Crystallization of a Desired Metastable Polymorph by Pseudoseeding

The server is currently under maintenance and some features are disabled. Share Article. ACS Network; Twitter; Facebook; Google+; CiteULike; Email...
1 downloads 0 Views 173KB Size
Download PDF
Crystallization of a Desired Metastable Polymorph by Pseudoseeding, Crystal Structure Solution from Its Powder X-ray Diffraction Data, and Confirmation of Polymorphic Transition

CRYSTAL GROWTH & DESIGN 2003 VOL. 3, NO. 6 959-965

Hidenori Miura,† Takaniro Ushio,† Keiko Nagai,† Daisuke Fujimoto,§ Zsolt Lepp,§ Hiroki Takahashi,§ and Rui Tamura*,§ Taiho Pharmaceutical Co. Ltd., Kamikawa-machi, Kodama-gun, Saitama 367-0241 Japan, and Graduate School of Human and Environmental Studies, Kyoto University, Kyoto 606-8501, Japan Received April 3, 2003;

Revised Manuscript Received June 9, 2003

ABSTRACT: Described are the successful, selective crystallization and characterization of one (δ-form) of the metastable polymorphs of (()-[2-[4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoyl]ethyl]dimethylsulfonium p-toluenesulfonate (1a), which is assumed to exist as a transient key-intermediate crystalline phase relevant to the mechanism of Preferential Enrichment, an unusual enantiomeric resolution phenomenon observed upon crystallization of a certain kind of racemates from solvents. By pseudoseeding the supersaturated solution with the δ-form seed crystals of an anlogous compound, the desired δ-form crystals of (()-1a could be obtained as a monophasic powder sample. This selective crystallization can be interpreted in terms of the interplay between an inhibition of the nucleation or crystal growth process of the undesired stable R-polymorphic form and a heterogeneous nucleation of the desired metastable δ-form through epitaxy. The physicochemical properties of the δ-form crystal such as melting point and solubility have been compared with those of the stable R-form one to evaluate the relative stability of the metastable δ-form. It has also been confirmed that polymorphic transition of the metastable δ-form crystal to the stable R-form one occurs in contact with a solvent. On the basis of the δ-form crystal structure solved from its powder X-ray diffraction data measured with a laboratory X-ray source by means of the direct-space approach employing the Monte Carlo method and the subsequent Rietveld refinement, the origin of the metastability of the δ-form crystal has been discussed. Introduction Although recently the strategies to elaborate an expected supramolecular structure in the crystalline phase by designing a molecular structure have been considerably exploited,1 the control of polymorphism for a given organic substance is still an urgent subject to be solved in connection with the development of crystal engineering closely associated with organic materials science. This is because in general polymorphs differ dramatically with regard to their electronic properties such as electric or thermal conductivity, color, and magnetism2-4 as well as their physicochemical properties including thermal stability, solublity, and dissociation rate,5 which are especially relevant to the pharmaceutical industry.6 It can also be envisaged that controlled production of different polymorphs for a given organic substance would lead to the elucidation of the mechanism of multistage polymorphic transitions which are supposed to occur often in a process of nucleation or crystal growth at the beginning of crystallization from solvents.7-9 For this aim, the crystal structures of the individual metastable polymorphic forms and their relative stability must be clarified, and the occurrence of the expected phase transition between two or more of the polymor* Corresponding author: Dr. Rui Tamura, Telephone: +81-75-7536815, Fax: +81-75-753-7915, E-mail: [email protected]. kyoto-u.ac.jp. † Taiho Pharmaceutical Co. Ltd. § Kyoto University.

phic forms in contact with a solvent should be proved. Eventually such information on the mechanism of polymorphic transition will be fed back to the development of the methodology for the control of polymorphism and thereby crystal engineering. In this context, it has been reported that changing the crystallization conditions such as solvents and temperatures,9 pseudoseeding the supersaturated solution with a crystal of desired structure on the basis of an epitaxy protocol,10,11 or adding impurities or additives to inhibit the nucleation or the crystal growth of an undesired polymorph12 can afford a desired polymorph. Of these methods, the induced nucleation with the adequate seed crystals possessing an analogous target crystal structure is the most straightforward and promising for designed crystallization if the seed crystals are available, because the activation energy for heterogeneous nucleation on the surfaces of seed crystals is small enough to induce the assembly of molecules into supramolecular motifs affording the desired polymorph during the formation of prenucleation aggregates which give crystal nuclei after phase transition.10 However, very often it was not an easy task to determine the crystal structure of a metastable crystalline phase due to the usual inaccessibility of single crystals suitable for X-ray crystallographic analysis. Recently, such difficulties have been overcome by the contemporary advances in the procedures for structure solution by using powder X-ray diffraction data measured with

