Investigating the Solvent Effect on Crystal Nucleation of Etoricoxib

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Investigating the Solvent Effect on Crystal Nucleation of Etoricoxib Yinghui Chai, Liping Wang, Ying Bao, Rugang Teng, Yumin Liu, and Chuang Xie Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b01571 • Publication Date (Web): 06 Feb 2019 Downloaded from http://pubs.acs.org on February 8, 2019

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Crystal Growth & Design

Investigating the Solvent Effect on Crystal Nucleation of Etoricoxib Yinghui Chai1,2, Liping Wang1,2, Ying Bao*1,2,3, Rugang Teng1,2, Yumin Liu1,2,4, Chuang Xie1,2 1. School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China 2. The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin 300072, China 3. Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, Tianjin University, Tianjin, 300072, People’s Republic of China 4. School of Chemical Engineering and Analytical Science, University of Manchester, Manchester M13 9PL, England * Corresponding authors: [email protected]

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Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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ABSTRACT

Induction time measurement experiments for etoricoxib (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 (MD) simulations and density functional theory (DFT) 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.

Keywords: Nucleation rate, solute-solvent interaction, DFT calculation, desolvation


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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. 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 coworkers,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 interactions. 7-9 However, In the recent published article, Zeglinski10 found that the solvent effect on the nucleation of tolbutamide not only exist in the difference of solute-solvent interactions but also in the formation of various conformation 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 induction time experimental data. Besides, solution spectroscopy methods (such as IR 7-10, Raman7, NMR12-13) are frequently used to explore the link between solution chemistry and certain macroscopic processes in crystallization. In the work of Rasmuson and coworkers,7-10 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. Etoxoxib (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 (form I-V) and two hydrates16-18 of ETR have been reported so far. Form I and form V are enantiotropic and form V is more stable at room temperature.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


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its 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 sulfonyl dimer synthon (the stick model highlighted in the Figure 2) which constructs the crystal structure as an asymmetric unit.

Figure 1. Molecular structure of ETR

Figure 2. Molecular packing along the ac plane in the crystal structure of the ETR form I. H-bonds shown as dotted lines.



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 METHORDS

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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 100 mL sealed conical flask in 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


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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 seconds elapsed between 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 pipette to measure the crystal morphology with a microscope.



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Computational methods

1. Solute-solvent interactions Solute-solvent interactions were captured by DFT 1:1 solute-solvent binding energies and molecular dynamic (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 Materials Studio package.21 The details are recorded in the Supporting Information. DFT calculations Density Functional Theory (DFT) calculations were performed using the Gaussian 09 package.22 The four solvents used in our experiment represent different polarity and H-bond capability. Ethanol is both a H-bond donor and acceptor, acetone and acetonitrile are only H-bond acceptors, while toluene is not capable of making strong H-bonds, although it can interact through π-π stacking. The (1:1) solute-solvent binding energies are probed at seven sites of the ETR molecule with aid of the electrostatic potential map (EPM) as shown in Figure 3. The EPM is related to the 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 electronrich regions are highlighted in red at the heteroatoms O1, O2, N1 and N3.


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Seven sites representing all the important binding features of the ETR molecule were selected: (1) polar sites containing heteroatoms O, N and halogen atom Cl (site 1, 2, 3 and 4), (2) tolyl (site 5) and pyridine ring (site 6 and 7). Especially, site 1 was selected to compare the calculated solute-solvent binding energies at the ETR sulfonyl group with the corresponding experimentally determined shifts of sulfonyl group in the FTIR spectrum. The calculation details are recorded in the Supporting Information.

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). 2. Crystal morphology simulations Using Materials Studio package, crystal morphology simulations were implemented based on the modified attachment energy (AE) model considering solvent effect. The calculation details are recorded in the Supporting Information.



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Spectroscopic methods IR spectrum of the solid material and solutions were both collected using Bruker Alpha FTIR-ATR instrument in the region of 4000-400 cm−1 with 2 cm−1 resolution and 16 scans per spectrum. All the spectral data were collected at ambient temperature (30-32 ℃). ◼

RESULTS

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Solubility.

