Resolution of sertraline with (R)-mandelic acid: Chiral discrimination mechanism study

Article abstract of DOI:10.1002/chir.21033

The chiral discrimination mechanism in the resolution of sertraline with mandelic acid was investigated by examining the weak intermolecular interactions (such as hydrogen bond, CH/π, and van der Waals interactions) and molecular packing difference in crystal structures of the resulting diastereomeric salts. A new one-dimensional chain-like hydrogen-bonding network and unique supramolecular packing mode are disclosed. The investigation demonstrated that stable hydrogen-bonding pattern, herringbone-like arrangement of aromatic rings, and planar boundary surface in the hydrophobic region are the three most important structural characteristics expected in less soluble diastereomeric salts. The existence and magnitude of hydrogen bond, CH/π interaction, and van der Waals interaction related to three characteristic structures, determine the stability of diastereomeric salt. The hydrogen bond is not necessarily the dominant factor while the synergy and optimization of all weak intermolecular interactions attribute to the chiral recognition.

Full text of DOI:10.1002/chir.21033

CHIRALITY 24:119–128 (2012)
Resolution of Sertraline with (R)-Mandelic Acid: Chiral
Discrimination Mechanism Study
*
QUAN HE, SOHRAB ROHANI, JESSE ZHU, AND HASSAN GOMAA
Department of Chemical and Biochemical Engineering, The University of Western Ontario, London, Ontario, Canada
ABSTRACT
The chiral discrimination mechanism in the resolution of sertraline with man-
delic acid was investigated by examining the weak intermolecular interactions (such as hydrogen
bond, CH/p, and van der Waals interactions) and molecular packing difference in crystal struc-
tures of the resulting diastereomeric salts. A new one-dimensional chain-like hydrogen-bonding
network and unique supramolecular packing mode are disclosed. The investigation demonstrated
that stable hydrogen-bonding pattern, herringbone-like arrangement of aromatic rings, and planar
boundary surface in the hydrophobic region are the three most important structural characteris-
tics expected in less soluble diastereomeric salts. The existence and magnitude of hydrogen
bond, CH/p interaction, and van der Waals interaction related to three characteristic structures,
determine the stability of diastereomeric salt. The hydrogen bond is not necessarily the dominant
factor while the synergy and optimization of all weak intermolecular interactions attribute to the
C
VV
chiral recognition. Chirality 24:119–128, 2012.
2011 Wiley Periodicals, Inc.
KEY WORDS: sertraline; mandelic acid; crystallization resolution; diastereomeric salt; chiral
discrimination; chiral recognition; hydrogen bond; CH/p interaction; crystal
packing
INTRODUCTION
salts. The optimal resolving agent was screened and
designed based on computationally predicting the crystal
structure of diastereomeric salt pairs and calculating the lat-
tice energy difference between a pair of diastereomeric salts.
However, the prediction of crystal structure of salts is very
challenging in that the smallest asymmetric unit in a salt
crystal contains two crystallographically independent ions
resulting in significant increase in the number of possible
packing arrangements. Furthermore, it is not easy to accu-
rately calculate the lattice energies as the predicted energy
difference is particularly sensitive to the balance between the
intramolecular and intermolecular forces since the ions are
very flexible in three-dimensional orientation. Therefore, the
method is applicable in very limited systems.
A promising method to study chiral discrimination mecha-
nism and further provide the criteria for resolving agent
selection is to experimentally obtain crystal structure of dia-
stereomeric salts followed by qualitative analysis of the differ-
ence in weak intermolecular interactions of their crystal struc-
tures. The method is widely employed by many researchers
and a number of successful resolutions were developed using
resolving agent selected on the basis of the method.10–15
In this method, the efficiency of resolution depends on the
solubility difference between the pair of diastereomeric salts
formed between racemate and the resolving agent. This solu-
bility difference is related to the stability difference of salts
and stability of salts originates from their crystal structures.
