Article

Cite This: Cryst. Growth Des. 2019, 19, 1660−1667 pubs.acs.org/crystal

Investigating the Solvent Effect on Crystal Nucleation of Etoricoxib

Yinghui Chai,†,‡ Liping Wang,†,‡ Ying Bao,*,†,‡,§ Rugang Teng,†,‡ Yumin Liu,†,‡,∥ and Chuang Xie†,‡
†
School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
‡
The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin 300072, China
§
Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, Tianjin University, Tianjin 300072, People’s Republic of
China
∥
School of Chemical Engineering and Analytical Science, University of Manchester, Manchester M13 9PL, England
*
S Supporting Information
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ABSTRACT: Induction time measurement experiments for etor-

icoxib (ETR) were carried out in four solvents. The results suggest
the crystal nucleation of ETR becomes increasingly more difficult in
the order: toluene, acetone, acetonitrile, and ethanol, and this order
is well correlated with the interfacial energies determined by the
classical nucleation theory. The solute−solvent interaction was
investigated by solution infrared spectroscopy, molecular dynamic
simulations, and density functional theory computed 1:1 solute−
solvent binding energies. The strength of binding energy at the
sulfonyl on the ETR molecule is not only related to the infrared
spectral shift of the sulfonyl band but also related to the nucleation
rate. The needle-like crystal morphology along the b-axis of ETR
form I in four solvents indicates that the molecular arrangement
along the ac plane is extremely limited in cluster growth during
nucleation. The sulfonyl, as a hydrogen bond acceptor, participates in the formation of several hydrogen bonds in the two-
dimensional structure of the ac plane. Thus, the combination of solvent on the sulfonyl retards the nucleation of ETR. The
stronger the solvent interacts with the sulfonyl on the ETR molecule, the more energy is required for desolvation, and the
slower the ETR nucleation becomes.

■ INTRODUCTION
Crystallization, as an important separation and purification
operation, is widely used in the chemical industry such as
pharmaceuticals, food, and agriculture. Nucleation is the key
step in the crystallization process and has an important
influence on the polymorphism and particle size distribution.1
However, the understanding of nucleation is still insufficient
since nucleation is sensitive to experimental conditions and
difficult to observe directly.
Solvent generally has an important influence on crystal
nucleation involving the crystal polymorph and the nucleation
rate.2 The link between solution chemistry and crystal
structure has become a hot issue in polymorphism research.
In certain systems, it has been confirmed that there exists a
clear link between the growth synthon formed in solution and
the structural synthon packed in the crystal. Through
molecular dynamics simulations, Chen3 found that strong
interactions between tetrolic acid (TTA) and solvent
molecules (ethanol or dioxane) prevent the formation of
carboxylic acid dimers in solution and thus promote the
crystallization of TTA in a catemer-based form or a solvate
form. While weak interactions between TTA and solvent
molecules (carbon tetrachloride or chloroform) facilitate the
formation of carboxylic acid dimers in solution and thus
promote the crystallization of a dimer-based crystal. A similar
link has also been found in 5-fluorouracil4 and tolbutamide.5
However, this link is not applicable for all substances, such as
mandelic acid.6
Molecular computational model is a useful tool to
investigate the mechanism of nucleation at the molecular
scale. In several papers reported by Rasmuson and co-
workers,7−10 a DFT computational model of the first solvation
shell and the 1:1 solute−solvent specific site binding energy
was used to study the nucleation behavior of solutes in
different solvents. In general, the influence of solvent on
nucleation is mainly dependent on solute−solvent interac-
tions. 7−9 However, In the recently published article,
Zeglinski10 found that the solvent effect on the nucleation of
tolbutamide exists not only in the difference of solute−solvent
interactions but also in the formation of various conformations
and species of the solute molecular in different solvents.
Lynch11 successfully predicted nucleation of isonicotinamide
in seven different organic solvents by the DFT computed
solvent−solute interactions in the absence of nucleation
Received: October 19, 2018
Revised: January 27, 2019
Published: February 6, 2019

