- Email: [email protected]
Effect of solvent and molecular structure on the crystallization of polymorphs of BPT esters
ARTICLE IN PRESS Journal of Crystal Growth 310 (2008) 3067– 3071
Contents lists available at ScienceDirect
Journal of Crystal Growth journal homepage: www.elsevier.com/locate/jcrysgro
Effect of solvent and molecular structure on the crystallization of polymorphs of BPT esters M. Kitamura , Y. Hayashi, T. Hara Department of Mechanical and System Engineering, University of Hyogo, 2167 Shosha, Himeji 671– 2201, Japan
a r t i c l e in fo
abstract
Article history: Received 6 March 2008 Accepted 9 March 2008 Communicated by T.F. Kuech Available online 12 March 2008
The polymorphic crystallization behaviors for methylester (Me-est) and isobutyl ester (i-But-est) of BPT in cyclohexane (c-Hxn) and acetonitrile (MeCN) solutions at 298 K were investigated, and the solvent effect was discussed in comparison with the previous results. In the crystallization of Me-est, only one form with needle-like morphology was obtained in c-Hxn and MeCN solutions at any supersaturation. Two polymorphs of A and B forms appeared in the crystallization of i-But-est in c-Hxn solutions and solution-mediated transformation occurred. The morphology of the stable B form is prismatic and that of the metastable A form is needle-like. From MeCN solutions only, the stable B form with the prismatic morphology crystallized. The polymorphic crystallization behavior of i-But-est is similar to that of Pr-est and different from that of Me-est. The solubility of each ester increases with the dipole moment of the solvents, indicating that solute–solvent interaction increases with dipole moment. In the case of i-But-est and Pro-est, the meta-stable form can crystallize from solvents with weak interaction (EtOH and c-Hxn), but only the stable form crystallizes from solvents with large interaction (MeCN). In the crystallization of Me-est, no polymorphs appear, even in EtOH and c-Hxn. It is presumed that the especially strong hydrogen bonding between two molecules may disturb the formation of the polymorphs. & 2008 Elsevier B.V. All rights reserved.
Keywords: A1. Crystal morphology A1. Crystal structure A1. Nucleation A1. Solubility A1. Solvents
1. Introduction The control of the crystallization process of polymorphs and solvated crystals is important in the pharmaceutical industry because this process affects the bioavailability, stability, solubility, and morphology of pharmaceutical products [1–3]. The crystallization process is influenced by various operational factors, such as additives [4,5], solvents [6–8], and interfaces [5,9]. In the pharmaceutical industry, the effect of solvents on polymorphic crystallization is very important because generally, crystallization is performed using various solvents. Furthermore, anti-solvent crystallization is frequently used to increase the efficiency of the yield. In the anti-solvent crystallization of 2-(3-cyano-4-(2methylpropoxy)-phenyl)-4-methyl-thiazole-5-carboxylic acid (BPT), we observed that the changing rate of the solvent composition greatly influences the polymorphic crystallization behavior [7]. On the other hand, a partial change in molecular structure of solute (e.g. a functional group) affects the polymorphism, and some law may be present governing the relationship between the polymorphism and the molecular structure. For example, the Corresponding author. Tel./fax: +81792 674 850.
E-mail address: [email protected] (M. Kitamura). 0022-0248/$ - see front matter & 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jcrysgro.2008.03.014
difference between the polymorphism of L-glutamic acid and that of L-histidine was previously correlated with the difference between the molecular structures of these amino acids [3]. Knowing the relationship between molecular structure and polymorphism will shed light on the control of the polymorphism. In previous papers [10,11], we prepared methyl (Me-est), propyl (Pro-est) and isobutylesters (i-But-est) of BPT (Fig. 1), BPT, which is an enzyme inhibitor, and the dependence of the polymorphism on molecular structure was examined in ethanol solutions. It was found that the crystallization behavior of the polymorphs depends on the size of the alkyl group in BPT esters. In this paper, we have investigated further the effect of solvents on the polymorphic crystallization behavior of methyl ester (Me-est) and isobutyl ester (i-But-est) in comparison with the previous results for propyl ester (Pro-est).
