Polymorph Generation in Capillary Spaces: The Preparation and

Micronization of nabumetone using the rapid expansion of supercritical solution (RESS) process. Chie-Shaan Su , Muoi Tang , Yan-Ping Chen. The Journal...
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CRYSTAL GROWTH & DESIGN 2002 VOL. 2, NO. 6 505-510

Articles Presented in part at the Crystal Engineering to Crystal Growth: Design & Function Symposium, ACS 223rd National Meeting, Orlando, Florida, April 7-11, 2002

Polymorph Generation in Capillary Spaces: The Preparation and Structural Analysis of a Metastable Polymorph of Nabumetone Leonard J. Chyall,*,‡ Jeanette M. Tower,‡ David A. Coates,‡ Travis L. Houston,‡ and Scott L. Childs§ SSCI, Inc., 3065 Kent Avenue, West Lafayette, Indiana 47906, and Design Science Research, LLC, 1256 Briarcliff Road Northeast, Atlanta, Georgia 30306 Received July 26, 2002

ABSTRACT: Crystallization studies of nabumetone (4-(6-methoxy-2-naphthalenyl)-2-butanone) performed in capillary tubes yielded a metastable polymorph. The single-crystal X-ray structure of this high-energy form is presented and compared to the structure of the known low-energy form. The metastable form of nabumetone readily converts to the low-energy form in the solid state upon grinding or seeding with the low-energy polymorph. The instability of the metastable form is believed to be due to the presence of weaker C-H‚‚‚O interactions when compared to the thermodynamically more stable form. Introduction We are developing capillary-based crystallization techniques to prepare new polymorphs of organic compounds. Evaporation of solutions in capillaries offers advantages over conventional crystallization experiments in that the evaporation is nonturbulent and convection is minimized. These factors provide quiescent growth environments and may promote the generation of crystal forms not easily attainable using traditional methods. Evaporation of solutions from capillaries has also been shown to provide higher levels of saturation near the meniscus,1 which may provide an environment conducive to the nucleation of a metastable form. In addition, the slow evaporation rate of solvents from capillary tubes provides conditions that favor the growth of crystals suitable for single-crystal X-ray analysis. Studies of crystallizations in capillaries performed to date have been primarily directed toward protein crystallization in Earth-based and zero-gravity environments.2,3 However, the use of capillary techniques to

generate novel polymorphs of organic molecules has not been investigated. As part of our ongoing development of technologies to identify new polymorphs, we studied the crystallization of nabumetone (Figure 1) in capillaries and in conventional glass vials. Nabumetone is a nonsteroidal antiinflammatory drug (NSAID) that has been sold commercially for nearly two decades. The crystal structure of this molecule was recently reported;4 however, we were unaware of any publications describing polymorphs or solvates of this compound. Here, we present the application of capillary-based evaporations to provide a novel polymorph of nabumetone. The structural details and physical properties of this new polymorph are compared to the known form of nabumetone. In addition, we present some preliminary microscopy studies on the generation of the metastable form of nabumetone outside of capillaries and discuss the phase transformation to the more stable form. Experimental Procedures

* To whom correspondence should be addressed. Tel: 765.463.0112 ext. 336. Fax: 765.497.2649. E-mail [email protected]. ‡ SSCI, Inc. § Design Science Research, LLC.

Nabumetone was obtained from Sigma Chemical (St. Louis, MO) and used as received. Solvents (high-performance liquid chromatography (HPLC) grade or higher) and other reagents

10.1021/cg0200311 CCC: $22.00 © 2002 American Chemical Society Published on Web 09/19/2002

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Chyall et al. Table 1. Crystallographic Data and Refinement Details for Nabumetone Polymorphs

