Structural Correspondence of the Oriented Attachment Growth

Article pubs.acs.org/Langmuir

Structural Correspondence of the Oriented Attachment Growth Mechanism of Crystals of the Pharmaceutical Dirithromycin Zuozhong Liang,† Yuan Wang,† Wei Wang,† Xianglong Han,† Jian-Feng Chen,*,†,‡ Chunyu Xue,*,§ and Hong Zhao*,† †

State Key Laboratory of Organic−Inorganic Composites, ‡Research Center of the Ministry of Education for High Gravity Engineering and Technology, and §Biomass Energy and Environmental Engineering Research Center, Beijing University of Chemical Technology, Beijing 100029, China S Supporting Information *

ABSTRACT: The oriented attachment (OA) mechanism is promising for designing novel nanomaterials, yet an intensive understanding of the relationship between the crystal structure and attachment orientation is still lacking. In this work, we report layered hexagonal crystals of the pharmaceutical dirithromycin (DIR) containing multiple layers fabricated via a solvothermal method for a certain period of time at 40 °C. These elongated hexagonal crystals experience an OA that is preferentially on the face (001) of the initial crystals to assemble the final crystals into layered stacks. Through agreement with molecular modeling calculations, we predicted the final crystal growth morphology and confirmed the favored attachment surface based on the energy change ΔE following an OA event. These simulation results at the molecular level yielded good agreement with the crystal growth experiments. This study demonstrates the critical importance of combining experiments with a computational approach to understand the intrinsic molecular details of the OA growth mechanism of other compounds and to design nanomaterials with a desirable morphology and physical and chemical properties.

1. INTRODUCTION Understanding crystal growth mechanisms is critical in controlling the crystal structure, size, and morphology.1 These characteristics affect the physical and chemical properties and potential promising applications.2 Typically, crystals grow at the expense of surrounding small particles, so-called Ostwald ripening.3 Recently, oriented attachment (OA) has played an important role in crystallization of synthetic materials systems.4 Many contributions have described materials experiencing oriented growth through experiments involving metals (e.g., Ag5−7 and Au8), oxides (e.g., ZnO,9 TiO2,10 and Mn3O411), composites (e.g., KxWO312), semiconductor compounds (e.g., CdS,13 CdSe,14 PbS,15 and PbSe16), metallic alloys (e.g., PtAg17), carbonates (e.g., CaCO318), etc. Recent progress has indicated that an increasing number of materials were reported based on OA.19,20 Son et al.21 recently demonstrated the OA growth mechanism of organic nanotubes, while these nanotubes were amorphous. Although the OA growth process has often been investigated for inorganic nanomaterials, its observation in the growth mechanism of crystalline organic compounds has been, to the best of our knowledge, rarely reported. Regarding this issue, computational simulations have enabled the prediction of thermodynamic morphology and provided insights into the details of OA by calculating the energies of each exposed crystal surface. For example, Sarkar et al.22 © 2015 American Chemical Society

calculated the formation energy of ZnSe for coupled dots and the corresponding rod by density functional theory (DFT), and these results agreed well with experimental observations. Peng et al.17 studied the formation of Pt−Ag nanowires experimentally, together with DFT calculation and molecular dynamics (MD) simulation, and found that OA is driven by several factors of both thermodynamics and kinetics. Furthermore, Zhang et al.23 calculated the orientation-dependent OA energies of 30 different compound crystals using molecular energetic calculations and specifically indicated that OA energies are primarily determined by crystal structure. It should be noted that we still lack a full and comprehensive understanding of the relationship between OA events and crystal structure. Accordingly, a deep exploitation of this emerging growth mechanism at the molecular level based both experimental characteristics and theoretical calculations has great significance for designing new materials and practical applications, and has yet to be reported. In this work, we crystallized an organic pharmaceutical molecule into an elongated hexagonal shape and, subsequently, assembled them into multilayered structures using a solvothermal method with an OA growth mechanism. Received: August 4, 2015 Revised: October 12, 2015 Published: December 3, 2015 13802