2. Experimental procedure BPT methyl ester (Me-est: Methyl 2-(3-Cyano-4-(2-methylpropoxy)-phenyl)-4-methyl-thiazole-5-carboxylate) and BPT isobutyl ester (i-But-est: 2-methylpropyl 2-(3- Cyano-4-(2-methylpropoxy)-phenyl)-4-methyl-thiazole-5-carboxylate) were used for these crystallization experiments. Crystallization was carried out
ARTICLE IN PRESS 3068
M. Kitamura et al. / Journal of Crystal Growth 310 (2008) 3067–3071
CH3 O
CH3
S
NC
COOCH3
(7.87 mM). The initial supersaturations (S ¼ Co/C*) were calculated from the solubility as 1.71–2.83 for c-Hxn, and 1.29–1.42 for MeCN. These results indicate that polymorphs do not appear at all supersaturations in c-Hxn and MeCN at 298 K, similar to the results obtained in EtOH [11].
N CH3
3.2. Crystallization behaviors of i-But-est in cyclohexane (c-Hxn)
CH3 O
CH3
NC
S COOC3H7 N CH3
CH3 CH3
O S
NC N
The rapid cooling crystallization of i-But-est was performed in c-Hxn solutions at initial concentrations (Co) between 21.0 and 30.0 mM. The initial concentrations are larger than those in the case of Me-est in c-Hxn. This accords to the higher solubility of iBut-est than that of Me-est. It was observed that two steps of concentration change clearly occur at high initial concentrations (29.5, 26.8 mM) in the crystallization from c-Hxn solutions (Fig. 6). The XRD diffraction patterns of the crystals obtained at 100 and 900 min in the crystallization process (Co ¼ 29.5 mM) are shown in Fig. 7(a) and (b). It appears that they are the polymorphs of the A (100 min) and B forms (900 min), which were previously obtained in EtOH solutions [11]. The morphology of both crystals
COOCH2CH(CH3)2 CH3
Fig. 1. Molecules of BPT esters: methylester (Me-est)(a), propylester (Pr-est) (b) and isobuthylester (i-But-est) (c).
using the rapid cooling method in cyclohexane (c-Hxn) and acetonitrile (MeCN) solutions. Different amounts of these esters were dissolved in the solvents at 323 K, and the solution was rapidly cooled to 298 K. Therefore, crystallization was performed at a constant temperature (298 K). The slurry was sampled and filtered to separate the crystals from the solution. The concentration of the solution was measured by a UV spectroscopic method at a wavelength of 254 nm. The polymorphic crystal structure was examined by powder X-ray diffraction (XRD) using the RINT2200 (Rigaku).
3. Results and discussion 3.1. Crystallization behaviors of Me-est in cyclohexane (c-Hxn) and acetonitrile (MeCN) solutions The rapid cooling crystallization of Me-est was performed in cHxn solutions at initial concentrations (Co) between 3.6 and 6.0 mM. Fig. 2 shows the change in the concentration of the solution (C) during each run. After a simple decrease in concentration due to crystallization, the concentration reached a constant value. From the XRD measurement (Fig. 3), it is clear that there is only one crystallized form for all supersaturations in the experimental range, which is the same form as that previously obtained in ethanol (EtOH) solutions [10]. From the concentration that was attained in the end, the solubility (C*) of Me-est in c-Hxn is 2.12 mM. Fig. 4 shows a photo of the crystals obtained in c-Hxn solutions, indicating that the morphology of the crystals is needlelike. In the case of MeCN, crystallization was carried out at much higher initial concentrations than in c-Hxn, i.e. between 47 and 52 mM, because the solubility of Me-est in MeCN is much greater (Fig. 5). From MeCN solutions, needle-like crystals similar to those appearing in c-Hxn were obtained. The decrease in concentration is also simple and similar to that in c-Hxn in Fig. 2. From XRD measurement, it appears that the same form as that obtained in cHxn and EtOH at all supersaturations in the experiments crystallized. The solubility (C*) of Me-est in MeCN was estimated as 36.6 mM, which is higher than those in c-Hxn (2.12 mM) and EtOH
Fig. 2. Concentration change in crystallization of Me-ester in c-Hxn solutions.
