Methylchalcone - American Chemical Society

Part of the Special Issue: Facets of Polymorphism in Crystals

Disappearing and Reappearing Polymorphism in p-Methylchalcone

CRYSTAL GROWTH & DESIGN 2008 VOL. 8, NO. 1 63–70

Inna Barsky,† Joel Bernstein,*,† Peter W. Stephens,‡ Kevin H. Stone,‡ Eugene Cheung,§ Magali B. Hickey,§ and Jan-Olav Henck4 Department of Chemistry, Ben-Gurion UniVersity of the NegeV, P.O. Box 653, Be’er SheVa, Israel, 84105, Department of Physics & Astronomy, State UniVersity of New York, Stony Brook, New York 11794, and TransForm Pharmaceuticals, Inc., 29 Hartwell AVenue, Lexington, Massachusetts 02421, and Aptuit, West Lafeyette, Indiana 47906 ReceiVed August 15, 2007; ReVised Manuscript ReceiVed October 4, 2007

ABSTRACT: One stable form (Form I) and two metastable forms (Forms II and IV) of p-methylchalcone have been obtained, with Form II having previously been reported to be a disappearing polymorph. To prevent the conversion of Form II, which has a melting point of 89–91 °C, into the stable form it was produced in conditions free from seeds of the stable form. Form IV was discovered serendipitously as a single crystal that appeared in the preparation of a powder of Form II. Forms I and II have also been characterized by optical microscopy, differential scanning calorimetry (DSC), variable temperature powder X-ray diffraction, and spectroscopic analysis. The crystal structures of these three forms have been solved, Forms I and IV by single-crystal methods and Form II from synchrotron powder diffraction. This investigation highlights the fact that the challenges of reproducing experimental results (i.e., the production of a particular crystal form) may be overcome by a systematic search for new conditions under which previously obtained results can be regained. Introduction A substance is said to be polymorphic if it exists in different crystalline forms, with the possibility of exhibiting different physical properties. As a particular polymorphic modification may have desirable properties, it may be necessary to develop a robust method to ensure consistency and reproducibility in production of that polymorphic modification.1 We have previously described a number of cases in which it became difficult or impossible to obtain a given polymorphic form using the same process by which it had been previously obtained sometimes over long periods of time - so-called “disappearing polymorphs”.1–3 The factors that might have an impact on the crystallization process are many, and it is often difficult to determine for a particular system the precise circumstances that triggered the appearance of a new crystal form. Often unintentional seeding is a factor in the phenomenon of disappearing polymorphs.4 Once a new form appears, the presence of seeds of that form in the surroundings may make the crystallization of the previously obtained form very difficult under the same conditions, if not impossible. According to Ostwald’s Rule5 later appearing crystal forms are usually more stable than their predecessors, which can further increase the difficulty of obtaining the disappeared or metastable polymorphs. Disappearing polymorphs can also be a serious impediment to attempts to engineer crystals with particular structural features.1–3,6 Notwithstanding, we believe that the frustration of not being able to reproduce an experimental result that was unquestionably obtained earlier may in principle be overcome by a systematic search for the usually new conditions under which this form can be regained. * To whom correspondence should be addressed. E-mail: [email protected]. † Ben-Gurion University of the Negev. ‡ State University of New York. § TransForm Pharmaceuticals. 4 Aptuit.

Chalcones or 1,3-diaryl-2-propen-1-ones are abundantly present in nature from ferns to higher plants.7 They have been reported to show anti-inflammatory, analgesic, and antipyretic activity.8 Some derivatives possess bactericidal, antifungal, and insecticidal activity,9 while another was reported to be antimutagenic.10 Moreover, methyl and hydroxyl substituted compounds are known as potent antioxidants.11 In 1942, Deffet12 published his Repertoire des Composes Polymorphs, summarizing the literature sources and the polymorphic behavior of over 1000 organic compounds, including chalcones. According to this summary, polymorphism in chalcones is a fairly common phenomenon. In particular, the polymorphic behavior of p-methylchalcone (p-MC) was investigated quite extensively by Weygand in 1929.13 He reported the existence of three polymorphic forms. The stable modification melts at 96.5 °C and two metastable forms melt at 91 and 86 °C. In an environment in which seeds of the stable form are present the two metastable modifications readily convert into the stable form - behavior that is often typical of disappearing polymorphs.2 Additional studies on the compound were conducted in 1974 by Warshel et al.,14 who reported crystallographic constants and lattice energy calculations on p-methylchalcone Form I. Since then, no further studies of this polymorphic system have been reported. The goals of our reinvestigation of the p-methylchalcone

system were the preparation of as many as possible of the previously reported polymorphs,13 their characterization using various analytical techniques, and the development of strategies

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Barsky et al.