10.1021/cg034051u CCC: $25.00 © 2003 American Chemical Society Published on Web 07/10/2003

960

Crystal Growth & Design, Vol. 3, No. 6, 2003

Scheme 1. Sulfonium Sulfonates: Grouping and Six Variable Torsional Angles for the Structure-solution of the δ-Form Crystal of (()-1a

laboratory X-ray sources, albeit there are still some limitations.13 We have recently found an unusual enantiomeric resolution phenomenon caused by polymorphic transition during crystallization of a certain kind of racemic mixed crystals (pseudoracemates or solid solutions) composed of the two enantiomers such as 1a and 1b

Miura et al.

(Scheme 1) and referred to this phenomenon as Preferential Enrichment.14 The mechanism of Preferential Enrichment has been proposed to be accounted for by (i) the initial formation of a metastable γ-form crystalline phase retaining homochiral R and S supramolecular structures and (ii) the subsequent solvent-assisted solidto-solid type of polymorphic transition of the γ-form crystal to give the stable heterochiral R- or δ-form at the beginning of crystallization (Figure 1).15 Of 10 racemates which so far showed the phenomenon of Preferential Enrichment, X-ray crystallographic analyses of seven racemates have been finished; the stable δ-form crystal structures were noted for the six compounds,14-17 while the R-form crystal was obtained as the stable form for only one compound [(()-1a] (Scheme 1 and Figure 1).16,18 By comparison of the crystal structure of the R-form with that of the δ-one, we have predicted that the R-form crystal of (()-1a should be produced by further polymorphic transition of the once formed δ-form intermediate in a process of nucleation. We report in this paper (i) the selective crystallization of the predicted metastable δ-form of (()-1a as a

Figure 1. Schematic respresentation of the intermolecular interactions in the (a) expected metastable γ-form of (()-1a (X ) CH3) and (()-1b (X ) Cl), (b) stable R-form of (()-1a (see ref 16) and (c) stable δ-form of (()-1b with the positional disorder of the sulfonium sulfur atom (see ref 16).

Crystallization of a Metastable Polymorph

Figure 2. DSC curves of (a) δ-form and (b) R-form crystals of (()-1a.

monophasic powder sample by the interplay between an inhibition of the nucleation or crystal growth process of the stable R-form and a heterogeneous nucleation of the metastable δ-form through epitaxy with the δ-form seed crystals of an analogous compound, (ii) the characterization of the δ-form crystal including the structure solution from its powder X-ray diffraction data by means of the direct-space approach with the Monte Carlo method and the subsequent Rietveld refinement, and (iii) the confirmation of the occurrence of polymorphic transition of this metastable δ-form crystal to the stable R-one. Experimental Section General. Differential scanning calorimetry (DSC) was performed at the scanning rate of 5 °C/min on Shimadzu DSC 50. The in situ FTIR spectra were recorded in solution or suspensions by using the attenuated total reflection (ATR) method on ReactIR 4000 (ST Japan). HPLC analysis was carried out by using a chiral stationary phase column (Daicel Chiralcel OD-H, 0.46 × 25 cm), a mixture of hexane, ethanol, trifluoroacetic acid, and diethylamine (800:200:5:1) as the mobile phase at the flow rate of 0.5 mL/min, and a UV-vis spectrometer (254 nm) as the detecter.19 Powder X-ray diffraction pattern was recorded at a continuous scanning rate of 0.02° 2θ/min using Cu KR radiation (40 kV, 20 mA) with

