Solvent Effect on Polymorphism in Crystallization of BPT Propyl Ester

was carried out from ethanol (EtOH), acetonitrile (MeCN), and cyclohexane ... form, a nitrile group and a methyl group on the thiazole ring are locate...
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Solvent Effect on Polymorphism in Crystallization of BPT Propyl Ester Mitsutaka Kitamura,*,† Takayuki Hara,†,‡ and Midori Takimoto-Kamimura‡ Department of Mechanical and System Engineering, UniVersity of Hyogo, 2167 Shosha, Himeji 671-2201, Japan, and Pharmaceutical DiscoVery Research Laboratories, Teijin Parma Limited, 4-3-2, Asahigaoka, Hino, Tokyo 191-8512, Japan

CRYSTAL GROWTH & DESIGN 2006 VOL. 6, NO. 8 1945-1950

ReceiVed September 11, 2005; ReVised Manuscript ReceiVed March 10, 2006

ABSTRACT: BPT propyl ester (propyl 2-(3-cyano-4-(2-methylpropoxy)phenyl)-4-methylthiazole-5-carboxylate) was synthesized, and the solvent effect in the polymorphic crystallization of the BPT propyl ester was investigated. The rapid-cooling crystallization was carried out from ethanol (EtOH), acetonitrile (MeCN), and cyclohexane (c-Hxn) solutions. From EtOH and c-Hxn solutions at high initial concentrations, a metastable form first appeared, and after that, a subsequent transformation to a stable form occurred. On the other hand, at low concentrations the stable form crystallized directly. Crystallization from MeCN solutions resulted in only a stable form under all the conditions. X-ray analysis indicates that both the stable and metastable forms are constructed by stacking of the sheet structures of the molecules (the phenyl and thiazole rings and ester group are on the same plane). In the metastable form, a nitrile group and a methyl group on the thiazole ring are located in cis positions. On the other hand, in the stable form, these groups are in trans positions. The structure of the stable form is stabilized by hydrogen bonding through the nitrile and carbonyl groups. The two-step nucleation mechanism of the metastable and stable forms in EtOH and c-Hxn solutions and the nucleation mechanism of only the stable form in MeCN solution are described. 1. Introduction The formation of polymorphs and solvated crystals is generally observed for pharmaceuticals. The control of polymorph formation is important, because it affects the bioavailability, stability, solubility, and morphology of pharmaceutical products.1-3 Polymorphs and solvated crystals crystallize by competitive nucleation, growth, and transformation from a metastable form to a stable form.3 The crystallization process is influenced by various operational factors. To selectively crystallize polymorphs, the mechanism of each elementary step in the crystallization process in relation to the operational conditions3 must be elucidated. Furthermore, the crystallization of polymorphs is affected by additives,4,5 solvents,6,7 and interfaces.5,8 In the pharmaceutical industry, the effect of solvents in polymorphic crystallization is very important, because generally the crystallization is performed using various solvents. However, the mechanism of the solvent effect on the polymorphic crystallization behavior is not clearly understood. Previously, we reported the polymorphism of a thiazole derivatives2-(3-cyano-4-(2-methylpropoxy)phenyl)-4-methylthiazole-5-carboxylic acid (BPT)swhich is one of the enzyme inhibitors and has at least three polymorphs and two solvated crystals.7,9 In this study, we have synthesized the propyl ester of BPT (Figure 1) and the mechanism of the solvent effect on the polymorphic crystallization of the propyl ester of BPT was investigated in relation to the molecular structure and the crystal structure. 2. Experimental Section 2.1. Compounds and Solvents. BPT propyl ester (Pr-est; propyl 2-(3-cyano-4-(2-methylpropoxy)phenyl)-4-methylthiazole-5-carboxylate) was prepared by the esterification of BPT, as described below. All the chemicals and solvents used for synthesis were of reagent grade. To the mixture of BPT and potassium carbonate in N,N-dimethylformamide was added n-propyl bromide. After the mixture was stirred * To whom correspondence should be addressed. E-mail: mkitamura@ eng.u-hyogo.ac.jp. † University of Hyogo. ‡ Teijin Parma Limited.

