Article pubs.acs.org/crystal
Insights into Cocrystal Polymorphic Transformation Mechanism of Ethenzamide−Saccharin: A Combined Experimental and Simulative Study Yao Tong, Zhanzhong Wang, Entao Yang, Bochen Pan, Leping Dang,* and Hongyuan Wei School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, People’s Republic of China S Supporting Information *
ABSTRACT: In this work, the solvent-mediated phase transformation of the metastable form (Form II) to the stable form (Form I) of ethenzamide− saccharin cocrystal in isopropanol was investigated. Solubility of Form I and Form II in pure isopropanol was also measured. The transformation mechanism from Form II to Form I was analyzed by some online and off-line tools including attenuated total reflectance Fourier transform infrared (ATRFTIR) spectroscopy, Raman spectroscopy, and polarizing microscopy. The results demonstrate that the transformation process consists of three steps, involving the dissolution of Form II, the nucleation of Form I, and the following growth of Form I. The ATR-FTIR and Raman results show that the polymorphic transformation from Form II to Form I is controlled by the nucleation and growth of Form I. Furthermore, the microscope photographs clearly reveal that the Form I preferably nucleates and grows on the (100) surface of Form II. The molecular simulation results indicate that higher adsorption energy and the exposure of more activity groups make the molecule adsorbed more strongly on the (100) surface, which is in agreement with the experimental observation. The results drawn in this work will be of great significance to control the formation of a desired polymorphic final product of ethenzamide−saccharin cocrystal.
1. INTRODUCTION Polymorphism is a common phenomenon, which means a compound may exist in more than one crystalline form and each of which displays different physical or chemical properties, such as stability, solubility, melting temperature, hygroscopicity, dissolution rate, bioavailability, etc.1,2 Polymorphism is explored widely in single-component crystals, but less in multicomponent crystals, e.g., cocrystals. Pharmaceutical cocrystals, which are intensely beneficial for pharmaceutical engineering, are multicomponent crystals in which active pharmaceutical ingredients (APIs) is held by noncovalent interactions with acceptable compounds.3,4 In the field of cocrystals, the study of the polymorphic transformation process is of significance since it is crucial to understand the transformation behaviors of all polymorphs and determine the final forms of the products.5−8 Therefore, it is indispensable to systematically study the mechanism of the cocrystal polymorphic transformation process. Generally, crystallization of polymorphs involves competitive nucleation and crystal growth of various polymorphs, and a metastable form will attempt to transform into the stable form.9,10 It is reported that the polymorphic transformation mechanism involves solution-mediated polymorphic transformation (SMPT) and solid-state polymorphic transformation (SSPT).11 SMPT takes place through the dissolution of the metastable form and the crystallization of stable form, while SSPT involves the ion or molecule rearrangement in the solid © 2016 American Chemical Society
state. Considering these two mechanisms, the former is relatively simple because of the solvent participation,12−14 which usually obeys Ostwald’s rule of stages. It is composed of three essential stages: (a) dissolution of the metastable phase, (b) nucleation of the stable phase, and (c) growth of the stable phase.15−17 Polymorphic transformation is difficult to control due to the complication of these steps. O’ Mahony et al.18 defined four principal scenarios including dissolution, growth, dissolution−nucleation, and nucleation−growth, which can be used to determine the overall transformation rate. As far as 2,6dihydroxybenzoic acid is concerned, Davey et al.19 found that the transformation rate was governed by the secondary nucleation of the stable form. It is generally believed that nucleation is a crucial step in the process of polymorphic transformation.19,20 In general, the stable form nucleates separately from the nucleation of the metastable form during the polymorphic transformation process. However, recent studies have revealed that the surface of the metastable form can facilitate the nucleation of the stable one. For the SMPT of piracetam in ethanol, Maher et al. confirmed that the nucleation step of Form III dominated the transformation rate, which was speculated to take place on the surface of Form II.21 For cocrystals of carbamazepine and Received: May 5, 2016 Revised: August 4, 2016 Published: August 15, 2016 5118
DOI: 10.1021/acs.cgd.6b00688 Cryst. Growth Des. 2016, 16, 5118−5126
Crystal Growth & Design
