A Whole Output Strategy for Polymorph Screening ... - ACS Publications

We now demonstrate further development of this “whole output strategy” by ..... The observed diflunisal network has the binary graph set correspon...
0 downloads 0 Views 452KB Size
CRYSTAL GROWTH & DESIGN 2003 VOL. 3, NO. 2 151-158

Articles A Whole Output Strategy for Polymorph Screening: Combining Crystal Structure Prediction, Graph Set Analysis, and Targeted Crystallization Experiments in the Case of Diflunisal Wendy I. Cross, Nicholas Blagden, and Roger J. Davey* The Molecular Materials Centre, Department of Chemical Engineering, UMIST, P.O. Box 88, Manchester M60 1QD, United Kingdom

Robin G. Pritchard Department of Chemistry, UMIST, P.O. Box 88, Manchester M60 1QD, United Kingdom

Marcus A. Neumann Accelrys Ltd., 334 Cambridge Science Park, Cambridge CB4 0WN, United Kingdom

Ronald J. Roberts and Raymond C. Rowe AstraZeneca Plc., Hurdsfield Industrial Estate, Macclesfield, Cheshire SK10 2NA, United Kingdom Received September 27, 2002;

Revised Manuscript Received November 21, 2002

ABSTRACT: This paper describes the combined application of crystal structure prediction and targeted experimental crystallization to diflunisal, a fluorinated, aromatic carboxylic acid. Graph set analysis has been used to analyze and classify the structural predictions, and crystallization solvents have been selected to promote the formation of crystals containing the most commonly predicted hydrogen-bonding motifs. Accordingly, four new crystal structures of this material were solved, two solvates and two new polymorphs. This example further highlights both the insight offered by crystal structure prediction software and the limitations of current solution crystallization strategies. Introduction Polymorphism is defined as the ability of a molecule to adopt more than one crystalline form. This phenomenon occurs widely among organic compounds where several crystal packing possibilities exist via variations in intermolecular hydrogen bonding of functional groups. Different packing arrangements of organic molecules result in different physical properties such as melting point, solubility, hardness, and density. Therefore, in many industries in which crystallization is often used for purification and isolation, controlling the crystallization process and ensuring the isolation of the correct polymorph is crucial.1 When a novel pharmaceutical compound has been developed, it is a regulatory requirement2 that all reasonable experiments are performed in order to identify and characterize the maximum number of crystalline forms (polymorphs). This is often done by recrystallizing the compound from various solvents (a “solvent screen”). Despite current application

of high throughput methodologies to such screens,3 there are no guarantees that all possible polymorphs will be isolated; hence, the ability to predict the possible polymorphs for new molecules would be invaluable. To this end, the computational techniques of crystal structure prediction have been developed over the past decade.4-6 The methods generally produce an output of hundreds of theoretical structures ranked by their calculated lattice energies and densities. These techniques are still in their infancy, and as a result, the ranking process is still unreliable7 such that even a known crystal structure will often not be found high up in the ranked output. Given this present unreliability, we previously proposed an alternative strategy8 in which the crystal structure prediction output was not used to identify specific polymorphs; rather, the whole output was examined and common packing motifs were identified and characterized. Once the full range of hydrogen-bonding motifs had been explored, the crystal-

10.1021/cg025589n CCC: $25.00 © 2003 American Chemical Society Published on Web 12/18/2002

152

Crystal Growth & Design, Vol. 3, No. 2, 2003

Figure 1. Known structure of diflunisal. (a) Ortep diagram of FAFWIS showing the disordered fluorine. (b) Packing diagram of FAFWIS.