Table 1 gives the saturation concentration of ETR form I in the four solvents at 10 °C. Reference values taken from the literature19 are also included, and there is no report on the solubility of ETR in toluene. Table 1. Comparison of the solubility of ETR form I at 10 °C measured in this work and reported in literature

◼

Solvent

Measured mole fraction

Literature mole fraction

toluene

0.0113

-

acetone

0.0343

0.0336

ethanol

0.00312

0.00306

acetonitrile

0.0191

0.0157

Nucleation rate

Jiang and ter Horst20 proposed that the probability of detection of crystal nucleus in time t at small volumes could be expressed as the form of a Poisson distribution. 𝑃(𝑡) = 1 − exp (−𝐽𝑉(𝑡 − 𝑡𝑔 ))

(1)


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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 shorted measured induction time.20 Induction time distribution of ETR in acetone at different supersaturation are shown in Figure 4. The probability P(t) more rapidly approaches 1 as the supersaturation increases, indicating higher nucleation rates. Induction time distributions in toluene, acetonitrile and ethanol can be found in the Supporting Information.

Figure 4. Induction time distributions of ETR in acetone at 10 °C. The nucleation rate can be obtained by fitting a linearized version of eq 1: − ln(1 − 𝑃(𝑡)) = 𝐽𝑉(𝑡 − 𝑡𝑔 )

(2)

By plotting − ln(1 − 𝑃(𝑡)) versus (𝑡 − 𝑡𝑔 ), the nucleation rate J can be obtained from the slope of the straight line.



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Figure 5 shows the linear dependence between − ln(1 − 𝑃(𝑡)) and (𝑡 − 𝑡𝑔 ) of ETR in acetone. Please refer to the Supporting Information for more details on the linear relationship of ETR in the other three solvents. Thus, the steady-state nucleation rate J can be determined for the range of solutions employed.

Figure 5. Relationship between induction time and cumulative probability according to eq 2 of ETR in acetone at 10 °C. According to the classical nucleation theory, the nucleation rate can be written as following: 𝐽 = 𝐴exp (

−16𝜋𝛾 3 𝑉𝑠2 1 ) 3𝑘𝐵3 𝑇 3 𝑙𝑛2 𝑆

(3)

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 ln𝐽 = ln𝐴 −

16𝜋𝛾 3 𝑉𝑠2 1 3𝑘𝐵3 𝑇 3 𝑙𝑛2 𝑆

(4)


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the nucleation rates can be obtained using the linear relationship of ln𝐽 versus 1/ln2S, then the preexponential 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 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-3s-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 by acetone, acetonitrile, and finally ethanol in which the highest supersaturation is required. An evaluation within the 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.

Figure 6. Relationship of nucleation rate vs supersaturation in different solvents.



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Table 2. Values of derived parameters A and γ evaluated by Classic nucleation theory

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Solvent

γ (mJ m-2)

A (m-3s-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 energies for a solute molecule (ETR) in equilibrium with bulk solvent are given in Table 3. The solute-solvent 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 is 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 MD trajectory. Figure 8 shows the RDFs between the O atom on the sulfonyl of the ETR molecule and the H atom on the four solvent molecules. The RDFs show a sharp peak at an OETR-Hethanol distance of 1.7 Å, confirming that ethanol molecule interacts


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with ETR molecule by hydrogen bond in ethanol solution, while no hydrogen bonds are formed in the other three solutions. 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

Figure 7. Snapshot showing the hydrogen-bond between ETR and ethanol. Hydrogen bonds (distances less than 2.5 Å) are shown as blue dotted line.



Figure 8. RDFs between the O atom on the ETR molecule and the H atoms on four different solvent molecules. 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) < acetone (-10.05 kJ mol-1) < acetonitrile (-17.46 kJ mol-1) < ethanol (-21.56 kJ mol-1), and this order is completely consistent with the order of nucleation rate. Toluene has the stronger binding at nonpolar site 5, 6 and 7 than polar sites 1, 2, 3 and 4 since it tends to form π-π interactions with ETR. Among all the solute-solvent binding energies, the


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energy of ETR-toluene at site 6 is the largest, because the toluene and the pyridine ring of ETR molecule not only interact through C-H…N weak hydrogen bonds but also through π-π stacking. The second largest is the energy of ETR-ethanol at site 4, which can be explained by the formation of a strong hydrogen bonds with reasonable spatial orientation. The arithmetic mean of the binding energies over the seven sites was further calculated and the order is the same as the site 1: toluene (16.92 kJ mol-1) < acetone (18.36 kJ mol1)