Article
Figure 1. Diagram of EA−SAC cocrystal (a) Form I, (b) Form II. experiment was carried out. After the completion of the transformation process at about 1000 min, the pure stable Form I was obtained by isolating the solid samples from the suspension. The obtained solid samples were characterized by several off-line techniques, including powder X-ray diffraction (PXRD), Fourier transform infrared (FT-IR) spectroscopy, Raman spectroscopy, and scanning electron microscopy (SEM). The crystal habits were observed using a SEM (JEOL Carry Scope scanning electron microscope JCM-5700). The PXRD investigations were carried out on a D/max-2500 diffractometer (Rigaku, Tokyo, Japan) at 40 kV, 100 mA with a Cu Kα radiation (1.5406 Å). The PXRD patterns were recorded from 2° to 40° in 2θ, with a scan speed of 8° min−1. The FT-IR spectra of solid samples were obtained by a TENSOR 27 spectrometer (Bruker, Germany) using KBr powder as the background, with wavenumber ranges from 3600 to 400 cm−1. An ATR-FTIR ReactIR 45m reaction analysis system equipped with a Duradisc DiComp probe (Mettler Toledo, Switzerland) was used to in situ monitor the concentration of EA and SAC in solutions by tracking the peak intensity at 1665 cm−1 for EA and at 1743 cm−1 for SAC. ATR-FTIR spectra from 2800 to 685 cm−1 were collected and analyzed by using the IC IR software. The Raman spectra was obtained by a Raman spectrometer (RXN2, Kaiser Optical Systems, Inc., Ann Arbor, MI), with wavenumber ranges from 1890 to 150 cm−1. This system is equipped with both a PhAT probe head and an MR probe head. The PhAT probe head with noncontact optics was used off-line to collect the powder Raman spectra of different samples, while the MR probe head was utilized as an immersion optics to in situ monitor the transformation process from Form II to Form I by tracking the peak intensity at 1715 cm−1 for Form I and at 1738 cm−1 for Form II. The spectral resolution is 5 cm−1. The instrument configuration, data acquisition, and process analysis are done by using the IC Raman software. A polarizing microscope (Olympus BX51, Tokyo, Japan) was used to observe the morphologies of cocrystals. 2.3. ATR-FTIR Calibration. The law of Lambert−Beer is the basic equation, which describes the relationship between the incident and transmitted radiation intensities in vibrational spectroscopy. It can be expressed as follows:
isonicotinamide, the plate-like crystals (Form I) grow at the expense of the needle-like crystals (Form II) during the transformation.22 However, the role of metastable form surface on inducing the nucleation of stable form is not completely understood at either the experimental or molecular level in the cocrystal polymorphic transformation process. Ethenzamide (CAS: 938-73-8, 2-ethoxybenzamide, EA) is a nonsteroidal anti-inflammatory drug, which is widely used in combination with other ingredients for the treatment of pain, inflammation, fever, and rheumatism.23,24 Saccharin (CAS: 8107-2, 1,1-dioxo-1,2-benzothiazol-3-one, SAC) is often employed as a pharmaceutically acceptable cocrystal former. EA and SAC can give an equimolar cocrystal which has a metastable polymorph (Form II) and a stable polymorph (Form I) (Figure 1).8,25,26 To determine the mechanism of the polymorphic transformation and confirm that pure polymorphs are produced, it is necessary to study the polymorphic transformation process of EA−SAC cocrystal. In this work, the solubility of the two cocrystal forms in isopropanol was measured. The transformation process between the two forms was investigated by applying some online and off-line approaches including attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, Raman spectroscopy and polarizing microscopy. The rate-determining step and the phenomenon of Form I nucleation on the surface of Form II were investigated and determined. Finally, the reason for the surface nucleation was revealed with the assistance of the molecular simulation.
2. EXPERIMENTAL AND MODELING METHODS 2.1. Materials. EA (Alfa Aesar Co. Ltd.) and SAC (AladdinReagent Technology Co. Ltd.) were used without any further purification. Their mass fraction purity is higher than 99.0%, which was determined by HPLC (Type Agilent 1100, Agilent Technologies, USA). Analytic grade isopropanol (purchased from Tianjin jiangtian Chemical Reagent Co. Ltd., the molar purities are higher than 99.5%) was used as solvent. 2.2. Preparation and Characterization of EA−SAC Cocrystal. The pure Form I and Form II were obtained with the assistance of Raman spectroscopy, which was used to ensure the identity of Form I and Form II. To produce the pure metastable Form II, EA (1.0 g, 6.05 mmol) and SAC (1.1 g, 6.05 mmol) were dissolved into 22.0 mL of isopropanol at 323.15 K, and then the solution was cooled at a constant cooling rate of 4 K·h−1 until it reached 298.15 K. Nucleation of Form II started at about 308 K. And at about 500 min, the suspension was filtered, washed, and dried. Then the pure metastable Form II was obtained. To produce the pure stable Form I, a similar