Figure 1. (a) Microscopic observation of Form II fine needles. (b) The chunky prisms of Form I after transformation from Form II.

Figure 2. DSC thermogram of several heating/cooling cycles of p-MC.

that will enable us to gain control over the preparation of the polymorph of interest, avoiding crystallization of undesired forms. In the course of this study we obtained two metastable forms called Forms II and IV. Form II was obtained under conditions free from seeds of the stable form and had a melting point of 89–91 °C, apparently one of the previously reported metastable forms of Weygand.13 Form IV was discovered serendipitously in a powder prepared as Form II. The crystal structure of Form II was determined from synchrotron powder diffraction at room temperature, while that of Form IV was determined from single crystal data collected at 100 K. The stable Form I, presumably Weygand’s high-melting modification,13 was prepared from crystals or powder of Form II by a solvent-mediated transformation or upon standing under dry ambient conditions. According to Weygand and from our own experience once Form I was obtained, subsequent crystallizations yielded solely the stable form. The crystal structure of Form I was determined by single crystal methods at room temperature. Forms I and II have also been characterized by optical microscopy, differential scanning calorimetry (DSC), variable temperature powder X-ray diffraction studies, and spectroscopic analysis.

collected at TransForm Pharmaceuticals and measured at 100(2) K on a Bruker kappa APEX II CCD area detector system supplied with a graphite monochromator and a Mo KR fine-focus sealed tube (λ ) 0.71069 Å), which operates at 50 kV, 30 mA. A total of 942 frames were collected with a scan width of 0.5° in ω and an exposure time of 120 s/frame. The total data collection time was 28 h. The frames were integrated with the Bruker SAINT19 software package using a narrowframe integration algorithm. The structure was solved using SIR 97 and refined using SHELXL 97.22 Synchrotron X-ray Powder Diffraction. High-resolution synchrotron PXRD patterns were collected on the X16C beamline at the National Synchrotron Light Source, Brookhaven National Laboratory. X-rays of wavelength 0.70030(7) Å were selected with a Si(111) double crystal monochromator. After the sample, the diffracted beam was analyzed using a Ge(111) crystal and detected by a NaI scintillation counter. Wavelength and diffractometer zero were calibrated using a sample of NIST Standard Reference Material 1976 (a sintered plate of Al2O3). The sample was loaded into a thin walled glass capillary of nominal diameter 1.5 mm and rotated about the longitudinal axis during data collection. Data were collected from 2θ ) 2° to 2θ ) 35° in steps of 0.005°. Collection times were increased from 4 s per point at low angle to 6 s at highest angle. FT-IR. FT-IR microscopy was performed on a Bruker spectrometer, using an Equinox 55 connected to an IRScope II using Opus software. Additional IR measurements were performed on KBr disks using a Nicolet Impact 410 spectrometer. Differential Scanning Calorimetry (DSC). DSC was performed on a Mettler Toledo 822e. All measurements were run in sealed Al pans. Hot Stage Microscopy (HSM). HSM examinations were carried out on a Wagner and Munz Kofler Hot Stage equipped with digital video recorder facilities.

Experimental Section Synthesis. p-Methylchalcone was synthesized by condensation of 4-methylbenzaldehyde 96% (Fluka) and acetophenone 99% (Aldrich) as reported earlier.13 Powder X-ray Diffraction (PXRD). PXRD patterns were obtained using a D/Max Rapid X-ray diffractometer15 equipped with a copper source (Cu KR 1.5406Å), manual x-y stage, and 0.3 mm collimator. The sample was loaded into a 0.3 mm boron-rich glass capillary tube16 by sectioning off one end of the tube and tapping the open, sectioned end into a bed of sample. The loaded capillary was mounted in a holder that was secured into the x-y stage. A powder diffractogram was acquired17 under ambient conditions at a power setting of 46 kV at 40 mA in reflection mode, while oscillating about the omega-axis from 0 to 5 degrees at 1 deg/s and spinning about the phi-axis at 2 deg/s The exposure time was 10 min. The diffractogram obtained was integrated over 2-theta from 5 to 40 degrees and chi (1 segment) from 0 to 360 degrees at a step size of 0.02 degrees using the cylint utility in the RINT Rapid display software18 provided with the instrument. The dark counts value was set to 8 as per the system calibration; normalization was set to average; the omega offset was set to 180°; and no chi or phi offsets were used for the integration. Single-Crystal X-ray Diffraction. Single-crystal–crystallographic data for Form I were collected at room temperature on a Bruker Smart 6000K diffractometer using Mo KR radiation (λ ) 0.71073 Å) with a graphite monochromator. All the heavy and hydrogen atoms were located from the difference Fourier maps. The data were reduced by SAINT,19 while absorption corrections were applied using SADABS.20 The structure was solved using SHELXS,21 and then refined with SHELXL22 in SHELXTL.23 The intensity data for Form IV were