© 2019 American Chemical Society 1660 DOI: 10.1021/acs.cgd.8b01571

Cryst. Growth Des. 2019, 19, 1660−1667
Crystal Growth & Design
induction time experimental data. Besides, solution spectros-
copy methods (such as IR,7−10 Raman,7 NMR12,13) are
frequently used to explore the link between solution chemistry
and certain macroscopic processes in crystallization. In the
work of Rasmuson and co-workers,7−10 the infrared spectrum
was used as a probe of the solute−solvent interaction to
explain the solvent effect on nucleation, and the carbonyl
frequency shift in the solution spectrum increases as the
solute−solvent interaction increases.
Etoricoxib (ETR) is a selective cyclooxygenase-2 (COX-2)
inhibitor for the treatment of osteoarthritis, rheumatoid
arthritis, and acute gouty arthritis.14,15 ETR is a medium-
sized (358.84 g mol−1) molecule with conformational
flexibility. The molecular structure of ETR is shown in Figure
1. Five polymorphs (forms I−V) and two hydrates16−18 of
Figure 1. Molecular structure of ETR.
ETR have been reported so far. Form I and form V are
enantiotropic and form V is more stable at room temper-
ature.19 In the present work, only form I was recorded in the
induction time measurement experiments; therefore, the
polymorphism phenomenon was not taken into account in
the solvent effect. The crystal structure of ETR form I was
determined by Grobelny18 in 2011, and Figure 2 shows its
Figure 2. Molecular packing along the ac plane in the crystal structure
of the ETR form I. H-bonds shown as dotted lines.
molecular arrangement. Despite the absence of strong
hydrogen bonds due to the lack of hydrogen bond donor in
the ETR molecule, weak hydrogen bonds are possible and are
seen in the form of C−H···OS hydrogen bonds. The
sulfonyl accepts hydrogen bonds from the activated C-H
groups in the molecule and forms a sulfonyl dimer synthon
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(the stick model highlighted in the Figure 2) which constructs
the crystal structure as an asymmetric unit.
In this study, we obtained the nucleation kinetic data of ETR
in four different solvents through the induction time
measurement experiments. Solute−solvent interactions were
investigated by infrared spectroscopy, molecular computational
models, and crystal structure analysis. Finally, we propose a
mechanism for the solvent effect on ETR nucleation.
■
MATERIALS AND METHODS
Materials. Etoricoxib (>99%), form III, was purchased from
Wuhan Hongruikang Reagent Co., Ltd., and used without further
purification. Form I was prepared by rapid cooling in acetone. All
solvents (toluene, acetone, acetonitrile, and ethanol) were of
analytical reagent and were purchased from Tianjin Kemiou Chemical
Reagent Co., Ltd.
Solubility Measurement. Solubility data for ETR form I was
measured in this work for each solvent at 10 °C using a laser
monitoring dynamic method. Detailed solubility measurement
methods are recorded in the Supporting Information.
Induction Time Measurement. Nucleation rates were calculated
from induction time distributions using the probability method.20
Although the precise saturation temperatures (Tsat) for the solutions
were not known, previous solubility measurements18 indicated all Tsat
were less than 40 °C for the range of solutions employed.
Stock solutions were prepared in a 100 mL sealed conical flask in a
water bath by weighing appropriate amounts of ETR form I and
solvent according to our solubility data at 10 °C. An equilibration
period at 50 °C was allowed overnight, with agitation provided with a
PTFE (polytetrafluoroethylene) coated magnetic stirrer at 500 rpm.
Solutions were dispensed via preheated syringes and 0.2 mm PTFE
filters, into sixteen 10 mL glass vials. A magnetic stirring bar was
added to each vial prior to sealing with a plastic screw cap with a
PTFE seal. Solutions were then subjected to a second equilibration
period at 50 °C overnight before the crystallization experiments were
performed.
Then, solutions were transferred from bath A at 50 °C to bath B
held at 10 °C to obtain supersaturation. Agitation was provided at 500
rpm via a magnetic stirrer under the water bath. The induction time
was measured as the difference between the time when the solution
becomes cloudy and the time when the vials were transferred to bath
B. Once all vials had nucleated, they were transferred back to water
bath A where complete dissolution occurred. Before performing the
next nucleation experiment, all the solutions were dissolved
completely and kept at this state for 1 h to ensure equilibrium.
This cycle was repeated five times, giving a maximum total of 80
induction time measurements at each chosen supersaturation.
Solid samples were isolated by filtration, and the crystal form was
determined by PXRD. In all cases, the solid phase was pure ETR form
I. PXRD patterns of crystals obtained in different solvents are shown
in Figure S1 in the Supporting Information.
It is worth mentioning that ETR exhibits burst nucleation in all
cases of the induction time measurement experiments. Around 30 s
elapsed between the first detection of faint cloudiness in the solution
and the apparent end point of crystallization, at which stage the
solutions were white slurries. Subsequently, the crystal was quickly
sucked out with a pipet to measure the crystal morphology with a
microscope.
Computational Methods. Solute−Solvent Interactions. Sol-
ute−solvent interactions were captured by DFT 1:1 solute−solvent
binding energies and molecular dynamics (MD) computed solute−
bulk solvent interaction energies with a solvation model.
The crystal structure of ETR form I was directly obtained from the
Cambridge Structural Database (855682), and then the ETR
molecule was extracted from the ETR form I crystal.
MD Calculation. MD calculations of solute−bulk solvent
interaction energies were performed by the Materials Studio
package.21 The details are recorded in the Supporting Information.
DOI: 10.1021/acs.cgd.8b01571
Cryst. Growth Des. 2019, 19, 1660−1667
Crystal Growth & Design Article