A = abc = log10
I0 I
(1)
where A refers to the absorbance, a is the absorption coefficient, b is the effective path length, c is the sample concentration, I0 and I stand for the radiation emitted by the spectrometer and the transmitted radiation of the sample, respectively.27 All IR spectra were collected by using the IC IR software, and each spectrum consisted of 128 scans with a resolution of 4 cm−1. To determine the concentrations of EA and SAC in isopropanol, several solutions of certain concentration have been prepared at 323.15 K, and the height of the carboxyl stretching band (CO) at 1665 cm−1 for EA and at 1743 cm−1 for 5119
DOI: 10.1021/acs.cgd.6b00688 Cryst. Growth Des. 2016, 16, 5118−5126
Crystal Growth & Design
Article
SAC in the IR spectra were used to obtain the calibration as shown in Figure S1 and Figure S2 (Supporting Information). 2.4. Solubility Determination. The solubility of Form I in isopropanol was measured as a function of temperature from 288.15 to 318.15 K using a gravimetric method. Excess Form I was added into the isopropanol to obtain the saturate solution. After being stirred for at least 24 h at various temperatures, the upper solution was filtered through a membrane (0.45 μm). Samples of the saturated solution were dried for more than 12 h under vacuum oven at 318.15 K until the solvent completely evaporated. The solubility was determined from the mass of the remaining crystalline material and the total mass of the solution. The solubility of Form II in isopropanol was measured in the temperature range of 288.15−318.15 K with the assistance of Raman spectroscopy, which was used to ensure the identity of Form II. The slurries of Form II were obtained by mixing isopropanol and Form II. Raman spectra were recorded with an interval of 1 min. During each experiment, a sample of the upper solution was taken using a syringe with a 0.45 μm membrane filter before a decrease of Raman intensity of Form II was observed. The rest of the steps were consistent with Form I. 2.5. Polymorphic Transformation Experiments. All transformation experiments from Form II to Form I were performed on an Easymax TM 102 (Mettler Toledo, Switzerland) with a 100 mL vessel. EA (1.0 g, 6.05 mmol) and SAC (1.1 g, 6.05 mmol) were added in 22.0 mL of absolute isopropanol at 323.15 K with an impeller at 300 rpm. After complete dissolution, the clear solution was cooled at a constant cooling rate of 4 K·h−1 until it reached 298.15 K. Two probes were used to visualize the cocrystallization and polymorphic transformation process in real time. The MR probe head of Raman spectrometer was immersed in the solution to determine the cocrystal form during the polymorphic transformation process. The ATR-FTIR system was employed to trace the concentration of solution online. The measurement durations were both set at 1 min. The suspension was periodically sampled and analyzed by polarizing microscopy and PXRD to verify its crystal form.
of the vacuum was 50 Å to make sure the nonbonded interactions reach their asymptotic values. One molecule was placed randomly in the center of a given surface. Minimization was carried out first in order to find an appropriate initial position. Then molecular dynamics (MD) calculations were performed to study the optimal adsorption structure on the surface of Form II with NVT ensemble. Usually 10 different initial positions and orientations of the docked molecule were investigated to ensure the global minimum energies. The simulation temperature was 298.15 K, and the Anderson method was used as the thermostat. The time step was 1 fs, and a 20 ps was calculated to reach equilibrium, followed by 200 ps sampling. The adsorption energy of the molecule with energetically favorable adsorption structure was defined as
Eadsorption = Esystem − (Esurface + Eadsorbate)
(2)
where Eadsorption is the adsorption energy of the molecule on the surface of Form II, Esystem is the total energy of the surface and the molecule, Esurface is the energy of the crystal surface alone, and Eadsorbate is the energy of the molecule alone. It is noted that the adsorption energy was normalized by the molecule number of the surface.
3. RESULTS AND DISCUSSION 3.1. Identification of EA−SAC Cocrystal Polymorphs. The PXRD patterns of Form I and Form II were measured and are shown in Figure 2. It can be observed that the PXRD
Scheme 1. Schematic Diagram of the Experimental Setup
Figure 2. PXRD patterns of (a) experimental Form II; (b) experimental Form I; (c) simulated Form II; (d) simulated Form I.