Crystal Growth & Design, Vol. 3, No. 6, 2003 961

Figure 3. X-ray diffraction patterns (a) measured for the δ-form polycrystalline sample of (()-1a and (b) simulated from the X-ray crystallographic data of (()-1b. the intensity of diffracted X-rays being collected at intervals of 0.01° 2θ on Rigaku RINT 2200 Ultima+/PC. A Ni filter was used to remove Cu Kβ radiation. (()-1a and (()-1b were prepared according to the published procedure.14a Preparation of δ-Form Crystal of (()-1a. (()-1a (1.00 g, 2.0 mmol) was dissolved in 2-PrOH (4.0 mL) on heating. After cooling of the sample to 25 °C, to the supersaturated solution was added finely powdered δ-form crystals (2∼3 mg) of (()-1b.16,17 After one month, the deposited δ-form crystals (0.30 g) were separated from the mother liquor by filtration. Crystal Structure Solution from Powder X-ray Diffraction Data of the δ-Form Crystal of (()-1a. For all calculations, a software module Reflex Plus in Materials Studio which includes the following softwares was used.20 The powder pattern of the δ-form crystal of (()-1a was indexed by TREOR90 program21 using 27 reflections (2θ < 45°); figures of merit for the best solution are M(27) ) 11 and F(27) ) 24 (0.0189, 64). The obtained cell and the function profile parameters were refined by the Pawley method (data range: 5° < 2θ < 110°, 3165 profile points, Rwp ) 0.0652) and used.22 The space group was determined to be P1 h (no. 2) (Z ) 2) by a trial and error method using the Pawley method among the space group candidates consistent with the systematic absences. After the initial model molecular conformation of the δ-form of (()-1a was assigned, the subsequent structure solution was performed by the Monte Carlo/parallel tempering method using a software Powder Solv.27 For the refinement of atomic

962

Crystal Growth & Design, Vol. 3, No. 6, 2003

Figure 4. Comparison of in situ FTIR spectra, monitered by means of React IR spectroscopy during crystallization from the supersaturated 2-PrOH solution of (()-1a (0.063 mol/L), at the beginning (solid line, s) and the end (after 24 h: dashed line, ---) of crystallization with the spectra in the solid state of the R-form (broken line, - - -) and the δ-form (dotted line, ‚‚‚).

Miura et al.

Figure 6. Observed (red dotted line), calculated (blue solid line), and difference (black solid line) profiles of the Rietveld refinement of the δ-form of (()-1a. Table 1. X-ray Analytical Data for the δ-Form Crystal of (()-1a and the Original δ-Form Crystal of (()-1b cell parameters

δ-polymorph of (()-1a

(()-1ba

crystal system space group a, Å b, Å c, Å R, deg β, deg γ, deg V, Å3 Z Rpb, Rwpc

triclinic P1- (no. 2) 9.895 15.030 8.909 98.24 90.28 108.15 1242.0 2 0.147; 0.190d

triclinic P1- (no. 2) 9.9099(7) 14.940(1) 8.901(1) 99.02(1) 91.098 (8) 108.112(6) 1233.7(2) 2 (0.049; 0.077)e

a Quoted from ref 15. b R )[Σ | cYsim(2θ ) - Iexp(2θ ) - Yback(2θ ) p i i i | / Σ | Iexp(2θi) |]. c Rwp)[(Σwi(cYsim(2θi) - Iexp(2θi) - Yback(2θi))2)/ Σwi(Iexp(2θi))2]1/2. d After the Monte Carlo calculations, followed by the Rietveld refinement. e R, Rw values.

torsional angles around all single bonds. The Monte Carlo calculations and the subsequent Rietveld refinement were repeated until the Rwp value became below 0.20 and constant.

Figure 5. DSC curve of a mixture of a very small amount of δ-form and a large amount of R-form crystals of (()-1a. positions inside the crystal, all atoms of each ionic molecule were assigned to one motion group so that the atoms were not allowed to move independently and they were translated and rotated as part of the motion group. Inside an asymmetric unit, six single bonds varying the torsional angles were defined in the long-chain cation so as to limit the total degrees of freedom to eighteen which consists of six for these defined torsional angles and another six (three translations and three rotations) each for the two ionic motion groups (Scheme 1). For the subsequent Rietveld refinement,23 the following conditions were applied: (i) The Pseudo Voight function was used for simulating the peak shape. (ii) The background was determined by linear interpolation using 20 terms. (iii) The BerarBaldinozzi method was used for asymmetric refinement. (iv) The March-Dollase method was applied to correct the effects of preferred orientation. For temperature factors refinement, global isotropic factors were used, because the powder diffraction pattern does not contain enough information to use more accurate atomic temperature factors. Inside each of the motion groups, the molecular conformation was refined by varying the