Figure 1. Structure of BPT propyl ester. for 3 h at 333 K, the reaction mixture was extracted with ethyl acetate. Concentration of the organic layer after drying on sodium sulfate and its recrystallization from ethanol afforded the title compound. 1 H NMR (CDCl3, ppm): δ 8.18 (d, J ) 2.4 Hz, 1 H); 8.10 (dd, J ) 2.4, 8.8 Hz, 1 H); 7.01 (d, J ) 8.8 Hz, 1 H); 4.26 (t, J ) 6.8 Hz, 2 H); 3.90 (d, J ) 6.4 Hz, 2 H); 2.77 (s, 3 H); 2.1-2.3 (m, 1 H); 1.7-1.9 (m, 1 H); 1.09 (d, J ) 6.8 Hz, 6 H); 1.03 (t, J ) 7.2 Hz, 3 H). As the solvents for crystallization, we selected ethanol (EtOH; polarprotic), acetonitrile (MeCN; polar-aprotic), cyclohexane (c-Hxn; nonpolar). These solvents are special grade purchased from Wako Pure Chemical Industries, Ltd. 2.2. Instrumental Methods. 1H NMR measurements was performed for BPT propyl ester (Pr-est) in deuterated solvents (C2D5OD, CD3CN, and C6D12) using a JEOL JNM AL-400 spectrometer (399.65 MHz). The concentration of the solution was measured by UV spectroscopic methods at a wavelength of 254 nm. The crystal structure was examined by powder X-ray diffraction (XRD; RINT2200 (Rigaku)) and by FTIR (Spectra BXII (Perkin-Elmer)). The crystal structures were analyzed using a single crystal on the Rigaku R-AXIS diffractometer with Mo KR or Cu KR radiation. The energy calculation of the conformer was performed by MOPAC using the PM5 parameter in a CAChe system. 2.3. Crystallization of BPT Propyl Ester (Pr-est). The crystallization of BPT propyl ester (Pr-est) was carried out by the rapid-cooling method in ethanol (EtOH), acetonitrile (MeCN), and cyclohexane (cHxn) solutions. Various amounts of Pr-est crystals were dissolved in EtOH (initial concentrations were 20.2, 21.2, 23.3, and 26.0 mM), MeCN (initial concentrations were 46.8, 51.5, and 55.1 mM), or c-Hxn (initial concentrations were 16.3, 21.0, and 24.3 mM) in a batch crystallizer equipped with a jacket at 323 K. After complete dissolution, the solution was rapidly cooled to 298 K by the exchange of circulating water in the jacket (this takes about 10 min). The slurry was sampled at constant intervals and filtered to separate the crystal and solution. After the crystal was dried, XRD and FTIR analyses were carried out. The concentration of the solution was measured by UV spectroscopic methods.

10.1021/cg050464e CCC: $33.50 © 2006 American Chemical Society Published on Web 06/30/2006

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Figure 2. Change in concentration of Pr-est in the crystallization from MeCN solutions.

3. Results and Discussion 3.1. Crystallization of Pr-est from MeCN Solutions. The rapid-cooling crystallization of Pr-est from MeCN solutions was performed. The initial concentrations of the solution were 46.8, 51.5, and 55.1 mM. Figure 2 shows the changes in the

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concentration of the solution during each run. After a decrease in the concentration due to crystallization, the concentration reached constant values. During the experiment, crystals were collected 1000 min after the crystallization commenced and they were subjected to XRD (Figure 3a) and FTIR (Figure 4a) measurements. From the results of the analysis, it was found that the diffraction and absorption patterns were almost the same under all the conditions. Thus, the crystallizations of Pr-est from MeCN solutions at initial concentrations of 46.8, 51.5, and 55.1 mM resulted in the same crystal form. These crystals have a prismatic morphology. 3.2. Crystal Structure of Pr-est from MeCN Solutions. 3.2.1. Conformation of Pr-est in the Crystal Form. The X-ray analysis of a single crystal from an MeCN solution was performed. The following data were obtained: space group P21/ a; a ) 8.1526(9) Å; b ) 19.637(3) Å; c ) 12.2979(17) Å, and β ) 100.117(5)°. We collected data using the RAXIS RAPID-S instrument and solved the structure with the SIR88 instrument. The final R factor was 0.066 for a total of 4426 reflections. Figure 5a shows the molecular conformation of Pr-est in the crystal form. In this crystal, a phenyl ring, thiazole ring, and ester group lie in the same plane. It seems that the energy of the molecule is stabilized by the delocalization of the π-electrons of the phenyl ring, thiazole ring, carbonyl group, and oxygen atoms of ester and ether groups. It is found that the propyl group of the ester and the methyl group of the thiazole ring are located on different sides. This may be due to the steric hindrance

Figure 3. XRD patterns of the Pr-est crystal: (a) from MeCN solutions; (b) from EtOH solutions at initial concentrations of 23.3 and 26.0 mM (180 min).