patterns of the two forms are consistent with the simulated results according to the single crystal data. There are characteristic peaks at 9.459°, 10.757°, 14.843°, 12.978°, 13.324° for Form I and 5.721°, 11.457°, 12.720°, 13.780°, 15.134°, 16.061°, 16.417° for Form II, respectively. These differences in characteristic peaks can not only be used to identify and distinguish different crystal forms but can also be applied to monitor the transformation process from Form II to Form I. Figure 3 illustrates the SEM images of Form I and II obtained in experiments and the crystal habits simulated from the AE model. As shown in Figure 3a, Form II presents an irregular block-like habit instead of a block-like crystal of Form I (Figure 3b). The simulated crystal habits in Figure 3c,d are consistent with the experimental results. All the main crystal surfaces could be observed in the simulated crystal habits. The effect of different crystal surfaces is analyzed in the following discussion. The FTIR spectra of Form I and Form II, as shown in Figure 4, can be used to further identify the two forms of EA−SAC cocrystal. It can be considered that the N−H stretching
2.6. Molecular Simulation. In this study, the COMPASS force field was selected due to its widely application in various types of covalent systems.28 The Ewald techniques and the atom based were adopted for the summation of van der Waals and electrostatic interactions, respectively. The Smart Minimizer method was employed in the iteration process. All the work was performed by using the Materials Studio from Accelrys. The molecular mechanics (MM) minimization was carried out before the crystal morphology simulation. The habits of Form I (ref code VUHFIO01) and Form II (ref code VUHFIO) were predicted using the attachment−energy (AE) model. On the basis of the optimized unit cell, the surface of Form II was cleaved, extended, and rebuilt into three-dimensional periodic boxes. Each of the surface dimensions was larger than 30 Å, and the thickness 5120
DOI: 10.1021/acs.cgd.6b00688 Cryst. Growth Des. 2016, 16, 5118−5126
Crystal Growth & Design
Article
Figure 3. SEM photographs of Form II (a) and Form I (b) of the EA−SAC cocrystal; crystal habits of the EA−SAC cocrystal calculated using the attachment−energy (AE) theory, (c) Form II, (d) Form I.
vibration 3459 cm−1 of Form II shifts to 3428 cm−1 of Form I due to the different crystal structures. Raman spectroscopy was successfully applied to identify the crystal forms, as illustrated in Figure 5. The Raman spectra of the two forms exhibit significant differences, which can be used to identify the polymorphic transformation. In this study, the peaks at 1715 and 343 cm−1 were selected to represent the Form I, whereas the Form II has two characteristics peaks at 1738 and 335 cm−1. 3.2. Solubility of EA−SAC Cocrystal. The solubility of polymorph is important thermodynamic data for determining the relative stability and relationship between different polymorphs. The solubility data of Form I and Form II in isopropanol were measured experimentally. The results are summarized in Table S1 (Supporting Information) and in
Figure 4. Infrared spectra of EA−SAC cocrystal Form I and Form II.
Figure 5. Raman spectra of EA−SAC cocrystal Form I and Form II. 5121
DOI: 10.1021/acs.cgd.6b00688 Cryst. Growth Des. 2016, 16, 5118−5126
Crystal Growth & Design
Article
Figure 6. The solubility of Form II was higher than that of Form I at the experimental temperatures. According to the
Figure 7. Time variations of the temperature (black solid line) and of the characteristic peak height of EA at 1665 cm−1 and SAC at 1743 cm−1 (red = EA; blue = SAC) during the solution-mediated transformation from Form II to Form I of EA−SAC cocrystal by using in situ ATR-FTIR spectroscopy.
Figure 6. Mole fraction solubility of the Form I and Form II of EA− SAC cocrystal in isopropanol. Solid lines are calculated data by the Van’t Hoff model.
thermodynamic rule,29,30 Form II is the metastable form, and the two forms have a monotropic relationship.8 It can also be seen that both the solubility values and the solubility difference between the two cocrystals are positively related to temperature. To better understand the trend of the solubility, the Van’t Hoff equation was employed to fit the solubility data of the two forms.31 ΔHd ΔSd + (3) RT R where x is the mole fraction of the EA−SAC cocrystals, and ΔHd and ΔSd are the dissolution enthalpy and entropy, respectively, which depend on the solid-state properties and the solution properties. T is the absolute temperature of the system, and R is the gas constant. The values of parameters and the coefficient of determination (R2) are listed in Table S2 (Supporting Information). It could be observed that the values of R2 are higher than 0.98, indicating the excellent accuracy and reliability of the Van’t Hoff equation (Figure S3). 3.3. Transformation Behaviors of Different Forms of EA−SAC Cocrystal. The transformation from Form II to Form I in isopropanol was investigated by various online and off-line analysis tools including ATR-FTIR spectroscopy, polarizing microscopy, SEM, and PXRD, and the results are shown in Figures 7−10, respectively. (In Figure 7, t = 0 min indicates the beginning of the whole experiment. In Figures 8, 10, and 11, t = 0 min indicates the time when the concentrations reached the solubility of Form II.) Figure 7 illustrates the exact change of concentrations of both EA and SAC as a function of time by controlling the temperature via in situ ATR-FTIR spectroscopy. It can be divided into two stages. During stage 1 (① in Figure 7), the concentrations of EA and SAC started to drop stoichiometricly at ca. 35 °C. This decrease can be attributed to the nucleation of Form II. Then the concentrations of EA and SAC dropped progressively, corresponding to the growth of Form II. This stage ended when EA and SAC concentrations reached equilibrium values. These values corresponded to the solubility of Form II in solution at 25 °C and remained constant for a period of 200 min. Stage 2 (② in Figure 7) began with the decline of EA and SAC concentrations again, which can be ln x = −
Figure 8. Morphology variation during the polymorphic transformation from Form II to Form I of EA−SAC cocrystal: (a) 0 min; (b) 150 min; (c) 210 min; (d) 350 min; (e) 460 min; (f) 560 min (scale bar: 100 μm). The red oval marks the location of the Form I crystals observed.