Results and Discussion Preparation and Properties of Metastable δ-Form Crystal of Nearly Racemic 1a. A new polymorphic form of nearly racemic 1a was obtained by seeding the supersaturated soulution of (()-1a (1.00 g) in 2-PrOH (4.0 mL) with structurally defined δ-form crystals (2∼3 mg) of (()-1b at 20 °C with full reproducibility. Crystallization began after 14 days and gradually proceeded, and finally 0.30 g of crystals were obtained after one month. The deposited crystals were monophasic as verified by DSC measurement (Figure 2a). Concurrently, the phenomenon of Preferential Enrichment occurred, i.e., enantiomeric enrichment of 1a up to ca. 10% ee was observed in the mother liquor.19 As the control experiment, crystallization began within 24 h in the same supersaturated 2-PrOH solution in the absence of the δ-form seed crystals, resulting in a substantial enantiomeric enrichment of 1a up to 70% ee in the mother liquor together with the exclusive formation of the R-form crystals.18 This difference in the

Crystallization of a Metastable Polymorph

Crystal Growth & Design, Vol. 3, No. 6, 2003 963

Figure 7. (a) Crystal structure of the δ-form of (()-1a. The carbon, oxygen, nitrogen, and sulfur atoms are represented by gray, red, blue, and yellow circles, respectively. (b) Schematic representation of the intermolecular interactions in the same δ-form crystal.

crystallization rate can well be interpreted by assuming that the added δ-form seed crystals of (()-1b serve both as the additive to inhibit the nucleation or crystal growth process of the R-form12 and as the substrate for heterogeneous nucleation of the δ-form of 1a.10,11 The reached low ee value of 1a in the mother liquor in the crystallization with the δ-form seed crystals is supposed to be correlated with the slow crystallization, because even slow crystallization of the R-form crystals of (()-1a conducted at the lower concentrations does not give a high ee value of the solute in the mother liquor. By comparison of the powder X-ray diffraction (XRD) patterns as shown in Figure 3, the crystal structure of the new polymorphic form of (()-1a has turned out to be isomorphous with that of the δ-form crystal of (()-1b. The melting point (74.7 °C) of the new δ-form crystals of (()-1a by DSC measurement was distinctly lower than that (86.8 °C) of the original R-form (Figure 2). Similarly, the solubility (17.0 mg/mL) of the δ-form crystals in 2-PrOH at 25 °C was higher than that (10.6 mg/mL) of the R-form. These results indicate that the δ-polymorphic form of nearly racemic 1a is thermodynamically less stable than the R-form at ambient temperature Phase Transition. We already reported that (()-2a and (()-2b in which the ethoxy oxygen atoms in (()-1a and (()-1b were replaced by CH2 groups (Scheme 1), respectively, failed to effect Preferential Enrichment, although they existed in the stable R-form after crystallization due to no structural possibility of giving the corresponding δ-form.16,24 These results lend support to our hypotheses that the formation of the δ-form crystalline phase during crystallization is essential for successful Preferential Enrichment of (()-1a and (()-1b and that the R-form crystalline phase is formed by polymorphic transition of the once formed δ-form phase, since the δ-form is thermodynamically less stable with respect to (()-1a. When the δ-form crystals of nearly racemic 1a deposited by the aforementioned crystallization with seed crystals were further kept in the same saturated solu-