DOI: 10.1021/acs.langmuir.5b02901 Langmuir 2015, 31, 13802−13812

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Scanning electron microscopy (SEM) images were observed by an electron microscope (JEOL, JSM-7800, Japan) at 5 and 10 kV. Transmission electron microscopy (TEM), high-resolution TEM (HRTEM) images, and selected area electron diffraction (SAED) data were obtained by a microscope (JEOL, JEM-2100, Japan). The crystal structure of DIR was determined by an X-ray single crystal diffractometer with MoKα radiation (λ = 0.7107 Å) in the range of 2θ = 6.12−52° at 100.3 K (Agilent, Gemini E, America). A total of 23 039 reflection points were collected, and 9659 points were independent [R(int) = 0.0416]. The morphology of single DIR crystals in a saturated solution of DMF was observed using optical microscopy (Olympus BX-41, Japan) and recorded with a camera that was connected to a computer. 2.4. Simulation. In this work, all of the MD simulations were carried out with Materials Studio 6.0 (Accelrys Software Inc., CA, 2012). The theoretical X-ray powder patterns were calculated based on the corresponding unit cell by the Reflex module of Materials Studio. We first predicted the ideal morphology of DIR from its internal crystal structure in the Morphology module. The equilibrium morphology of DIR was computed by calculating the surface energy Esurf. The equilibrium morphology of a crystal structure is determined by minimizing the surface energies of all relevant crystal faces at a temperature of 0 K.24 The growth morphology method,25 which assumes that the growth rate is proportional to the attachment energy (Eatt) of a crystal face, was used under the COMPASS force field. Eatt is calculated for a series of slices (hkl) and is the released energy when a new slice is attached on a growing crystal surface. The growth morphology method based on the attachment energy (AE) model does not take the external solvent effects into consideration. Therefore, a modified AE (MAE) model accounted for the solvent effects by reducing the vacuum Eatt using the solvent/crystal interface interactions.26 Subsequently, the exposed morphologically important faces (hkl) were obtained, cleaved, and extended with a depth of 2 × dhkl. Then, a 3D periodic superstructure of 3a × 3b, named the crystal layer, was built with an 80 Å vacuum gap along the c direction normal to the cleaved surface. Furthermore, the crystal layer was optimized by MD simulation, and the resulting potential energy was defined as Ecrystal. Then, the solvent layer was constructed, which contains a random arrangement of DMF molecules based on the experimental density in the Amorphous Cell module. The subsequent MD simulation was performed with an isothermal-isovolumetric ensemble (NVT − constant particles N, constant volume V, and constant temperature T) for 5 ps using an Andersen thermostat as the temperature control algorithm with ΔT = 10 K. The electrostatic interactions were calculated by the Ewald summation, with an accuracy of 0.001 kcal/mol with COMPASS-force-field assigned charges. van der Waals interactions were computed using an atom-based summation with a cutoff distance of 12.5 Å. Similarly, the geometry configuration was performed using the Smart algorithm and with 500 as the maximum number of iterations. The potential energy was expressed as Esolvent. Eventually, the interfacial model was constructed, which contains the fixed crystal layer, unconstrained solvent layer and a vacuum layer (50 Å) to eliminate the boundary effects. The MD simulation of the interfacial model was also conducted, and the ultimate potential energy was named Ebox. The interfacial interaction energy Econtact between the solvent layer and the crystal layer was calculated using the following formula:

Dirithromycin (DIR), an important macrolide antibiotic pharmaceutical, was selected as a model for crystallization and subsequent growth. The specific structural feature of DIR is its 14-membered lactone ring with two sugar moieties affiliated by a glycosidic bond (Scheme 1). N,N-Dimethylformamide Scheme 1. Molecular Structure of Dirithromycin: C42H78N2O14or (2R,3R,6R,7S,8S,9R,10R,12R,13S,15R,17S)9-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6methyloxan-2-yl]oxy}-3-ethyl-2,10-dihydroxy-7{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2yl]oxy}-15-[(2-methoxyethoxy)methyl]-2,6,8,10,12,17hexamethyl-4,16-dioxa-14-azabicyclo[11.3.1]heptadecan-5one

(DMF) was used as the solvent in the solvothermal preparation. Herein, we will present that computational simulation can provide a means to study the relationship between crystal structure and crystal morphology and make it feasible to study the OA growth process. A schematic model illustrating the construction of layered crystals is proposed based on evidence for the growth process from both experimental and computational results. This work will be useful for the investigation of other layered growth materials and will have significant potential for integrated OA growth mechanisms.

2. EXPERIMENTAL SECTION 2.1. Materials. Commercial dirithromycin (DIR, C42H78N2O14, 98.5%) was purchased from Hunan Jiudian Pharmaceuticals Corporation, and DMF (C3H7NO) was purchased from Beijing Chemical Works. 2.2. Sample Preparation. In a typical experiment, the multilayered hexagonal crystals were obtained by a solvothermal process. The commercial raw drug DIR (3 g) was dissolved in DMF (50 mL) at room temperature. The resulting solution, as a precursor, was stirred for 5 min by a magnetic stirrer and then transformed into a stainless steel autoclave for the solvothermal treatment at 40 °C for 24 or 48 h. To obtain the corresponding structure of single DIR crystals in DMF, the slow solvent evaporation method was used at room temperature. Raw DIR material (0.4 g) was dissolved in 10 mL of DMF to prepare a saturated solution. Over a period of 5 days, elongated hexagonal crystals were obtained. 2.3. Characterization. X-ray powder diffraction (XRD) pattern of the crystallized product was measured using a X-ray diffractometer (Bruker, D8 Advance, Germany) with CuKα radiation (λ = 1.54 Å) at 140 mA and 30 kV, respectively. The CP/MAS 13C solid-state NMR spectrum of DIR raw materials was recorded at 75.47 kHz (Bruker, AV300, Germany). The thermal gravity (TG) and differential scanning calorimetry (DSC) analyses were carried out by a simultaneous thermal analyzer (Netzsch, STA-449C, Germany) between 20 and 500 °C at constant heating rate of 10 °C/min in an Ar atmosphere.

