New Metastable Packing Polymorph of Donepezil ... - ACS Publications

Apr 21, 2016 - SSCI, a Division of AMRI, 3065 Kent Avenue, West Lafayette, Indiana 47906, United States. §. Department of Chemistry, Chungnam Nationa...
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New Metastable Packing Polymorph of Donepezil Grown on Stable Polymorph Substrates Yeojin Park,† Stephan X. M. Boerrigter,‡ Jisun Yeon,† Sun Hye Lee,† Sung Kwon Kang,§ and Eun Hee Lee*,† †

College of Pharmacy, Korea University, 2511 Sejong-ro, Sejong 339-700, Republic of Korea SSCI, a Division of AMRI, 3065 Kent Avenue, West Lafayette, Indiana 47906, United States § Department of Chemistry, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 305-746, Republic of Korea ‡

S Supporting Information *

ABSTRACT: We obtained a new metastable packing polymorph of donepezil, designated as form K, epitaxially grown on substrate crystals of the more stable form F, or solely by increasing the concentration. Although donepezil is a highly flexible molecule, crystal structure analysis reveals that the molecular conformation is the same as in form F. Donepezil does not form hydrogen bonds and has no appreciable electrostatic interactions. Form K crystals can be grown homogeneously, i.e., without seeds, from highly supersaturated solutions (S > 12). However, in the presence of form F substrates, formation of form K is observed at supersaturations as low as S ≈ 2−3. This suggests form F can serve as a template to form K crystals. Both polymorphs share a structurally identical, common feature of inversion-related molecules. The structures differ in their translational symmetry; hence, they are packing polymorphs. By superimposing the structures and conducting structure fragment calculation using the XPac program, a common twodimensional plane was identified, the (010) of form F and the (011̅ ) of form K. Using calculated BFDH morphologies, oriented in their superimposed orientations, epitaxial growth of form K on form F substrate crystals can be made plausible to occur in this fashion. The template effect can thus be understood as resulting from the 2D lattice match, resulting in a low interfacial energy, therefore leading to a low nucleation barrier.

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INTRODUCTION

when directional interactions, most notably hydrogen bonding, contribute significantly to the heat of fusion.8 Due to nucleation kinetics, crystallization may produce a metastable polymorph. Homogeneous nucleation of a metastable form could be explained by the Ostwald rule of stages.9 Impurities can have a notable effect on the occurrence of metastable polymorphs, and when these are deliberately introduced to steer crystallization toward a particular polymorph, they are referred to as tailor-made additives.10−13 Heterogeneous nucleation occurs on a substrate, different in either chemical nature or physical nature in the case of a polymorphic substrate.14−16 Relevant to heterogeneous nucleation, the literature describes cross nucleation,17−19 lattice matching,20−22 ledge-directed epitaxial growth,23,24 and chemotaxy.25 The metastable form can be grown as a part of the stable form via “intergrowths” of two polymorphic domains.26,27 For example, Bond et al. proposed that the intergrowth phenomenon of aspirin might be favored by the small energy

Polymorphism occurs when molecules with the same chemical composition adopt different crystal structures.1 Polymorphism can be classified in two categories: packing and conformational polymorphism.2 Conformational polymorphs contain distinctly different molecular conformations which are commonly observed for molecules that have flexible moieties. Packing polymorphs contain nearly identical molecular conformations and differ in their crystal packing, i.e., in how the molecules interact and how they are arranged in the three-dimensional structure. Due to their conformational flexibility, pharmaceutical compounds rarely exhibit packing polymorphism and only a few have packing polymorphs.3−6 In organic crystals, intermolecular interactions, such as van der Waals interactions, hydrogen bonding, and electrostatic interactions, govern the crystalline structural architecture.7 Attractive van der Waals forces promote close packing of the molecules in the crystal structure. Close packing therefore typically results in a favorable heat of fusion, i.e., the change in enthalpy due to the formation of the crystal structure, ΔH. However, the most densely packed polymorph is not necessarily the most stable one. This is especially the case © XXXX American Chemical Society