lization conditions were manipulated via solvent selection in an attempt to produce polymorphs containing some of these packing modes. We now demonstrate further development of this “whole output strategy” by using graph set analysis to characterize the hydrogen-bonding motifs and hence classify the predicted structures and guide the experimental protocol. In our previous study,8 each theoretical polymorph was examined by visual inspection, a process that was not only extremely time-consuming but also prone to ambiguity. Using graph sets,9 each theoretical polymorph can be analyzed and catalogued in a readily recognizable notation. Briefly, complicated patterns can be reduced to combinations of four simple motifs (designators): rings (R), chains (C), intramolecular hydrogen bonding (S), and discrete patterns (D). As a motif is a pattern containing only one type of hydrogen bonding, the three-dimensional packing structure of the molecule may be defined by a full list of the motifs present. Thus, a motif is described by the unitary (first level) graph set, N1, while binary (second level) graph sets, N2, are produced by combining pairs of unitary graph sets and N3 or ternary (third level) graph sets consist of combinations of three hydrogen-bonding motifs. Diflunisal (Figure 1a), a nonsteroidal antiinflammatory drug, was chosen for the study as it is reported, on the basis of powder X-ray data, to have at least four polymorphic crystal forms of which only one structure has been solved.10 Cotton and Hux11 described the existence of three nonsolvated polymorphs, I-III, but gave no preparative details. Martinez-Oharriz et al.12 reported the existence of a fourth form, IV, and gave the experimental conditions for crystallizing each polymorph together with their IR spectra and powder X-ray

Cross et al.

diffraction (XRD) patterns. Briefly, forms I, III, and IV were made by crash cooling (from 60 to 6 °C) a solution of diflunisal in, respectively, chloroform, ethanol, and toluene while form II appeared on combined drowningout and cooling of a saturated solution of ethanol with water at room temperature. Here, we have followed the existing numbering scheme12 and note that Cotton and Hux11 found the order of stability at 30 °C, determined from aqueous solubility experiments, to be I < III < II (most stable). The original IR spectra and powder XRD patterns11,12 were confirmed by our own samples, although in our experience, form I crystallized from toluene and form IV crystallized from chloroform not vice versa as recorded in ref 12. More recently, Perlovich et al. have reported the crystal structure of two solvates13,14 and further characterized the polymorphic forms of diflunisal using powder XRD, Fourier transform IR (FTIR), and thermal methods.15 In each solvated structure, the solvent, hexane or water, occupies channels within the crystal lattice and the diflunisal molecules are packed as carboxylic acid dimers. Of the polymorphic phases, Perlovich et al. report four distinct structures, which, contrary to previous nomenclature, they now label A, B, C, and D15 but which they equate with the previously defined forms I, II, and III, respectively, while form D is a new polymorph. Overall, our work confirms these assignments although we have not found their form D. The available nonsolvated crystal structure of diflunisal in the CCDC (ref 16; refcode, FAFWIS) was reported by Kim and Park.10 Crystals of this form were grown at room temperature by slow evaporation of a solution of diflunisal in an acetone-water mixture. Crystals are monoclinic, space group C2/c with unit cell dimensions a ) 34.666(6) Å, b ) 3.743(1) Å, c ) 20.737(1) Å, β ) 110.57(2)°, and vol ) 2519.4(4) Å3. The crystal packing for this structure, which is based on carboxylic acid dimers, is shown in Figure 1b. The simulated powder XRD pattern of this structure does not match any of the patterns reported in refs 12 or 15; hence, we have denoted it form V. Crystal Structure Prediction As a starting point for the structure predictions, it was noted that in the reported crystal structure of form V and in the hexane solvate, one of the fluorine atoms is disordered over the two ortho sites on the aromatic ring, each with a site occupancy factor of 0.5. This arises because of the torsional flexibility around the single bond linking the aromatic rings. In an attempt to incorporate this disordered fluorine into the simulations, a conformational analysis was performed on the diflunisal molecule using MOPAC17 together with the CONFORMER module within Cerius2 18 and Dreiding 2.21 force field.19 The two lowest energy conformers A (fluorine atoms anti to the carboxylic acid group) and B (fluorine atoms syn to the carboxylic acid group) with torsions (43.8° and the intramolecular motif, S(6), were selected, and the crystal structure prediction simulation was undertaken in each conformer. The structure prediction simulations were executed using the Polymorph Predictor module within Cerius2 18 in the five most common space groups, P1 h , C2/c, P21, P212121, and P21/c for organic molecules.20 Details of the

Output Strategy for Polymorph Screening for Diflunisal

Crystal Growth & Design, Vol. 3, No. 2, 2003 153

Figure 2. Lattice energy/density plot for predicted structures, color-coded to reveal occurrence of secnd level graph sets A-AA.