Fig. 3. XRD pattern of Me-est crystal.
ARTICLE IN PRESS M. Kitamura et al. / Journal of Crystal Growth 310 (2008) 3067–3071
is shown in Fig. 8. It appears that the metastable A form has a needle shape (Fig. 8(a)), while the stable B form is prismatic (Fig. 8(b)). The two steps of concentration change indicate that the transformation from the metastable A to the stable B is due to the solution-mediated mechanism. If the transformation process is controlled by the crystallization rate of the stable form, i.e. the dissolution rate much higher than the crystallization rate of the stable form in the transformation process, the concentration of the plateau in the concentration change may agree with the solubility of the metastable A form. The solubility of the metastable form A was estimated as 14.8 mM, while the solubility of the stable B form is given by the finally attained concentration (9.0 mM). The supersaturation ratio of the initial concentration of the B form (S ¼ Co/ C*(B)) is calculated as 2.34–3.28. These values appear to be larger than those in the case of Me-est. At the plateau, transformation occurs and the length of the plateau can be considered to correspond to the amount of the metastable form. At a low initial concentration (21.5 mM) the concentration almost simply decreased. This indicates that almost the pure stable form crystallized under this supersaturation. This may
3069
suggest that Ostwald’s step rule is established and at high supersaturations, the prevalent nucleation of the metastable form occurs.
3.3. Crystallization behavior of i-But-est in acetonitrile (MeCN) The crystallization was also done in MeCN solutions at initial concentrations of 62.4–65.0 mM. A simple decreasing curve was obtained only with changes in concentration, as shown in Fig. 9. From XRD analysis, it is clear that the crystal obtained is only of the B form at all initial concentrations. The morphology of the crystals is prismatic, but it is different from that of the stable form
Fig. 6. Concentration change in crystallization of i-But-est- in c-Hxn solutions.
Fig. 4. Me-est crystals obtained from c-Hxn solutions.
Fig. 5. Concentration change in crystallization of Me-ester in MeCN solutions.
Fig. 7. XRD pattern of (a) A form and (b) B form of i-But-est.
ARTICLE IN PRESS 3070
M. Kitamura et al. / Journal of Crystal Growth 310 (2008) 3067–3071
Fig. 9. Concentration change in crystallization of i-But-est in MeCN solutions.
Fig. 8. Morphology of i-But-est crystals obtained in c-Hxn solutions: A form(a), B form (b).
obtained in c-Hxn, as shown in Fig. 10. This is due to the solvent effect on the morphology of the stable B form. The solubility of the B form in MeCN is estimated as 31.4 mM (the supersaturation is 1.99–2.07). The polymorphic crystallization behavior of i-But-est (no polymorphs) in MeCN is similar to that of Pro-est [10]. 3.4. Discussion of the effect of solvents on the nucleation of polymorphs In the crystallization of i-But-est in c-Hxn and EtOH solutions, at high supersaturations, the metastable A form preferentially crystallized and solution-mediated transformation proceeded. Conversely, at low supersaturations, only the stable B form was obtained. In MeCN solutions, only the stable B form crystallized at all supersaturations. These results indicate that the effect of solvents on the polymorphic crystallization behavior of i-But-est is very similar to that of Pr-est [10], i.e. for both esters, Ostwald’s step rule is established for c-Hxn and EtOH solutions and not for MeCN solution. However, in the crystallization of Me-est, only one form was obtained in all solvents. When the solubilities of each ester are compared, it is observed that the solubility of each ester increases with the dipole moment of the solvents (0.332 (c-Hxn), 1.44 (EtOH), 3.93 (MeCN)). This
Fig. 10. Morphology of i-But-est crystals obtained in MeCN solutions.