Received: November 17, 2015 Revised: April 8, 2016

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follows: 350−400 mg of donepezil powder was dissolved in 0.5 mL of ethanol at 50 °C. Subsequently, the solution was filtered through a nylon filter of 0.2 μm pore size and then cooled to room temperature. After 1 day, the crystals were filtered and dried. The ground crystals were used both as a reference and in further analysis. Powder X-ray Diffraction (PXRD). The powder patterns of donepezil polymorphs were evaluated using a D8 ADVANCE with Davinci (Bruker AXS Inc., GmbH, Germany) using Cu Kα radiation and equipped with a high-speed LynxEye detector. Samples were analyzed over a 2θ range of 4−40° with increments of 0.02° at a rate of 6°/min. The data were analyzed using DIFFRACplus Eva (Bruker AXS Inc.). Using the powder instrument, an X-ray pattern was collected for a form F crystal that was placed on its (0 1 0) face in the middle of the X-ray sample holder. Reference powder patterns from single crystal structures of forms F and K were calculated with preferred orientation using March−Dollase parameters of 0.3 with respect to the (0 1 0) face of form F and the (0 1̅ 1) face of form K (Mercury 3.6). Differential Scanning Calorimetry (DSC). Thermal analysis was conducted using a Q2000 DSC (TA Instruments, New Castle, DE, USA). The temperature scale and heat flow were calibrated by measuring the onset temperature and the enthalpic response of an indium standard. Low mass sample pans were used, and the samples were heated from 0 to 120 °C at a rate of 5 °C/min. The data were acquired and analyzed using Universal Analysis 2000 software v. 4.1D (TA Instruments). Fourier-Transform Infrared (FTIR) Spectroscopy. The FTIR spectra of the donepezil polymorphs were measured using a Nicolet Nexus 6700 FTIR with a DTGS detector and KBr beam splitter (Thermo-Nicolet, Madison, WI, USA). The scan range was 650−4000 cm−1 with a 4 cm−1 resolution, and each spectrum was the sum of 128 scans. Smart multibounce horizontal attenuated total reflectance (HATR) accessory (Thermo-Nicolet) with a ZnSe cell (International Crystal Lab, Garfield, NJ, USA) was used for these measurements. X-ray Data Collection and Structure Determination. X-ray intensity data were collected on a Bruker SMART APEX-II CCD diffractometer using graphite-monochromated Mo Kα radiation (λ = 0.71073 Å) at a temperature of either 296 or 123 K. The structures were solved by applying the direct method using SHELXS-2013 and refined by full-matrix least-squares on F2 using SHELXL-2013.30 All non-hydrogen atoms were refined anisotropically. Amine H atoms were located from the difference map and refined freely (refined distances; N−H = 0.73(3) and 0.96(2) Å). Other H atoms were positioned geometrically and refined using a riding model, with C−H distances = 0.93−0.98 Å. The isotropic displacements, Uiso, of the hydrogen atoms were constrained to 1.2 Ueq of the carrier C atom on aromatic and methylene moieties and 1.5 Ueq of the carrier C atom on methyl groups. Due to the rotatable bond extending out of the dimethoxy-1-indanone moiety, the carboxy oxygen (O10) appears on both opposite sides on the molecule in the crystal structure and was modeled by a disorder parameter. 2D Supramolecular Construct Calculation. A two-dimensional supramolecular construct calculation was carried out using the XPac program.31−33 Filter parameters for angular deviation, interplanar angular deviation, and molecular centroid distance deviation were set as 10°, 15°, and 0.1 Å, respectively. Morphology Simulation. The crystal morphologies of forms F and K were computed using Mercury 3.3,29 which implements the Bravais−Friedel−Donnay−Harker (BFDH) method. The crystallographic information files (.cif) of the single crystal structures of form F, previously obtained in our laboratories,28 and of form K were used for this purpose. Crystal growth of form K on form F seed was simulated by superimposing two molecules or, alternatively, “building blocks”, one from form K and the other from form F, and then adding the calculated BFDH morphology.