Figure 4. FTIR spectra of the Pr-est crystal: (a) from MeCN solutions; (b) from EtOH solutions at initial concentrations of 23.3 and 26.0 mM (180 min).

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Figure 5. Crystal structure of Pr-est from MeCN solutions: (a) molecular conformation; (b) crystal structure; (c) molecules in the sheet structure.

between the propyl group of the ester and the methyl group in the thiazole ring. Energy calculations of the conformation by MOPAC indicates that the conformation energy is lower than that of the conformation in which the propyl group and the methyl group are located on the same side, and the results of this calculation are in agreement with the experimental results. It also appears that the nitrile group in the phenyl ring and the methyl group in the thiazole ring have a trans geometry. 3.2.2. Crystal Packing of Pr-est. Figure 5b shows the crystal structure of Pr-est. It is found that the crystal is constructed by stacking the sheets of the molecules. In the same plane, two hydrogen bonds are formed between a couple of molecules through the nitrogen atom of the nitrile group and a hydrogen atom in the phenyl ring of another molecule; this is because the distance between the two atoms appears to be 2.49 Å (Figure 5c).10 In addition, hydrogen bonding between an oxygen atom of the carbonyl group and a hydrogen atom of the phenyl ring is also observed in the same plane, because the distance between the two atoms appear to be 2.37 Å. Hence, the pairs of molecules are connected with each other to form a sheet structure. These sheet structures stack due to π-π interactions. Thus, this crystal is constructed by hydrogen bonding in the sheet structure and π-π interactions between the sheet structures. 3.3. Crystallization of Pr-est from EtOH Solutions. The crystallization was carried out in EtOH solutions, and their initial concentrations were 20.2, 21.2, 23.3, and 26.0 mM. Figure 6 shows the changes in the concentration of the solution during each run. With regard to the crystallization at initial concentrations of 23.3 and 26.0 mM, the concentration decreased 50 or 150 min after the experiment was started and attained a constant value of 18.1 mM. Subsequently, the concentration decreased again at about 500 min and reached a constant value of 11.6 mM. The crystals were sampled at 180 and 1250 min; the result of XRD analysis of the crystal sampled at 180 min is shown in Figure 3b, and that at 1250 min is the same as in Figure 3a. In this figure, the characteristic peaks for the crystal at 180 min were observed at 2θ values of 5, 10, and 17° (Figure 3b), while those at 1250 min were observed at 2θ values of 12, 13, and 20° (Figure 3a). These results indicate that two polymorphs crystallized from the EtOH solution. The FTIR spectrum of each

Figure 6. Change in concentration of Pr-est in the crystallization from EtOH solutions.

crystal was also measured; the result of the analysis of the crystal sampled at 180 min is shown in Figure 4b, and that at 1250 min is the same as in Figure 4a. In this case, differences were also observed in the absorption patterns. For example, the characteristic absorbances of the crystal at 180 min are 1263.2, 1299.8, and 1710.6 cm-1, while those at 1250 min are 1264.6, 1276.3, and 1700.9 cm-1. These differences are also caused by the structural difference of the two crystals. The two steps in the concentration changes are considered to be due to the solution-mediated transformation from the metastable to the stable form. Thus, the crystals obtained at 180 min are in the metastable form, while those obtained at 1250 min are in the stable form. We refer to the metastable form as the A form and the stable form as the B form. Under these conditions only the metastable A form crystallizes initially, and after that the stable B form nucleates and the solution-mediated transformation proceeds; i.e., the Ostwald step rule is established. In Figure 7 a microscopic photograph of crystals during the transformation is shown. It appears that the A form has a needlelike morphology and the B form has a prismatic shape. Furthermore, the constant