method and evaluation are widely discussed in the literature,21 and these simulations were run as described previously,8 generating structures with values of Elatt < -35 kcal/mol and densities between 1.6 and 1.2. Graph Set Analysis of the Output. Each theoretical model was saved in the SHELX *.res file format and read into RPluto, a molecular visualization program provided by the CCDC.12 RPluto was then used for the automatic assignment of graph sets up to the second level, N2. As a check of the use of RPluto, the unitary and binary graph sets of each model were also analyzed by visual inspection in Cerius2. Having determined the graph sets of these (300) predictions, a database of their structures and graph set assignments was created. This could be searched using the Quest software16 providing a fast method of analyzing the whole output of the prediction and for determining (via a match of unit cells) whether a crystal structure produced experimentally matched any of the simulation results. Results The top 30 ranked structures were examined for each conformer in all five space groups producing a total of 300 theoretical structures. A lattice energy/density plot of the output (Figure 2) reveals a good spread of the data indicating that a well-distributed search of packing space was achieved. Unitary (First Level) Analysis. From the simulated output for the two conformers, 16 unitary graph sets were identified. Some examples of the unitary graph sets observed are illustrated in Figure 3, which shows the intramolecular hydrogen-bonded ring, S(6), together with the carboxyl dimer, the -OH‚‚‚F- chain and the

-OHhyd dimer. As there are two -OH groups present in diflunisal, the subscript hyd indicates contacts using -OH in the carboxylic acid functional group and ph indicates contacts using the phenoxy functional group. Binary Graph Set Analysis. Combinations of pairs of unitary graph sets produced 27 distinctive hydrogenbonded classes, which, for notational simplicity, were labeled alphabetically. The histograms for the A and B conformers shown in Figure 4 reveal preferential packing of the diflunisal molecule toward certain graph sets. It is clear that the top five graph sets (G, E, C, F, and B, discussed in turn below) are common to both suggesting that the position of the ortho F is not influential in the packing. While anionic fluoride acts as a very strong proton acceptor, there remains some conjecture as to whether covalently bound fluorine can form hydrogen bonds of the form C-F‚‚‚H.22 To explore the effect of eliminating such interactions, a subset of the output was created excluding all of the models containing close intermolecular C-F‚‚‚H contacts. This eliminated 17 of the binary graphs sets leaving only 10 of which graph set E was the most frequently occurring followed by graph sets F and D. These six most commonly occurring binary graph sets, G, E, C, F, B, and D, are discussed below, and these were ultimately chosen as the basis for selective crystallization experiments. Graph Set G. This is the most frequently occurring graph set in the simulation output, and an example of a predicted structure incorporating this motif is seen in Figure 5a. The diflunisal molecules hydrogen bond into long chains via C(11)hyd motifs in which the carboxylic hydroxyl group forms a hydrogen bond with the adjacent fluorine atom. It is noted that structures

154

Crystal Growth & Design, Vol. 3, No. 2, 2003

Cross et al.

Graph Set D. This graph set, which only becomes significant when the H-bonds to fluorine are ignored, utilizes both the R22(8) carboxyl and the R22(4) hydroxyl dimers. It is illustrated in Figure 5f. Crystallization Experimental Strategy

Figure 3. Examples of unitary graph sets.

containing this motif cannot include the carboxylic acid R22(8) dimers. Graph Set E. In this motif, the carboxylic acid groups form the R22(8) dimer as shown in Figure 5b. The known crystal structure (FAFWIS) and the two recently reported solvate structures belong to this graph set. Graph Set C. The diflunisal molecules form long C(11)ph chains, which are cross-linked by the R22(8) dimer motif forming a ladder type motif as illustrated in Figure 5c. Graph Set F. At first sight (Figure 5d), graph set F looks similar to graph set E in which diflunisal forms dimers. However, in this case, the carboxylic acid groups do not form dimers but instead hydrogen bond to form a helical chain with unitary motif C(4). Graph Set B. The diflunisal molecules hydrogen bond to form C(11)ph chains. The chains are cross-linked via the carboxylic acid groups, but again, as with set F, the carboxylic acid groups form C(4) helical chains rather than R22(8) dimers. This is seen in Figure 5e.