difference between the two forms and their consistent layer surfaces.26 The heterogeneous growth phenomenon described here is the epitaxial growth of a metastable form, where a crystal of the stable form serves as a substrate. This phenomenon was observed earlier by one of the authors and was explained to be due to the faster growth kinetics of the metastable form than the stable form due to a more favorable two-dimensional nucleation mechanism at the crystal growth interface.14 The polymorphism of donepezil (Figure 1) was investigated in our laboratories, previously.28 Crystal structure analysis of

Figure 1. Molecular structure of donepezil.

donepezil polymorphs including forms I, II, C, and F reveals that the four known polymorphs are conformational polymorphs. The flexibility of the molecule is characterized by six more or less independent torsion angles and the potential of switching between the boat and the chair conformation of the piperidine moiety. It should be noted that donepezil has no hydrogen bond donors, and therefore, unsolvated polymorphs cannot exhibit hydrogen bonding. Here, we report a new metastable polymorph of donepezil, which we have designated as form K. Form K has the same molecular conformation as form F and as such may be regarded to be a packing polymorph with respect to form F. The growth behavior of form K on seed crystals of form F was investigated. The relation between the two polymorphs can be understood using the respective morphologies, which were visualized using the BFDH morphology prediction model (implemented in Mercury 3.3).29 Three-dimensional nucleation was investigated by growing form K with solutions of varying degrees of supersaturation. The epitaxial growth behavior of form K on form F crystals was observed and explored. The solid state properties as well as the thermodynamic relationship between forms K and F were investigated.

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EXPERIMENTAL SECTION

Materials. The hydrochloride salt of donepezil (donepezil HCl) was purchased from Cangzhou Senary Chemical S. & T. Co., Ltd. (Hebei, China). The neutral form of donepezil was prepared following the procedure used previously.28 Isopropyl alcohol (IPA) was obtained from Sigma-Aldrich (St. Louis, MO), sodium hydroxide from Jin Chemical Pharmaceutical Co., Ltd. (Gyunggi-do, Republic of Korea), and ethanol from Pharmco (Brookfield, CT). Water was doubledistilled and filtered through a Milli-Q ultrapure water purification system (Billerica, MA). Preparation of Form F Seeds. Form F was prepared by slurrying approximately 5 g of donepezil powder in 10 mL ethanol at room temperature for 3−4 days. The resulting solids were filtered and dried at 40 °C for 24 h prior to use. Crystallization of Form K on Form F Seeds. A solution was prepared by dissolving 100−150 mg of donepezil powder in 1 mL ethanol, and filtered using a nylon filter of 0.2 μm pore size. A small amount of form F powder or a crystal was added to the solution. Subsequent crystal growth over time was observed under the microscope. Crystallization of Form K from a Highly Supersaturated Solution. A supersaturated solution of donepezil was prepared as

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RESULTS AND DISCUSSION Epitaxial Crystallization of Form K on Form F Seed Crystals. Form K was obtained serendipitously while trying to B

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obtain form F crystals. In the previous attempts conducted in our laboratories, form F crystals were obtained only by slurry conversion or by keeping solutions containing other polymorphic forms, such as form I, II, or C, at room temperature for more than 6 months without stirring, via solution-mediated polymorphic transformation. We tried to obtain large form F crystals by adding form F seed crystals to a supersaturated solution, but the resulting solids were form K instead of form F. This observation was especially interesting because of the known donepezil polymorphs. Form F, at the time, was believed to be the most stable form.28 Crystal Structure Analysis of Forms K and F of Donepezil. The crystallographic data for form K obtained by single crystal X-ray structure analysis are summarized in Table 1. For comparison purposes, the crystallographic data of form F from ref 28 was used.

Figure 2. Overlaid molecules of form F (in blue) and form K (in red) of donepezil showing that the conformations are practically identical. (RMSD/Å = 0.0624).