Figure 1. Chemical structure of nabumetone. were obtained from various commercial suppliers and used as received. Capillaries were obtained from Charles Supper Company (Natick, MA). Crystallization Techniques. Nabumetone was dissolved in various solvents and filtered through a 0.2 µm filter into the vessel to be used for crystallization. For evaporation experiments performed in 20 mL scintillation vials, the vials were either left open or partially covered and the solvent was allowed to evaporate at room temperature. Capillary tubes with nominal internal diameters of 1.0 and 0.7 mm were charged with filtered solutions of nabumetone, and the solvent was allowed to evaporate at room temperature. The solutions were added by using either a centrifuge to force the solution to the bottom of the tube or capillary action to fill an openended capillary from the bottom and then sealing one of the openings with Critoseal capillary tube sealant. X-ray Powder Diffraction (XRPD). Analyses of samples that were not prepared in capillary tubes were carried out on a Shimadzu XRD-6000 X-ray powder diffractometer using Cu KR radiation. The instrument was equipped with a fine focus X-ray tube. The tube voltage and amperage were set to 40 kV and 40 mA, respectively. The divergence and scattering slits were set at 1°, and the receiving slit was set at 0.15 mm. Diffracted radiation was detected by a NaI scintillation detector. A θ-two θ continuous scan at 3°/min (0.4 s/0.02° step) from 2.5 to 40° 2θ was used. The samples were placed in either lowbackground quartz or silicon sample holders for analysis. XRPD analyses on samples crystallized in capillaries were analyzed directly from the crystallization vessel using an Inel XRG-3000 diffractometer equipped with a CPS (curved position sensitive) detector with a 2θ range of 120°. The tube voltage and amperage were set to 40 kV and 30 mA, respectively. The monochromator slit was set at 5 mm by 80 µm. Each capillary was mounted onto a goniometer head that was motorized to permit spinning of the capillary during data acquisition. Real time data were collected using Cu KR radiation starting at approximately 4° 2θ at a resolution of 0.03° 2θ. Typically, data were collected over a period of 300 s. The peak position calibration for both instruments was verified using a silicon reference standard. Microscopy. Ambient temperature and hot stage microscopy were performed using a Kofler hot stage mounted on a Leica DM LP microscope equipped with a Sony DXC-970MD 3CCD camera for collecting images. Images were captured using Linksys version 2.27 software. Samples used for melting point determinations were placed on a glass slide with a small amount of perfluoroether oil to cover the sample. A coverslip was then placed over the sample, and the melting point was visually observed as the stage was heated. The temperature of the hot stage was measured using a Testo 6000-903 thermocouple and a Testo 720 digital readout. The hot stage was calibrated using USP melting point standards. For microscopy studies of the phase transformation of nabumetone, the compound was added to a small amount of 2′-hydroxyacetophenone and heated to dissolve the solids completely. Microscope images were collected at 40× magnification as the sample cooled to ambient temperature. Single-Crystal X-ray Diffraction. A single crystal of the thermodynamically stable form of nabumetone (form I) was obtained by allowing a solution of 37 mg of the compound in 2.0 mL of ethanol to evaporate at room temperature from a 20 mL glass scintillation vial that was covered with a piece of aluminum foil containing five pinholes. A single crystal of the metastable form of nabumetone (form II) was obtained by allowing a solution in 1:3 (v:v) water:acetone at an initial concentration of 53.8 mg/mL to evaporate slowly at room temperature from a 1.0 mm diameter capillary over a period of several days.

formula Mr crystal size (mm) temperature (K) wavelength (Å) crystal system space group a (Å) b (Å) c (Å) R (°) β (°) γ (°) V (Å3) Z Dcalcd (g cm-3) µ (mm-1) total data unique data observed data [Fo2 > 2σ( Fo2)] no. of parameters Rint R1 (Fo)a wR2 (Fo2)b goodness-of-fit a

form I

form II

C15 H16O2 228.29 0.41 × 0.38 × 0.35 150 0.71073 monoclinic P21/c (no. 14) 21.8603(5) 5.33350(10) 22.2337(6) 90 111.9288(11) 90 2404.71(18) 8 1.261 0.077 18550 5441 5438

C15 H16O2 228.29 0.43 × 0.35 × 0.05 150 0.71073 monoclinic P21/c (no. 14) 26.9485(4) 5.8773(4) 7.8960(18) 90 91.767(3) 90 1250.0(2) 4 1.213 0.074 9487 2746 2744

312 0.044 0.044 0.108 1.008

157 0.074 0.060 0.152 0.997

R1 ) ∑||Fo| - |Fc||/∑|Fo|. b wR2 ) [∑w(|Fo2| - |Fc2|)2/∑w|Fo2|2]1/2.