ascribed to the transformation from Form II to Form I. It took about 415 min to reach equilibrium, corresponding to the solubility of Form I.10,21 Figure 8 shows the morphology variation of EA−SAC cocrystals during the polymorphic transformation process captured by optical microscopy. It can be clearly observed that the irregular block-shaped Form II is dominated in the solution at the beginning of the transformation (t = 0 min, Figure 8a). After about 150 min (Figure 8b), a small number of block-shaped crystals (Form I) nucleate on the surface of Form II. In order to confirm that the block-like Form I does nucleate on the surface of the irregular block-like Form II, the SEM images are provided in Figure 9. The results demonstrate that the block-like crystals surely nucleate and grow on the surface of the irregular block-like Form II instead of adhering to the surface. With the transformation proceeding, the quantity of 5122
DOI: 10.1021/acs.cgd.6b00688 Cryst. Growth Des. 2016, 16, 5118−5126
Crystal Growth & Design
Article
according to the Raman spectroscopy, indicating the ending of the induction stage and the beginning of nucleation and growth of Form I. But the solution concentration still remained unchanged. In this stage, the growth of Form II is the controlling factor. With the further transformation, the Form II dissolved and Form I grew continuously. The solution concentration was consumed as well according to the decrease of IR intensity. Finally, the Raman peak intensities were no longer changed after enough time, which indicated that Form II had transformed to Form I completely. As a consequence, on the basis of the changes in the relationship between polymorph content and solution concentration described by O’Mahony et al.,18 it is concluded that the polymorphic transformation process of EA−SAC cocrystal from Form II to Form I is controlled by the nucleation and growth of Form I.
Figure 9. SEM images (a, c) and a close view of a selected area (b, d) of a block-like crystal (Form I) growing on the surface of Form II.
Form I increases and its crystal size turns larger. Interestingly, it can be observed in Figure 8 that the crystal growth rate of Form I is the fastest on (100) face of Form II (Figure 8c−e) according to the Figure 3c. This may be triggered by the preferential adsorption of molecular on the (100) surface. In addition, the dissolving process of Form II can be obtained by comparing Figure 8d with Figure 8e. This result also indicates that the different surfaces have a different capability to act as nucleation templates for the stable form. The progress of the transformation was also monitored by off-line PXRD. Figure 10 shows the PXRD patterns of EA−
Figure 11. Changes of Raman relative intensity and IR peak height during the transformation process from form II to form I of EA−SAC cocrystal in isopropanol solvent.
3.5. Modeling and Mechanism Discussion. Molecular simulation is an advantageous tool in crystallization research, which could provide not only molecular-level insights concerning the nucleation and growth of cocrystals in solutions but also the controlling issues such as supersaturation, surface chemistry, additives and solvents, etc.32−36 Molecular simulation also helps probe the molecular events in polymorphic transformation, which is arduous to track in experiments.37,38 3.5.1. Lattice Matching between the Surfaces of Two Polymorphs of EA-SAC. The nucleation and growth of crystals on substrates have usually been interpreted as epitaxy, which is characterized by comparing the two-dimensional lattice parameters of the substrate with that of the overlayer of a growing crystal.39,40 Accordingly, the possible contacting surfaces of Form I and Form II were primarily examined by using EpiCalc 5.0. A dimensionless potential energy parameter V/V0 was calculated, which indicates the goodness-of-fit between the substrate and overlay lattices. The results may be divided as follows: commensurate, complete matching of the crystal faces, V/V0 = 0; coincidence, partial matching, V/V0 = 0.5; and incommensurate, no matching between the crystal faces, V/V0 = 1. The interface between substrate lattices (Form II) and overlayer lattices (Form I) can be described by several parameters aII, bII, and ωII (lattice constants of Form II), aI, bI, and ωI (lattice constants of Form I) and orientation angle θ, defining as the azimuthal angle of the overlayer in regard to the
Figure 10. Change of PXRD patterns during the polymorphic transformation from Form II to Form I of EA−SAC cocrystal: (a) 0 min; (b) 150 min; (c) 210 min; (d) 350 min; (e) 460 min; (f) 560 min.
