Effect of Molecular Structure Change of BPT-Esters on Crystal Structure and Solubility Takayuki Hara,† Kosuke Adachi,† Midori Takimoto-Kamimura,‡ and Mitsutaka Kitamura*,† Department of Mechanical and System Engineering, UniVersity of Hyogo, 2167 Shosha, Himeji, 671-2201, Japan, and Pharmaceutical DiscoVery Research Laboratories I, Teijin Pharma Limited, 4-3-2, Asahigaoka, Hino, Tokyo, 191-8512, Japan
CRYSTAL GROWTH & DESIGN 2009 VOL. 9, NO. 7 3031–3035
ReceiVed February 27, 2008; ReVised Manuscript ReceiVed April 5, 2009
ABSTRACT: Methyl 2-(4-(2-metylpropoxy)-phenyl)-4-methyl-thiazole-5-carboxylate (Me-est(H)), propyl 2-(4-(2-metylpropoxy)phenyl)-4-methyl-thiazole-5-carboxylate (Pr-est(H)), and 2-methyllpropyl 2-(4-(2-metylpropoxy)-phenyl)-4-methyl-thiazole-5carboxylate (i-But-est(H)) were prepared, and the relationship between the molecular structure, and crystal structure and solubility was investigated. The crystallization of Me-, Pr-, and i-But-est(H) from methanol (MeOH), ethanol (EtOH), and acetonitrile (MeCN) solutions by a rapid cooling method resulted in only one crystal form for each ester. Crystallographic analysis using a single crystal indicated that the crystal was constructed by stacking the sheet of molecules, the phenyl ring, the thiazole ring, and the ester group along the same plane in all esters. The hydrogen bonding by the carbonyl group was observed in the case of Pr- and i-But-est(H), whereas no hydrogen bonding was observed in the Me-est(H) crystal. From solubility measurements in MeOH, EtOH, MeCN, and c-hexane (c-Hxn), it was found that each ester has the lowest solubility in MeOH and the highest solubility in c-Hxn. These results indicate that the decrease of polarity of the solvents make the solubility increase. However, MeCN shows irregular behavior suggesting the presence of interactions between the ester and MeCN. In the esters, i-But-est(H) showed the lowest solubility in every solvent. This may correspond to the highest fusion enthalpy and the crystal structure, in which a dimer of molecules is formed by strong hydrogen bonding. In comparison with the previous work, it was indicated that the presence of nitrile group creates the additional possibilities for hydrogen bonds and therefore creates the possibility of other crystal forms.
1. Introduction Control of polymorphism is a very important technology for the development of new materials such as pharmaceuticals.1 This is because polymorphs and solvated crystals (pseudopolymorphs) affect the bioavailability, stability, solubility, and morphology of crystal products such as pharmaceuticals.2-8 The polymorphic crystallization depends on various operational factors as temperature, supersaturation degree, solvent, and additives.9-12 Furthermore, the controlling factors for the polymorphism change with the operation method of the crystallization. Finding the key controlling factor in each operation is essential for the control of the polymorphism. For example, it was found previously that the addition rate of the antisolvent and initial concentration are very important key factors for antisolvent crystallization of the thiazole derivative 2-(3-cyano4-(2-methylpropoxy)-phenyl)-4-methyl-thiazole-5-carboxylic acid (BPT),13,14 which is a xanthine oxidase inhibitor. On the other hand, some reports deal with the crystallographic analysis of the polymorphs in relation to the molecular structure.15,16 However, the dependence of the polymorphic crystallization behavior on the molecular structure is hardly known. Previously, we have reported that in the crystallization of L-glutamic acid and L-histidine10 the nucleation behaviors and transformation rate of polymorphs depend on the molecular structures of these amino acids. If the relationship between the molecular structure and polymorphic crystallization behavior is known, it may give very useful information for the control of polymorphism. To examine the effect of the molecular structure quantitatively we especially prepared the methyl, propyl, and i-butyl esters of BPT17,18 (BPT-esters(CN), Figure * To whom correspondence should be addressed. E-mail: mkitamura@ eng.u-hyogo.ac.jp; tel/fax: +81-792-67-4850. † University of Hyogo. ‡ Teijin Pharma Limited.
Figure 1. Molecular structure of BPT esters.
1), and the crystallization and the transformation behaviors were investigated for each ester. In this paper, we have further changed the molecular structure of the BPT ester systemically; that is, nitrile group in the esters was changed to hydrogen and methyl(Me-est(H)), propyl(Pr-est(H)), and i-buthyl esters(i-Butest(H)) (BPT-esters(H), Figure 1) were prepared, and the effect of the molecular structure change on polymorphic crystallization behaviors was investigated in various solvents.