Preliminary examination and data collection were performed with Mo KR radiation (λ ) 0.71073 Å) on a Nonius KappaCCD. The space group for each structure was determined using the program ABSEN.5 The structure was solved by direct methods using SIR-976 and refined by full-matrix least squares on F2 data using SHELLXTL. The remaining atoms were located in succeeding difference Fourier syntheses and refined anisotropically. Hydrogen atoms were included in the refinement (isotropically) but restrained to ride on the atom to which they were bonded. Powder patterns were calculated from the single-crystal data using PowderCell 2.3.7 The crystallographic and refinement data for both polymorphs of nabumetone are summarized in Table 1. More details can be found in the corresponding CIF files, which are included as Supporting Information. The room temperature cell parameters for nabumetone form I were obtained from a single crystal (0.11 mm × 0.15 mm × 0.4 mm) that was grown by slow evaporation of a solution in ethanol. The crystal was mounted on a Bruker D8 AXIS singlecrystal X-ray diffractometer equipped with a Bruker APEX SMART CCD area detector. The orientation matrix and unit cell parameters were determined from diffraction intensities collected at 23 °C using Mo KR graphite monochromated radiation (0.71073 Å). The cell parameters (a ) 22.17 Å, b ) 5.34 Å, c ) 22.52 Å, β ) 110.85°) were used with the hkl data collected for form I at 150 K to model a room temperature powder pattern.

Results and Discussion When nabumetone was crystallized from solutions contained in 20 mL scintillation vials, only one polymorph was obtained. This was evident by examination of the corresponding XRPD patterns for the solids that formed upon evaporation of the nabumetone solutions to dryness. For these crystallizations, roughly 25 common organic solvents and mixtures of selected organic solvents with water were used to prepare the solutions. In addition to varying the solvent and the initial concentration of the solution, the solvent evaporation

Metastable Polymorph of Nabumetone

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Figure 2. Representative experimental XRPD patterns of nabumetone form I (bottom) and form II (top).

rate was varied by partially covering the top of the vial. Approximately 100 evaporative crystallizations were performed. Crystallization of nabumetone by evaporation of solutions from either 1.0 or 0.7 mm diameter capillary tubes provided two different solid phases. The XRPD pattern of the solid phase more commonly observed in the capillary experiments corresponds to the XRPD pattern that was obtained from the solids crystallized in 20 mL vials. We designated this solid phase as nabumetone form I (Figure 2). The XRPD patterns for the solids obtained in approximately 20% of nearly 150 crystallizations were distinctly different than that for nabumetone form I. This new solid phase was designated form II (Figure 2). The crystallization of nabumetone to form II did not depend on the use of a particular solvent or evaporation condition, and replicate experiments often provided either of the two forms. In addition to the differences in the XRPD patterns, form I and form II could be distinguished by their crystal morphology. Form I typically crystallized in an acicular habit, while form II crystallized as plates. An example of an experiment that produced nabumetone form II in a capillary tube is shown in Figure 3. Preliminary attempts to remove nabumetone form II crystals from the capillaries resulted in their transformation to form I. However, form II was eventually isolated by carefully breaking away the glass surrounding a crystal contained in a capillary and immediately protecting the crystal with perfluoroether oil. Analysis of form II crystals by hot stage microscopy provided a melting point onset of 68 °C. The onset of melting of form I using the same technique was observed to be 82 °C. From the facile transformation to form I at room temperature and the lower melting point, it is clear that form II is a metastable polymorph of nabumetone, at least at and above room temperature. While crystallization experiments of nabumetone in capillaries provided form II, we found that this polymorph could also be grown on a microscope slide from the melt or by cooling a solution of the compound in 2′hydroxyacetophenone. In these experiments, form II was characterized by its morphology and melting point, as well as the rapid transformation to form I needles upon seeding or mechanically disturbing the crystals with a probe. An example of the transformation of form

Figure 3. Plates of nabumetone form II in a 1.0 mm diameter capillary that were grown by solvent evaporation from a solution in 1:3 water:acetone.