SAC cocrystals solid sampled at different times, which clearly indicate the transformation process from Form II to Form I in the solution. As transformation starts, the intensity of peak at 5.721° and 12.720° (peaks of Form II) decreases, while that at 9.459° and 14.843° (peaks of Form I) increases. 3.4. Measurement of the Rate-Determining Step in the Polymorphic Transformation. To investigate the ratedetermining step in the polymorphic transformation, the SMPT from Form II to Form I of EA−SAC cocrystal was monitored by using in situ Raman and ATR-FTIR spectroscopies. First, Form I could not be detected, and the content of Form II was constant as well as the solution concentration before ca. 150 min. At this time, the solution was saturated with respect to Form II according to the IR spectroscopy. In this stage, the nucleation of Form I is the controlling step. Then in the next 50 min, the content of Form II decreased, and Form I emerged 5123
DOI: 10.1021/acs.cgd.6b00688 Cryst. Growth Des. 2016, 16, 5118−5126
Crystal Growth & Design
Article
substrate.40,41 The value used for overlayer size was 25b1 × 25b2 in every case. The lattice parameters of Form II and Form I are summarized in Table 1. It should be noted that the minimum
probabilities of the Form I nucleation on (011), (111), and (001) surfaces of the Form II at the molecular level. 3.5.2. Adsorption of Molecules on the Surfaces of Form II. The adsorption ability of molecule to different surfaces of the Form II mainly depends on the surface structure and molecular conformation. As shown in Figure 12, it can be observed that different functional groups with diverse orientations are exposed on the surfaces of Form II. In the six surfaces of Form II, all the four surfaces except (001) and (110) surface possess an exposed group which can form a hydrogen bond with the adsorption molecules on the surface. As an example, there are both H atoms from the N−H bond and the carbonyl O atom in EA as well as O atoms from the SO bond in SAC molecules exposed on the (100) face of Form II, which may be beneficial to form a hydrogen bond with the molecules absorbed on the surface. Therefore, the adsorption process on the four surfaces ((010), (011), (100), and (111)) was mainly studied in the following discussion. In general, the average values of adsorption energies can be used to determine the adsorption capability of the molecules on different surfaces.42,43 Table 3 presents the results of adsorption energies calculated according to eq 1, which are the average values over the 10 different initial orientations of the docked molecule. The standard deviation is given in Table S3 in the Supporting Information. It is obvious that the adsorption energy of different surfaces with the adsorbed molecular is negative. It is recognized that the average value of the adsorption energy follows the order (100) > (011) > (010) > (111), which indicates that the adsorption capability of the molecules with the (100) surface is much stronger than that of the other three surfaces. Therefore, the crystal will grow better and faster on the (100) surface, which is consistent with the experimental results in Figure 8.
Table 1. Lattice Parameters of Form II and Form I Form
crystal surface (hkl)
aII (Å)
bII (Å)
ωII (deg)
II II II II II II Form
(001) (100) (111) (011) (110) (010) crystal surface (hkl)
7.214 7.492 8.506 7.214 15.456 15.456 aI (Å)
7.492 15.456 16.595 16.595 8.506 7.214 bI (Å)
70.65 85.14 104.51 84.74 91.25 86.43 ωI (deg)
I I I I
(011) (020) (110) (101)
8.613 11.183 11.183 14.287
20.021 8.613 18.707 16.607
89.19 91.45 90.67 90.00
V/V0 results of Form I on the surface of Form II were presented by using parameters of unit cell or supercell of Form II and Form I. The results including V/V0 and θ are shown in Table 2. It can be obtained that the (110) surface of Form II Table 2. Calculation Results for Potential Lattice Matching between the Contacting Surface of Form II and Form I II face (hkl)
I face (hkl)
θ (deg)
V/V0
(001)
(011) (020) (110) (101) (011) (020) (110) (101) (011) (020) (110) (101) (011) (020) (110) (101) (011) (020) (110) (101) (011) (020) (110) (101)
24.25 107.75 39.75 150.50 44.25 43.00 47.50 175.25 180.00 104.50 0.00 104.50 154.50 49.00 44.50 54.50 90.75 180.00 62.25 0.00 69.75 145.75 139.75 149.75
0.97 0.79 0.92 0.95 0.99 0.98 0.97 0.96 0.94 0.94 0.98 0.91 0.98 0.98 0.66 0.52 0.79 0.77 0.98 0.49 0.98 0.98 0.54 0.61
(100)
(111)
(011)
(110)
(010)
4. CONCLUSIONS In summary, the SMPT from Form II to Form I of EA−SAC cocrystal was studied by some online and off-line tools. The solubilities of Form I and Form II in isopropanol were experimentally determined. From the solubility data, it was found that the Form II is more soluble than the Form I and it will transform to Form I. The transformation process involves three stages, i.e., the dissolution of Form II and nucleation and growth of Form I. The results show that the transformation rate is regulated by the nucleation and growth of Form I and it belongs to scenario (d) as outlined by O’Mahony et al. In addition, this work clearly demonstrates that nucleation of the stable Form I occurs on the surfaces of the metastable Form II, via monitoring by optical microscopy. It is also found that the Form I preferably nucleates and grows on the (100) surface of Form II. Furthermore, the molecular simulation indicates that the molecule is adsorbed most strongly on the (100) surface by calculating the adsorption energy, which is consistent with the experimental results. Therefore, according to the transformation behaviors, a desired EA−SAC cocrystal form can be isolated by controlling the system temperature or transformation time in the crystallization processes, which lays a foundation for controlling the solvent-mediated phase transformation from Form II to Form I of EA−SAC cocrystal in the future.