DFT Calculations. Density functional theory (DFT) calculations Table 1. Comparison of the Solubility of ETR Form I at 10
were performed using the Gaussian 09 package.22 The four solvents °C Measured in This Work and Reported in Literature
used in our experiment represent different polarity and H-bond
capability. Ethanol is both a H-bond donor and acceptor, acetone and solvent measured mole fraction literature mole fraction
acetonitrile are only H-bond acceptors, while toluene is not capable of toluene 0.0113
making strong H-bonds, although it can interact through π−π acetone 0.0343 0.0336
stacking. The (1:1) solute−solvent binding energies are probed at
ethanol 0.00312 0.00306
seven sites of the ETR molecule with the aid of the electrostatic
potential map (EPM) as shown in Figure 3. The EPM is related to the acetonitrile 0.0191 0.0157

volumes could be expressed as the form of a Poisson

distribution
P(t ) = 1 − exp( −JV (t − tg )) (1)
where J is the nucleation rate, V is the volume of solution, t is
the detection time. A key parameter in this equation is the
growth time, tg, accounting for the delay in detection arising
from growth. For a given supersaturation, this time was taken
as the shortest measured induction time.20
Induction time distribution of ETR in acetone at different
supersaturation are shown in Figure 4. The probability P(t)

Figure 3. Electrostatic potential isosurface and definition of

interaction sites in ETR molecule for probing 1:1 solvent−solute
binding energies (blue - positive, red - negative, green - neutral
potential).