II to form I as observed by optical microscopy is given in Figure 4. Both polymorphs of nabumetone were characterized by single-crystal X-ray analysis. The cell parameters for form I are in agreement with those obtained by Prabhakar et al.4 However, the powder diffraction pattern calculated from the single-crystal data for form I does not provide a close match to the experimental XRPD pattern (Figure 5). The differences between the two data sets are most likely due to the fact that the single-crystal data were collected at 150 K, while the experimental powder patterns were obtained at ambient temperature. To investigate the effect of temperature on the XRPD pattern of nabumetone form I, a single crystal of form I was indexed at room temperature and the corresponding unit cell parameters were used with the hkl data obtained at 150 K to calculate a powder diffraction pattern. As shown in Figure 5, the agreement is significantly better between this calculated powder pattern and the experimental data. As we observed for form I, the calculated powder diffraction pattern for form II does not exactly match the experimental powder patterns (Figure 6). Again, this difference is attributed to the different temperatures used for the collection of the single crystal and powder diffraction data. In addition, samples of nabumetone form II were analyzed by XRPD directly from the capillaries, which probably provided patterns with preferred orientation effects due to the presence of single crystals with platey morphologies. In extreme cases, only the diffraction peaks corresponding to the n00 hkl planes of nabumetone form II were observed in certain experimental powder patterns in which the sample was not rotated during analysis. Grinding form II to remove the effects of preferred orientation was not successful because this operation resulted in the transformation of the crystals to form I. The rapid conversion of form II into form I prompted us to compare the nonbonded interactions and packing

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Figure 4. Transformation of nabumetone form I into form II in a solution of 2′-hydroxyacetophenone. (a) Plates of nabumetone form II. (b) The growth of form I starting on the left side of the image. (c) Continuation of the transformation. (d) Complete conversion to form I. The time scale for the transformation was on the order of 1 min.

Figure 5. Calculated and experimental XRPD patterns for nabumetone form I. Top: calculated from single-crystal data collected at 150 K. Middle: experimental pattern obtained at room temperature. Bottom: diffraction pattern calculated using room temperature unit cell parameters (see text).

motifs and correlate this information with the relative thermodynamic stability of these polymorphs. Both

Figure 6. Calculated (top) and experimental (bottom) powder patterns for nabumetone form II.

forms I and II crystallize in the P21/c space group. However, the asymmetric unit of form I comprises two molecules (Figure 7), while there is only one molecule in the asymmetric unit of form II (Figure 8). The structures for both polymorphs contain layers that are

Metastable Polymorph of Nabumetone

Crystal Growth & Design, Vol. 2, No. 6, 2002 509 Table 2. Nabumetone Form I C-H‚‚‚O Interactions C-H‚‚‚O

H‚‚‚O distance (Å)

C‚‚‚O distance (Å)

CHO angle (°)

C(174)-H(17E)‚‚‚O(221) C(274)-H(27F)‚‚‚O(273) C(122)-H(12B)‚‚‚O(273) C(174)-H(17G)‚‚‚O(221) C(271)-H(27B)‚‚‚O(173) C(174)-H(17F)‚‚‚O(173) C(222)-H(22B)‚‚‚O(173) C(272)-H(27C)‚‚‚O(121) C(171)-H(17B)‚‚‚O(273)

2.448 2.565 2.572 2.629 2.640 2.686 2.700 2.714 2.735

3.530 3.614 3.653 3.455 3.539 3.686 3.721 3.548 3.655

178 163 176 133 140 153 157 134 143

Table 3. Nabumetone Form II C-H‚‚‚O Interactions

Figure 7. ORTEP diagram of the asymmetric unit of nabumetone form I with ellipsoids drawn at the 50% probability level.

Figure 8. ORTEP diagram of the asymmetric unit of nabumetone form II with ellipsoids drawn at the 50% probability level.

Figure 9. Packing diagram for nabumetone form I. The view is of the ac plane, and the C-H‚‚‚O contacts are shown in yellow.

Figure 10. Packing diagram for nabumetone form II. The view is of the ac plane, and the C-H‚‚‚O contacts are shown in yellow.

defined by the hydrophobic interactions within the respective bc planes. Form I has a corrugated layer structure (Figure 9), while the layers of form II are welldefined with the herringbone packing of the naphthalene moieties dominating the organization within the layer (Figure 10). Values for the C-H‚‚‚O interactions were obtained using C-H distances that were normalized to a value of 1.083 Å. All C-H‚‚‚O interactions with an H‚‚‚O

C-H‚‚‚O

H‚‚‚O distance (Å)

C‚‚‚O distance (Å)

CHO angle (°)

C(84)-H(84A)‚‚‚O(83) C(32)-H(32B)‚‚‚O(31) C(84)-H(84B)‚‚‚O(83) C(32)-H(32C)‚‚‚O(31)