Table 1. Crystallographic Data of Donepezil Forms F and K Obtained by Single Crystal X-ray Analysis parameter Chemical formula Temperature Space group Crystal system a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Density (mg/m3) Z Reflections Collected/unique R1-Factor (%) [I > 2sigma(I)] R1-Factor (%) [all data] wR2-Factor (%) [I > 2sigma(I)] wR2-Factor (%) [all data]

donepezil form F

28

C24H29NO3 173(2) K P1̅ triclinic 5.9523 (8) 11.8173(18) 15.072 (2) 79.253 (3) 84.287 (2) 75.924 (2) 1008.66 (11) 1.249 2 31331/4958 [Rint (%) = 3.47] 4.39 5.73 11.48 12.21

are expanded further in their superimposed orientations, it becomes obvious that there exists a common layer, 2D supramolecular construct.31−33 This is shown in Figure 3. The common layer exists parallel to both the c axis of the form F unit cell (Figure 3a) and the a axis of the form K unit cell (Figure 3b). As such, this represents the (010) plane of form F. The packing of the molecules along the b axis of form F corresponds closely to that of the vector b + c in Form K. Therefore, the identical packing is in the (011̅) plane of Form K. The respective slice cell vectors are listed in Table 2. The slice cell vector lengths are slightly incommensurate causing the molecules to diverge further and further going away from the center of the figure. Figure 3 b shows the close match in the length of the respective a axes, not only by the width of the unit cells, but also by how close the positions of the molecules are throughout the figure. Figure 4 shows a side-by-side comparison of the top view of the two faces. Neighboring layers above and below this central layer show that the orientation of the pairs of molecules are still identical between the two crystal structures; however, they are translated with respect to each other. The green double-headed arrows in the figure indicate the relative displacement. Because the two unit cells, in this overlay, have a nearly common origin, it can be seen that these displacement vectors correspond to the distance between the unit cell vertices in the respective layers. As such, from this figure it can be visually estimated that the form K layers are displaced by a vector of about 1/2 c and slightly less than 1/2 a, expressed in form F unit cell vectors. Another way to visualize the structural relationship between forms F and K is shown in Figure 5, which shows the packing diagrams of forms F and K. This figure explicitly highlights that both structures have bilayers in common and the only difference between the two forms is the difference in displacement between adjacent layers. The double layers are separated by red lines in the figure. Crystallization of Form K on Form F Seed Crystal. Our previous studies never produced form K.28 Form K was serendipitously obtained while attempting to obtain a large form F crystal by seeding. Two types of seeds were used to induce the crystallization of form K. Figure 6 shows the growth of form K on form F powder seeds over time (Figure 6a−c). On this type of substrate, form K crystals grew like the petals of a flower, protruding from the particles in random orientations. When a large crystal of form F was used as a substrate, the growth behavior of form K was not as easily discerned (Figure

donepezil form K C24H29NO3 173(2) K P1̅ triclinic 5.7883 (3) 12.9301 (8) 14.5967 (9) 111.899 (5) 95.370 (2) 90.7250 (9) 1007.94 (2) 1.250 2 27401/5049 [Rint (%) = 4.56] 4.62 5.91 12.53 13.24

Both forms K and F crystallized in the triclinic crystal system in the space group P1̅. Unit cell lengths appear to be similar: form K has unit cell length parameters of a = 5.79 Å, b = 12.93 Å, and c = 14.60 Å, and form F has a = 5.95 Å, b = 11.82 Å, and c = 15.07 Å. However, the two forms show different unit cell angles. Form K has unit cell angle parameters of α = 111.9°, β = 95.4°, and γ = 90.7°, whereas form F has angles of α = 79.3°, β = 84.3°, and γ = 75.9°. The carbonyl oxygen in form K is disordered. For the sake of clarity, the disorder was not visualized in the figures. Figure 2 shows the superimposed molecules as they appear in forms K and F. The RMSD was calculated using Mercury 3.3 for which the disordered O10A of form F and disordered parts of form K were removed prior to calculation. The RMSD is only 0.0624 Å, which is remarkably small. This shows that the molecular conformations of the respective crystal structures are practically identical and that the two crystal structures differ primarily in their molecular packing. This is remarkable considering that donepezil is a highly flexible molecule. For a given pair of superimposed molecules the inversion center is positioned identically, meaning that both molecules in the unit cell can be superimposed. When the crystal structures C

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Figure 3. Superimposed view of crystal structures of forms F (blue) and K (red). (a) View along the common crystallographic a axis; (b) view at a 90° angle, where the a axes run horizontally in the plane of drawing. Pairs of molecules in the center superimpose, whereas the layers above and below are translated with respect to each other. The layer-to-layer translation is indicated by the green double-headed arrows.