tion, the deposited crystals were very slowly transformed into the R-form. The polymorphic transition was completed after three months, while the same δ-form crystals never underwent phase transition in the absence of solvents. A solvent-mediated polymorphic transition including dissolution-recrystallization processes, according to the Ostwald’s law of stages,25 is most likely to be responsible for this slow phase transition due to the large lattice energy of grown crystals. In a process of nucleation under the standard Preferential Enrichment conditions, however, such a polymorphic transition may quickly occur thanks to the much smaller lattice energy of incipient nuclei. In fact, by means of the in situ FTIR measurement using ReactIR spectroscopy which can detect absorptions by small particles less than 1 µm as well as both solute and solvent molecules in suspension, the seemingly single phase change from the γ-form supramolecular structure (two absorption bands at 1237 and 1215 cm-1 corresponding to S-O stretching vibrations) in solution, which seems to contain the δ-form species to some extent, to the R-form crystalline phase (three absorption bands at 1246, 1202, and 1193 cm-1) was observed during normal crystallization of (()-1a from 2-PrOH in the absence of seed crystals (Figure 4). Furthermore, occasionally we have obtained a mixture of a very small amount of δ-form and a large amount of R-form crystals after crystallization of (()-1a from EtOH/isoPr2O (v/v 1:1) (Figure 5). These results also support the possibility of the transient presence of the δ-form crystalline phase of 1a during crystallization. Crystal Structure of δ-Polymorphic Form of (()-1a. To investigate the origin of the metastability of the δ-form crystal of (()-1a compared to the R-form, the crystal structure of the δ-form has been solved from its powder X-ray diffraction (XRD) data by the directspace approach with the Monte Carlo method, followed by the Rietveld refinement.13,16 Since the XRD pattern of the δ-form crystal of (()-1a is very similar to that of (()-1b (Figure 3), the molecular structure taken from the δ-form crystal structure of (()-1b was used as the

964

Crystal Growth & Design, Vol. 3, No. 6, 2003

initial model molecular conformation of 1a after the chlorine atom on the benzenesulfonate ion of 1b was replaced by a methyl group and the positional disorder of the sulfonium sulfur atom was rectified. After two cycles of the Monte Carlo calculations (266 million trial structures per cycle) and the subsequent Rietveld refinement, the Rwp value was converged to 0.190 (Table 1). The experimental and calculated diffraction patterns and the corresponding difference profile are shown in Figure 6. The crystal structure of the δ-form of (()-1a is similar to that of the δ-form of (()-1b (Table 1 and Figures 1c and 7) and is characterized by a heterochiral onedimensional chain structure which is composed of two kinds of centrosymmetric cyclic dimers; one is formed by the hydrogen bonds between the hydroxy groups and the ethoxy oxygen atoms (O‚‚‚O distance: 2.558 vs 2.735(3) Å in 1b) in a pair of R and S molecules to give a head-to-head cyclic dimer (type C), and the other is formed by the hydrogen bond between an oxygen atom of the sulfonate ion and the nearest amide NH (O‚‚‚N distance: 3.428 vs 2.866(3) Å in 1b) and the electrostatic interactions between the same oxygen atom of the sulfonate ion and the sulfonium sulfur atom in the neighboring long-chain cation (S+‚‚‚O- distance: 3.689 vs 3.380(5) Å in 1b) to give a head-to-head cyclic dimer (type B′ vs type B in 1b). Only difference between the two δ-form crystal structures of (()-1a and (()-1b is that only one oxygen atom of the sulfonate ion is used to form the type B′ cyclic dimer for (()-1a, while two oxygen atoms are used to form the type B cyclic dimer for (()-1b (Figure 7 and Figure 1c). Consequently, the interatomic distances in the type B′ cyclic dimer of the δ-form of (()-1a are longer than those in the type B cyclic dimer of (()-1b. The same argument can be applied to the two crystal structures of the R- and δ-forms of (()-1a; the interatomic distances in the type B′ cyclic dimer of the δ-form of (()-1a are mostly longer than those in the type B cyclic dimer of the R-form of (()-1a (O‚‚‚N distance: 2.878(3) or 2.910(3) Å, S+‚‚‚O- distance: 3.122(2) or 3.834(2) Å). This fact seems responsible for the metastability of the δ-form of (()-1a. Conclusions We have proven the existence of the metastable δ-polymorphic form of (()-1a, which is expected to be a transient key-intermediate crystalline phase relevant to the mechanism of Preferential Enrichment, by means of (i) the selective crystallization of the δ-form through the interplay between an inhibition of the nucleation or crystal growth of the stable R-form and a heterogeneous nucleation of the metastable δ-form with the δ-form seed crystals of an analogus compound, and (ii) the observation of polymorphic transition of the δ-form to the stable R-form in contact with solvents. The metastability of the δ-form crystal has been rationalized on the basis of its crystal structure which was solved by the direct-space approach with the Monte Carlo method and the subsequent Rietveld refinement. This strategy for the preparation and characterization of a metastable polymorphic form would be applicable to other systems in which the occurrence of polymorphic transition of an expected metastable polymorph to the stable one during crystallization needs to be confirmed.