Econtact = E box − Ecrystal − Esolvent

(1)

Because Eatt is based on the unit cell, the solvent effect Es used to modify Eatt can be obtained by the following formula: Es =

EcontactAhkl NA box

(2)

where Ahkl is the surface area of the most exposed face (hkl) in the unit cell, Abox is the total surface area of the supercell, and N is the number of DIR molecules in each crystal layer. Therefore, the modified attachment energy Emod can be modified by introducing Es: 13803


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Figure 1. Experimental X-ray diffraction pattern (a) and SEM image (b) of DIR raw materials.

Figure 2. XRD and SEM characterization of DIR crystals in DMF solvent prepared by the solvothermal method at 40 °C for 24 h (a,b) and 48 h (c,d).

Emod = Eatt − Es

vacuum gap was built, and the geometry was optimized. The energy of this part was named Eup. Then, we constructed the interface of the two supercells to model the OA of the initial crystals. After the geometry optimization, we obtained the final total energy of the model, named Eattached. Finally, the OA energy change, ΔE, is the difference between the energy after they were attached Eattached and the energy when they were initially “infinitely” far away, Eup and Edown. This means that the energy change ΔE of the OA on the interface can be defined by the following equation:

(3)

Eventually, Emod was used to generate the modified crystal morphology of DIR under the effect of the DMF solvent. Moreover, we described the interactions in crystal interfaces using the force field method and calculated the total energy Eattached and energy change ΔE of the initial crystals arising from the OA using geometry optimization. First, 3D periodic supercells of the cleaved (hkl) surface with dimensions 2a × 2b × 1c and a vacuum gap (50 Å) along the c direction was built. Then, the geometry optimization was carried out in the Forcite module. The simulation involved 500 iterations using the Smart algorithm under a convergence tolerance of 0.001 kcal/mol for energy and 0.5 kcal/mol/Å for farce. Similarly, the electrostatic interactions were computed by the Ewald summation with an accuracy of 1 × 10−3 kcal/mol. The van der Waals interactions were computed using an atom-based summation method with a cutoff of 12.5 Å. The energy of this supercell with the vacuum layer was named Edown. Second, a 3D periodic supercell of the same size but without the

ΔE = Eattached − (Eup + Edown)

(4)

ΔE can reflect the stability of the constructed structure and the possibility of the OA event occurring on this surface. Here, we calculated the ΔE of five possible OA events [(001)/(001), (100)/ (100), (110)/(110), (100)/(001), and (001)/(100)] in which two supercells are attached on the most exposed (001), (100), and (110) surface. 13804


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Figure 3. TG−DSC curves of DIR raw materials (a) and the prepared DIR products at 40 °C for 24 h in DMF solvent (b).

3. RESULTS AND DISCUSSION 3.1. Elongated Hexagonal Crystals of DIR. To date, the OA crystal growth of an organic compound sharing a common crystallographic orientation has not been reported, to the best of our knowledge. DIR, as a standard small-molecular pharmaceutical molecule, is one of a new generation of the macrolide antibiotic family. The crystalline phase and shape of commercial DIR raw materials were analyzed using XRD and SEM, as shown in Figure 1. The measured XRD pattern is clearly distinguishable in the pattern of DIR (JCPDS file no. 502292) (Figure 1a). Furthermore, the experimental XRD pattern is mainly consistent with the polymorphic form II of reported27 and calculated diffraction patterns (Supporting Information Figure S1). However, the different diffraction peaks appeared at 2θ = 7.7°, 10.3°, and 11.5° can be indexed to form I (JCPDS file no. 50-2293) of DIR. This indicates that there is a possible admixture of another polymorphic form in the raw material. The 13C solid-state NMR spectrum of the raw material (Figure S2) further confirms the existence of form I.28 However, the form I of DIR is metastable27 or a less stable28 polymorphic form. Therefore, the presence of such an admixture (form I) cannot dramatically affect the crystallization pathway of DIR in DMF solvent. A panoramic view of the SEM image (Figure 1b) reveals that the raw material consisted of small particles with nonuniform morphology and crystal size. The diameter of the particles ranged from 10 to 100 μm. Before solvothermal treatment, a supersaturated solution (3 g/50 mL) was prepared by dissolving excess DIR raw material into DMF solvent. DIR crystals formed very fast at the beginning of the dissolution and recrystallization process in the supersaturated environment. The resulting precursors showed a hexagonal morphology with a broad crystal size distribution (∼5−50 μm; Figure S3). Our study on the control of crystal growth was mainly carried out through a time-based experiment. Figure 2 presents the XRD patterns and SEM images of the DIR products after solvothermal treatment in the same concentrations of DMF (3 g/50 mL) at 40 °C for 24 and 48 h. The XRD patterns from the samples after different hydrothermal reaction times show extremely similar diffraction peaks, indicating that the crystalline phase was the same in the samples. The sharp characteristic peaks of the powder XRD patterns also confirmed that the degree of crystallinity of the solvothermally synthesized samples was very high. At the same time, the diffraction peak at 2θ = 9° of the DIR crystals prepared solvothermally for 48 h clearly decreased (Figure 2c). The most intense peak (110) indicates the fast growth direction of the morphology (Figure 2a). Therefore, the decreased relative peak intensity can be