may indicate that interaction between the esters and solvents increases with the dipole moment. It seems to be that for the solvents with weak interaction (EtOH and c-Hxn), the meta-stable form can crystallize at high supersaturations. However, for the solvents with large interactions (MeCN), only the stable form crystallizes (it is noted that the supersaturation range in MeCN solutions is relatively low). It is also believed that even if the metastable form nucleates in MeCN solutions, the transformation should proceed quickly because the solubility is very high and the thermodynamic stability of the metastable form is very low. If the presence of the conformer according to each polymorph in solution is assumed, the relative nucleation rates may be related to the conformer or conformation of molecules in solutions [11]. In the solvents with weak interactions (EtOH and c-Hxn), the Pr-est and i-But-est molecules may take conformations according to the meta-stable form, but in the solvents with large interactions (MeCN), they may take only the conformation of the stable form. In the case of Me-est, even in EtOH and c-Hxn,
ARTICLE IN PRESS M. Kitamura et al. / Journal of Crystal Growth 310 (2008) 3067–3071
only one conformation will be present in solutions. Previous research [11] using crystallographic analysis made clear that all of the Me-, Pro- and i-But-esters are formed by stacking the sheet structure. In the metastable form of i-But-est (A form), the sheet was formed by hydrogen bonding between the carbonyl group and the hydrogen atom in the phenyl ring of neighboring molecules. In the stable B form of i-But-est, hydrogen bonding through the nitrile group and the hydrogen atom in the phenyl ring contributes to the formation of the layer structure. However, in the case of Me-est crystal, the pair of molecules is formed by two strong hydrogen bonds and the phenyl and thiazole rings are stacked between the sheet structures by p–p interaction. In Meest, the methyl group in the ester and that in the thiazole ring take the conformation of the cis-position, whereas in the Pro- and iBut-esters, the alkyl group in the ester and the methyl group in the thiazole ring take the trans-position. It is suspected that such especially strong hydrogen bonding between two molecules of Me-est may also be present in solutions and may disturb the formation of the polymorphs.
4. Conclusion 1. In the crystallization of Me-est, only one form with needle-like morphology was obtained in c-Hxn, MeCN and EtOH solutions at any supersaturation. 2. The polymorphic crystallization behavior of i-But-est is similar to that of Pr-est and different from that of Me-est. Two polymorphs of i-But-est of the A and B forms appeared in cHxn and EtOH solutions at high supersaturations, and solu-
3071
tion-mediated transformation occurred. The morphology of the stable B form is prismatic and that of the metastable A form is needle-like. In MeCN solutions, only the stable B form preferentially crystallized. 3. The solubility of each ester increases with the dipole moment of the solvents, indicating that solute-solvent interaction increases with the dipole moment. Therefore, this seems to indicate that in the crystallization of i-But-est from solvents weak interaction (EtOH and c-Hxn), the meta-stable form crystallizes at high supersaturations, but from solvents with large interaction (MeCN), only the stable form crystallizes. 4. In Me-est crystal, two molecules are formed by two strong hydrogen bonds. It is suspected that such especially strong hydrogen bonding between a couple of molecules may disturb the formation of the polymorphs.
References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]
J.M. Rollinger, E.M. Gstrein, A. Burger, Eur. J. Pharm. Biopharm. 53 (2002) 75. C. Gu, V. Young, D. Grant, J. Pharm. Sci. 90 (2001) 1878. M. Kitamura, J. Crystal Growth 237–239 (2002) 2205. M. Kitamura, T. Ishizu, J. Crystal Growth 192 (1998) 225. L. Addadi, Z. Berkovitch-Yellin, I. Weissbuch, J.V. Mil, L.J.W. Shimon, M. Lahav, L. Leiserowitz, Angew. Chem. Int. Ed. Engl. 24 (1985) 466. T. Threlfall, Org. Process Res. Dev. 4 (2000) 384. M. Kitamura, M. Sugimoto, J. Crystal Growth 257 (2003) 177. C. Roelands, S. Jiang, M. Kitamura, J. ter Horst, H. Kramer, P. Jansens, Crystal Gowth Des. 6 (2006) 955. Bao-Dong Chen, et al., J. Am. Chem. Soc. 120 (1998) 1625. M. Kitamura, T. Hara, M.T. Kamimura, Crystal Growth Des. 6 (2006) 1945. T. Hara, Y. Hayashi, M. Kitamura, Crystal Growth Des. 7 (2007) 147.