7a,b). Crystals of form K appeared to grow protruding from a form F crystal substrate (Figure 7). Morphology Modeling of Form K Grown on Form F Seed Crystal. The BFDH morphology model implemented in Mercury 3.3 was used to visualize the morphology of a form K crystal grown on a form F seed. The relative orientation of the

unit cells of the two polymorphs was determined by superimposing the building block molecules of each of the unit cells, similar to what was done to create Figure 3. The petal-like form K crystals shown in Figure 6 were grown on form F powder globules. The crystals grow spherulitically in random orientations out of the powder globule, as the powder D

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Crystallization of Pure Form K from a Highly Supersaturated Solution. Pure form K was obtained by keeping a solution with a degree of supersaturation of more than S = 12 (where S = the solution concentration/the equilibrium solubility at the given temperature) in ethanol at 50 °C, and cooling it to room temperature. The polymorphic forms resulting from different levels of supersaturation are summarized in the Supporting Information. As the level of supersaturation increases, so does the frequency of obtaining form K. Previously, the level of supersaturation used for the crystallization of donepezil polymorphs I, II, C, and F was medium S = 2 to 3. This explains why form K had never been found in our previous studies.28 It seems that form K can only be obtained in the presence of the stable form F seed at medium supersaturation or from highly supersaturated solutions. In this previous study donepezil forms I, II, and C showed concomitant polymorphism.28 It seems that the relative rates of nucleation and growth of the three polymorphs governs the final polymorphic form obtained. From our observations, we generally conclude that form I nucleates rapidly, but grows more slowly than form II. As a result, form I appears first, followed by form II. Due to its higher growth rate, form II dominates at the end of crystallization. Form C nucleates more slowly than either form I or II. It is difficult to observe form F early in crystallization. As a general observation, it can also be concluded that, given a set of experimental conditions, the polymorphic form that has the highest rate of growth at those conditions will be observed as the dominant form at the end of crystallization. Form K was never obtained previously as it requires high supersaturating conditions to grow.28 The rate of nucleation of form K is slow, even slower than that of form F. However, at sufficient supersaturation, the growth rate of form K becomes faster than that of form F. At these conditions, nucleation becomes a less important factor as form K can grow both heterogeneously (on form F) as well as homogeneously. It has been established that above a certain supersaturation an abrupt increase in growth rate can be obtained due to kinetic roughening.34−36 Kinetic roughening is essentially caused by the loss of the nucleation barrier for two-dimensional nucleation. It is likely that this phenomenon can explain the growth behavior of form K with respect to form F. A detailed

Table 2. Slice Cell Parameters for the Matching Planes F (010) and K (011̅ ) parameter

form F a,c (010)

form K a, b + c (011̅ )

Δ

u (Å) v (Å) γ (deg)