and the (101) surface of Form I are coincident, whereas our experiment results indicated that the (110) of the Form II is not the most preferable surface to nucleate the Form I (see Section 3.3). Therefore, it demonstrated that a greater lattice match may not mean that the (101) surface of Form I will preferably grow on the (110) surface of Form II. In other words, lattice matching may not the dominant reason for the nucleation of Form I on the surface of Form II.37,39 Therefore, molecular simulation is carried out to understand the different 5124
DOI: 10.1021/acs.cgd.6b00688 Cryst. Growth Des. 2016, 16, 5118−5126
Crystal Growth & Design
Article
Figure 12. Morphologically important surfaces of EA−SAC cocrystal Form II: C gray, H white, N blue, O red, S yellow.
Table 3. Adsorption Energy (kcal·mol−1) of the Molecules on the Surfaces of Form II
■
surface
(010)
(011)
(100)
(111)
adsorption energy (kcal·mol−1)
−38
−39
−44
−30
(8) Aitipamula, S.; Chow, P. S.; Tan, R. B. H. CrystEngComm 2009, 11, 889−895. (9) Kitamura, M. J. Cryst. Growth 2002, 237-239, 2205−2214. (10) Croker, D.; Hodnett, B. K. Cryst. Growth Des. 2010, 10, 2806− 2816. (11) Du, W.; Yin, Q. X.; Hao, H. X.; Bao, Y.; Zhang, X.; Huang, J.; Li, X.; Xie, C.; Gong, J. B. Ind. Eng. Chem. Res. 2014, 53, 5652−5659. (12) Su, W. Y.; Hao, H. X.; Barrett, M.; Glennon, B. Org. Process Res. Dev. 2010, 14, 1432−1437. (13) Wu, H.; Reeves-McLaren, N.; Jones, S.; Ristic, R. I.; Fairclough, J. P. A.; West, A. R. Cryst. Growth Des. 2010, 10, 988−994. (14) Maher, A.; Seaton, C. C.; Hudson, S.; Croker, D. M.; Rasmuson, Å. C.; Hodnett, B. K. Cryst. Growth Des. 2012, 12, 6223−6233. (15) Liu, W. J.; Wei, H. Y.; Black, S. Org. Process Res. Dev. 2009, 13, 494−500. (16) Jiang, S.; Jansens, P. J.; ter Horst, J. H. Cryst. Growth Des. 2010, 10, 2541−2547. (17) Maher, A.; Rasmuson, Å. C.; Croker, D. M.; Hodnett, B. K. J. Chem. Eng. Data 2012, 57, 3525−3531. (18) O’Mahony, M. A.; Maher, A.; Croker, D. M.; Rasmuson, Å. C.; Hodnett, B. K. Cryst. Growth Des. 2012, 12, 1925−1932. (19) Davey, R. J.; Blagden, N.; Righini, S.; Alison, H.; Ferrari, E. S. J. Phys. Chem. B 2002, 106, 1954−1959. (20) Mnyukh, Y. Fundamentals of Solid-State Phase Transitions, Ferromagnetism and Ferroelectricity; AuthorHouse: Bloomington, IN, 2001. (21) Maher, A.; Croker, D. M.; Rasmuson, Å. C.; Hodnett, B. K. Cryst. Growth Des. 2012, 12, 6151−6157. (22) ter Horst, J. H.; Cains, P. W. Cryst. Growth Des. 2008, 8, 2537− 2542. (23) Ozawa, M.; Hasegawa, K.; Yonezawa, Y.; Sunada, H. Chem. Pharm. Bull. 2002, 50, 802−807. (24) Uehara, H.; Otsuka, H.; Lzumi, K. Cancer Lett. 1998, 135, 83− 90. (25) Tong, Y.; Zhang, P.; Dang, L. P.; Wei, H. Y. Chem. Eng. Res. Des. 2016, 109, 249−257. (26) Tong, Y.; Wang, Z. Z.; Dang, L. P.; Wei, H. Y. Fluid Phase Equilib. 2016, 419, 24−30. (27) Schrader, B., Ed. Infrared and Raman Spectroscopy; VCH: Weinheim, 1995. (28) Sun, H. J. Phys. Chem. B 1998, 102, 7338−7364. (29) Grant, D. J. W. Marcel Dekker: New York, 1999; pp 1−33. (30) Grunenberg, A.; Henck, J. O.; Siesler, H. W. Int. J. Pharm. 