explained by the further growth of the most exposed surrounding faces (100) and (001) and the suppression of the crystal growth along the y direction with additional reaction time.29 However, extensive comparison of the XRD patterns of the synthesized samples and raw materials indicates the great difference of the diffraction peaks (Figure 1a, Figure 2a,c). Such differences are likely due to the changes in the intrinsic crystal structures at the molecular level. SEM analysis reveals that the obtained DIR crystals grown for 24 and 48 h have elongated hexagonal-like morphologies with multiple layers (Figure 2b,d). This indicates that the DIR molecules prefer to form elongated hexagonal crystals and grow along all directions normal to the most exposed surfaces (i.e., (110) and (100)) during the solvothermal growth process. Note that the most distinct changes in the observed crystals were their increasing thickness from ∼2 μm to ∼7 μm with the increase in reaction time (Figure 2b,d). Furthermore, the SEM images clearly show that the crystals appear as layered stacks of closely attached thinner ones. After 24 h of solvothermal treatment, the crystals experienced layered growth along the x-axis and formed elongated hexagonal shapes with 3−7 layers (Figure 2b and Figure S4). With a further increase in reaction time (48 h), crystals with more layers (10−15) were obtained (Figure 2d and Figure S5). The layered crystal structure was also confirmed by the TEM image (Figure S6). In addition, the HETEM image and SAED profile from a part of the crystal show a well-resolved DIR (300) (0.476 nm) crystalline lattice, indicating the highly crystalline nature of prepared DIR crystals (Figure S7). The increase in crystal layers leads to an increase in crystal thickness, which is a sign of an OA growth mechanism. The thickness of the prepared crystals clearly increases, which is also directly evidenced by the XRD observations. As a result, OA growth takes place for DIR crystals with solvothermal treatment. The structure of the DIR raw materials and the DIR samples solvothermally prepared at 40 °C for 24 h in DMF solvent were investigated by the simultaneous TG and DSC curves, as shown in Figure 3. One can see that the mass loss of the DIR raw material remained constant in the beginning without any weight loss and dropped rapidly from 250 to 350 °C due to the decomposition of DIR (Figure 3a). However, there was a gradual mass loss from 120 to 140 °C for the solvothermally prepared samples (Figure 3b), which is mainly attributed to the desolvation of the DMF solvent molecule. A similar phenomenon was reported by Yi et al.,30 who measured the TG−DSC curve of DIR solvate in acetone. Furthermore, the simultaneously recorded DSC curve also shows a small endothermic peak at approximately 128 °C in accordance 13805


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Figure 4. Optical microscopy of the DIR single crystals in DMF solvent (a,b), unit cell of the crystal structure (c), and calculated X-ray diffraction pattern (d) of the DIR single crystals. The dotted lines (c) represent the intermolecular and intramolecular H-bonds.

with the gradual weight loss (Figure 3b). These results indicate that the solvent molecule DMF entered into the crystal structure. Conversely, the sharp endothermic peak at 188 °C (Figure 3a,b) with no associated weight loss was due to the melting point of these samples, in accordance with the reported values (189 °C).27 The wide and broad endothermic peak within the temperature range of 290−320 °C (Figure 3a,b) corresponded to the distinct thermal decomposition of the DIR molecules. These results suggest the obvious distinction of the crystal structures between the DIR raw material and the solvothermally prepared DIR products. To further assess the intrinsic structure of the DIR crystals in DMF solvent, the slow evaporation method, which is a very common crystallization method, was used. The DIR raw material was dissolved in DMF solvent to crystallize at room temperature. The obtained DIR single crystals and an individual DIR crystal are shown in Figure 4a,b. The DIR crystals have a low aspect ratio with uniform morphology (Figure 4a). The width changes in the range of ∼10−40 μm, and the length is in the range of ∼20−70 μm. The elongated hexagonal crystal has very similar morphology as the solvothermally synthesized crystals (Figure 2b,d). The single crystal was enclosed by surrounding faces (100) and (001) and the top face (1−10) (Figure 4b). The perfect single crystal was further analyzed by single-crystal X-ray diffraction to obtain the crystal structure (Figure 4c), and the details of the crystallographic data obtained from the structural determination are reported in Table 1. DIR in DMF solvent crystallized in the monoclinic P21 space group with lattice parameters of a = 14.3719(8), b = 11.6958(5), and c = 14.695(3) Å. These unit cell parameters of DIR in DMF solvent were in good agreement with other reported DIR solvates in 1-propanol28 and acetone,30 which means that the guest solvent molecules were incorporated in an enclosed space of a similar crystal lattice (Figure 4c). Because