electron density, electronegativity, and the partial charges on the

different atoms of the molecule, which is very useful for identifying
hydrogen bond interaction sites. The EPM indicates that the electron-
deficient regions are highlighted in blue at the hydrogens, while the
electron-rich regions are highlighted in red at the heteroatoms O1, O2,
N1, and N3.
Seven sites representing all the important binding features of the Figure 4. Induction time distributions of ETR in acetone at 10 °C.
ETR molecule were selected: (1) polar sites containing heteroatoms
O, N and halogen atom Cl (sites 1, 2, 3, and 4), (2) tolyl (site 5), and
pyridine ring (sites 6 and 7). Especially, site 1 was selected to
compare the calculated solute−solvent binding energies at the ETR more rapidly approaches 1 as the supersaturation increases,
sulfonyl group with the corresponding experimentally determined indicating higher nucleation rates. Induction time distributions
shifts of the sulfonyl group in the FTIR spectrum. The calculation in toluene, acetonitrile, and ethanol can be found in the
details are recorded in the Supporting Information. Supporting Information.
Crystal Morphology Simulations. Using the Materials Studio The nucleation rate can be obtained by fitting a linearized
package, crystal morphology simulations were implemented based on version of eq 1:
the modified attachment energy (AE) model considering solvent
effect. The calculation details are recorded in the Supporting −ln(1 − P(t )) = JV (t − tg ) (2)
Information.
Spectroscopic Methods. IR spectra of the solid material and By plotting −ln(1 − P(t)) versus (t − tg), the nucleation rate J
solutions were both collected using a Bruker Alpha FTIR-ATR can be obtained from the slope of the straight line.
instrument in the region of 4000−400 cm−1 with 2 cm−1 resolution Figure 5 shows the linear dependence between −ln(1 −
and 16 scans per spectrum. All the spectral data were collected at P(t)) and (t − tg) of ETR in acetone. Please refer to the
ambient temperature (30−32 °C). Supporting Information for more details on the linear

■ RESULTS
Solubility. Table 1 gives the saturation concentration of
relationship of ETR in the other three solvents. Thus, the
steady-state nucleation rate J can be determined for the range
of solutions employed.
ETR form I in the four solvents at 10 °C. Reference values According to the classical nucleation theory, the nucleation

ij −16πγ 3Vs2 1 yz
rate can be written as follows
taken from the literature19 are also included, and there is no

J = A expjjj zz
j 3k 3T 3 ln 2 S zz
report on the solubility of ETR in toluene.

k {
Nucleation Rate. Jiang and ter Horst20 proposed that the
probability of detection of a crystal nucleus in time t at small B (3)

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Crystal Growth & Design Article

classical nucleation theory (CNT) was also carried out, and

interfacial energies and pre-exponential factors are given in
Table 2. The interfacial energy increases in the same order as
the nucleation difficulty in different solutions.

Table 2. Values of Derived Parameters A and γ Evaluated by

Classic Nucleation Theory
solvent γ (mJ m−2) A (m−3 s−1)
toluene 2.24 1876.25
acetone 2.47 2448.30
acetonitrile 2.92 2004.50
ethanol 3.42 5117.44

Molecular Computations. MD-calculated interaction

Figure 5. Relationship between induction time and cumulative
probability according to eq 2 of ETR in acetone at 10 °C.
where J is the rate of nucleation, A is the pre-exponential
factor, γ is the solid−liquid interfacial energy, Vs is the
molecular volume, T is the nucleation temperature, and S is the
supersaturation. Taking the logarithm on both sides of eq 3 can
give
16πγ 3Vs2 1
ln J = ln A −
3kB3T 3 ln 2 S (4)
The nucleation rates can be obtained using the linear
relationship of ln J versus 1/ln2 S; then the pre-exponential
kinetic factor A and the thermodynamic parameter interfacial
energy γ can be derived from the intercept and the slope. The
linear plots are shown in Figure 6. In order to reach the same
energies for a solute molecule (ETR) in equilibrium with
bulk solvent are given in Table 3. The solute−solvent
Table 3. Interaction Energies of an ETR Molecule
Interacting with Bulk Solvent at 298 K
solvent interaction energies (kJ mol−1)
toluene −171.39
acetone −167.51
acetonitrile −185.77
ethanol −225.50
interaction energies range from −167.5 kJ mol−1 in acetone
to −225.5 kJ mol−1 in ethanol, and increase in the order:
acetone < toluene < acetonitrile < ethanol. This order deviates
from the nucleation rate order reported above, which suggests
the solute−solvent interaction energies in toluene are stronger
than in acetone. This can be attributed to the π−π stacking
interaction between ETR and toluene. Neither ETR sulfonyl
dimer nor other types of dimers were observed in the MD
trajectory of the four solvents. In the MD trajectory of the
ETR-ethanol system, the hydrogen bond formed between the
O atom on the ETR molecule and the hydroxyl group H atom
on the ethanol molecule is captured, and a representative
snapshot of the hydrogen bond is shown in Figure 7. Solute−
solvent interactions at site 1 were further studied by analyzing
the radial distribution functions (RDFs) based on harvested