1996, 129, 147−158. (31) Nordstrom, F. L.; Rasmuson, C. Eur. J. Pharm. Sci. 2009, 36, 330−344. (32) Yani, Y.; Chow, P. S.; Tan, R. B. H. Mol. Pharmaceutics 2011, 8, 1910−1918.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.6b00688. Calibration curves of peak height against known concentrations; experimental mole fraction solubility of EA−SAC in isopropanol at various temperatures and the corresponding results fitted by using the Van’t Hoff equation; adsorption energy and standard deviation of the molecules on the surfaces of Form II (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Tel: +86-22-27405754. Fax: +86-22-27400287. Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS We thank the financial support by the National Natural Science Foundation of China (21576196, 21406158) and Doctoral Fund of Ministry of Education of China (20130032120020) for their financial assistance in this project.
■
REFERENCES
(1) Vippagunta, S. R.; Brittain, H. G.; Grant, D. J. W. Adv. Drug Delivery Rev. 2001, 48, 3−26. (2) Bernstein, J. Cryst. Growth Des. 2011, 11, 632−650. (3) Qiao, N.; Li, M.; Schlindwein, W.; Malek, N.; Davies, A.; Trappitt, G. Int. J. Pharm. 2011, 419, 1−11. (4) Aitipamula, S.; Chow, P. S.; Tan, R. B. H. CrystEngComm 2014, 16, 3451−3456. (5) Vishweshwar, P.; McMahon, J. A.; Bis, J. A.; Zaworotko, M. J. J. Pharm. Sci. 2006, 95, 499−516. (6) Aitipamula, S.; Wong, A. B. H.; Chow, P. S.; Tan, R. B. H. CrystEngComm 2012, 14, 8193−8198. (7) Zaworotko, M. J. Cryst. Growth Des. 2007, 7, 4−9. 5125
DOI: 10.1021/acs.cgd.6b00688 Cryst. Growth Des. 2016, 16, 5118−5126
Crystal Growth & Design
Article
(33) Anuar, N.; WanDaud, W. R.; Roberts, K. J.; Kamarudin, S. K.; Tasirin, S. M. Cryst. Growth Des. 2012, 12, 2195−2203. (34) Yang, X. Y.; Qian, G.; Duan, X. Z.; Zhou, X. G. Cryst. Growth Des. 2013, 13, 1295−1300. (35) Yang, X. Y.; Qian, G.; Duan, X. Z.; Zhou, X. G. Ind. Eng. Chem. Res. 2012, 51, 14845−14849. (36) Hou, X. X.; Feng, Y. N.; Zhang, P.; Wei, H. Y.; Dang, L. P. Cryst. Growth Des. 2015, 15, 4918−4924. (37) Liang, S. S.; Duan, X. Z.; Zhang, X. Y.; Qian, G.; Zhou, X. G. Cryst. Growth Des. 2015, 15, 3602−3608. (38) Childs, S. L.; Chyall, L. J.; Dunlap, J. T.; Smolenskaya, V. N.; Stahly, B. C.; Stahly, G. P. J. Am. Chem. Soc. 2004, 126, 13335−13342. (39) O’Mahony, M. A.; Seaton, C. C.; Croker, D. M.; Veesler, S.; Rasmuson, A. C.; Hodnett, B. K. Cryst. Growth Des. 2013, 13, 1861− 1871. (40) Hillier, A. C.; Ward, M. D. Phys. Rev. B: Condens. Matter Mater. Phys. 1996, 54, 14037−14051. (41) Chadwick, K.; Chen, J.; Myerson, A. S.; Trout, B. L. Cryst. Growth Des. 2012, 12, 1159−1166. (42) Qian, G.; Wu, Y. Y.; Yang, X. Y.; Duan, X. Z.; Zhou, X. G. J. Cryst. Growth 2013, 373, 78−81. (43) Walker, E. M.; Roberts, K. J.; Maginn, S. J. Langmuir 1998, 14, 5620−5630.
5126
DOI: 10.1021/acs.cgd.6b00688 Cryst. Growth Des. 2016, 16, 5118−5126