There is a growing demand for enantiopure drugs in the
pharmaceutical industry as a pair of enantiomers of racemate
can present different biological effect.1 Crystallization resolu-
tion via diastereomeric salt formation continues to be one of
the most efficient and practical techniques to produce enan-
tiopure drugs on an industrial scale. Statistical data demon-
strates that more than half of the chiral drugs in the current
pharmaceutical market are produced by this method.2
The method of diastereomeric resolution involves an enan-
tiopure resolving agent that reacts with the racemate to form
a pair of diastereomeric salts. The solubility difference
between the pair of resulting salts allows an efficient enantio-
separation by crystallization of the less soluble salt. After re-
moval/recovery of the resolving agent, the desired enan-
tiomer can be isolated. Development of an efficient diastereo-
meric resolution relies heavily on the selection of a suitable
resolving agent. However, the general understanding of chi-
ral recognition ability of a resolving agent is very limited.
The selection of resolving agent for a given racemate is still
based on an experimental trial and error procedure.
For the past several decades, numerous efforts have been
made to understand the chiral discrimination mechanism
and thus to develop a quick and rational way to screen opti-
mal resolving agent for a target racemate. Some research-
ers3–5 proposed a methodology to choose resolving agents
based on thermal analysis of the diastereomeric salts. If the
pair of diastereomeric salts formed with a certain resolving
agent exhibited large difference in melting point and heat of
fusion, the resolving agent would be a good candidate. How-
ever, the method needs a number of experiments to collect
basic physicochemical data, before applying them to the tar-
get resolution. In addition, the method requires pure enan-
tiomers which limit its application. Leusen6,7 and Price8,9
quantitatively correlated the resolution efficiency to the lat-
tice energy difference between resulting diastereomeric
Additional Supporting Information may be found in the online version of this
article.
Contract grant sponsor: NSERC.
*Correspondence to: Sohrab Rohani; Department of Chemical and Biochemi-
cal Engineering, The University of Western Ontario, London, Ontario, N6G
4R3, Canada. E-mail: srohani@uwo.ca
Received for publication 27 September 2010; Accepted 10 August 2011
DOI: 10.1002/chir.21033
Published online 16 December 2011 in Wiley Online Library
(wileyonlinelibrary.com).
C
VV
2011 Wiley Periodicals, Inc.

120
HE ET AL.
Fig. 1. Resolution of sertraline with (R)-mandelic acid.
The arrangement and packing of molecules in a crystal lat-
tice, depends on numerous weak intermolecular forces such
as hydrogen bonds, CH/p interactions, and van der Waals
interactions. Therefore, the stability difference between the
less and more soluble diastereomeric salts depends on the
existence and/or magnitude of these intermolecular interac-
tions in the crystals. By examining these weak intermolecu-
lar interactions as well as supramolecular assembly mode in
diastereomeric salts, dominant interactions and characteristic
packing features that favor the stability of distereomeric salts
will be identified.
The hydrogen-bonding network has been considered to be
the most important factor contributing to the chiral discrimi-
nation since the hydrogen bond is stronger than other inter-
molecular interactions to determine the stability of crystal
structure. The hydrogen-bonding patterns in less and more
soluble diastereomeric salts are usually different. Hydrogen-
bonding networks of less soluble salts in the high efficiency
resolutions have certain characteristics in common. Some
characteristic hydrogen-bonding patterns such as 21 col-
umn,10,16,17 closed globular cluster,18,19 and two-dimensional
(2D) sheet20,21 have been identified to be able to stabilize
the less soluble salt leading to the success of resolution. The
existence of hydroxy group in resolving agent is believed to
cause formation of additional hydrogen bonds to link the 21
hydrogen-bonding columns, thus leading to a reinforced
hydrogen-bonding network.10,11
network, stacking pattern of aromatic groups, planar hydro-
phobic boundary surface, and similar molecular length fac-
tors are important structural features. The chiral discrimina-
tion is largely dependent on the existence and magnitude of
intermolecular interactions related to these structural charac-
teristics.