Figure 6. Relationship of nucleation rate vs supersaturation in

different solvents.

nucleation rate, the order of supersaturation required is

followed by toluene, acetone, acetonitrile, and ethanol. For
example, in the case of a nucleation rate of 200 m−3 s−1, the
corresponding supersaturation is 1.66, 1.74, 2.10, 2.22,
respectively. Thus, within the experimental range, the
nucleation appears to be relatively easy in toluene, followed Figure 7. Snapshot showing the hydrogen bond between ETR and
by acetone, acetonitrile, and finally ethanol in which the ethanol. Hydrogen bonds (distances less than 2.5 Å) are shown as
highest supersaturation is required. An evaluation within the blue dotted line.

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 Crystal Growth & Design Article

MD trajectory. Figure 8 shows the RDFs between the O atom

on the sulfonyl of the ETR molecule and the H atom on the

Figure 8. RDFs between the O atom on the ETR molecule and the H
atoms on four different solvent molecules.

four solvent molecules. The RDFs show a sharp peak at an

OETR−Hethanol distance of 1.7 Å, confirming that the ethanol
molecule interacts with the ETR molecule by a hydrogen bond
in ethanol solution, while no hydrogen bonds are formed in the
other three solutions.
The ETR molecule possesses a variety of binding
configurations with solvent molecules due to its relatively
large and complex structure. Here seven sites were considered
to probe the strength of the interaction between solute and
solvent. Figure 9 shows the DFT-calculated 1:1 solute−solvent
binding energies for seven different sites at the ETR molecule.
At site 1, ethanol is binding stronger than the other solvent
molecules because a moderate O−H···O hydrogen bond is
formed between ETR and ethanol molecule, while the other
three solvent molecules can only interact with ETR by C−H···
O weak hydrogen bonds. The solute−solvent binding energies
at site 1 increase in the order: toluene (−7.45 kJ mol−1) < Figure 9. Optimized geometry of ETR-solvent dimers. Binding energy
acetone (−10.05 kJ mol−1) < acetonitrile (−17.46 kJ mol−1) < in kJ mol−1, calculated at B97-D3/def2-QZVP level.
ethanol (−21.56 kJ mol−1), and this order is completely
consistent with the order of nucleation rate. Toluene has the numbers compared to the solid infrared spectrum, suggesting
01 stronger binding at nonpolar sites 5, 6, and 7 than polar sites 1, the expected weaker interactions of the sulfonyl in solution.
2, 3, and 4 since it tends to form π−π interactions with ETR. Symmetrical stretching peaks of the sulfonyl of the four
upanjali Prasad Among all the solute−solvent binding energies, the energy of solutions are almost at the same position with only 1−2 cm−1
ETR-toluene at site 6 is the largest, because the toluene and difference, while the difference in the position of the
the pyridine ring of the ETR molecule interact not only asymmetric stretching peaks of the sulfonyl in the four
through C−H···N weak hydrogen bonds but also through π−π solutions is obvious. Therefore, the asymmetric stretching
stacking. The second largest is the energy of ETR-ethanol at vibration band of the sulfonyl was selected as a probe for
02 site 4, which can be explained by the formation of strong solute−solvent interaction.
hydrogen bonds with reasonable spatial orientation. The The asymmetric stretching vibration region of the sulfonyl in
upanjali Prasad arithmetic mean of the binding energies over the seven sites ethanol shows a shoulder peak at 1306 and 1317 cm−1. In
was further calculated, and the order is the same as the site 1: order to identify the assignment of two peaks in the shoulder
toluene (16.92 kJ mol−1) < acetone (18.36 kJ mol−1) < peak, ETR-ethanol solution spectra of different concentrations
acetonitrile (18.92 kJ mol−1) < ethanol (21.11 kJ mol−1). were carried out, as shown in Figure 11. In the case of the
Solution Spectroscopy. Compared to the solid spectrum lowest solution concentration of 25.32 g/kg, the peak at 1306
of ETR, the solution spectra have significant differences in the cm−1 is covered by the peak at 1317 cm−1, thereby showing
3-4 sulfonyl stretching vibration band. The IR spectra of solid only one broad peak. As the ETR concentration increases, the
2 notes: crystalline material of ETR form I (Figure 10) show strong peak intensity at 1306 cm−1 gradually increases, showing a