Once we identified the most commonly occurring structural patterns in the predicted structures, the next objective of the study was to attempt to isolate crystal forms containing at least some of these motifs. The crystallization strategy employed followed our previous work8,23-25 and involved the attempted manipulation of the hydrogen-bonding motifs via solvent selection. Thus, for example, we used acetic acid in an attempt to prevent the formation of R22(8) carboxyl dimers and encourage the formation of graph sets G, F, and B. We expected that an alcohol could be used to mimic -OH groups and thus inhibit intermolecular hydrogen bonding via the phenoxy group as well as inhibit close C-F‚‚‚H-O- contacts. It would thus be hoped that any polymorphs crystallized from an alcohol (e.g., forms II and III) would belong to graph sets E or F. Acetone might similarly be anticipated to block the interactions between phenoxy groups, and indeed, the isolated dimer R22(8) is observed in the known crystal structure FAFWIS, which was crystallized from acetone/ water and belongs to graph set E. Chloroform might similarly be expected to form weak -C-H‚‚‚F- or -CH‚‚‚O- interactions with diflunisal and hence inhibit the formation of graph set G, D, B, or C and again direct the crystallization toward E or F. Finally, an aprotic solvent such as toluene would not be expected to disrupt hydrogen-bonding interactions and would therefore encourage maximum hydrogen-bonding contacts to give structures based on graph sets C or D. Crystallization and Structure Determination. Crystals were grown from acetone, ethanol, water/ ethanol, toluene, and chloroform by following the original recipes10,12 in which a saturated solution was prepared in an appropriate solvent at 60 °C (45 °C for acetone), filtered through a 0.2 µm PVDF syringe filter, and cooled to 5 °C. In this way, crystals with identical powder patterns to the previous forms I-V were easily obtained. A similar crystallization procedure using acetic acid as a solvent yielded a new form VI. Overall, significant problems were encountered growing crystals large enough for single crystal X-ray studies. In particular, despite significant experimentation on forms II and III, we were unable to grow crystals of suitable size for single crystal X-ray studies. However, in the case of form III, powder X-ray data were used to enable structure solution with subsidiary solid state NMR, FTIR, and Raman spectroscopy being used to check the result. For single crystals of forms IV and VI, data collection was performed with a Nonius Kappa CCD area detector diffractometer at -123 °C using graphite-monochromated Mo KR radiation (λ ) 0.71069A), with the CCD detector placed at a minimum distance of 33 mm from the sample via a mixture of 1° φ and ω at different θ and κ settings. The crystal data for form I were collected at room temperature using a RAXIS diffractometer in 120 × 3° φ oscillations of 7 min per exposure. All

Output Strategy for Polymorph Screening for Diflunisal

Crystal Growth & Design, Vol. 3, No. 2, 2003 155

Figure 4. Histograms sorted by conformer type.

Figure 5. Examples of the commonly occurring graph sets G, E, C, F, B, and D.

structures were solved using SHELXS-9726 and were refined by full-matrix least squares refinement (on F2) using SHELXL-97. All nonhydrogen atoms were refined with anisotropic displacement parameters. Powder X-ray diffractograms were recorded at room temperature in rotating Lindemann tubes using a Bruker AXS D8 with a scintillation detector. The powder diffraction pattern was indexed with X-Cell.27 All subsequent steps of the crystal structure determination procedure were carried out using the modules Reflex Plus,28,29 DMol3,30,31 Discover, and Compass in the materials modeling environment Materials Studio.18 FTIR spectra were recorded between 700 and 4000 cm-1 using a Nicolet Atvar spectrometer fitted with a germanium ATR cell, while dispersive Raman spectra were recorded over the same range using a Dilor

Labram microscope system. 13C NMR spectra were acquired on a Chemagnetics CMX200 spectrometer, operating at 50.329 MHz for 13C. The samples were spun at 4.5 kHz at the magic angle (54.7°). A π/2 pulse of 5 µs for 1H was used, with a contact time of 2 ms and a pulse delay of 77 s. A 50 kHz 1H-decoupling field was applied during acquisition; 700 transients were collected, each transient containing 2048 data points. The free induction decay was zero-filled to 8 K data points and Fourier-transformed with 10 Hz line broadening.32 Results of CrystallizAtion Experiments Acetic Acid. Crystallization from glacial acetic acid produced needle crystals, which X-ray analysis revealed to be a new solvate, form VI. The diflunisal molecules

156

Crystal Growth & Design, Vol. 3, No. 2, 2003

Cross et al.