Sertraline is an antidepressant of the selective serotonin
reuptake inhibitor class which was introduced to the market
by Pfizer in 1991. In 2007, it was the most prescribed antide-
pressant on the U.S. retail market, with 29,652,000 prescrip-
tions.31 Its chemical name is (1S, 4S)-4-(3, 4-dichlorophenyl)-
1, 2, 3, 4-tetrahydro-N-methyl-1-naphthaleneamine. There are
a number of approaches reported for the synthesis of enan-
tiomer sertraline. Most of them involve introducing the chir-
ality to sertraline by the resolution of racemate cis-sertraline
with (R)-mandelic acid as the resolving agent in methanol
and ethanol.32,33 The resolution efficiency can reach 82%,
which is extremely high compared with other industrial scale
resolution processes. Therefore, it is a good example to
investigate the chiral discrimination mechanism.
In this work, to reveal the excellent chiral discrimination
ability of (R)-mandelic acid in the case of sertraline, we syn-
thesized the corresponding pair of diastereomeric salts,
namely, less soluble salt (1S,4S)-sertralineÁ(R)-mandelic acid
(hereafter (1S,4S)-sertralineÁ(R)-MA) and more soluble salt
(1S,4S)-sertralineÁ(S)-mandelic acid (hereafter (1S,4S)-
sertralineÁ(S)-MA). (1S,4S)-SertralineÁ(S)-mandelic acid is the
enantiomer of the more soluble salt (1R,4R)-sertralineÁ(R)-
mandelic acid, which has the same properties as it. The ther-
mal properties such as melting point, enthalpy of fusion, and
solubility of these salts were measured. The crystal structure
of diastereomeric salts was determined by an X-ray crystallo-
graphic analysis and structural characteristics and weak inter-
molecular interaction of less soluble salt were systematically
examined. The chiral discrimination was well interpreted in
terms of the contribution of various intermolecular interac-
tions on the stability of the less soluble salt. The resolution of
sertraline with (R)-MA is illustrated in Figure 1.
The molecular lengths of racemate and resolving agent
have been identified to be another significant factor to the
chiral recognition. It is generally believed that the same or
close molecular lengths of racemate and resolving agent is
favorable to form planar boundary surface of hydrophobic
layers. The planar boundary surface is beneficial to realize
the tight packing of molecules in terms of enhancing the van
der Waals interactions.10,12,22,23
Recently, CH/p interaction that was conventionally
believed to be very weak24,25 has raised much attention.11,26–
29
Improved resolution efficiency was achieved by intention-
ally introducing the CH/p interaction sites such as naphthyl
groups that enhanced the interaction.11,26,27 In our previous
work,30 it was demonstrated that CH/p interaction could
become the dominant interaction in chiral recognition of 4-
chloromandleic acid/3-chloromandelic acid by (R)-phenyle-
thylamine since the hydrogen-bonding patterns were almost
identical in less and more soluble salts.
Although, up to now, there is no general agreement on
dominant factors accounting for the stability of diastereo-
meric salts, it is widely accepted that the hydrogen-bonding
TABLE 1. Thermal properties of diastereomeric salts
Diastereomeric
salt
Melting
point (C)
Heat of fusion
Solubilitya
(g/100 mL)
(kJ mol21
)
Less soluble salt
More soluble salt
191.7
87.3
65.6
48.3
0.42
3.61
aAll data in table 1 are a average value of triple measurements; solubility was
measured in ethanol at room temperature 23 C.
Chirality DOI 10.1002/chir

CHIRAL DISCRIMINATION MECHANISM
121
Fig. 2. The DSC and TGA curves of less soluble salt. [Color figure can be
viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 3. The DSC and TGA curves of more soluble salt. [Color figure can
be viewed in the online issue, which is available at wileyonlinelibrary.com.]
EXPERIMENTAL
Materials
cal shifts were recorded on a Varian INOVA 600 spectrometer at 258C
and DMSO-d6 as solvent. The X-ray powder diffraction spectra were col-
lected on a Rigaku-Miniflex powder diffractometer (Carlsbad, CA) using
Sertraline enantiomer and sertraline racemate hydrochloride salts
were donated by Apotex PharmaChem (Canada). (R)-Mandelic acid with
99% purity and (S)-mandelic acid with 99% purity was purchased from
Alfa Aesar, A Johnson Matthey Company (Ward Hill, MA). All solvents
were HPLC grade and were used without further purification.