bands for the symmetric and asymmetric stretching frequencies shoulder peak. Considering the infrared spectrum of pure
of the sulfonyl at 1142 and 1295 cm−1, respectively. The ethanol and the relatively low solubility of ETR in ethanol, we
5-6 solution spectra in all four solvents shift to higher wave- can infer that the peak at 1306 cm−1 should be attributed to
2 notes:
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 Crystal Growth & Design
7-8
2 notes:
Figure 10. Solid-state IR spectrum of ETR form I and solution
spectra of saturated concentrations at 25 °C of ETR in different
solvents.
Figure 11. Solution IR spectroscopy at different concentrations
(25.32, 32.24, 39.18, 46.14 g/kg) of ETR in ethanol.
the sulfonyl asymmetric stretching vibration, and the peak at
1317 cm−1 should be attributed to the in-plane bending
09 vibration of ethanol.
The shift in the asymmetric stretching vibration band of the
upanjali Prasad sulfonyl increases in the order: toluene < acetone < acetonitrile
< ethanol, and this order is consistent with the order of
nucleation difficulty. The shifts of the sulfonyl frequency
suggest that, at site 1, the ethanol are strongly bound and
followed by acetone and acetonitrile, and the toluene is
relatively weakly interacting at this site.
Furthermore, the concentration effect on the spectra was
also analyzed for toluene, acetone, and acetonitrile solutions
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and there was no clear difference in the spectra due to the
different concentrations, and the details can be obtained in the
Supporting Information. The solution spectra in all four
solvents shift to higher wavenumbers compared to the solid
infrared spectrum, indicating the absence of sulfonyl dimers in
the four solutions. Therefore, the species of ETR in solution is
mainly monomer solvated to different degrees.
■
DISCUSSION
ETR form I is a kinetic dominant crystal form that crystallizes
in the manner of burst nucleation in all cases of the induction
time measurement experiments in this study. The crystal
morphology of ETR form I obtained after burst nucleation in
different solvents is shown in Figure 12. Regardless of the
Figure 12. Microscope images of ETR form I crystallized in induction
time measurement experiments and corresponding predicted crystal
morphology by the AE model in the four solvents: (a) toluene, (b)
acetone, (c) acetonitrile, (d) ethanol.
slight difference caused by the influence of solvent, the crystal
particles of ETR form I obtained in different solvents are
needle-like in general. The morphology of ETR form I under
solvent conditions was predicted with the growth morphology
method based on the modified attachment energy (AE) model,
and Figure 12 (upper right corner) gives the predicted
morphology of ETR form I in different solvents. With a slight
difference, the predicted morphology in different solvents
generally shows a rod shape along the b-axis, which matches
closely with the experimentally observed needle shape.
Moreover, the predicted morphology of ETR form I under
vacuum is also a rod shape along the b-axis, supporting that the
solvent effect on the morphology of ETR form I is not very
significant. The predicted morphology of ETR form I under
vacuum can be obtained in the Supporting Information. Along
the b-axis direction, ETR form I is linked by π−π stacking
interactions and Cl···π halogen bond, and the cluster growth
during nucleation in this direction is the fastest and solvent-
independent. So the limit step of the formation of the ETR
nucleus is the molecular arrangement along the ac plane. Along
DOI: 10.1021/acs.cgd.8b01571
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the a-axis, the two oxygen atoms of the sulfonyl interact with
the hydrogen atom of the methyl group of an adjacent ETR
molecule and the hydrogen atom of the pyridine ring of
another adjacent ETR molecule through C−H···O weak
hydrogen bonds, respectively, forming an ETR molecular
chain with the sulfonyl dimer as basic unit. In addition, along
the c-axis direction, an oxygen atom of the sulfonyl participates
in the connection between the ETR chains. It is evident that
sulfonyl plays an important role in the construction of the
crystal structure of ETR form I. The combination of solvent on
the sulfonyl retards the nucleation of ETR.
The results of nucleation induction time measurement
experiments show that crystal nucleation of ETR in different