5.952 15.072 84.29

5.789 15.475 84.33

−2.7% +2.6%

obviously does not offer a particular orientational bias. The BFDH morphology (Figure 6) was built after overlaying the molecules as shown in Figure 3a. The simulated crystal morphology of form K grown on form F seeds is colored in red, and the simulated crystal morphology of form F itself is in white. In terms of Figure 6d, the white BFDH morphology represents the F form powder seed, and the red BFDH morphology represents one of the petals. Figure 7a shows a large form F substrate crystal on which, presumably form K, crystals were grown on the (010) face. The red crystal shown in Figure 7 c is the BFDH morphology of form K superimposed on the BFDH morphology of form F (white) such that the epitaxial crystal appears on the (010) face of the substrate. Again, the BFDH morphologies are shown in the orientation dictated by Figure 3. The simulated morphologies in Figures 6 and 7 are shown at the aspect ratio and relative orientation matching that of the experimentally observed crystals. Figure 7a shows an experimentally observed morphology, where the only difference with respect to Figure 7b is that these were grown at lower donepezil concentration. Several form K crystals have grown so as to protrude from the form F crystal substrate (circled in the figure). The orientation of the crystal was confirmed by a PXRD measurement. The powder pattern of the top face of form F matches well with that of the calculated (0 1 0) face of form F indicating that the top face of modeled morphology in Figure 8 is indeed the (0 1 0) face of form F. A discrepancy between the peak positions in the calculated powder pattern and the experimentally obtained powder pattern is due to the sample displacement error of the sample in the X-ray sample holder, because the top of the crystal was not flush with the edge of the sample holder. The structural similarity between forms F and K is illustrated by the similarity of the patterns using the respective March−Dollase parameters.

Figure 4. Top views of the (010) face of form F (left) and the (01̅1) face of form K (right). E

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Figure 5. Crystal packing diagrams of (a) form F and (b) form K showing similar “supramolecular constructs” but different packing arrangements thereof.

Further Solid State Characterization of Donepezil Form K. Form K, grown from high supersaturation, and form F, obtained by slurry conversion, were used as references. Form K has unique diffraction peaks (2θ) at 6.4° and 12.2°, while form F has characteristic peaks at 8.85° and 10.48° (Figure 9). The powder pattern of form K grown on form F seeds does not exactly produce a linear combination of the two reference patterns. While the powder pattern of form K grown on form F crystals shows distinct peaks resembling those of the form K reference pattern, the powder pattern of form K grown on form F powder seeds shows distinct peaks resembling that of the form F reference pattern. The melting point (onset temperature) and heat of fusion of form F are 94.43 °C and 86.39 J/g, respectively, while those of form K reference are 90.15 °C and 77.80 J/g, respectively (Figure 10). These values differ significantly, and also indicate that form F is more stable than form K and monotropically related according to the Burger−Ramberger heat of fusion rule.8 This is a very important observation, because it denies the possibility that heating the solution could have induced nucleation of form K. The densities of the two polymorphs are very similar. The physical mixtures of form F and form K references show two overlapping yet individual endotherms and do not show any significant changes in the melting points of the individual forms (Supporting Information). On the other hand, form K grown on form F shows a gradual change in melting

Figure 6. Micrographs of the growth of form K on form F powder seeds: pictures were taken (a) at 0 h, (b) after 70 h, and (c) after 136 h. (d) Calculated BFDH morphology of form K.

Hartman−Perdok study and/or Monte Carlo simulations can show the supersaturation levels at which forms F and K undergo kinetic roughening. This work is out of scope in the current work, however, and is subject to future research.

Figure 7. Micrographs of form K crystals grown on a form F crystal seed obtained from solutions containing (a) 150 mg/mL and (b) 130 mg/mL donepezil. (c) Simulated morphology of form K (red) grown on the (010) face of a form F crystal seed (white). F

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Figure 8. Stacked powder patternsthe calculated form K powder pattern with preferred orientation using a March−Dollase parameter of 0.3 with respect to the (0 1̅ 1) face, the calculated form K powder pattern with preferred orientation using a March−Dollase parameter of 0.3 with respect to the (0 1̅ 1) face, and experimentally obtained powder pattern of the top face of form F (from top to bottom).