Contents lists available at ScienceDirect
Journal of Crystal Growth journal homepage: www.elsevier.com/locate/jcrysgro
Effect of solvent and molecular structure on the crystallization of polymorphs of BPT esters M. Kitamura , Y. Hayashi, T. Hara Department of Mechanical and System Engineering, University of Hyogo, 2167 Shosha, Himeji 671– 2201, Japan
a r t i c l e in fo
abstract
Article history: Received 6 March 2008 Accepted 9 March 2008 Communicated by T.F. Kuech Available online 12 March 2008
The polymorphic crystallization behaviors for methylester (Me-est) and isobutyl ester (i-But-est) of BPT in cyclohexane (c-Hxn) and acetonitrile (MeCN) solutions at 298 K were investigated, and the solvent effect was discussed in comparison with the previous results. In the crystallization of Me-est, only one form with needle-like morphology was obtained in c-Hxn and MeCN solutions at any supersaturation. Two polymorphs of A and B forms appeared in the crystallization of i-But-est in c-Hxn solutions and solution-mediated transformation occurred. The morphology of the stable B form is prismatic and that of the metastable A form is needle-like. From MeCN solutions only, the stable B form with the prismatic morphology crystallized. The polymorphic crystallization behavior of i-But-est is similar to that of Pr-est and different from that of Me-est. The solubility of each ester increases with the dipole moment of the solvents, indicating that solute–solvent interaction increases with dipole moment. In the case of i-But-est and Pro-est, the meta-stable form can crystallize from solvents with weak interaction (EtOH and c-Hxn), but only the stable form crystallizes from solvents with large interaction (MeCN). In the crystallization of Me-est, no polymorphs appear, even in EtOH and c-Hxn. It is presumed that the especially strong hydrogen bonding between two molecules may disturb the formation of the polymorphs. & 2008 Elsevier B.V. All rights reserved.
Keywords: A1. Crystal morphology A1. Crystal structure A1. Nucleation A1. Solubility A1. Solvents
1. Introduction The control of the crystallization process of polymorphs and solvated crystals is important in the pharmaceutical industry because this process affects the bioavailability, stability, solubility, and morphology of pharmaceutical products [1–3]. The crystallization process is influenced by various operational factors, such as additives [4,5], solvents [6–8], and interfaces [5,9]. In the pharmaceutical industry, the effect of solvents on polymorphic crystallization is very important because generally, crystallization is performed using various solvents. Furthermore, anti-solvent crystallization is frequently used to increase the efficiency of the yield. In the anti-solvent crystallization of 2-(3-cyano-4-(2methylpropoxy)-phenyl)-4-methyl-thiazole-5-carboxylic acid (BPT), we observed that the changing rate of the solvent composition greatly influences the polymorphic crystallization behavior [7]. On the other hand, a partial change in molecular structure of solute (e.g. a functional group) affects the polymorphism, and some law may be present governing the relationship between the polymorphism and the molecular structure. For example, the Corresponding author. Tel./fax: +81792 674 850.
E-mail address: [email protected] (M. Kitamura). 0022-0248/$ - see front matter & 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jcrysgro.2008.03.014
difference between the polymorphism of L-glutamic acid and that of L-histidine was previously correlated with the difference between the molecular structures of these amino acids [3]. Knowing the relationship between molecular structure and polymorphism will shed light on the control of the polymorphism. In previous papers [10,11], we prepared methyl (Me-est), propyl (Pro-est) and isobutylesters (i-But-est) of BPT (Fig. 1), BPT, which is an enzyme inhibitor, and the dependence of the polymorphism on molecular structure was examined in ethanol solutions. It was found that the crystallization behavior of the polymorphs depends on the size of the alkyl group in BPT esters. In this paper, we have investigated further the effect of solvents on the polymorphic crystallization behavior of methyl ester (Me-est) and isobutyl ester (i-But-est) in comparison with the previous results for propyl ester (Pro-est).