Miura et al.

Acknowledgment. The present work was supported by the Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Culture, Sports and Technology of Japan. R.T. is grateful for support from the Asahi Glass Foundation, the Mitsubishi Foundation, and the Takeda Science Foundation. Supporting Information Available: Crystal structural information file (CIF) is available for the δ-polymorph of (()-1a (alternative name, ST). This material is available free of charge via the Internet at http://pubs.acs.org.

References (1) (a) Schneider, H.-J.; Yatsimirsky, A. K. Principles and Methods in Supramolecular Chemistry; Wiley: New York, 2000. (b) Lehn, J.-M. Supramolecular Chemistry; VCH: Weinheim, 1995. (c) Vo¨gtle, F. Supramolecular Chemistry; Wiley: New Work, 1991. (2) Organic Conductors: Fundamental and Applications; Farges, J.-P., Ed.; Marcel Dekker: New York, 1994. (3) Herbst, M.; Hunger, K. Industrial Organic Pigments; VCH: Weinheim, 1993. (4) Magnetism: Molecules to Materials II; Miller, J. S., Drillon, M., Eds.; Wiley-VCH: Weinheim, 2001. (5) Organic Molecular Solids: Properties and Applications; Jones, W., Ed.; CRC Press: Boca Raton, FL, 1997. (6) Polymorphism in Pharmaceutical Solids (Drugs and the Pharmaceutical Sciences, Vol. 95), Brittain, H. G., Ed.; Marcel Dekker: New York, 1999. (7) Dunitz, J. D.; Bernstein, J. Acc. Chem. Res. 1995, 28, 193200. (8) Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates and Resolutions; Krieger Publishing Co.: Malabar, FL, 1994. (9) (a) Maruyama, S.; Ooshima, H. J. Cryst. Growth 2000, 212, 239-245. (b) Kitamura, M.; Ueno, S.; Sato, K. Molecular Aspects of the Polymorphic Crystallization of Amino Acids and Lipids. In Crystallization Processes; Ohtaki, H., Ed.; Wiley: Chichester, 1998; pp 99-129. (c) Kitamura, M. J. Cryst. Growth 1989, 96, 541-546. (d) Bernstein, J.; Davey, R. J.; Henck, J-o Angew. Chem. Int. Ed. 1999, 38, 34403461. (10) (a) Ward, M. D.; Bonafede, S. J.; Hiller, A. C. Directing Nucleation and Molecular Crystals on Ordered Substrates: The Role of Epitaxial Interactions. In A Modular Chemistry (NATO ASI Ser., Ser. C, Vol. 499); Michl, J., Ed.; Kluwer Academic Publishers: Dordrecht, 1997; pp 637-649. (b) Hooks, D. E.; Fritz, T.; Ward, M. D. Adv. Mater. 2001, 13, 227-241. (c) Bonafede, S. J.; Ward, M. D. J. Am. Chem. Soc. 1995, 117, 7853-7861. (d) Mitchell, C. A.; Yu, L.; Ward, M. D. J. Am. Chem. Soc. 2001, 123, 10830-10839. (11) (a) Koshima, H.; Miyauchi, M. Cryst. Growth Des. 2001, 1, 355-357. (b) Koshima, H.; Honke, S.; Miyauchi, M. Enantiomer 2000, 5, 125-127. (12) (a) Weisbuch, I.; Leiserowitz, L.; Lahav, M. Tailor-Made Additives and Impurities. In Crystallization Technology Handbook; Mersmann, A., Ed.; Marcel Dekker: New York, 1995; pp 401-457. (b) Davey, R. J.; Blagden, N.; Potts, G. D.; Docherty, R. J. Am. Chem. Soc. 1997, 119, 1767-1772. (c) Blagden, N.; Davey, R. J.; Rowe, R.; Roberts, R. Int. J. Pharm. 1998, 172, 169-177. (13) (a) Harris, K. D. M.; Tremayne, M.; Kariuki, B. M. Angew. Chem. Int. Ed. Engl. 2001, 40, 1626-1651. (b) Harris, K. D. M.; Tremayne, M.; Lightfoot, P.; Bruce, P. G. J. Am. Chem. Soc. 1994, 116, 3543-3547. (c) Engel, G. E.; Wilke, S.; Konig, O.; Harris, K. D. M.; Leusen, F. J. J. J. Appl. Cryst. 1999, 32, 1169-1179. (d) Stephenson, G. A. J. Pharm. Sci. 2000, 89, 958-966. (14) (a) Tamura, R.; Ushio, T.; Takahashi, H.; Nakamura, K.; Azuma, N.; Toda, F.; Endo, K. Chirality 1997, 9, 220-224. (b) Takahashi, H.; Tamura, R.; Ushio, T.; Nakajima, Y.; Hirotsu, K. Chirality 1998, 10, 705-710. (c) Tamura, R.; Takahashi, H.; Hirotsu, K.; Nakajima, Y.; Ushio, T. Mol. Cryst. Liq. Cryst. 2001, 356, 185-194. (d) Tamura, R.; Takahashi, H.; Hirotsu, K.; Nakajima, Y.; Ushio, T.; Toda, F. Angew. Chem. Int. Ed. 1998, 37, 2876-2878. (e) Taka-

