylen, V.; Leyssens, T.
Towards the determination of the thermodynamic and the metastable
solubilities of the two morphs of enantiotropically related polymorphic
systems: application to Etiracetam in methanol. Org. Process Res. Dev.
2011, 15 (4), 774−782.
Materials and Methods; binary melting phase diagrams of
levetiracetam and R/S-tartaric acid; ternary phase diagrams at 9
°C and at −10 °C. This material is available free of charge via
the Internet at http://pubs.acs.org.
(15) Herman, C.; Leyssens, T.; Debaste, F.; Haut, B. Detection of the
II-I etiracetam solvent-mediated polymorphic transformation through
the online monitoring of the suspension apparent viscosity. J. Cryst.
Growth 2012, 342, 57−64.
(16) Herman, C.; Leyssens, T.; Vermylen, V.; Halloin, V.; Haut, B. A
new approach for the estimation of the melting enthalpy of metastable
crystalline compounds using differential scanning calorimetry. J.
Therm. Anal. Calorim. 2012, 107, 777−788.
(17) Herman, C.; Haut, B.; Douieb, S.; Larcy, A.; Vermylen, V.;
Leyssens, T. Use of in situ Raman, FBRM and ATR-FTIR probes for
the understanding of the solvent-mediated polymorphic trans-
formation of II-I etiracetam in methanol. Org. Process Res. Dev 2012,
16 (1), 49−56.
(18) Sekhon, B. S. Pharmaceutical co-crystals − A review. Ars Pharm.
2009, 50 (3), 99−117.
(19) Hurtado, B.; Koepp, M. J.; Sander, J. W.; Thompson, P. J. The
impact of levetiracetam on challenging behavior. Epilepsy Behav. 2006,
8, 588.
(20) Isoherranen, N.; Yagen, B.; Soback, S.; Roeder, M.; Schurig, V.;
Bialer, M. Pharmacokinetics of levetiracetam and its enantiomer (R)-α-
ethyl-2-oxo-pyrrolidine acetamide in dogs. Epilepsia 2001, 42 (7),
825−830.
(21) Kotkar, S. P.; Sudalai, A. A short enantioselective synthesis of
the antiepileptic agent, levetiracetam based on proline-catalyzed
asymmetric α-aminooxylation. Tetradron Lett. 2006, 47, 6813−6815.
(22) Springuel, G.; Norberg, B.; Robeyns, K.; Wouters, J.; Leyssens,
T. Advances in pharmaceutical co-crystal screening: effective co-crystal
AUTHOR INFORMATION
■
Corresponding Author
*Address: Institute of Condensed Matter and Nanosciences
́
Molecules, Solids and Reactivity, Universite Catholique de
Louvain, Place Louis Pasteur 1, bte L4.01.03 B-1348 Louvain-
La-Neuve, Belgium. 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
■
The authors would like to thank the UCL for financial support.
REFERENCES
■
(1) McConnell, O.; Bach II, A.; Balibar, C.; Byrne, N.; Cai, Y.; Carter,
G.; Chlenov, M.; Di, L.; Fan, K.; Goljer, I.; He, Y.; Herold, D.; Kagan,
M.; Kerns, E.; Koehn, F.; Kraml, C.; Marathias, V.; Marquez, B.;
McDonald, L.; Nogle, L.; Petucci, C.; Schlingmann, G.; Tawa, G.;
Tischler, M.; Williamson, R. T.; Sutherland, A.; Watts, W.; Young, M.;
Zhang, M.-Y.; Zhang, Y.; Zhou, D.; Ho, D. Enantiomeric separation
and determination of absolute stereochemistry of asymmetric
molecules in drug discoveryBuilding chiral technology toolboxes.
Chirality 2007, 19 (9), 658−682.
3377
dx.doi.org/10.1021/cg300307z | Cryst. Growth Des. 2012, 12, 3374−3378

Crystal Growth & Design
Communication
screening through structural resemblance. Cryst. Growth Des. 2012, 12
(1), 475−484.
(23) Vishweshwar, P.; McMahon, J. A.; Bis, J. A.; Zaworotko, M. J.
Pharmaceutical co-crystals. J. Pharm. Sci. 2006, 95 (3), 499−516.
(24) Viertelhaus, S.; Hilfiker, R.; Blatter, F. Piracetam co-crystals with
OH-group functionalized carboxylic acids. Cryst. Growth Des. 2009, 9
(5), 2220−2228.
(25) Sekhon, B. S. Enantioseparation of chiral drugs − an overview.
Int. J. ChemTech Res. 2010, 2 (2), 1584−1594.
(26) Schultheiss, N.; Newman, A. Pharmaceutical cocrystals and their
physicochemical properties. Cryst. Growth Des. 2009, 9 (6), 2950−
2967.
(27) Shan, N.; Zaworotko, M. J. The role of co-crystals in
pharmaceutical sciences. Drug Discovery Today 2008, 13, 440−446.
(28) Jones, W.; Motherwell, W. D. S.; Trask, A. V. Pharmaceutical
co-crystals: an emerging approach to physical property enhancement.
MRS Bull. 2006, 31, 875−879.
(29) Cheney, M. L.; Shan, N.; Healey, E. R.; Hanna, M.; Wojtas, L.;
Zaworotko, M. J.; Sava, V.; Song, S.; Sanchez-Ramos, J. R. Effects of
crystal form on solubility and pharmacokinetics: a crystal engineering
case study of lamotrigine. Cryst. Growth Des. 2010, 10 (1), 394−405.
(30) Thorey, P.; Bombicz, P.; Szilag
́
yi, I. M.; Molnar
́
, P.; Ban
́ ́
saghi,
G.; Szekely, E.; Simandi, B.; Parkanyi, L.; Pokol, G.; Madaras
́
́
́
́
́
z, J. Co-
crystal of (R,R)-1,2-cylohexanediol with (R,R)-tartaric acid, a key
structure in resolution of the ( )-trans-diol by supercritical extraction,
and the related ternary phase system. Thermochim. Acta 2010, 497,
129−136.
(31) Brittain, H. G. Vibrational spectroscopic studies of cocrystals
and salts. 4. Cocrystal products formed by benzylamine, α-
methylbenzylamine, and their chloride salts. Cryst. Growth Des. 2011,
11, 2500−2509.
(32) Chen, S.; Xi, H.; Henry, R. F.; Marsden, I.; Zhang, G.G.Z..
Chiral cocrystal solid solution: structures, melting point phase
diagram, and chiral enrichment of (ibuprofen)2(4,4-dipyridyl).
CrystEngComm 2010, 12, 1485−1493.
(33) Srisanga, S.; ter Horst, J. H. Racemic compound, conglomerate,
or solid solution: phase diagram screening of chiral compounds. Cryst.
Growth Des. 2010, 10 (4), 1808−1812.
(34) Leyssens, T.; Springuel, G.; Montis, R.; Candoni, N.; Veesler, S.
Importance of solvent selection for stoichiometrically diverse cocrystal
systems: caffeine/maleic acid 1:1 and 2:1 cocrystals. Cryst. Growth Des.
2012, 12, 1520−1530.
(35) For a convenient reading, we will call zone X, the zone in which
the solid state X is the stable phase in suspension.
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