2. Experimental Section Methyl ester (Me-est(H): methyl 2-(4-(2-metylpropoxy)-phenyl)-4methyl-thiazole-5-carboxylate) was synthesized by adding methyl iodide to a mixture of 2-(4-(2-metylpropoxy)-phenyl)-4-methyl-thiazole-5carboxylic acid and potassium carbonate in N,N-dimethylformamide. Propyl ester (Pr-est(H): propyl 2-(4-(2-metylpropoxy)-phenyl)-4-methylthiazole-5-carboxylate) and isobutyl ester (i-But-est(H): 2-methyllpropyl 2-(4-(2-metylpropoxy)- phenyl)-4-methyl-thiazole-5-carboxylate) were synthesized in a similar manner; however, propyl bromide or isobutyl bromide was added to the mixture instead of methyl iodide. The
10.1021/cg800216j CCC: $40.75 2009 American Chemical Society Published on Web 05/12/2009
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Hara et al. Table 1. Crystallographic Data for Me-, Pr-, i-But-est(H)
a (Å) b (Å) c (Å) crystal system space group R (°) β (°) γ (°) Z density (g/cm3)
Figure 2. XRD pattern of Me-, Pr-, and i-But-est(H); (a) Me-est(H), (b) Pr-est(H), (c) i-But-est(H). synthesized esters were confirmed by 1H-NMR spectra (JEOL JNM AL-400 (399.65 MHz)) in a deuterated chloroform solution with tetramethyl silane as the internal reference (the NMR spectra are available as Supporting Information). Crystallization of Me-est(H), Pr-est(H), and i-But-est(H) was carried out by a rapid cooling method in methanol (MeOH), ethanol (EtOH), and acetonitrile (MeCN) solutions.17 The crystallization temperature for Me- and Pr-est(H) was 288 K, whereas that for i-But-est(H) was 298 K. The slurry was filtered to separate the crystals from the solution and the concentration of the solution was measured by the UV spectroscopic method. After the separated crystals of each ester were dried, the crystals were subjected to powder X-ray diffraction (XRD) using the RINT2200 (Rigaku). Crystal morphology was observed by scanning electron microscopy (SEM). Differential scanning calorimetry (DSC) measurements were carried out to measure melting point and fusion enthalpy. Using a single crystal, the crystal structures were determined by a Rigaku R-AXIS with Cu KR radiation. Solubility of each ester was measured at various temperatures in MeOH, EtOH, MeCN, and c-hexane (c-Hxn). The excess amount of each crystal was
Me-est(H)
Pr-est(H)
i-But-est(H)
5.7683(19) 11.3522(13) 13.5733(9) triclinic P1j 92.946(7) 100.272(5) 94.591(6) 2 1.166
15.483(7) 7.404(3) 31.943(14) orthorhombic Pbca 90.0 90.0 90.0 8 1.210
5.687(7) 12.733(14) 15.133(16) triclinic P1j 68.69(5) 85.84(8) 89.01(6) 2 1.133
added to the solvent in a glass vessel in a thermostatic bath, and the concentration of the solution was measured continuously by a UV spectroscopic method. When the concentration attained to the equilibrium value, the solubility was determined. After the solubility measurement, the crystals were submitted to XRD measurements to confirm the crystal structure.
3. Results and Discussion 3.1. Crystallization Behavior and Crystal Structure of Me-est(H). Rapid cooling crystallization of Me-est(H) was performed in MeOH, EtOH, and MeCN solutions. As the solubility is largely different between the solvents, the crystallization was carried out at different concentrations in each solvent. The initial concentrations (C0) of MeOH, EtOH, MeCN solutions were set as 0.20 to 0.22, 0.30 to 0.37, and 0.54 to 0.57 mol/L, respectively. However, it appeared that crystals obtained at different concentrations in each solvent showed the same XRD pattern (Figure 2a). This result indicates that no polymorphs crystallize and the crystals with the same structure were obtained in each solvent. The crystals were observed by SEM, and it appeared that each crystal has a needle-like morphology as shown in Figure 3a.
Figure 3. Morphology of BPT-esters(H) obtained in EtOH; (a) Me-est(H), (b) Pr-est(H), (c) i-But-est(H).