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Figure 7. Microscopic photograph of crystals during the transformation. Table 1. Crystallographic Data for Pr-est

a (Å) b (Å) c (Å) R (deg) β (deg) γ (deg) space group Z

A form

B form

7.1146(8) 33.901(13) 16.253(3) 90.0 90.0 90.0 Cmca 8

8.1526(9) 19.637(3) 12.2979(17) 90.0 100.117(5) 90.0 P21/a 4

concentration value at 18.1 mM shows that the dissolution rate of the A form is faster than the precipitation rate of the B form. Therefore, the concentration attained after the first decrease in the concentration change (18.1 mM) is considered as the solubility of the A form. On the other hand, the concentration finally attained is the solubility of the B form in EtOH at 298 K (11.6 mM). In the case of crystallization at initial concentrations of 20.2 and 21.2 mM, a single decrease was observed in the concentration change, and it reached a constant value of 11.6 mM, which is the solubility of the B form. From the XRD

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pattern and FTIR spectrum of the crystals from MeCN solutions, it is evident that only the B form crystallizes. Thus, these results indicate that, under these conditions, only the stable form is directly crystallized. This may indicate that the supersaturation has a great influence on the polymorphic crystallization in EtOH solutions. 3.4. Crystal Structure of the Metastable Form of Pr-est from EtOH Solutions. 3.4.1. Conformation of the Metastable Form of Pr-est in the Crystal State. An X-ray analysis of a single crystal with the A form was performed. The following data were obtained: space group Cmca, a ) 7.1146(8) Å, b ) 33.901(13) Å, and c ) 16.253(3) Å. The structural data for the A and B forms are given in Table 1. In the crystal of the A form, atoms in the molecule almost exist on the mirror plane (a ) 0.5 Å), and all the atoms are refined with isotropic thermal factors. We collected data by using the RAXIS RAPID-S diffractometer and solved the structure using the SIR88 instrument. The final R factor is 0.165 for a total of 21 446 reflections. Figure 8a shows the molecular conformation of Pr-est in the A form. In the crystal, the phenyl ring, thiazole ring, and ester group also lie in the same plane in a way similar to that for the B form. On the other hand, the nitrile group in the phenyl ring and methyl group in the thiazole ring in the A form have a cis geometry. This appears to be different from the case for the B form. 3.4.2. Crystal Packing of the Metastable Form of Pr-est (A Form). Figure 8b shows the crystal structure of the A form. In this crystal, the molecules line up on the same plane to form a sheet structure in the bc face, and the crystal is constructed by stacking of the sheet structures, as is the case for the B form. In the sheet structure, there is no hydrogen bonding. With regard to the interaction of the intersheet structures, a π-π interaction seems to exist. However, hydrogen bonding for intersheet structures is not observed. From the FTIR analysis of the crystals, the absorbance of the carbonyl group of the A form is higher than that of the B form by 10 cm-1; this result also indicates the weakness of the hydrogen bonding by the carbonyl group in the A form. From these results, the A form is formed mainly by π-π interactions between the sheet structures. In

Figure 8. Crystal structure of Pr-est (A form): (a) molecular conformation; (b) crystal structure.

Polymorphism in Crystallization of BPT Propyl Ester

Figure 9. Change in concentration of Pr-est in the crystallization from c-Hxn solutions.

the case of the B form, π-π interactions are also observed, in addition to the hydrogen bonding of nitrile and carbonyl groups. These interactions cause the B form to be stable in comparison with the A form. It is suspected that when the nitrile group in the phenyl ring and methyl group in the thiazole ring have a cis geometry, the isobutyl group may disturb the hydrogen bonding between the nitrogen of the nitrile group and the hydrogen of the phenyl ring. At the same time the formation of hydrogen bonds through the carbonyl group becomes very difficult. 3.5. Crystallization of Pr-est from c-Hxn Solutions. Crystallization was carried out from c-Hxn solutions. The initial concentrations for the crystallization were 16.3, 21.0, and 24.3 mM. Figure 9 shows the concentration changes of the solution during each run. With regard to the crystallization at the initial concentration of 24.3 mM, the concentration decreased to 9.76

Figure 10. 1H NMR spectrum of Pr-est in each solvent.