Table 1. Crystal Data and Structure Refinement of DIR DMF Solvate name empirical formula formula weight temperature/K crystal system space group a/Å, b/Å, c/Å α/°, β/°, γ/° volume/Å3 Z ρcalc/mg mm−3 μ, absorption coefficient/mm−1 F(000) crystal size/mm3 2Θ range for data collection index ranges reflections collected independent reflections data/restraints/parameters goodness-of-fit on F2 final R indexes [I > 2σ (I), i.e., Fo > 4σ (Fo)] final R indexes [all data] largest diff. peak/hole/e Å−3 flack parameters completeness

DIR DMF solvate C42H78N2O14·C3H7NO 908.16 g mol−1 100.3 Monoclinic P21 14.3719(8), 11.6958(5), 14.695(3) 90.00, 94.890(8), 90.00 2461.1(5) 2 1.225 0.091 992 0.45 × 0.45 × 0.40 6.12 to 52° −17⩽h⩽17, − 14⩽k⩽14, − 18⩽l⩽16 23039 9659[R(int) = 0.0416 (inf-0.9 Å)] 9659/1/588 1.019 R1 = 0.0510, wR2 = 0.1134 R1 = 0.0600, wR2 = 0.1201 0.610/−0.266 −1.2(7) 0.997

the hydrogen-bond (H-bond) exists both in the intermolecular and intramolecular (Figure 4c), the DMF solvent appears to play an important role in the assembly of single crystals. Based 13806


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Figure 5. Equilibrium morphology, growth morphology, and modified morphology of DIR calculated as described in the text.

Table 2. Attachment Energy Eatt, Solvent Interaction Es, Modified Attachment Energy Emod, (kcal/mol), and Total Surface Areas (%) for Morphological Importance (MI) Faces of Growth Morphology Predicted by Growth Morphology Method and Modified Morphology Obtained by the MAE Method

on the measured unit cell of DIR in DMF solvent, the theoretical XRD patterns were calculated and are shown in Figure 4d. The calculated XRD patterns are highly consistent with the experimental XRD patterns of DIR crystals obtained at room temperature (Figure 4d), as well as DIR samples prepared via solvothermal treatment (Figure 2a,c). These results indicate that we have access to the molecular-level structure of solvothermally prepared layered crystals. 3.2. Molecular Modeling Studies. On the basis of the obtained crystal structure, we are able to gain in-depth knowledge of the intrinsic formation mechanism of layered crystals by MD simulation. To accomplish this, we began by calculating both the surface (Esurf) and attachment (Eatt) energies to assess each reasonable exposed surface and the ideal crystal morphology. Esurf was first calculated by an equilibrium morphology method. The equilibrium morphology is defined by the following main forms: {001}, {110}, {111̅}, {100}, {101}̅ , {011}, and {111} (each form is a collection of all equivalent faces by symmetry, Figure 5a). Face {001} has the dominant surface area (18.56%) (Figure 5a and Table S1). Faces {110} and {100} take up 16.05% and 7.74% of the total surface area, respectively (Table S1). Esurf varied from 0.136 to 0.204 J/m2, and van der Waals (vdW) interactions have a major contribution to the total surface energies (Table S1). Crystal faces with relatively high surface energies exhibit fast growth rate and are minimized in the final crystal morphology (Esurf(111) = 0.179 J/m2 and total area of surface (111) = 1.66%; Figure 5a and Table S1). Furthermore, the Eatt of each crystal surface was obtained based on the growth morphology method. The growth morphology of DIR (Figure 5b) is mainly determined by three surrounding faces ({001}, {100}, and {1̅01}) and two top faces ({110} and {011}). The surrounding face {001} has the largest surface area with 35.52% of the total facet area, while face {100} takes up 24.98% (Figure 5b and Table 2). The top faces (110) and (011) grow faster than other faces and only take up 15.67% and 1.53%, respectively (Figure 5b and Table 2). The calculated Eatt of low-indexed faces varied from −81.56 to −44.95 kcal/mol (Table 2). Faces with lower Eatt are the slower growing faces and, therefore, have the largest morphological importance (MI).25 Eatt values are listed in Table 2 in decreasing order of their MI (MI (001) > MI (100) > MI (110) = MI (11̅0) > MI (101̅) > MI (011) = MI (01̅1)). However, the predicted equilibrium and growth morphology are not the best fit to the observed morphology (Figure 4b). Although the morphology of crystals is usually related to the intrinsic crystalline structure, the same crystalline material can exhibit diverse shapes.31 On one hand, this phenomenon is due to the different surface energies or attachment energies of the

growth morphology

modified morphology

faces

Eatt

Area

Es

Emod

Area

(001) (100) (101̅) (011) (011̅ ) (110) (11̅0)