˚
Cu-Ka (k for Ka 5 1.54059A) radiation obtained at 30 kV and 15 mA.
The scans were run from 5.08 to 40.08 2y, increasing at a step size of
0.028 2y with a counting time of 5 s for each step. Specific rotations of
salts were measured by Autopol IV Digital Polarimeter Rudolph America
(Hackettstown, NJ) at 589 nm, equipped with a quartz cell of 100-mm
path length.
Single crystals of (1S, 4S)-sertraline-(R)-mandelate were grown from a
concentrated ethanol solution by slow evaporation at room temperature.
The single crystal was mounted on a glass fiber and data were collected
at the temperature of 228C on a Nonius kappa-CCD area detector diffrac-
Analytical Methods
The melting point and heat of fusion of diastereomeric salts were
determined by Mettler Toledo DSC 822e differential scanning calorime-
ter (Greifensee, Switzerland) with heating rate 58C/min. 1H NMR chemi-
Fig. 4. Atomic-numbering scheme of less soluble salt. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Chirality DOI 10.1002/chir

122
HE ET AL.
˚
TABLE 3. Hydrogen bond geometry (d in A and angle in 8)
TABLE 2. Crystal structure data of less soluble salt
(1S,4S)-sertralineÁ(R)-MA
D-H. . .A
d(D-H)
d(H. . .A)
d(D. . .A)
<(DHA)
Empirical formula
C
25H25Cl2NO3
458.36
N13-H13A. . .O22a
N13-H13B. . .O21
0.90
0.90
1.92
1.89
2.781(4)
2.756(4)
158.2
160.6
Formula weight (g/mol)
Temperature (K)
293
˚
Wavelength (A)
0.71073
Monoclinic
P 1 21 1
7.8029(2)
9.0423(4)
16.3615(8)
90
95.594(3)
90
1148.91(2)
1.325
a2x, y11/2, 2z.
Crystal system
Space group
˚
a (A)
(1S, 4S)-sertraline hydrochloride by the method described in the litera-
ture.36 To a solution (1S, 4S)-sertraline (10 g, 0.033 mol) in 100 ml etha-
nol, (R)-MA (5.0 g, 0.033 mol) were added gradually to afford white crys-
tals. The slurry was heated to reflux and then cooled to room tempera-
ture slowly. The suspension was put in fridge overnight. The crystals
were collected by filtration and washed with 48C ethanol twice (2 3 20
mL) to give optical pure (1S, 4S)-sertralineÁ(R)-MA (14.2 g, yield 94%).
Melting point was 192.67–191.578C (onset of DSC). 1H NMR (d6-di-
methyl sulfoxide (DMSO)/tetramethylsilane (TMS)), d (ppm): 1.87–2.11
(m, 4H), 2.53 (s, 3H), 4.12 (m, 2H), 4.68 (s, 1H), 6.74 (d, 1H),7.17–7.27
(m, 6H), 7.38 (d, 2H),7.52 (m, 2H), 7.55 (d, 1H).
˚
b (A)
˚
c (A)
a ()
b ()
g (8)
3
˚
V (A )
Dcalc (g/cm3)
Z
2
Crystal size (mm)
Reflections collected
Goodness-of-fit on F2
Final R indices [I > 2r(I)]
0.04 3 0.05 3 0.26
8819
1.019
R1 5 0.045
wR2 5 0.1087
R1 5 0.0679
wR2 5 0.1223
Preparation of More Soluble Salts
More soluble salts were synthesized by enantiopure (1S, 4S)-sertra-
line and (S)-MA. To a solution (1S, 4S)-sertraline (10 g, 0.033 mol) in a
mixture of solvents (70% hexane and 30% ethanol, v/v), (S)-MA (5.0 g,
0.033 mol) were added gradually to afford a clear solution. The solution
was heated to reflux and then cooled to room temperature. The solution
was put under a fume hood to evaporate solvent to afford white crystal.