Molecular Structure Change of BPT-Esters
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Figure 4. Crystal structure of Me-est(H); (a) molecular conformation; (b) crystal structure. Table 2. Geometry Relationship between Substituents
\R
Me
Pr
i-But
A-B B-C
cis trans
trans trans
trans cis
The X-ray analysis of a single crystal of Me-est(H) was performed. The final R factor was 0.1111 for a total of 3707 reflections. The crystallographic data are shown in Table 1. Figure 4 shows the crystal structure and the molecular conformation of Me-est(H). In the crystal, a phenyl ring, thiazole ring, and ester group lie along the same plane as the Me-est(H) molecule (Figure 4a). It is observed that the isobutoxy group (A) on the phenyl ring and the methyl group on the thiazole ring (B) exhibit cis-geometry (Table 2). It is also found that the methyl group in the ester (C) and on the thiazole ring (B) are located in the trans-position (Table 2). Figure 4b shows molecular arrangement of the Me-est(H) in crystal. Intermolecular hydrogen bonds were not observed in Me-est(H). In the crystal, molecules are stacked between the phenyl and thiazole rings to form the sheet structure by the π-π interaction. 3.2. Crystallization Behavior and Crystal Structure of Pr-est(H). The rapid cooling crystallization was also performed for the Pr-est(H) in MeOH, EtOH, and MeCN solutions. The initial concentrations (C0) were set as 0.18 to 0.25, 0.31 to 0.42, and 0.32 to 0.42 mol/L for MeOH, EtOH, and MeCN solutions. The XRD patterns of crystals obtained at different concentrations
in each solution (Figure 2b) indicated that every crystal has the same structure. All the crystals of Pr-est(H) also have needlelike morphology as shown in Figure 3b. The X-ray analysis of a single crystal of Pr-est(H) was performed. The final R factor was 0.0654 for a total of 14 537 reflections, and the crystallographic data are shown in Table 1. The crystal structure and the molecular conformation in the crystal are shown in Figure 5. In the crystal, a phenyl ring, thiazole ring, and ester group lie along the same plane as Meest(H) (Figure 5a). The hydrogen bond forms between the carbonyl group and a hydrogen atom on the phenyl ring of the neighboring molecule (the distance between the two atoms was observed to be 2.42 Å), forming a network. It is also found that the propyl group of the ester(C) and the methyl group in the thiazole ring (B) are located on the opposite side (Table 2). On the other hand, it is observed that the isobutoxy group (A) in the phenyl ring and the methyl group in the thiazole ring (B) exhibit trans-geometry (Table 2) in the same way as Me-est(H). Figure 5b shows the molecular arrangement of the Pr-est(H) in crystals. It is observed that the crystal is constructed by stacking the zigzag sheets of the molecules. The phenyl and the thiazole rings stack due to the π-π interaction. 3.3. Crystallization Behavior and Crystal Structure of i-But-est(H). The crystallization of i-But-est(H) was performed in MeOH (C0 ) 0.10-0.12 mol/L), EtOH (C0 ) 0.15-0.18 mol/L), and MeCN (C0 ) 0.16-0.20 mol/L) solutions. With XRD measurements, it appeared that the crystals obtained at each concentration in the different solvents have the same structure (Figure 2c); that is, no polymorphs crystallize in the same way as Me-est(H) and Pr-est(H). The morphology of the crystals is also needle-like (Figure 3c). In the crystallographic analysis of i-But-est(H) (Table 1), the final R factor was 0.0799 for a total of 4813 reflections. Figure 6 shows the crystal structure and molecular conformation of the i-But-est(H) crystal. In the crystal, a phenyl ring, thiazole ring, and ester group lie along the same plane similar to Me- and Pr-est(H) (Figure 6a). Trans-geometry is observed between the methyl group in the thiazole ring (B) and the isobutoxy group (A), and the methyl group in the thiazole (B) ring and the isobutyl group in ester (C) take cis-geometry (Table 2). Figure 6b shows molecular arrangement of the i-But-est(H) in the crystal. The crystal is also constructed by stacking sheets of molecules the same as Me-est(H) and Pr-est(H). The i-Butest(H) molecule forms a dimer through two hydrogen bonds with the partner molecule as shown in Figure 6a (the distance between the two atoms is observed to be 2.62 Å). We assume that the polarity of carbonyl group may be larger in the order of i-But-est, Pr-est, Me-est. The formation of the dimer may be due to the strong polarity of the carbonyl group.
Figure 5. Crystal structure of Pr-est(H); (a) a couple of molecules; (b) crystal structure.
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Figure 6. Crystal structure of i-But-est(H); (a) a dimer of molecules; (b) crystal structure.