2. Experimental procedure BPT methyl ester (Me-est: Methyl 2-(3-Cyano-4-(2-methylpropoxy)-phenyl)-4-methyl-thiazole-5-carboxylate) and BPT isobutyl ester (i-But-est: 2-methylpropyl 2-(3- Cyano-4-(2-methylpropoxy)-phenyl)-4-methyl-thiazole-5-carboxylate) were used for these crystallization experiments. Crystallization was carried out
ARTICLE IN PRESS 3068
M. Kitamura et al. / Journal of Crystal Growth 310 (2008) 3067–3071
CH3 O
CH3
S
NC
COOCH3
(7.87 mM). The initial supersaturations (S ¼ Co/C*) were calculated from the solubility as 1.71–2.83 for c-Hxn, and 1.29–1.42 for MeCN. These results indicate that polymorphs do not appear at all supersaturations in c-Hxn and MeCN at 298 K, similar to the results obtained in EtOH [11].
N CH3
3.2. Crystallization behaviors of i-But-est in cyclohexane (c-Hxn)
CH3 O
CH3
NC
S COOC3H7 N CH3
CH3 CH3
O S
NC N
The rapid cooling crystallization of i-But-est was performed in c-Hxn solutions at initial concentrations (Co) between 21.0 and 30.0 mM. The initial concentrations are larger than those in the case of Me-est in c-Hxn. This accords to the higher solubility of iBut-est than that of Me-est. It was observed that two steps of concentration change clearly occur at high initial concentrations (29.5, 26.8 mM) in the crystallization from c-Hxn solutions (Fig. 6). The XRD diffraction patterns of the crystals obtained at 100 and 900 min in the crystallization process (Co ¼ 29.5 mM) are shown in Fig. 7(a) and (b). It appears that they are the polymorphs of the A (100 min) and B forms (900 min), which were previously obtained in EtOH solutions [11]. The morphology of both crystals
COOCH2CH(CH3)2 CH3
Fig. 1. Molecules of BPT esters: methylester (Me-est)(a), propylester (Pr-est) (b) and isobuthylester (i-But-est) (c).
using the rapid cooling method in cyclohexane (c-Hxn) and acetonitrile (MeCN) solutions. Different amounts of these esters were dissolved in the solvents at 323 K, and the solution was rapidly cooled to 298 K. Therefore, crystallization was performed at a constant temperature (298 K). The slurry was sampled and filtered to separate the crystals from the solution. The concentration of the solution was measured by a UV spectroscopic method at a wavelength of 254 nm. The polymorphic crystal structure was examined by powder X-ray diffraction (XRD) using the RINT2200 (Rigaku).
3. Results and discussion 3.1. Crystallization behaviors of Me-est in cyclohexane (c-Hxn) and acetonitrile (MeCN) solutions The rapid cooling crystallization of Me-est was performed in cHxn solutions at initial concentrations (Co) between 3.6 and 6.0 mM. Fig. 2 shows the change in the concentration of the solution (C) during each run. After a simple decrease in concentration due to crystallization, the concentration reached a constant value. From the XRD measurement (Fig. 3), it is clear that there is only one crystallized form for all supersaturations in the experimental range, which is the same form as that previously obtained in ethanol (EtOH) solutions [10]. From the concentration that was attained in the end, the solubility (C*) of Me-est in c-Hxn is 2.12 mM. Fig. 4 shows a photo of the crystals obtained in c-Hxn solutions, indicating that the morphology of the crystals is needlelike. In the case of MeCN, crystallization was carried out at much higher initial concentrations than in c-Hxn, i.e. between 47 and 52 mM, because the solubility of Me-est in MeCN is much greater (Fig. 5). From MeCN solutions, needle-like crystals similar to those appearing in c-Hxn were obtained. The decrease in concentration is also simple and similar to that in c-Hxn in Fig. 2. From XRD measurement, it appears that the same form as that obtained in cHxn and EtOH at all supersaturations in the experiments crystallized. The solubility (C*) of Me-est in MeCN was estimated as 36.6 mM, which is higher than those in c-Hxn (2.12 mM) and EtOH
Fig. 2. Concentration change in crystallization of Me-ester in c-Hxn solutions.