The crystals were collected by filtration and washed with 48C mixture
solvent (2 3 10 mL) to give optical pure (1S, 4S)-sertralineÁ(S)-MA (13.6
g, yield 91%). Melting point: 86.89–87.38C (onset of DSC). 1H NMR (d6-
DMSO/TMS), d (ppm): 1.05 (t, 3H from ethanol CH3), 1.84–2.07 (m,
4H), 2.53 (s, 3H), 3.44 (q, 2H, from ethanol CH2), 4.02 (t, 1H), 4.12 (d,
1H), 4.70 (s, 1H), 6.735 (d, 1H), 7.17–7.24 (m, 4H), 7.27 (m, 2H), 7.375
(m, 2H), 7.455 (d, 1H), 7.48 (d, 1H) 7.56 (d, 1H).
R indices (all data)
tometer with COLLECT using monochromatic Mo-Ka radiation (k 5
˚
0.71073A). The structures were solved with direct method using the
SHELXS-97 program and refined on F2’s by full-matrix least-squares with
SHELXS-97 program.
Preparation of Less Soluble Salts
The less soluble salts were synthesized by enantiopure (1S, 4S)-ser-
traline and (R)-MA. Enantiopure (1S, 4S)-sertraline was isolated from
Fig. 5. Hydrogen-bonding network. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Chirality DOI 10.1002/chir

CHIRAL DISCRIMINATION MECHANISM
123
Fig. 6. Molecular layers packing in crystals. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
The TGA trace of more soluble salt clearly showed 3.5%
weight loss between 78 and 888C. The NMR analysis indi-
cated 3.2% ethanol existing in more soluble salt, which was
consistent with TGA results. The differential scanning calo-
rimetry (DSC) and TGA curves of more and less soluble salts
are shown in Figures 2 and 3.
The comparison of the above thermal properties strongly
suggests that the less soluble salt is much more stable than
the more soluble salt. Consequently, excellent resolution effi-
ciency is expected from such large stability difference.
RESULTS AND DISCUSSION
Thermal Properties of Less and More Soluble
Diastereomeric Salts
The standard less and more soluble salts of sertraline and
mandelic acid were synthesized as described in the ‘‘Experi-
mental’’ section. The thermal properties of the resulting salts
were determined and are listed in Table 1.
As it can be seen, the melting point difference and the sol-
ubility difference are significant. The melting point of less
soluble salt exceeds that of corresponding more soluble salt
by >1008C. The solubility ratio of more soluble salt to less
soluble salt in ethanol is 9:1, which is very large. Experimen-
tally, it was also found that the more soluble salt resulted in
an ethanolate. The ratio of incorporated solvent to sertraline
mandelate was 1:3 based on thermal gravimetric analysis
(TGA) and Nuclear Magnetic Resonance (NMR) analysis.
Investigation of Chiral Discrimination Mechanism
Based on Crystal Structure of Less Soluble Salt
(1S, 4S)-SertralineÁ(R)-Mandelic Acid
The large physicochemical property difference between
the corresponding less and soluble salts is closely related to
their crystal structures.
Chirality DOI 10.1002/chir

124
HE ET AL.
Fig. 7. Supramolecular packing of less soluble salt viewed from three axes. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.
com.]
The good quality single crystals of less soluble salt of (1S,
monium cations and mandelic acid carboxylate anions, sup-
ported by electrostatic, hydrogen bond, and van der Waals
interactions. The detailed structural features and non-bonded
interactions are examined as follows:
4S)-sertralineÁ(R)-mandelic acid were obtained for X-ray crystal-
lographic analysis. The colorless needle-like crystals belong to
monoclinic space group P1 21 1 and the unit cell contains two
(1S, 4S)-sertraline cations and two (R)-mandelic acid anions.
Figure 4 graphically illustrates the atomic-numbering schemes.
Crystallographic lattice parameters and hydrogen bond geome-
try are summarized in Tables 2 and 3, respectively. Detailed
crystal data are included in Supporting Information.