−44.95 −47.26 −62.69 −81.56 −81.56 −65.28 −65.28

35.52 24.98 3.09 1.53 1.53 15.67 15.67

−23.21 −21.82 −23.25 −18.43 −17.14 −18.22 −19.23

−21.74 −25.44 −39.44 −63.13 −64.42 −47.06 −46.05

44.63 30.17 0 0 0 12.60 12.60

crystal faces. On the other hand, the external growth environment, such as solvent effects, also can influence the crystal shape. In general, the solvent effects originate from the preferential adsorption of solvent molecules on specific growth sites of the crystal surfaces.32 This leads to a decrease in the growth rate of these faces compared to the other faces. Such a delay results in a change in the final crystal behavior in solvents. To establish the dimensions of the delay, we built the interface model and computed the solvent/crystal interaction Es between the solvent layer and the crystal layer. The detailed parameters of the interfacial modeling box are listed in Table S2. The face (01̅1) has the lowest Es (Es(01̅1) = −17.14 kcal/mol, Table 2); hence, it is less sensitive to the solvent molecules because the solvent/crystal interaction cannot compete with the solute/ crystal interaction. The face (110) has a relatively smooth surface structure (Figure S8) with low correction factor S (1.216; Table S3), which quantitatively indicates the roughness of a crystal face.30 Therefore, it is moderately affected by the solvent interaction (Es(110) = −18.22 kcal/mol, Table 2) since the solvent can adsorb easily on the relatively large solvent accessible surface (Figure S8 and Table S3). In contrast, the faces (001) and (100) with a generally high Es (Es(001) = −23.21 kcal/mol and Es(100) = −21.82 kcal/mol, Table 2) are most affected by solvent molecules because of the relatively large S values (S(001) = 1.238 and S(100) = 1.344, Table S3). Additionally, the modified attachment energies of all of the MI faces experience a decrease due to the solvent effects. Hence, the reduced attachment energy Emod implies that the Eatt on a face is reduced by Es: Emod(hkl) = Eatt(hkl) − Es(hkl).33 It has been reported that a more negative Emod leads to a faster growth rate in a particular direction.34 From Table 2, one can clearly see that the faces (011) and (01̅1) have a more negative 13807


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Langmuir Emod (Emod(011) = −63.13 kcal/mol and Emod(011̅ ) = −64.42 kcal/mol, Table 2) than the other faces, indicating relatively faster growth rates that lead to the disappearance of the faces (011) and (01̅1) in the final modified morphology, as shown in Figure 5c. The face (001) still remains the most MI face with the smallest absolute value of Emod (Emod(001) = −21.74 kcal/ mol, Table 2) and takes up 44.63% of total surface area. The face (100) has a relatively small Emod (Emod(100) = −25.44 kcal/mol, Table 2) due to the strong solvent interaction discussed above. Conversely, the top faces (110) and (11̅0) grow faster and with relatively large Emod (Emod(110) = −47.06 kcal/mol and Emod(11̅0) = −46.05 kcal/mol, Table 2) due to the relatively weak solvent/crystal interface interactions. The growth rate of each crystallographic surface was also evidenced by the density profile of a DIR crystalline slab (Figure S9). The corrugate peaks indicate the amount of DIR and DMF molecules at each surface, with the larger magnitude suggesting that the surface (110) grows faster than that at the surface (001) or (100).35,36 Additional illustration of interfacial distribution of compounds along with the density profiles at each plane was clearly present side by side in Figure S10. As a result, the modified crystal habit is dominated by three surfaces, the {001}, {100}, and {110} facets. It is the changes in the relative growth rates of MI surfaces between growth morphology and the modified morphology that lead to the increased aspect ratio from 1.96 to 2.97, which presents as yelongated hexagonal growth. Notably, the final modified morphology is in good agreement with the corresponding experimental crystals in the DMF solvent (Figure 4b), which demonstrates that the MAE model accurately reproduces the experimentally observed crystal growth morphology. In general, it is more favorable for the OA of nanocrystals to occur on the facet that has a high surface energy. For example, the OA of TiO2 particles typically occurs on the high surfaceenergy plane {112}.37 Despite this, there are many faces on which OA occurs without the highest surface energies. Consistent with this conclusion, preferential attachment on relatively low-energy faces have also often been reported. For instance, α-Fe2O3 and ZnS OA events occur on low-energy surfaces {001}38 and {110},39 respectively. Herein, our calculations show that the faces (100) and (001) have relatively high surface energies with Esurf(100) = 0.158 J/m2 and Esurf(001) = 0.151 J/m2, respectively (Table S1). In contrast, surface (110) has the lowest energy (Esurf(110) = 0.136 J/m2; Table S1). Experimentally, the OA event occurring on the surface {001) indicates that the surface energy cannot accurately predict the experimentally observed attachment events. The energy change (ΔE) of an OA event is also reported as a driving force, except for the surface energy, for crystal growth via OA according to thermodynamics.23 In general, the OA growth of nanocrystals involves single attachment events in which numbers of small particles are attached on a specific surface. As a result, the orientation of an attachment event is a key factor that determines the total energy change. There are five possible configurations (i (001)/(001), ii - (100)/(100), iii - (110)/(110), iv - (001)/ (100), and v - (100)/(001), Figure 6) that initial crystals are attached to on an (hkl) surface. Accordingly, 3D periodic supercell models (Figure S11) were built, and the initial energy (Eup and Edown) as well as final total energy Eattached upon attachment to the corresponding (hkl) surfaces were calculated and are summarized in Table 3. The OA growth configuration i has the lowest total energy (Eattached{(001)/(001)} = −1809.01