Figure 6. Projections of the new crystal forms of diflunisal.

are hydrogen-bonded into chains by para-F C11(11)ph contacts. These chains are then connected in pairs, by R22(8) carboxyl dimers, and pairs of chains in each layer are hydrogen-bonded to the layer above via every alternate carboxylic acid as seen in Figure 6a. The C2C1-C7-C8 torsion is -37.5° as compared to 43.5° in all of the other structures reported here. The acetic acid molecules, which lie in channels between the pairs of chains, are not involved in the hydrogen-bonding network. The acetic acid is clearly unable to disrupt the formation of the carboxylic acid dimer as proposed by the crystallization strategy. The observed diflunisal network has the binary graph set corresponding to R in Figure 2. There are nine structural models belonging to this graph set category in the simulation output. Six of the graph sets in this category had the same packing arrangement as form VI while the other three formed an extended sheet network. Binary graph set analysis

is unable to distinguish between the two different types. Ternary analysis of the network would have revealed the difference, but this is as yet unavailable in RPluto. Toluene. Single lamellar crystals were successfully grown from toluene and found to be of suitable size for single crystal X-ray analysis. Visual inspection of the hydrogen-bonding pattern in the structure (Figure 6b) reveals the diflunisal molecules to pack as dimers via the R22(8) carboxylic acid motif. These dimers are then connected via intermolecular R22(4) phenoxy contacts to form long chains. This structure clearly belongs to graph set D as expected from the crystallization strategy. The simulated X-ray powder pattern was compared to those of the reported polymorphic forms and found to be consistent with the form I of ref 12. A search of the predicted structures showed this to be a good match for the high-density structure based on graph set D and identified in Figure 2.

Output Strategy for Polymorph Screening for Diflunisal

Crystal Growth & Design, Vol. 3, No. 2, 2003 157

Table 1. Crystal Structure Data for Forms I, III, IV, and VI formula Fwt (gmol-1) crystal system space group crystal color a (Å) b (Å) c (Å) R β γ vol (Å3) Z abs coeff (mm1) T (K) independent reflnsa Rint Rb Rwc GOF a

I

IV

VI

IIId

C13H7F2O3 249.19 triclinic P1 h colorless 3.800(5) 6.770(4) 21.650(3) 82.30(2) 83.990(14) 81.980(17) 544.4(8) 2 0.130 293(2) 1109 0.000 0.0492 0.1333 1.131

C13.5H8ClF2O3 291.65 monoclinic C2/c colorless 34.2819(18) 3.6771(2) 20.7361(13) 90.0 110.376(2) 90.0 2450.4(2) 8 0.339 153(2) 2162 0.1654 0.0642 0.1449 1.045

C13.77H7F2O3.77 270.68 monoclinic P21/n colorless 16.499(2) 3.7290(4) 18.746(3) 90.0 92.202(4) 90.0 1152.5(3) 4 0.135 150(2) 1945 0.0841 0.0643 0.1514 1.003

C13H7F2O3 249.19 orthorhombic P212121 colorless 39.7001 14.1292 3.8356 90.0 90.0 90.0 2151.5 8

Observation criterion I > 2σ(I). b R ) ∑| |Fo| - |Fc| |/∑ |Fo|. c Rw ) [∑w(Fo2 - Fc2)2/∑w(Fo2)2]1/2.