Hydrogen-bonding network. The ammonium hydro-
gens of sertraline formed two hydrogen bonds with the car-
boxylate oxygens, one from neighboring mandelic acid mole-
cules, another from the opposite mandelic acid molecule,
namely N13-H13A. . .O22 (i) and N13-H13B-O21 as listed in
Table 3. Sertraline and mandelic acid were connected head
The less soluble salt presented a typical secondary amine
and carboxylic acid salt structure containing sertraline am-
Chirality DOI 10.1002/chir

CHIRAL DISCRIMINATION MECHANISM
125
Fig. 8. Stacking of aromatic rings in hydrophilic region. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
to head alternatively to form a zigzag chain-like hydrogen-
bonding network along the b-axis as shown in Figure 5a. To
our surprise, the hydroxy group in mandelic acid was not
involved in hydrogen bond formation in the case of sertraline
mandelate.
This one-dimension pattern is quite different from the
most commonly observed 21 columnar hydrogen-bonding
network formed in primary amines and carboxylic acids,
which is usually formed around a two-fold screw axis by am-
monium hydrogens and carboxylate oxygens as shown in
Figure 5b.10,16 In the 21 columnar hydrogen-bonding net-
work, there was also another hydrogen bond formed
between hydroxy hydrogen and the carboxylate oxygen,
which interlinked the two neighboring 21 columns to form a
2D hydrogen-bonding network extending throughout the
crystal.10
Packing of hydrophobic layers. The molecules in less
soluble salt assembled in a sandwich like structure illus-
trated in Figure 6a. The interesting observation was that the
resolving agent mandelic acid molecules were close to each
other and orientated along the b-axis to form the middle layer
(hydrophilic layer) in sandwich. The larger sertraline mole-
cules formed the outside two layers (hydrophobic layer)
which were face to face and linked by hydrogen-bonding
chain with the assistance of mandelic acid molecules. This is
significantly different from the molecular packing mode in
reported cases of amine and acid,10–12,16,20–22,26–30 where the
˚
Fig. 9. (a) Stacking of aromatic rings (b) CH/A interactions in hydrophobic region. [Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
Chirality DOI 10.1002/chir

126
HE ET AL.
First, a one-dimensional (1D) chain-like hydrogen-bonding
network was observed. The chain extended infinitely along
the b-axis, and the molecules were aligned around the chain
by hydrogen bonds to form the backbone of structure shown
in Figure 10. These parallel chains packed closely along a-
axis and c-axis to form a compact crystal structure as shown
in Figure 11. To the best of our knowledge, this kind of
hydrogen-bonding pattern has not ever been reported in dia-
stereomeric salts of mandelic acid and amine, or deeply hid-
den in literature. The mandelic acid and amine typically
formed 21 columnar hydrogen-bonding networks. The newly
found chain-like structure is assumed to be another stable
hydrogen-bonding pattern in less soluble salts besides the
well-known 21 column, closed globular cluster, and 2D sheet
hydrogen-bonding networks.16–21
Second, the sandwich-like supramolecular packing in less
soluble salt is novel. The resolving agent mandelic acid
assembled in hydrophilic layer and sertraline molecules con-
centrated in hydrophobic region. It has been proposed that
the hydrophobic boundary surface is expected to be planar,
which is favorable to van der Waals interaction to realize
close packing among the supramolecular layers.16,23 Based
on this consideration, it is widely accepted that the higher re-
solution efficiency will be achieved if the molecular lengths
of racemate and resolving agent are identical. If difference in
molecular length is one or more than one atoms determined
by the method proposed by Sakai,12 this difference can be
compensated by incorporating protic solvent into diastereo-
meric salt to realize the planar boundary surface. The
method is referred to as ‘‘space filler concept,’’ which was
successfully applied in the resolution of intermediate of
doluxine using water as space filler.35
Fig. 10. Schematic orientation of molecules along the hydrogen-bonding
chain. [Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
functional groups of amine and acid formed hydrogen-bond-
ing layer, and the resolving agent like phenylethylamine and
chiral recognized enantiomer chloromandelic acid coexisted
in hydrophobic region as shown in Figure 6b.