Results and Discussion Crystal Preparation. p-Methylchalcone crystallized in the reaction vessel upon completion of the condensation reaction between 4-methylbenzaldehyde and acetophenone (1:1). Results obtained by Weygand13 suggest that growing single crystals of thermodynamically unstable forms via solution crystallization experiments is not an easy task, especially when the stable form has already been obtained in the same environment. Even intentional seeding of solutions with Form II will yield solely Form I, which strongly implies that the presence of a Form I nucleus is sufficient to suppress the production of the less stable forms. Therefore, to crystallize the thermodynamically unstable forms of p-methylchalcone, a virgin container should be used. The transformation from Form II (thin needles) to Form I (chunky prisms) can be observed on the microscope (Figure 1). However, since our goal was to obtain at least one single crystal of each and every one of the previously reported unstable modifications appropriate for X-ray diffraction experiments, we attempted to carry out the condensation reaction and the crystallization with different solvents (methanol, ethanol, iso-

Polymorphism in p-Methylchalcone

Crystal Growth & Design, Vol. 8, No. 1, 2008 65

Figure 3. From left to right: melting of Form I at 97 °C, crystallization of Form II from the melt at 60 °C and its subsequent melting starting at 89 °C.

Figure 4. FT-IR spectra of Forms I and II measured on a KBr pellet.

Figure 5. Infrared-microscope spectra of Forms I and II in the region of 625–735 cm-1.

propanol, and n-butanol). All the experiments led to the crystallization of the thin needles as in the previously reported case13 of the Form II metastable modification with mp 91 °C (Figure 1a). In the course of the examination of crystals for the structure determination of Form II via single-crystal X-ray analysis, a single crystal from a batch previously identified by PXRD as Form II was chosen. It was mounted for diffraction experiments at 100 K, and after the structure solution and calculation of powder diffraction pattern of the unstable form it became clear that there was no match between the experimental diffractogram of Form II (at room temperature) and the calculated powder

diffraction pattern of the newly obtained modification. The structure solution surprisingly led to a new polymorphic form (Form IV). One possible interpretation is that there was a single unusually large crystal of Form II in that batch, which transformed to Form IV upon cooling. However, when a powder sample of Form II was cooled to 100 K, the material remained pure Form II. We therefore believe that a single nucleation event led to the formation and growth of the phase we identify as Form IV. Forms I and II can be easily distinguished by their morphology (Figure 1). Thermal Methods of Analysis. The thermal properties were examined using HSM and DSC. The DSC examination of Form I was performed employing heating/cooling cycles at a rate of 5 K/min. Figure 2 illustrates the DSC thermogram of Form I in which the endothermic peak at 96.3 °C corresponds to the melting point of this stable form, with ∆ Hf ) 27.9 kJ/mol. During the cooling stage at 63.3 °C an exothermic peak with ∆H ) -25.6 kJ/mol is seen. This crystallization from the melt leads to Form II as indicated by melting observed during subsequent reheating at 89.4 °C, with ∆ Hf ) 26.1 kJ/mol. According to the Burger-Ramberger heat-of-fusion rule,24 if the form with the higher melting point has a higher enthalpy of fusion, the two forms are likely to be monotropic. On the basis of the DSC data, it is possible to conclude that this system is indeed monotropic. The results obtained using HSM were consistent with the DSC data. The crystals obtained from chlorobenzene solution melted at 95–97 °C, and the melt was subsequently slowly cooled to 60 °C at which point the characteristic fine needles of metastable Form II crystallized. These were confirmed by the melting point

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Figure 6. Variable temperature PXRD measurements show the Form II thermal behavior and the transformation to Form I. The uppermost diffractogram belongs to the experimental powder diffraction of pure Form I at room temperature. The diffraction pattern of Form II is shown at 25 and 40 °C; 50 °C: beginning of a solid–solid phase change of Form II to Form I: 60 and 70 °C: diffraction pattern of Form I.