◼

< acetonitrile (18.92 kJ mol-1) < ethanol (21.11 kJ mol-1). Solution spectroscopy

Compared to the solid spectrum of ETR, the solution spectrums have significant differences in the sulfonyl stretching vibration band. The IR spectra of solid crystalline material of ETR form I (Figure 10) show strong bands for the symmetric and asymmetric stretching frequencies of the sulfonyl at 1142 and 1295 cm -1, respectively. The solution spectrums in all four solvents shift to higher wavenumbers compared to the solid infrared spectrum, suggesting the expected weaker interactions of the sulfonyl in solution. Symmetrical stretching peaks of the sulfonyl of four solutions are almost at the same position with only 1-2 cm-1 difference, while the difference in the position of the asymmetric stretching peaks of the sulfonyl in the four solutions is obvious. Therefore, the asymmetric stretching vibration band of the sulfonyl was selected as a probe for solute-solvent interaction. The asymmetric stretching vibration region of the sulfonyl in ethanol shows a shoulder peak at 1306 and 1317 cm-1. In order to identify the assignment of two peaks in the shoulder peak, ETR-ethanol solution spectra of different concentrations was carried out, as shown in Figure 11. In the case of the lowest solution



concentration of 25.32 g/kg, the peak at 1306 cm -1 is covered by the peak at 1317 cm -1, thereby showing only one broad peak. As the ETR concentration increases, the peak intensity at 1306 cm -1 gradually increases, showing a shoulder peak. Considering the infrared spectrum of pure ethanol and the relatively low solubility of ETR in ethanol, we can infer that the peak at 1306 cm -1 should be attributed to the sulfonyl asymmetric stretching vibration, and the peak at 1317 cm -1 should be attributed to the in-plane bending vibration of ethanol. The shift in the asymmetric stretching vibration band of the 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 analysed for toluene, acetone, and acetonitrile solutions 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 spectrums 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.


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Figure 9. Optimized geometry of ETR-solvent dimers. Binding energy in kJ mol-1, calculated at B97-D3/def2QZVP level.



Figure 10. Solid-state IR spectrum of ETR form I and solution spectra of saturated concentrations at 25 °C of ETR in different solvents.


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Figure 11. Solution IR spectroscopy at different concentrations (25.32, 32.24, 39.18, 46.14 g/kg) of ETR in ethanol.

◼

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 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 solventindependent. So the limit step of the formation of ETR nucleus is the molecular arrangement along the ac plane. Along 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.


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Figure 12. The microscope image 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. 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. ETR molecule can interact with 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-3s-1 and the binding energy at site 1. Carbonyl serves as a shared functional group of model drugs in several studies of Rasmuson and coworkers,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-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.


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Figure 13. The relationship between the supersaturation required to reach the same nucleation rate of 200 m-3s-1 and the binding energy at site 1.

Figure 14. The 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 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 do 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


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nucleation becomes.

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SUPPORTING INFORMATION

Solubility Measurements details and Computational methods. Figure S1: PXRD patterns of ETR form I. Figure S2-S4: Induction time distributions of ETR in toluene，acetonitrile and ethanol at 10 °C, respectively. Figure S5-S7: Relationship between induction time and cumulative probability according to eq 2 of ETR in toluene, acetonitrile and ethanol at 10 °C, respectively. Figure 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.

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AUTHOR INFORMATION

Corresponding Author *Phone: +86-13820852735. Fax: +86-27405754. E-mail: [email protected].

Notes The authors declare no competing financial interest.

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ACKNOWLEDGMENTS

The authors are grateful to the financial support of National Natural Science Foundation of China (21776203



and 21576187) and the Natural Science Foundation of Tianjin Municipal Science and Technology Commission (No. 18JCYBJC21100)

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REFERENCES

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For Table of Contents Use Only

Investigating the Solvent Effect on Crystal Nucleation of Etoricoxib Yinghui Chai1,2, Liping Wang1,2, Ying Bao1,2*, Rugang Teng1,2, Yumin Liu1,2,3, Chuang Xie1,2

Synopsis: The combined solution infrared spectrum and DFT binding energy calculation successfully capture the solute-solvent interaction. The stronger the solvent binds to the sulfonyl group on the ETR molecule, the slower the nucleation becomes.


Investigating the Solvent Effect on Crystal Nucleation of Etoricoxib

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