The boundary surface of hydrophobic layers of the less
soluble salt was planar and favorable to van der Waals inter-
actions to realize a close packing. The detailed crystal pack-
ing patterns viewed long a-, b-, and c-axis respectively are
depicted in Figure 7.
Stacking of Aromatic Groups, CH/p Interactions,
and p/p Interaction
Examining the packing of aromatic groups of mandelic
acids in hydrophilic region disclosed a T-shaped packing.
The aromatic rings were orientated to be vertical to each
other and the interplanar angle of aromatic rings was 77.68.
There was no strong CH/p interaction found in the region.
Besides the T-shaped packing, the aromatic groups were
arranged in parallel. The distance between p planes was
However, in the case of sertraline and mandelic acid, the
difference in molecular length is five atoms, which is very
large. The steric effect of big aromatic and six-membered
rings hindered the mandelic acid to form the traditional
hydrogen-bonding network as well as typical supramolecular
packing mode. If both mandelic acid and sertraline were
crowded into hydrophobic layer, there would be unavoidable
large spaces in crystal, which would deteriorate the stability
of crystal. The observed less soluble salt, sertraline mandel-
˚
7.047A, which was too far for attractive interactions to be
taken into consideration. The packing mode of aromatic
groups is depicted in Figure 8.
The packing of aromatic groups of sertraline in hydropho-
bic region also exhibited the T-shaped arrangement depicted
in Figure 9a. The interplanar angle of aromatic groups from
adjacent hydrophobic layers was 86.088. Based on the defini-
tion of CH/p34 as well as the consideration of measuring con-
venience, the CH/p interaction here was evaluated by the
distance between C atom and p plane. There was one kind of
CH/p interaction existing in the region. The CH/p interac-
tion happened between CH located at C17 of one sertraline
molecule and the ring of C2–C3–C5–C6–C7–C8 of adjacent
˚
sertraline molecule. The CH. . .p distance was 4.193A, which
˚
was not very strong compared with 3.50–4.10A in other cases
of less soluble salt.11,26,27,29 The aromatic groups of sertraline
were also assembled to one another in parallel. The p. . .p
˚
distance was 6.609A, which was not long enough either to
consider the possible attractive forces between p planes. Fig-
ure 9b clearly shows CH/p interactions between sertraline
molecules from the neighboring hydrophobic layers.
Summarizing the above crystal structure investigation, the
less soluble salt of sertraline mandelate possesses most char-
acteristic structural features that favor the stability of crystal,
such as stable hydrogen-bonding pattern, planar boundary
surface, and T-shaped aromatic group packing. However, the
crystal structure of (1S, 4S)-sertralineÁ(R)-mandelic acid with
these characteristic features was formed in different ways
from the reported conventional less soluble salts.
Fig. 11. Schematic diagram of superamolecular packing in less soluble
salt. [Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
Chirality DOI 10.1002/chir

CHIRAL DISCRIMINATION MECHANISM
127
ate, adapted into a new more efficient packing mode. The
small mandelic acid molecules were closely packed in core
layer and surrounded by sertraline molecules. The chair-
shape molecular structure of sertraline36 allowed the head of
sertraline fit into the void of mandelic acid layer through
hydrogen bond formation. The tail part of sertraline mole-
cules packed parallel to each other locating in external layer
and resulted in a planar hydrophobic surface as shown in
Figure 10. As shown in Figure 11, the hydrophilic layers are
located in the center. The hydrophobic layers are packed
layer by layer along both c-axis and a-axis to form a compact
packing (The red and blue circles represent hydrophilic and
hydrophobic regions, respectively). From the case study, we
believe that the molecular arrangement is determined not
only by the primary factor and hydrogen bond ability but
also by the size and shape of molecular. The molecules tend
to optimize the intermolecular interactions to realize a favor-
able packing. The observed structure provides the evidence
that if the molecular length of raccemate is significantly
larger than that of resolving agent, small resolving agent
should be employed, which can possibly fit into the void of
supramolecular layer formed by big molecules to realize the
chiral recognition. Vice versa, namely, if the racemate is a
small molecule, the commercial available resolving agent can
be elongated or enlarged to increase the chiral discrimina-
tion ability.