Figure 7. Solubility curve of BPT-esters; (a) Me-est (H), (b) Pr-est(H), (c) i-But-est(H).
It is clear from this research that only one crystal form was obtained in the crystallization of the Pr-est(H) and the i-Butest(H) in EtOH solutions. On the other hand, in the previous paper,17,18 we have reported that in the crystallization of Prest(CN) and i-But-est(CN) in EtOH solution two crystal forms
Hara et al.
Figure 8. Relationship between solubility and dipole moment of the solvent at 288 K.
appear. The Pr-est(CN) and i-But-est(CN) have a nitrile group instead of a hydrogen atom in the phenyl ring of the Pr-est(H) and the i-But-est(H). This suggests that the presence of the nitrile group is important for the formation of polymorph of BPTesters. In the stable form of Pr-est(CN) and i-But-est(CN), the hydrogen bonds through the nitrile group, and the hydrogen atom on the phenyl ring was observed between the neighboring molecules. On the other hand, Pr-est(H) and i-But-est(H) have no hydrogen bonding due to the nitrile group. These results indicate that the presence of nitrile group creates the additional possibilities for hydrogen bonds and therefore creates the possibility of other crystal forms. 3.4. Thermal Analysis and Solubility Measurement of Me-est(H), Pr-est(H), and i-But-est(H). The melting point and the fusion enthalpy were estimated by DSC measurements. The melting points of Me-, Pr-, and i-But-est(H) are 330, 332, and 337K, and fusion enthalpy values are 25.9, 27.7, and 37.2 kJ/ mol. The difference in the melting point and fusion enthalpy between Me-est(H) and Pr-est(H) is small. However, i-Butest(H) has a high melting point and large fusion enthalpy in comparison with Me-est(H) and Pr-est(H). This may be due to the relatively strong hydrogen bond in the i-But-est(H) crystal. Solubility of Me-, Pr-, and i-But-esters(H) was measured in MeOH, EtOH, MeCN, and c-Hxn (Figure 7a-c). It was confirmed by the XRD measurements that during the every solubility measurements no transformation occurs. It is observed that each ester has the lowest solubility in MeOH and the highest solubility in c-Hxn. In Figure 8, the solubility at 288 K was plotted against the dipole moment. It can be said that the decrease of the polarity of the solvents makes the solubility increase. This implies the interaction between Me-, Pr-, and i-But-esters(H) and solvents tends to decrease with the increase in the polarity of the solvents. However, MeCN shows the irregular behavior. Even though MeCN has a very large dipole moment due to the CN group, the solubility is relatively high. In our previous work,17,18 it showed that the nitrile group in BPT-est(CN) forms a hydrogen bond with the phenyl ring in the neighboring molecule. It is assumed that the characteristic interaction through the hydrogen bond between the nitrile group of MeCN and BPT-est(H) increases the solubility. Among the esters, the i-But-est(H) has the lowest solubility in every solvent. The strong hydrogen bond in i-But-est(H) crystals may decrease the interaction with solvents.
Molecular Structure Change of BPT-Esters
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4. Conclusion
References
(1) The crystallization of Me-, Pr-, and i-But-est(H) from methanol (MeOH), ethanol (EtOH), and acetonitrile (MeCN) solutions by a rapid cooling method resulted in only one crystal form for each ester. In addition, they have needle-like morphology. (2) In the Me-est(H) crystal, crystal was constructed by stacking the sheet of molecules, and a phenyl ring, thiazole ring, and ester group along the same plane. (3) In the case of Pr-est(H), the molecule had the plane conformation in the same way with Me-est(H); however, the crystal was constructed by stacking the zigzag sheets of the molecules, and hydrogen bonding between carbonyl group and hydrogen atom in phenyl ring was observed with neighboring molecules in the sheet, whereas no hydrogen bonding was observed in Me-est(H) crystal. (4) In the case of i-But-est(H) crystal, a phenyl ring, thiazole ring, and ester group lie along the same plane similar to Meand Pr-est(H). The i-But-est(H) molecule forms a dimer through two hydrogen bonds with the neighboring molecule. (5) The solubility of each ester is the lowest in MeOH, and the highest in c-Hxn. The i-But-est(H) showed the lowest solubility in the esters of each solvent. This may correspond to the highest fusion enthalpy. (6) It was indicated that the presence of nitrile group creates the additional possibilities for hydrogen bonds and therefore creates the possibility of other crystal forms.
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Supporting Information Available: NMR spectra are available free of charge via the Internet at http://pubs.acs.org.
CG800216J