Fig. 3. XRD pattern of Me-est crystal.
ARTICLE IN PRESS M. Kitamura et al. / Journal of Crystal Growth 310 (2008) 3067–3071
is shown in Fig. 8. It appears that the metastable A form has a needle shape (Fig. 8(a)), while the stable B form is prismatic (Fig. 8(b)). The two steps of concentration change indicate that the transformation from the metastable A to the stable B is due to the solution-mediated mechanism. If the transformation process is controlled by the crystallization rate of the stable form, i.e. the dissolution rate much higher than the crystallization rate of the stable form in the transformation process, the concentration of the plateau in the concentration change may agree with the solubility of the metastable A form. The solubility of the metastable form A was estimated as 14.8 mM, while the solubility of the stable B form is given by the finally attained concentration (9.0 mM). The supersaturation ratio of the initial concentration of the B form (S ¼ Co/ C*(B)) is calculated as 2.34–3.28. These values appear to be larger than those in the case of Me-est. At the plateau, transformation occurs and the length of the plateau can be considered to correspond to the amount of the metastable form. At a low initial concentration (21.5 mM) the concentration almost simply decreased. This indicates that almost the pure stable form crystallized under this supersaturation. This may
3069
suggest that Ostwald’s step rule is established and at high supersaturations, the prevalent nucleation of the metastable form occurs.
3.3. Crystallization behavior of i-But-est in acetonitrile (MeCN) The crystallization was also done in MeCN solutions at initial concentrations of 62.4–65.0 mM. A simple decreasing curve was obtained only with changes in concentration, as shown in Fig. 9. From XRD analysis, it is clear that the crystal obtained is only of the B form at all initial concentrations. The morphology of the crystals is prismatic, but it is different from that of the stable form
Fig. 6. Concentration change in crystallization of i-But-est- in c-Hxn solutions.
Fig. 4. Me-est crystals obtained from c-Hxn solutions.
Fig. 5. Concentration change in crystallization of Me-ester in MeCN solutions.
Fig. 7. XRD pattern of (a) A form and (b) B form of i-But-est.
ARTICLE IN PRESS 3070
M. Kitamura et al. / Journal of Crystal Growth 310 (2008) 3067–3071
Fig. 9. Concentration change in crystallization of i-But-est in MeCN solutions.
Fig. 8. Morphology of i-But-est crystals obtained in c-Hxn solutions: A form(a), B form (b).
obtained in c-Hxn, as shown in Fig. 10. This is due to the solvent effect on the morphology of the stable B form. The solubility of the B form in MeCN is estimated as 31.4 mM (the supersaturation is 1.99–2.07). The polymorphic crystallization behavior of i-But-est (no polymorphs) in MeCN is similar to that of Pro-est [10]. 3.4. Discussion of the effect of solvents on the nucleation of polymorphs In the crystallization of i-But-est in c-Hxn and EtOH solutions, at high supersaturations, the metastable A form preferentially crystallized and solution-mediated transformation proceeded. Conversely, at low supersaturations, only the stable B form was obtained. In MeCN solutions, only the stable B form crystallized at all supersaturations. These results indicate that the effect of solvents on the polymorphic crystallization behavior of i-But-est is very similar to that of Pr-est [10], i.e. for both esters, Ostwald’s step rule is established for c-Hxn and EtOH solutions and not for MeCN solution. However, in the crystallization of Me-est, only one form was obtained in all solvents. When the solubilities of each ester are compared, it is observed that the solubility of each ester increases with the dipole moment of the solvents (0.332 (c-Hxn), 1.44 (EtOH), 3.93 (MeCN)). This
Fig. 10. Morphology of i-But-est crystals obtained in MeCN solutions.