Chloroform. Crystallization from chloroform produced a further solvate (Figure 6c) in which diflunisal molecules form dimers with R22(8) motifs, graph set E. Although the chloroform molecules are disordered throughout the channels, in line with our strategy, they are linked into the packing via close -C-H‚‚‚F (2.8863.043 Å) and -C-H‚‚‚O (2.986 Å) contacts as expected. A predicted powder pattern shows this structure to be form IV of ref 12. Ethanol and Ethanol/Water Mixtures. While powders comprising very fine needles could be prepared, which had identical X-ray powder patterns to the reported forms II and III, we did not succeed in growing crystals suitable for single crystal diffraction. Only the powder XRD data for form III were of high quality and could be indexed and solved. An orthorhombic unit cell was found by X-Cell. Running the automatic space group determination tool in Reflex Plus, P212121 and P21212 were identified as the most likely space groups. The molecular geometry was obtained by energy minimization using the Compass force field in Discover. Structure solution was attempted in both space groups, each of the two independent molecules being described by a total of eight degrees of freedom (two torsions, three translations, and three rotations). Only in P212121 could a satisfying solution be obtained. As a result of this structure solution, it was found that the F atoms are completely ordered and that the molecules form pseudo-symmetric carboxylic dimers. Inspection of the structure solution revealed the formation of an internal hydrogen bond to be the only option for the hydroxyl groups. The existence of carboxyl dimers in this structure was confirmed by vibrational spectroscopy. The difference in wavenumbers between the carbonyl absorption in the infrared and Raman spectra was measured to be 26 cm-1, which according to the results of Vanderhoff et al.33 is typical for a carboxyl dimer. The NMR data similarly were consistent with the presence of both a carboxyl dimer and an intramolecular hydrogen-bonded hydroxyl hydrogen. Details of the packing are shown in Figure 6d. This result is consistent with our expectations of forming a

d

298 0.040 0.090

Solved from powder diffraction data.

structure based on graph set E from an alcoholic solution. A search of the database of predicted structures failed to find a match with any of the predictions, possibly because the structure has two molecules in the asymmetric unit, a situation not yet covered by the software. In addition, it is worth pointing out that this structure is much denser than either of the other polymorphic forms, I or V. This is certainly consistent with the reported solubilities,11 which indicate that form III is more stable than form I. Table 1 summarizes the crystallographic data for the four forms. Conclusions Overall, this combined approach of structure prediction and directed crystallization has yielded a significant number of new crystal forms from a limited experimental screen. Essentially, four solvents were chosen, each yielding a new crystalline material. This mirrors our previous experience8 with 2-amino 4-nitrophenol where we isolated three new forms from four solvents. In addition, this work has also highlighted the need to draw on as many sources of solid state characterization as possiblessingle crystal structure solution is always the preferred method but the use of powder diffraction data is becoming increasingly accepted particularly when it can be substantiated by other techniques such as solid state NMR and vibrational spectroscopy. In terms of our scientific understanding of the role of solution chemistry in driving nucleation processes, we still have much to learn. In selecting different solvents, we are trying to use our chemical intuition in an attempt to direct the formation of certain types of crystal growth unit, which might then become the eventual structural synthons of the resulting crystals.25 Much fundamental work remains to be done before we can begin to understand and have control over this process. References (1) Bernstein, J. Polymorphism in Molecular Crystals; IUCR Monographs on Crystallography 14; Oxford Science Publications: OUP, Oxford, U.K., 2002. (2) Byrne, S. R.; Pfeiffer, R. R.; Stowell, J. G. Solid State Chemistry of Drugs, 2nd ed.; SSCI Inc.: West Lafayette, IN, 1999; pp 489-498.