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mM. Subsequently, the concentration decreased again at around 800 min and reached a constant value of 6.95 mM. On the other hand, in the case of crystallization at initial concentrations of 16.3 and 21.0 mM, it was observed that the concentration decreased once and reached a constant value of 6.95 mM. With regard to the crystallization at the initial concentration of 24.3 mM, crystals were sampled at 500 and 1300 min and measured by XRD and FTIR analyses. The results of the analyses indicated that the crystal at 500 min corresponded to the A form (needlelike) and that at 1300 min corresponded to the B form (prismatic). This result indicates that the solution-mediated transformation from the metastable to the stable form occurs during the crystallization at the initial concentration of 24.3 mM, in the same manner as that in EtOH solutions. On the other hand, in the case of crystallization at initial concentrations of 16.3 and 21.0 mM, the XRD pattern and FTIR spectrum of the crystals obtained at 1300 min were the same as those for the B form. Thus, these results indicate that, under these conditions, only the stable form crystallized directly. Thus, the supersaturation has an influence on the polymorphic crystallization behaviors in c-Hxn solutions. 3.6. Discussion of the Solvent Effect on Nucleation Mechanism of Polymorphs. The crystallization was carried out from MeCN, EtOH, and c-Hxn solutions. It appears that from MeCN solutions only the stable form crystallizes, while from EtOH and c-Hxn solutions the metastable form is obtained. In a previous paper,3 we theorized that the nucleation behavior of polymorphs is related to the relative concentrations of conformers in solutions, which correspond to each polymorph. It was expected that in MeCN solution the conformer corresponding to the stable form is predominant and in EtOH and c-Hxn solutions at high concentrations the conformer corresponding to the metastable form may mainly be present. We measured 1H NMR spectra for Pr-est in each solvent. However, only small differences in the chemical shifts due to the phenyl proton (6.5-

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8.5 ppm) between the solvents were observed (Figure 10). Such differences in chemical shifts may be due to differences in the interaction between solute and solvent; however, they are not evidence of the conformational difference in each solvent. It is noted that the detection of the conformational difference in solution is be very difficult, especially for such linear BPT ester molecules. On the other hand, the solubility of the stable form is in the order MeCN, EtOH, c-Hxn. In MeCN solution the interaction strength between the solute and solvent may be the greatest. The difference in thermodynamic stability between the polymorphs A and B is also greater for the solvent offering greater solubility. Therefore, in MeCN solution the thermodynamic stability of the metastable form is extremely low due to the large solvent-solute interaction. This may correspond to the low concentration of the conformer corresponding to the metastable form. This results in the nucleation of only the stable form. Even if the metastable form nucleates, it should quickly transform to the stable form by the solution-mediated mechanism. In EtOH and c-Hxn solutions the concentrations of conformers corresponding to the A and B form are competitive and the nucleation process of the polymorph is determined by the supersaturation and kinetic processes. 4. Conclusion The rapid-cooling crystallization of Pr-est was carried out from EtOH, MeCN, and c-Hxn solutions to investigate the solvent effect in the polymorphic crystallization, and the following results were obtained. 1. From EtOH and c-Hxn solutions at high initial concentrations, the metastable form first appeared, and after that, subsequent transformation to a stable form occurred. 2. Crystallization from MeCN solutions directly resulted in only a stable form under all of the conditions.

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3. X-ray analysis of the single crystal indicated that both stable and metastable forms are constructed by stacking the sheet structures of the molecules (the phenyl and thiazole rings and ester group are on the same plane). 4. In the metastable form, a nitrile group and a methyl group on the thiazole ring are located in cis positions, and no hydrogen bonding was observed in the crystal. 5. In the stable form, a nitrile group and a methyl group on the thiazole ring are in trans positions. The structure of the stable form is stabilized by the hydrogen bonding through the nitrile and carbonyl groups. 6. The competitive nucleation mechanism of both polymorphs in EtOH and c-Hxn solutions and the predominant nucleation mechanism of the stable form in MeCN solution were shown. Supporting Information Available: CIF files giving X-ray crystallographic data for the compounds studied in this paper. This material is available free of charge via the Internet at http://pubs.acs.org.

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