solvents becomes increasingly more difficult in the order:
toluene < acetone < acetonitrile < ethanol. Nucleation kinetic
parameter interfacial energies were further derived according
to the classical nucleation theory, which increase in the same
order as the nucleation difficulty in different solvents.
Interaction energies between a solute and different bulk
solvents from MD simulation have a certain deviation from the
difficulty of nucleation. The ETR molecule can interact with
the solvent molecule at multiple sites due to its relatively large
size and complex structure. Seven sites representing all the
important binding features of the ETR molecule were selected
to calculate 1:1 solute−solvent binding energies. The strength
of solute−solvent binding energies at site 1 is highly correlated
with the nucleation rate. Figure 13 shows the relationship
between the supersaturation required to reach the same
nucleation rate of 200 m−3 s−1 and the binding energy at site 1.
Figure 13. Relationship between the supersaturation required to
reach the same nucleation rate of 200 m−3 s−1 and the binding energy
at site 1.
Carbonyl serves as a shared functional group of model drugs
in several studies of Rasmuson and co-workers,7−10 and the
stretching vibration band shift of it was selected as a probe to
study the strength of the solute−solvent interactions.
Generally, the stronger the solvent interacts with carbonyl,
the lower the frequency it absorbs. However, in the present
study, the carbonyl is not included in the ETR molecule
structure. Comparing the solution infrared spectrum of
different solvents, it can be found that the asymmetric
stretching vibration band of the sulfonyl shows significant
differences. Therefore, in this study, the shift of the stretching
vibration band of sulfonyl was used to characterize the solute−
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solvent interaction, and as a result, this shift was highly
correlated with the binding energy calculated by DFT. The
combined solution infrared spectrum and DFT binding energy
calculation successfully capture the solute−solvent interaction.
Figure 14 shows the relationship between the stretching
vibration frequency of sulfonyl and the binding energy at site 1.
Figure 14. Relationship between the stretching vibration frequency of
sulfonyl and the binding energy at site 1.
Therefore, the rate-determining step of ETR nucleation is
the desolvation of sulfonyl, and the nucleation process of ETR
is exactly determined by the interaction between the specific
sulfonyl and the solvent. The stronger the solvent binds to the
sulfonyl on the ETR molecule, the more energy is needed to
remove the solvent bonded to the sulfonyl during nucleation,
and the slower the nucleation rate becomes.
■ CONCLUSION
Previous research on ETR crystallization focused mainly on
polymorphs and co-crystal, while its nucleation kinetics have
been rarely studied to date. We sought to reveal the nucleation
mechanism of ETR through investigating the effect of solute−
solvent interaction on the crystallization behavior of ETR in
different solvents. The infrared spectral shift of the sulfonyl
group was used to characterize the solute−solvent interaction,
which increases in the order: toluene < acetone < acetonitrile <
ethanol, and this order is consistent with the nucleation
difficulty order. Computational models were also used to study
solute−solvent interactions. The strength of DFT solute−
solvent binding energies at site 1 is highly correlated with the
infrared spectral shift of the sulfonyl. The step of limiting the
formation of the ETR nucleus is the molecular arrangement
along the ac plane, and the sulfonyl plays an important role in
the construction of the crystal structure of ETR form I as the
hydrogen bond acceptor. The combined method of infrared
spectral, DFT calculation, and crystal structure analysis does
capture the binding strength of solvent molecules to the
sulfonyl on the ETR molecule. It can be concluded that the
rate-determining step of ETR nucleation is the desolvation of
sulfonyls, and the solvent effect on nucleation of ETR is
specifically determined by the interaction between the sulfonyl
and the solvent. The stronger the solvent binds to the sulfonyl
group on the ETR molecule, the slower the nucleation
becomes.
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■
Article