Figure 7. Calculated powder diffraction patterns of the three forms of p-MC. Table 1. Summary of DASH Solutionsa space group

a

b

c

R

β

γ

χ2 Rwp (DASH) (TOPAS)

P21 14.158 21.866 5.912 90 89.988 90 47.413 P21 14.171 5.915 21.88 90 90.005 90 82.912 P212121 28.328 21.875 5.913 90 90 90 107.164

14.745 14.928 23.379

a Figures of merit for DASH include refinement of torsion angles only. Figures of merit for TOPAS are from refinement of torsion angles, C-C bond lengths, and angles of the bridge connecting the two benzene rings.

of 89–91 °C observed during a subsequent heating cycle. The whole process can be observed in Figure 3. Spectroscopic Analysis. The infrared spectra for Forms I and II were obtained using both traditional IR spectroscopy on a KBr disk and FT-IR microscopy directly on a crystalline sample. The two techniques yielded similar results. The use of an FT-IR microscope can prevent damage to the substance, while the preparation of KBr pellets can lead to a polymorphic transformation under pressure.25 Unstable phases are often transformed during conventional sample preparation procedures (in KBr or even Nujol), with corresponding spectral changes. In the present case, at first sight the IR spectra of the

Figure 8. (a) Refinement of the original solution produced by DASH, note the untenable bonding angles and the proximity of the oxygen atom to carbons on the benzene ring, indicative of an incorrect starting configuration. (b) Refinement of the correct solution demonstrating no untenable bonding. Hydrogen atoms have been eliminated for clarity.

Figure 9. Histogram showing the distribution of Rwp values for the 64 possible configurations of the p-methylchalcone molecules. The molecule is shown with the axes of rotation leading to the possible configurations.

two forms look very similar (Figure 4) with the exception of one slight displacement in the fingerprint region which can serve for identification purposes: the shift of Form I band at 692 to 687 cm-1 in Form II is significant (Figure 5). Diffraction Methods of Analysis. Variable temperature PXRD measurements (Figure 6) were carried out on a sample of Form II, placed into a closed capillary in which the heating rate was not under thermostatic control. The heating of the metastable Form II leads to a solid–solid phase change to Form I which begins at 50 °C and continues to ∼60 °C. The powder diffraction pattern observed after the transformation was similar to the Form I pattern obtained at room-temperature. The shape of the background in the region 15° < 2 θ < 30° suggests the possible presence of some amorphous material contained in the sample, although we are not aware of any previous reports of an amorphous form of this compound. As noted above, some, although not all samples of Form II have been observed to convert to Form I over a period of several days or weeks. Forms I and IV crystal structures were solved by single-crystal methods, while Form II was solved from synchrotron powder diffraction. As noted above, the data for Form IV were collected at 100 K. The comparison between the calculated powder



Figure 10. Powder diffraction data points and Rietveld refinement. The residuals are shown below. Note the presence of a few sharp difference peaks, due to the presence of an unidentified impurity phase, also shown in the inset. Table 2. Crystallographic Data for the Three Polymorphs of p-Methylchalcone identification code

Form I

temp (°C) crystal system space group a (Å) b (Å) c (Å) β (°) volume (Å3) Z density (calc) (g/cm3) R1 Rw χ2

25 monoclinic P21/n 5.873(2) 16.762(5) 12.554(4) 93.499(9) 1233.6(6) 4 1.197 0.044 0.115

a

Form II

Form IV

25 monoclinic P21 14.1638(2) 21.8749(2) 5.9130(1) 89.947(1) 1832.03(5) 6 1.209

-183 monoclinic P21 14.154(6) 21.287(5) 5.836(2) 89.88(3) 1758.5(10) 6 1.259

0.065 9.954

9.388a

-173 monoclinic C2/c 26.237(9) 5.824(2) 15.541(5) 101.807(1) 2324.31(1) 8 1.270 0.033 0.092

Only lattice parameters refined.