hydrogen bond, CH/p interaction, and van der Waals interac-
tion related to these characteristic structures determine the
stability of diastereomeric salt. The hydrogen bond is not nec-
essarily the dominant factor. The synergy and optimization of
all three interactions will enhance the stability of salts and
can lead to extremely high resolution efficiency. In most
cases, these conditions cannot be completely matched, so
moderate resolution efficiency is achieved. The less soluble
salt of sertraline and mandelic acid match the three condi-
tions, a new kind of stable hydrogen-bonding network, CH/p
interaction, and a unique compact packing mode, which is a
good template for the selection and design of resolving agent.
CONCLUSIONS
The diastereomeric resolution of sertraline by mandelic
acid was investigated with respect to resolution mechanism.
Systematic examination of the intermolecular interactions
and packing features in crystal structure of less soluble salt
(1S, 4S)-sertralineÁ(R)-mandelic acid, elucidated the high re-
solution efficiency in the system. A new 1D chain-like charac-
teristic hydrogen-bonding network in diastereomeric salt
formed between amine and carboxylic acid was disclosed for
the first time. Novel sandwich supramolecular assembly was
observed. The structure resulted from adapting the specific
structures of racemate and resolving agent to realize T-
shaped packing of aromatic groups as well as planar bound-
ary surfaces. It is concluded that the stable hydrogen-bonding
pattern, herringbone-like arrangement of aromatic rings, and
planar boundary surface in hydrophobic region are the three
most important structural characteristics. The existence and
magnitude of hydrogen bonds, CH/p interaction, and van der
Waals related to characteristic structures determine the sta-
bility of less soluble salt. It is common that the less soluble
salt has one or two of three factors to offer moderate or high
resolution efficiency. If less soluble salt possesses all three
favorable structural features like sertraline mandelate, very
high resolution efficiency is expected. Resolving agent could
be selected and designed to favor the formation of diastereo-
meric salts with these structural features.
Third, the herringbone arrangement (T-shaped) of aro-
matic groups has been universally identified in both hydro-
phobic and hydrophilic regions. This packing motif is
believed to favor the stability of the crystal.24,25,37 The CH/p
interactions existing in neighboring hydrophobic layers also
stabilize the less soluble salt.
Fourth, the solvent ethanol was incorporated into more
soluble salt, which was a very rare case. It is generally
believed, in diastereomeric resolution, that the solvents are
more likely to be incorporated into less soluble salts and pro-
vide more hydrogen bond sites or fill space voids, which ben-
efit the stability of less soluble salts.12,38–40 We would argue
that in the case of sertraline resolved by mandelic acid, the
more soluble salt is a solvate with very high solubility and
leads to excellent resolution. The similar phenomenon was
observed in another system of lactic acid with 1-phenylethyl-
amine, one equivalent water molecule was incorporated in
the more soluble salt.41 We believe, the fact that fewer exam-
ples of more soluble salt solvate have been observed does
not mean it occurs less. It is more likely owing to the diffi-
culty in crystallization of the more soluble salt due to its
higher solubility. One safe conclusion can be made that the
solvent’s incorporation does play an important role in chiral
discrimination besides its role as a medium to the diastereo-
meric salts crystallization. The incorporation of solvents can
change the stability order among diastereomeric salts and
their solvates, which is attributed to the polymorphism na-
ture of diastereomeric salts. Unfortunately, we failed to get
crystal structure of more soluble salt for the comparison with
less soluble salt. The lower stability of more soluble salt can-
not be interpreted concretely.
It was also found that solvent is not incorporated into the
less soluble salt to stabilize the crystal. It existed, however in
the more soluble salt. The effects of solvent on the stability
of diastereomeric salt are more complicated than just provid-
ing more hydrogen bond sites or filling the space to realize
the close packing of crystal as generally believed. Further
investigation on the role of solvent in resolution is necessary.
ACKNOWLEDGMENTS
Authors are grateful to Apotex PharmaChem for providing
free chemicals.
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