2.666 2.713 2.733 2.768

3.721 3.459 3.616 3.777

164 126 138 155

distance less than 2.8 Å and a C-H-O angle greater than 110° are listed in Tables 2 and 3. The C-H‚‚‚O interactions in form I involve head-to-tail bonding between the methoxy group of one molecule and the ketone group of an adjacent molecule. In contrast, the C-H‚‚‚O interactions present in form II involve headto-head bonding between the ketone functional groups of adjacent molecules. The differences in the nonbonded interaction profiles for the two polymorphs correlate with their stability ordering. The thermodynamically more stable form I has a packing motif that allows for shorter C-H‚‚‚O interaction distances (Table 2) while simultaneously adopting a hydrophobic packing arrangement that results in a slightly more dense structure. The metastable form II has longer, and thus weaker, C-H‚‚‚O interaction distances (Table 3). For example, the metastable form has only one H‚‚‚O interaction distance below 2.7 Å, where form I has several interactions below this value. The metastable form, relying on the hydrophobic herringbone packing of the naphthalene moieties for stability, apparently cannot compete with the stronger C-H‚‚‚O interactions and more efficient overall packing present in form I. In the absence of stronger donors, it is felt that the combination of C-H‚‚‚O interactions and the π-π stacking of the naphthalene moieties are principally responsible for the stabilization of both structures. However, while each structure retains the naphthalene stacking motif, the differences in the C-H‚‚‚O distances between the two forms are significant enough to account for the stability ordering of the two polymorphs. The high instability of form II is evident in that this polymorph converts to form I in the solid state under mild mechanical stress or upon seeding (i.e., using a probe carrying seeds of form I). This facile transformation may be the primary reason that form II was not observed in conventional crystallization experiments where the solid form was packed in a sample holder prior to analysis. The rapid transformation of form II to the other crystalline form suggests that there is a relatively simple pathway that relates the two phases. A two step mechanism can be envisioned, which involves translation of molecules along the a-axis followed by a shift in the layers contained in the bc plane (Figure 11). In the first step, half of the molecules in the bc plane are translated by half a unit cell length in the a

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Figure 11. Possible pathway for the observed transformation of nabumetone form II (a) into form I (c). In the first step (a), layers of molecules in the ab plane are translated along the a-axis indicated by the blue arrows. In the second step (b), layers in the bc plane are translated along the c-axis.

direction. This has the effect of converting the parallel packing of the molecules in the bc plane of form II into the antiparallel, corrugated layer packing that characterizes the bc plane in form I. The second translation involves a shift of each hydrophobic layer of one-quarter of a unit cell along the c-axis. The transformation would change the interactions between layers from ketone-toketone and methoxy-to-methoxy interactions (form II) into ketone-to-methoxy interactions (form I). The orientation of the unit cell in form II and form I remains the same, and no significant molecular rotations or conformational changes are required to complete the transformation. While the actual mechanism has not been studied, the simple movements described are consistent with the observed ease of transformation and offer a relatively simple conceptual pathway that links the crystal packing of form II with form I.

by XRPD are distinct advantages that capillary-based polymorph screening methods offer over conventional techniques. We are continuing our investigation of the utility of this new methodology. Acknowledgment. We thank Dr. Phillip Fanwick (Purdue University) for performing the single-crystal analysis of the two polymorphs of nabumetone and Dr. Karl Hagen (Emory University) for obtaining the room temperature unit cell parameters for nabumetone form I. We also thank Drs. Patrick Stahly and Clare Keats (SSCI) for their help with the preparation of the manuscript. Supporting Information Available: X-ray crystallographic information files (CIF) for nabumetone forms I and II. This information is available free of charge via the Internet at http://pubs.acs.org.

References

Conclusions Crystallizations performed in capillary tubes provided a metastable polymorph of nabumetone that was characterized by single-crystal X-ray analysis and compared to the structure of the known crystal form. The metastable form of nabumetone readily converts to the more stable polymorph upon mechanical stress or seeding with the more stable form. The instability of the metastable form is best explained by the differences in the nonbonded interactions between the two polymorphs. The generation of form II of nabumetone in the microscopy experiments indicates that capillary-based crystallizations are not necessarily a requirement to generate the metastable form. However, we believe that the potential for high levels of supersaturation to be obtained in solutions evaporated from capillaries and the ability to analyze the crystallized material in situ

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