Figure 6. Diagram illustrating single layer crystal and five possible configurations i−v for the OA events. Configurations i−v [I - (001)/ (001), ii - (100)/(100), iii - (110)/(110), iv - (001)/(100), and v (100)/(001)] indicate five OA growth conditions that initial crystals are attached on an (hkl) surface.

Table 3. Up Layer Energy Eup, Down Layer Energy Edown, Final Total Energy Eattached, and Energy Change ΔE (kcal/ mol) of Five Attachment Growth Configurations (i - (001)/ (001), ii - (100)/(100), iii - (110)/(110), iv - (001)/(100), and v - (100)/(001)) configurations

i - (001)/ (001)

ii - (100)/ (100)

iii (110)/ (110)

iv (001)/ (100)

v - (100)/ (001)

Eup Edown Eattached ΔE

−924.91 −894.38 −1809.01 10.28

−902.53 −859.87 −1745.87 16.53

−840.86 −799.10 −1620.51 19.45

−924.91 −859.87 −1648.48 136.3

−902.53 −894.38 −1649.88 147.03

kcal/mol) after Forcite Geometry Optimization (Figure S12). The Eattached of two small crystals attached on a specific surface (hkl) determines the OA-based growth process normal to that surface via successive attachment events.23 Furthermore, we calculated the energy change ΔE (Table 3) between the final total energy after attachment Eattached and the initial energy when they are “infinitely” far away, Eup and Edown, for an OA event on a variety of surfaces. As reported, a lower ΔE for an OA event on a specific surface (hkl) results in a higher driving force for OA growth.21 Apparently, the facet-to-facet attachment of configuration i [(001)/(001)] has the lowest energy change ΔE (ΔE{(001)/(001)} = 10.08 kcal/mol < ΔE{(100)/ (100)} = 16.53 kcal/mol < ΔE{(110)/(110)} = 19.45 kcal/mol < ΔE{(001)/(100)} = 136.3 kcal/mol < ΔE{(100)/(001)} = 147.03 kcal/mol, Table 3) among the five configurations, indicating the highest driving force for OA growth. Note that the OA event in which the cleaved surface (001) supercell (up layer) is attached to a (100) surface (down layer) or vice versa has much larger ΔE than the other three configurations, which suggests an ignorable driving force of the OA event for these two configurations. In addition, the structural interaction of the same interface was analyzed at the molecular-scale (Figure 7). The face (001) is rich in molecular interactions including both H-bond and short contact (sum of vdW radii), with DMF molecules arranging on this plane (Figure 7a). Figure 7b clearly shows the coexistence of a H-bond between O (DMF) and H (DIR) and close contact between C (DMF) and H (DIR) in the interfacial region. By contrast, only short contact exists among DIR molecules at the interface (110) (Figure 7c). Note that there is no intermolecular interaction at the interface (100) (Figure 7d). Therefore, the OA event prefers to occur on the surface (001) due to the rich vdW interactions. For the OA 13808


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Figure 7. Structural interaction of DIR crystal surface (001) (a,b), (110) (c), and (100) (d) at the molecular-scale. The dotted lines stand for the HBond and short contact (sum of vdW radii).

Figure 8. A schematic model illustrating the layered small-molecular pharmaceutical DIR crystal. The energy change (ΔE, kcal/mol) stand for the energy barrier following an OA event.

the DIR raw material was crystallized in DMF solvent, yielding monoclinic solvate crystals with lattice parameters of a = 14.3719(8), b = 11.6958(5), and c = 14.695(3) Å (Table 1). The DMF molecules were doped in the holes of the DIR molecular layers and formed the O (DMF)···H (DIR) H-bond intermolecular interactions, as shown in the crystal structure of DIR (Figure 4c). Additionally, the OA growth process can be described as an attachment process that depends on the energy change ΔE. From the high-magnification SEM image (Figure 8), one can clearly see that the hexagonal crystals synthesized at 40 °C for 48 h are layered stacks of tightly attached thinner ones. Combined with simulation, we predicted the modified morphology (elongated hexagonal crystals), calculated the energy change ΔE (ΔE = 10.28 kcal/mol), and confirmed the

growth, vdW interaction is also reported as the driving force for both nanoparticles and nanorods.6,40 As a result, the most favorable OA configuration is (001)/(001) (Figure 6i) with the lowest ΔE and the strongest molecular interaction among all of the OA events, which is in good agreement with the experimental layered structures (Figure 2b,c). Similar results were reported by Weller et al.,41 who observed that the OAbased attachment growth face is {001} for hexagonal ZnO (zincite) nanorods. Therefore, the choice of initial OA surface is mostly determined by the energy change that results from an attachment event and the molecular interaction. 3.3. Crystal Growth Mechanism. Chemical environments such as solvents can significantly influence the interaction between nanoparticles and thus affect the OA growth.42 Herein, 13809