ASSOCIATED CONTENT
*
S Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.cgd.8b01571.
Solubility measurements details and computational
methods. Figure S1: PXRD patterns of ETR form I.
Figures S2−S4: Induction time distributions of ETR in
toluene, acetonitrile, and ethanol at 10 °C, respectively.
Figures S5−S7: Relationship between induction time
and cumulative probability according to eq 2 of ETR in
toluene, acetonitrile, and ethanol at 10 °C, respectively.
Figures S8−S10: Solution IR spectroscopy at different
concentrations of ETR in toluene, acetonitrile, and
ethanol, respectively. Figure S11: The computed
morphology in vacuum of ETR form I (PDF)
(9) Mealey, D.; Zeglinski, J.; Khamar, D.; Rasmuson, Å. C. Influence
of Solvent on Crystal Nucleation of Risperidone. Faraday Discuss.
2015, 179, 309−328.
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■ AUTHOR INFORMATION
Corresponding Author
Exchange Water in a Hydrate Structure: A Case Study of Etoricoxib.
CrystEngComm 2016, 18, 2825−2829.
(15) Bickham, K.; Kivitz, A. J.; Mehta, A.; Frontera, N.; Shah, S.;
Stryszak, P.; Popmihajlov, Z.; Peloso, P. M. Evaluation of Two Doses
*Phone: +86-13820852735. Fax: +86-27405754. E-mail: of Etoricoxib, A COX-2 Selective Non-steroidal Anti-inflammatory
yingbao@tju.edu.cn. Drug (NSAID), in the Treatment of Rheumatoid Arthritis in a
ORCID Double-blind, Randomized Controlled Trial. BMC Musculoskeletal
Ying Bao: 0000-0002-4461-8035 Disord. 2016, 17, 331.
(16) Clas, S. D.; Dalton, C.; Crocker, L. S.; McCauley, J. A.; Davis, I.
Notes U.S. Patent US6,441,002, 2002.
The authors declare no competing financial interest. (17) Crocker, L. S.; Davis, I. W.; Richard, R. G.; Kotliar, A. Patent

■ ACKNOWLEDGMENTS
The authors are grateful for the financial support of the
National Natural Science Foundation of China (21776203 and
21576187) and the Natural Science Foundation of Tianjin
Municipal Science and Technology Commission (No. 18JCY-
BJC21100).
WO02/096877A1, 2002.
(18) Grobelny, P.; Mukherjee, A.; Desiraju, G. R. Polymorphs and
Hydrates of Etoricoxib, A Selective COX-2 Inhibitor. CrystEngComm
2012, 14, 5785−5794.
(19) Zhang, T.; Wang, L. P.; Bao, Y.; Yang, Q.; Zhou, L. N.; Hao, H.
X.; Xie, C. Confirmation of More Stable Polymorphic Form of
Etoricoxib at Room Temperature. J. Pharm. Sci. 2018, 107, 1903−
1910.

■
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1667 DOI: 10.1021/acs.cgd.8b01571

Cryst. Growth Des. 2019, 19, 1660−1667
Annotations

Investigating the Solvent Effect on Crystal Nucleation of

Etoricoxib
Chai, Yinghui; Wang, Liping; Bao, Ying; Teng, Rugang; Liu, Yumin; Xie, Chuang

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