Figure 11. ORTEP diagram of the molecule in the Form IV structure showing the atomic numbering scheme employed. The numbering is identical for Forms I and II with literal suffixes to distinguish among the three molecules in the asymmetric unit. Anisotropic atomic displacement ellipsoids for the nonhydrogen atoms are shown at the 50% probability level. Hydrogen atoms are displayed with an arbitrarily small radius.

Table 3. Comparison of Literature and Experimental Unit Cell of Form I

Table 4. Torsion Angles of Forms I, II, and IV

14a

Form II (°)

literature data a (Å) b (Å) c (Å) β

obs

calc

experimental data

12.50 16.67 5.85 93.5

12.58 16.62 5.85 94.0

5.87 16.76 12.55 93.5

a The labeling of the a- and c-axis has been switched in these identical cells.

patterns of Form I and Form II to Form IV confirms the existence of three polymorphic forms of the substance (Figure 7). The software suite TOPAS Academic26 was used to index the powder diffraction pattern of Form II. The most likely space group was determined to be P21/c with lattice parameters a ) 14.162 Å, b ) 21.874 Å, c ) 5.913 Å and β ) 89.978°. Because of the low symmetry of the molecule, it is expected that each atom is on a general position. Under the assumption that each nonhydrogen atom in such an organic material will fill roughly 17 Å3, each independent molecule has a size of roughly 290 Å.3 Given that the volume of this unit cell is 1832 Å,3 we therefore expect to find six p-methylchalcone molecules in that unit cell. However, the multiplicity of the general position in

Form I (°)

molecule molecule molecule Form IV A B C (°)

C11-C10-C9-C8 11.6 -8.8 C10-C9-C8-C7 -177.1 180.0a C9-C8-C7-C6 -163.0 -170.9 C8-C7-C6-C1 25.8 -5.5

5.9 180.0a -165.2 28.7

24.8 180.0a -173.9 22.9

-7.1 179.9 170.7 14.3

a

In the Rietveld refinement of Form II, this torsion angle was fixed at 180°.

space group P21/c is 4, making six molecules impossible. There are two possible remedies for this conundrum: either change to a space group with a lower multiplicity of the general position (presumably P21), or double the unit cell. In addition, the nearness of the angle β to 90° leaves open both the possibility that the space group is not truly monoclinic and the possibility that we have chosen the wrong axis as being unique for the monoclinic space group. A doubled unit cell leads to the requirement that the final structure must cause a number of allowed reflections to have negligible intensity, an unlikely though not impossible scenario. As a consequence, the determination of the lattice and space group for this material was more difficult than just matching

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Figure 12. Molecular conformations of Form I (a), Form II (c), and Form IV (b). In all cases the carbonyl oxygen points out of the page.

observed and absent powder reflections. To truly determine the correct structure, it became necessary to attempt a structure solution and refinement for each candidate lattice and space group, at which point physical and chemical constraints, as well as the quality of fit, would provide the discriminating power necessary for determination of the actual solution. The simulated annealing program DASH27 was used to search for structure solutions in each of the possible space groups. Many space groups, such as P21/c with doubled lattice parameters, were immediately eliminated upon inspection due to physically unreasonable structures. DASH returned two viable structures for space group P21 (different choices of unique axis) and one for space group P212121 as summarized in Table 1. Subsequent refinement of structures was performed using TOPAS Academic. The orthorhombic structure in space group P212121 yielded a significantly worse Rwp value than for the monoclinic structures, and so it was provisionally rejected. Further refinements of the two candidate solutions in space group P21 yielded generally untenable bond lengths and angles, as may be seen in Figure 8. It was noted that due to the approximate mmm symmetry of the molecule, each molecule could be flipped about each of the two axes illustrated in Figure 9. Therefore, any candidate solution is actually the parent of 64 possible configurations of the three independent molecules (two axes for three molecules, 26 cases). At low resolution, it would be difficult to distinguish among these different orientations. To choose the correct one, separate refinements were run, starting from each of these 64 possible configurations. The bond distances were refined within appropriate limits. All bond angles were fixed at 120°, and the three torsion angles about the single bonds in the chain which connects the aromatic rings were allowed to refine with no constraint. These refinements resulted in 64 candidate structures for each of the two P21 lattices. A histogram showing the Rwp values for the lattice with parameters a ) 14.16 Å, b ) 21.87 Å, c ) 5. 91 Å, and β ) 89.988° is shown in Figure 9, one of which is significantly preferred. Neither the original approximate structure determination nor the Rietveld refinement was able to overcome the problem of 63 incorrect (metastable) solutions. This situation has occurred because the Rietveld refinement is not able to improve the fit incrementally by flipping the molecule over, and the simulated annealing process likewise gets stuck in one of the 64 nearly equal minima. Fortunately, full Rietveld refinements are able to distinguish the best one.