Crystallization of a Metastable Polymorph

(15) (16) (17) (18)

(19)

hashi, H.; Tamura, R.; Fujimoto, D.; Lepp, Z.; Kobayashi, K.; Ushio, T. Chirality 2002, 14, 541-547. (f) Tamura, R.; Takahashi, H.; Miura, H.; Lepp, Z.; Nakajima Y.; Hirotsu, K.; Ushio, T. Supramol. Chem. 2001, 13, 71-78. Tamura, R.; Fujimoto, D.; Lepp, Z.; Misaki, K.; Miura, H.; Takahashi, H.; Ushio, T.; Nakai, T.; Hirotsu, K. J. Am. Chem. Soc. 2002, 44, 13139-13153. Takahashi, H.; Tamura, R.; Lepp, Z.; Kobayashi, K.; Ushio, T. Enantiomer 2001, 6, 57-66. Tamura, R.; Ushio, T.; Nakamura, K.; Takahashi, H.; Azuma, N.; Toda, F. Enantiomer 1997, 2, 277-280. (a) Ushio, T.; Tamura, R.; Takahashi, H.; Yamamoto, K. Angew. Chem. Int. Ed. Engl. 1996, 35, 2372-2374. (b) Ushio, T.; Tamura, R.; Azuma, N.; Nakamura, K.; Toda, F.; Kobayashi, K. Mol. Cryst. Liq. Cryst. 1996, 276, 245-252. Ushio, T.; Yamamoto, K. J. Chromatogr. A, 1994, 684, 235242.

Crystal Growth & Design, Vol. 3, No. 6, 2003 965 (20) Materials Studio (version 2.0), Accelrys Inc. San Diego, 2001. (21) Werner, P. E.; Eriksson, L.; Westdahl, M. J. Appl. Cryst. 1985, 18, 367-370. (22) Pawley, G. S. J. Appl. Cryst. 1981, 14, 357-361. (23) (a) Rietveld, H. M. J. Appl. Cryst. 1969, 2, 65-71. (b) The Rietveld Method (IUCr Monographies of Crystallography 5); Young, R. A.; Ed.; Oxford University Press: Oxford, 1993. (24) Tamura, R.; Takahashi, H.; Ushio, T.; Nakajima, Y.; Hirotsu, K.; Toda, F. Enantiomer 1998, 3, 149-157. (25) (a) Ostwald, W. Grundriss der Allgemeinen Chemie, Leipzig, 1899. (b) McCrone, W. C. Polymorphism In Physics and Chemistry of the Organic Solid State; Fox, D.; Labes, M. M.; Weissberger, A., Eds.; Interscience: New York, 1965; Vol. II, pp 726-767.

CG034051U