Figure 9. Powder patterns of form K and form F references and form K grown on either form F powder seeds or on a form F crystal seed.

seed is used, the common belief is that the final polymorphic form produced by the crystallization process will necessarily be the same as the polymorphic form of the seed material. However, in this study we have shown that it is possible to obtain a metastable packing polymorph of donepezil, form K, using seeds of the more stable form F. This happens when the supersaturation is sufficiently high to overcome the barrier of heterogeneous (2D) nucleation. Forms F and K were shown to be monotropically related, so the effect of thermodynamically driven nucleation of a high-temperature-stable polymorph is excluded as a possible explanation. Therefore, this phenomenon is most likely explained due to kinetic roughening causing the growth rate of form K to dominate at high supersaturation. Form K can only be obtained by epitaxial growth on form F at medium supersaturation, or by itself at high supersaturation. The two modifications of donepezil polymorphs studied here, forms F and K, represent a case of packing polymorphism, even when donepezil is a highly flexible molecule. The packing

point with changing composition. This suggests that the boundary layers between the two forms manifest as a solid solution in the crystal. In our previous studies, the FT-IR spectra of four polymorphic forms I, II, C, and F were reported.28 The FTIR spectrum of form F was distinct from those of the other three polymorphic forms.28 The FT-IR spectrum of form K, however, was similar to that of form F. Given that FT-IR spectra in this spectral range are predominantly determined by the molecular conformation and hydrogen bonding (of which there is not any in donepezil), it is not surprising that the spectra of forms F and K are very similar (Supporting Information).

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CONCLUSION Seeding is a common method of obtaining a particular polymorphic form during crystallization. When a stable form G

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Figure 10. Stacked DSC thermograms of donepezil form F, form K grown on form F seeds (2×), and form K reference.

Accession Codes

polymorphs exhibit the same pair of molecules in the unit cell, related by the inversion symmetry. The packing motifs differ by translational symmetry. When the identical pairs in both structures are superimposed, it becomes obvious that there exists a closely related plane, corresponding to the (010) face of form F. Epitaxial crystals of form K are often observed to occur on the (010) face when single crystals of form F are used as substrates. Morphology modeling shows that the BFDH morphologies as well as their relative orientation closely resemble the experimental results. This suggests the epitaxial behavior is facilitated by the closely matching planes, which can be understood as being caused by the existence of low interfacial energy between the two forms when interacting accordingly. As such, form F substrates and seeds may promote form K formation by helping it overcome its slow nucleation rate and allow it to grow at medium supersaturations, at which this form was previously not observed. When morphologies are modeled in the corresponding orientations it is clear that the morphology and relative orientation of the epitaxial form K crystals can again be understood by the match in orientation of the molecules. Our present study shows that it is important to investigate the upper boundary of supersaturation when designing a seeding strategy for polymorphic control.

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CCDC 1438375 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Fax: (+82) 44-860-1606. Tel: (+82) 44-860-1620. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by a grant (14172MFDS189) from Ministry of Food and Drug Safety in 2014 and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2014R1A1A1006429).

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REFERENCES

(1) Byrn, S. R.; Pfeiffer, R. R.; Stowell, J. G. Solid state chemistry of drugs, 2nd ed.; SSCI Inc., 1999. (2) Lee, E. H. Asian J. Pharm. Sci. 2014, 9, 163−175. (3) Haisa, M.; Kashino, S.; Maeda, H. Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1974, B30, 2510−2512. (4) Haisa, M.; Kashino, S.; Maeda, H. Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1976, B32, 1283−1285. (5) Nichols, G.; Frampton, C. S. J. Pharm. Sci. 1998, 87, 684−693. (6) Braun, D. E.; Gelbrich, T.; Kahlenberg, V.; Laus, G.; Wieser, J.; Griesser, U. J. New J. Chem. 2008, 32, 1677−1685. (7) Kitaigorodskii, A. I. Organic Chemical Crystallography; Consultants Bureau: New York, NY, 1961. (8) Burger, A.; Ramberger, R. Microchim. Acta 1979, 72, 259−271.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.5b01626. Details of donepezil polymorphic forms grown from various levels of supersaturated solution, DSC thermograms of the physical mixtures of forms F and K, comparison of calculated vs experimentally obtained powder patterns of forms F and K, FT-IR spectra of forms K and F (PDF) H

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Crystal Growth & Design

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DOI: 10.1021/acs.cgd.5b01626 Cryst. Growth Des. XXXX, XXX, XXX−XXX