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Figure 9. Schematic illustration of the growth process of elongated hexagonal layered crystals of DIR in DMF solvent via OA growth mechanism.

the experimental observations. We also confirmed that the most favorable OA was on the surface (001) and that multilayered crystals result from not only the lowest ΔE of the facet-to-facet attachment of (001)/(001) but also the strong interface interactions (H-bonds and vdW interactions) that makes the solute and solvent molecules preferentially adsorb on the face (001). This work not only provides a better understanding of the OA growth mechanism based on crystal structure but also points to a new opportunity for studying layered crystal growth by combining MD simulation and experimental exploration. Considering that many materials are known to form layered structures by OA, such combinations may play a significant role in the study of the intrinsic growth mechanisms of other compounds.

most favorable surface (001) of the OA events. The surface configuration and molecular arrangement of the corresponding crystal facets (001) are also presented in Figure 8. Face (001) is rich in exposed methyl groups, oxygen atoms, and N,Ndimethyl amino groups, creating a relatively rough topography at the molecular level and an uneven atomic arrangement; hence, it is most affected by solute and solvent molecules. One can clearly see the intermolecular interactions (H-bonds and vdW forces) among each building block on the cleaved surface (001) (Figure 7). As a result, the OA occurs preferentially on the surface (001) with a generally low ΔE, and the solute and solvent molecules prefer to adsorb on the face (001) due to the strong interface interaction, which leads to the layered crystal growth of the small-molecule pharmaceutical DIR. Given all of these results, the OA growth process for the formation of layered DIR crystals via solvothermal treatment can be summarized as follows (Figure 9). In the beginning, the DIR raw material dissolved, recrystallized, and formed the precursor crystals, which clearly displayed the original hexagonal shapes. Then, these initial crystals experienced OA growth and formed multilayered hexagonal crystals (3−7 layers) under the supersaturated solvothermal environment at 40 °C for 24 h. By lengthening the solvothermal growth time to 48 h, the layers of elongated hexagonal crystals gradually increased, ranging from 10 to 15 layers. However, the nearly saturated solution at room temperature provides a good environment for nucleation and crystal growth during the solvent-evaporating crystallization. As a result, perfect elongated hexagonal single crystals were obtained rather than layered crystals. We, therefore, propose this model to illustrate the construction of layered small-molecule pharmaceutical microcrystals. Here, using theoretical computation and structural analysis in a MD simulation, it is feasible to connect nanoscale simulation, SEM, and the observed crystal morphologies from optical microscopy. These results also demonstrate that such a controllable layered self-assembly approach combined with MD simulation may be viable for preparing and predicting other orientation-attached compounds and may, consequently, be extended to design other hierarchical materials composed of nanostructures. Ultimately, OA is very common in the growth of layered crystals.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.langmuir.5b02901. Comparison of experimental and calculated (form II) XRD patterns of DIR raw materials; 13C solid-state NMR spectrum of DIR raw materials; description of SEM images of the DIR precursors and the solvothermally prepared DIR products at 40 °C for 24 h and 48 h in DMF solvent; TEM images, HRTEM image, and their SAED pattern of solvothermal synthesized DIR crystals at 40 °C for 48 h; surface energies and total surface areas for the theoretical equilibrium morphology of DIR; supercell parameters and corresponding surface areas when calculating the modified morphology; Connolly surfaces, accessible solvent surfaces, and density profiles of three crystal surfaces (001), (100) and (110); and the OA computational model and the Eattached of the OA configuration i during Forcite Geometry Optimization. (PDF) Related CIF information (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected], Tel: +86-10-64446466 *E-mail: [email protected], Tel: +86-10-64442375 *E-mail: [email protected], Tel.:+86-10-64433134

4. CONCLUSIONS In summary, we prepared a layered crystal of the smallmolecule pharmaceutical compound DIR for the first time via an OA growth mechanism using a solvothermal method. The formation mechanism of the elongated hexagonal crystals was confirmed by both experiments and computational simulation. Using MD simulation, the crystal growth morphology of DIR in DMF solvent was accurately predicted, which is consistent with

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work is supported by National Natural Science Foundation of China (No. 21121064), the 863 Program 13810


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(2015AA033501), Key Technologies Research and Development Program of China (2014BAE03B02). Finally, we would like to acknowledge useful discussions with Prof. Yan Dongpeng at Beijing Normal University.

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Structural Correspondence of the Oriented Attachment Growth

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