Barsky et al.

Having identified the correct orientation for the three independent molecules, a more complete refinement of the structure was performed. The carbon-carbon bonds were refined as four parameters, representing single, double, aromatic, and carbonCH3 bond lengths. The carbon-oxygen bond length was also refined as a single parameter for all three molecules. The three angles formed in the chain linking the two aromatic rings were refined, although constrained between 110° and 130°. The angle and torsion corresponding to the oxygen position were both freely refined for all molecules. The three torsions about the single bonds in the chain were allowed to refine without constraint. The fit to the data as well as the difference is shown in Figure 10. A number of unusually sharp peaks were also observed. Indeed, these peaks are too sharp to be due to a powder sample. The inset in Figure 10 demonstrates the exceptional sharpness of these peaks in relation to the ordinary powder peaks observed in the sample. This suggests that they are instead due to a few large grains of some impurity. Our attempts to index these, or fit them to one of the other known phases of p-MC or the precursor molecules, were unsuccessful. Crystallographic data of the three polymorphs of p-MC are given in Table 2. The dimensions of the unit cell of Form I are in good agreement with those reported earlier (Table 3) by Warshel et al.14 Forms I and IV crystallized in monoclinic space group with one molecule in the asymmetric unit. There is a similarity between the dimensions of the unit cell of the structures: the a-axis of the unit cell of Form I is similar to the c-axis in Form II and b-axis in Form IV. On the other hand, the c-axis of Form I is half of the crystallographic a-axis of Form IV. However, these similar cell dimensions are not manifested in any structural similarities. The hydrogen atoms of the methyl group in Form IV are statistically disordered in two orientations. The ORTEP diagram and atomic numbering for all forms of p-MC are presented in Figure 11. The most significant structural difference between the molecules in the three polymorphs lies in the torsion angles (Table 4) around the bridge connecting the two benzene rings of the molecule. The difference between all four torsion angles of Forms I and IV is responsible for the conformational difference between these two molecules, causing a twist in the Form I molecule on the one hand, and a relative planarity of the Form IV on the other (Figure 12). These two structures therefore also represent conformational polymorphs. The degree of planarity in the three molecules of Form II is also different (Table 4). It can be seen that the C9-C8-C7-C6 torsion angle in molecule B is the smallest. In addition, there are differences in the torsion angles of the phenyl rings around the bond C6-C7 and C9-C10. Molecule A in Form II is the most planar among all five independent molecular structures reported here. The packing arrangements of the molecules in the three structures are clearly different (Figure 13). Conclusions We have crystallized two polymorphic forms of p-methylchalcone: Forms I and II, which have been known since 1929. From previous studies and our own experiments, we determined that although the metastable Form II of p-methylchalcone may be considered a disappearing polymorph, it is possible to achieve conditions to reproducibly obtain it, namely, by carrying out the one-step condensation synthesis with virgin glassware and under conditions free of seeds of Form I. The phase transformation of Form II to stable Form I was observed between 50 and 60 °C and also more slowly at room temperature. Investigation



Figure 13. Packing diagrams of the three crystal structures. For ease of comparison, in all cases the view is chosen on the best plane of the ketone group darkened as a reference, with the C-O vector pointing up. (a) Form I, (b) Form II (the reference molecule is molecule C), (c) Form IV. The ketone group in the reference molecule is marked in black. Hydrogens have been eliminated for clarity.

of the thermal behavior of Forms I and II reconfirmed that Form I is the most stable form. Moreover, a third polymorphic form of p-methylchalcone (Form IV) was discovered in a unique single crystal. The question of the identity of the third form we have found and characterized with the crystal structure determination cannot be answered unequivocally since there are no common data between this form (single crystal structure only) and Weygand’s Form III (melting point only). The circumstantial evidence,

namely, that only three forms of p-MC have ever been reported and now found suggests that they may be one and the same Weygand’s Form III, but confirmation will have to await the availability of material melting at 86 °C with the diffraction of the form reported here. The success of this strategy has strengthened our earlier assertion2 that once a particular polymorph has been prepared, in principle it should always possible to find the conditions to prepare it again.