158

Crystal Growth & Design, Vol. 3, No. 2, 2003

(3) Peterson, M. L.; Morissette, S. L.; McNulty, C.; Goldsweig, A.; Shaw, P.; LeQuesne, M.; Monagle, J.; Encina, N.; Marchionna, J.; Johnson, A.; Gonzalez-Zugasti, J.; Lemmo, A. V.; Ellis, S. J.; Cima, M. J.; Almarsson, O. J. Am. Chem. Soc. 2002, 124, 10958-10959. (4) Fillipini, G.; Gavezotti, A. J. Am. Chem. Soc. 1995, 117, 12299-12302. (5) Beyer, T.; Day, G. M.; Price, S. L. J. Am. Chem. Soc. 2001, 123, 5086-5094. (6) Verwer, P.; Leusen, F. J. J. In Reviews in Computational Chemistry; Lipowitz, K. B., Boyd, D. B., Eds.; Wiley/VCH: New York, 1998; Vol. 12, Chapter 7, p 327. (7) Payne, R. S.; Roberts, R. J.; Rowe, R. C.; Docherty, R. J. Comput. Chem. 1998, 19, 1-20. (8) Blagden, N.; Cross, W. I.; Davey, R. J.; Broderick, M.; Pritchard, R. G.; Roberts, R. J.; Rowe, R. C. Phys. Chem. Chem. Phys. 2001, 3, 3819-3825. (9) Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N.-L. Angew. Chem., Int. Ed. Engl. 1995, 34, 1555-73. (10) Kim, Y. B.; Park, I. Y. J. Korean Pharm. Sci. 1996, 26, 5559. (11) Cotton, M. L.; Hux, R. A. Anal. Profiles Drug Subst. 1985, 14, 491-526. (12) Martinez-Oharriz, M. C.; Martin, C.; Goni, M. M.; RodriguezEspinosa, C.; Tros De Ilarduya-Apaolaza, M. C.; Sanchez, M. J. Pharm. Sci. 1994, 83, 174-177. (13) Hansen, L. Kr.; Perlovich, G. L.; Bauer-Brandl, A. Acta Crystallogr. 2001, E57, 477-479. (14) Hansen, L. Kr.; Perlovich, G. L.; Bauer-Brandl, A. Acta Crystallogr. 2001, E57, 604-606. (15) Perlovich, G. L.; Hansen, L. Kr.; Bauer-Brandl, A. J. Pharm. Sci. 2001, 91, 1036-1045. (16) Cambridge Crystallographic Data Centre: Allen, F. A.; Kennard, O. Chem. Des. Autom. News 1993, 8, 1 and 3137. (17) Stewart, J. J. P. J. Comput.-Aided Mol. Des. 1990, 4, 1-45. (18) Accelrys 2002. Reflex Plus, Discover, DMol3, Compass and Materials Studio; Accelrys Inc.: San Diego, CA 92121-3752.

Cross et al. (19) Mayo, S. L.; Olafson, B. D.; Goddard, W. A. J. Phys. Chem. 1990, 94, 8897-8909. (20) Desiraju, G. R. Crystal EngineeringsThe Design of Organic Solids; Materials Science Monographs, Vol. 54; Elsevier: Amsterdam, The Netherlands, 1989; p 229. (21) Lommerse, J. P. M.; Motherwell, W. D. S.; Ammon, H. L.; Dunitz, J. D.; Gavezzotti, A.; Hofmann, D. W. M.; Leusen, F. J. J.; Mooij, W. T. M.; Price, S. L.; Schweizer, B.; Schmidt, M. U.; van Eijck, B. P.; Verwer, P.; Williams, D. E. Acta Crystallogr. 2000, B56, 697-714. (22) Dunitz, J. D.; Taylor, R. Chem. Eur. J. 1997, 3, 89-98. (23) Blagden, N.; Davey, R. J.; Lieberman, H. F.; Williams, L.; Payne, P.; Roberts, R. J.; Rowe, R. C.; Docherty, R. J. Chem. Soc., Faraday Trans. 1998, 94, 1035-1044. (24) Davey, R. J.; Blagden, N.; Righini, S.; Alison, H.; Quayle, M. J.; Fuller, S. Cryst. Growth Des. 2001, 1, 59-65. (25) Davey, R. J.; Allen, K.; Blagden, N.; Cross, W. I.; Lieberman, H. F.; Quayle, M. J.; Righini, S.; Seton, L.; Tiddy, G. J. T. Cryst. Eng. Commun. 2002, 4, 257-264. (26) Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467-473. (27) Neumann, M. J. Appl. Crystallogr. Submitted for publication. (28) Engel, G. E.; Wilke, S.; Ko¨nig, O.; Harris, K. D. M.; Leusen, F. J. J. J. Appl. Crystallogr. 1999, 32, 1169-1179. (29) Neumann, M. A.; Leusen, F. J. J.; Engel, G. E.; Wilke, S.; Conesa-Moratilla, C. Int. J. Mod. Phys. 2002, B16 (1,2), 407-414. (30) Delley, B. J. Chem. Phys. 1990, 92, 508-517. (31) Delley, B. J. Chem. Phys. 2000, 113, 7756-7764. (32) Solid State NMR spectrometry was performed in the Department of Chemistry, University of Durham, U.K. The authors acknowledge useful discussions with Prof. R. Harris and Dr. Phuong Ghi. (33) Vanderhoff, P. A.; Lalancette, R. A.; Thompson, H. W. J. Org. Chem. 1990, 55, 1696-1698.

CG025589N