may indicate that interaction between the esters and solvents increases with the dipole moment. It seems to be that for the solvents with weak interaction (EtOH and c-Hxn), the meta-stable form can crystallize at high supersaturations. However, for the solvents with large interactions (MeCN), only the stable form crystallizes (it is noted that the supersaturation range in MeCN solutions is relatively low). It is also believed that even if the metastable form nucleates in MeCN solutions, the transformation should proceed quickly because the solubility is very high and the thermodynamic stability of the metastable form is very low. If the presence of the conformer according to each polymorph in solution is assumed, the relative nucleation rates may be related to the conformer or conformation of molecules in solutions [11]. In the solvents with weak interactions (EtOH and c-Hxn), the Pr-est and i-But-est molecules may take conformations according to the meta-stable form, but in the solvents with large interactions (MeCN), they may take only the conformation of the stable form. In the case of Me-est, even in EtOH and c-Hxn,
ARTICLE IN PRESS M. Kitamura et al. / Journal of Crystal Growth 310 (2008) 3067–3071
only one conformation will be present in solutions. Previous research [11] using crystallographic analysis made clear that all of the Me-, Pro- and i-But-esters are formed by stacking the sheet structure. In the metastable form of i-But-est (A form), the sheet was formed by hydrogen bonding between the carbonyl group and the hydrogen atom in the phenyl ring of neighboring molecules. In the stable B form of i-But-est, hydrogen bonding through the nitrile group and the hydrogen atom in the phenyl ring contributes to the formation of the layer structure. However, in the case of Me-est crystal, the pair of molecules is formed by two strong hydrogen bonds and the phenyl and thiazole rings are stacked between the sheet structures by p–p interaction. In Meest, the methyl group in the ester and that in the thiazole ring take the conformation of the cis-position, whereas in the Pro- and iBut-esters, the alkyl group in the ester and the methyl group in the thiazole ring take the trans-position. It is suspected that such especially strong hydrogen bonding between two molecules of Me-est may also be present in solutions and may disturb the formation of the polymorphs.
4. Conclusion 1. In the crystallization of Me-est, only one form with needle-like morphology was obtained in c-Hxn, MeCN and EtOH solutions at any supersaturation. 2. The polymorphic crystallization behavior of i-But-est is similar to that of Pr-est and different from that of Me-est. Two polymorphs of i-But-est of the A and B forms appeared in cHxn and EtOH solutions at high supersaturations, and solu-
3071
tion-mediated transformation occurred. The morphology of the stable B form is prismatic and that of the metastable A form is needle-like. In MeCN solutions, only the stable B form preferentially crystallized. 3. The solubility of each ester increases with the dipole moment of the solvents, indicating that solute-solvent interaction increases with the dipole moment. Therefore, this seems to indicate that in the crystallization of i-But-est from solvents weak interaction (EtOH and c-Hxn), the meta-stable form crystallizes at high supersaturations, but from solvents with large interaction (MeCN), only the stable form crystallizes. 4. In Me-est crystal, two molecules are formed by two strong hydrogen bonds. It is suspected that such especially strong hydrogen bonding between a couple of molecules may disturb the formation of the polymorphs.
References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]
J.M. Rollinger, E.M. Gstrein, A. Burger, Eur. J. Pharm. Biopharm. 53 (2002) 75. C. Gu, V. Young, D. Grant, J. Pharm. Sci. 90 (2001) 1878. M. Kitamura, J. Crystal Growth 237–239 (2002) 2205. M. Kitamura, T. Ishizu, J. Crystal Growth 192 (1998) 225. L. Addadi, Z. Berkovitch-Yellin, I. Weissbuch, J.V. Mil, L.J.W. Shimon, M. Lahav, L. Leiserowitz, Angew. Chem. Int. Ed. Engl. 24 (1985) 466. T. Threlfall, Org. Process Res. Dev. 4 (2000) 384. M. Kitamura, M. Sugimoto, J. Crystal Growth 257 (2003) 177. C. Roelands, S. Jiang, M. Kitamura, J. ter Horst, H. Kramer, P. Jansens, Crystal Gowth Des. 6 (2006) 955. Bao-Dong Chen, et al., J. Am. Chem. Soc. 120 (1998) 1625. M. Kitamura, T. Hara, M.T. Kamimura, Crystal Growth Des. 6 (2006) 1945. T. Hara, Y. Hayashi, M. Kitamura, Crystal Growth Des. 7 (2007) 147.