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Acknowledgment. We would like to thank Dr. Dimitry Mogilansky for assistance with additional powder diffraction measurements in Beer-Sheva and Dr. Andreas Lemmerer of the University of Witwatersrand for DSC measurements. Use of the National Synchrotron Light Source, Brookhaven National Laboratory, was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-8CH10886. Supporting Information Available: Crystallographic information files. This information is available free of charge via the Internet at http://pubs.acs.org. The structures of the three polymorphs have been deposited with the Cambridge Crystallographic Data Centre, depositions 652755 (Form I), 652154 (Form II) and 652756 (Form IV).

References (1) Henck, J.-O.; Bernstein, J.; Ellern, A.; Boese, R. J. Am. Chem. Soc. 2001, 123, 1834–1841. (2) Dunitz, J. D.; Bernstein, J. Acc. Chem. Res. 1995, 28, 193–200. (3) Rubin-Preminger, J. M.; Bernstein, J. Cryst. Growth Des. 2005, 5, 1343–1349. (4) Bernstein, J. Polymorphism in Molecular Crystals; Clarendon Press: Oxford, UK, 2002. (5) Ostwald, W. F. Z. Phys. Chem. 1897, 22, 289–330. (6) Bernstein, J.; Henck, J.-O. Cryst. Eng. 1998, 1, 119–128. (7) Star, A. W.; Marby, T. J. Phytochemistry 1971, 10, 2812–2817. (8) Satyanarayna, K.; Rao, M. N. A. Indian Drugs 1993, 30, 313–318. (9) Dhar, D. N. The Chemistry of Chalcones and Related Compounds; Wiley: New York, 1981, 213 pp. (10) Torigoo, T.; Arisawa, M.; Iloch, S.; Fujiu, M.; Mayuyama, H. B. Biochem. Biophys. Res. Commun. 1983, 112, 833–842.

Barsky et al. (11) Anto, R. J.; Sukumaran, K.; Kuttan, G.; Rao, M. N. A.; Subbaraju, V.; Kuttan, R. Cancer Lett. 1995, 97, 33–37. (12) Deffet, L. Repertoire des Compose’s Organique Polymorphs; Desoor: Liege, Belgium, 1942. (13) Weygand, C. Lieb. Ann. 1929, 472, 143. (14) Warshel, A.; Huler, E.; Rabinovich, D.; Shakked, Z J. Mol. Struct. 1974, 23, 175–191. (15) D/Max Rapid; Rigaku/MSC: The Woodlands, TX. (16) Charles Supper Company, 15 Tech Circle, Natick MA 01760–1024. (17) Control software: RINT Rapid Control Software, Rigaku Rapid/XRD, version 1.0.0; Rigaku Co.: The Woodlands, TX, 1999. (18) Analysis software: RINT Rapid display software, version 1.18; Rigaku/ MSC: The Woodlands, TX. (19) Bruker AXS: SAINT+, Release 6.22; Bruker Analytical Systems: Madison, WI,1997–2001. (20) Sheldrick, G. M. SADABS, Version 2.03, Program for Area Detector Absorption and Other Corrections; University of Gottingen: Germany, 2001. (21) Sheldrick, G. M. SHELXS-97, Program for the Solution of Crystal Structures; University of Gottingen: Germany, 1997. (22) Sheldrick, G. M.; Schneider, T. R. SHELXL-97, Program for the Refinement of Crystal Structures; University of Gottingen: Germany, 1997. (23) Sheldrick G. M., SHELXTL-Plus, Release 6.10; Bruker Analytical Systems: Madison, WI, USA, 2000. (24) Burger, A.; Ramberger, R. Microchim. Acta 1979, 2, 259–271. (25) Bugay, D. E. AdV. Drug DeliVery ReV. 2001, 48, 43–65. (26) Coelho, A. A. TOPAS-Academic, 2006, http://members.optusnet. com.au/∼alancoelho/. (27) David, W. I. F.; Shankland, K.; Streek, J.; Pidcock, E.; Motherwell, W. D. S.; Cole, J. C. DASH: A program for Crystal Structure Determination from Powder Diffraction Data. J. Appl. Crystallogr. 2006, 39, 910–915.

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