CRYSTAL GROWTH & DESIGN
Effect of Temperature on Antisolvent Crystallization and Transformation Behaviors of Thiazole-Derivative Polymorphs Mitsutaka Kitamura* and Shinichirou
Hironaka†
Department of Mechanical and System Engineering, UniVersity of Hyogo, 2167 Shosha, Himeji, 671-2201, Japan and Department of Chemical Engineering, Hiroshima UniVersity, Higashi-Hiroshima, Japan
2006 VOL. 6, NO. 5 1214-1218
ReceiVed NoVember 30, 2005
ABSTRACT: Crystallization of the thiazole-derivative (BPT) was performed by adding water, which is an antisolvent for the solute, to methanol solutions of BPT. BPT has three polymorphs (A, B, C) and two solvates (BH(hydrate) and D(methanolate)). The effect of temperature on the polymorphic crystallization and transformation behavior was investigated in relation to the effect of the addition rate of water and the initial concentration. In the crystallization at temperatures between 333 and 313 K, the stable C form did not crystallize. At 333 K, the metastable A and BH forms crystallized competitively. At low initial concentration and slow addition rate, the A form crystallized preferentially, though at a high initial concentration and high addition rate BH tended to crystallize. It was presumed that the nucleation process of the unsolvated A form is not controlled by the dissociation equilibrium of the BH and D forms but is controlled by the kinetic process. This nucleation behavior of polymorphs at 333 K is very different from that at 323 K, which was reported previously, i.e., at low initial concentration BH crystallized, and at higher concentration the D form crystallized with BH. Furthermore, after crystallization at 333 K transformation from the BH form to the A form was observed, and it was found that the transformation rate decreases with the addition rate and the initial concentration. Such tendency is similar to that observed at 323 K. Conversely, at 313 K, the D form tended to crystallize preferentially. At low concentration the BH form also appeared with the D form, and it transformed to the D form. With a decrease of the temperature to 313 K, the D form becomes much more stable than the A and BH forms. This may accelerate preferential crystallization of the D form at 313 K. l. Introduction Polymorphs and solvated crystals are increasingly prevalent problems in pharmaceutical industries because they affect the bioavailability, stability, solubility, and morphology of the products.1-3 The crystallization process of polymorphs and solvated crystals is composed of the competitive nucleation and growth of these crystals and the transformation process from a metastable form to a stable form.3 As these elementary processes occur simultaneously, the crystallization process of polymorphs is generally complicated. This crystallization process is influenced by various operational factors of crystallizations, e.g., additives,4,5 solvents,6,7 and interfaces.5,8 To perform a selective crystallization of polymorphs, the mechanism of each elementary process in the crystallization should be cleared in relation with the operational conditions and the key controlling factor for the selective crystallization should be known.3 Investigation of this problem will also lead to clarification of the crystallization mechanism of polymorphs. From the point of view mentioned above, we investigated the influential factor in the crystallization of polymorphs in various systems.3,9 In pharmaceutical industries antisolvents are frequently used in the crystallization. The solvent compositions including antisolvents frequently influence the crystallization behavior of the polymorphs. For example, we observed previously that the relative nucleation and growth rates, and the transformation rate of the polymorphs (A, B) of L-histidine are greatly affected by the composition of the solvent (mixture of water and ethanol).7 We also investigated the influence of the solvent composition on the transformation and crystallization behavior of the polymorphs using the thiazole derivative 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (BPT) (Figure * To whom correspondence should be addressed. Phone/Fax: 81-79267-4850. E-mail:
[email protected]. † Hiroshima University.
Figure 1. BPT molecule.
1), which is one of the enzyme inhibitors. BPT has three polymorphs (A, B, C) and two solvated crystals, i.e., a hydrated crystal, BH (BPT‚H2O), and a solvated crystal with methanol, D (BPT‚MeOH). We reported in the previous work9 that the thermodynamic stability and transformation behavior of these crystals changes with both temperature and solvent composition of methanol-water. Furthermore, in the antisolvent crystallization of BPT at 323 K it was clearly shown that the crystallization of the polymorphs remarkably depends on the addition rate of water and the initial concentration.10 In this work, the temperature effect on the antisolvent crystallization and transformation behavior of BPT polymorphs was further investigated in relation to the operational factors of the addition rate of water and the initial concentration in methanol-water mixture solvents. 2. Experimental Section The BPT of 0.5-2 g (323-333 K) and 0.3-0.5 g (313 K) was dissolved at a crystallization temperature of 313 and 323-333 K, respectively, in a mixture of methanol (38.0 mL) and water (2.0 mL) (the volume fraction of methanol (VMeOH) is 0.95). The initial concentration (C0) of BPT is 0.040-0.158 mol/L for 323 and 333 K and 0.0200.040 mol/L for 313 K. The crystallization was carried out by adding 14 mL of water to the methanol solution at a fixed position near the impeller with a dropwise motion on the surface of the stirred solution at the crystallization temperature, giving a final methanol composition of the solution (VMeOH) of 0.7. The rate of water addition (W) was changed from 0.2 to 2.0 mL/min. After all the water was added, the slurry was filtrated and subjected to X-ray diffraction.10 BPT has the three polymorphs (A, B, C) and two solvates (BH and D). The BH
10.1021/cg050635f CCC: $33.50 © 2006 American Chemical Society Published on Web 04/13/2006
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Figure 2. Crystallization behavior of polymorphs at 333 K. form is a hydrated crystal (BPT‚H2O), and the D form is a solvated crystal with methanol (MeOH) (BPT‚MeOH). In the atmosphere the BH crystal loses the water molecule and becomes the anhydrous crystal (B). The polymorphic composition in crystals was determined using the characteristic peak of each polymorph and solvated crystals with X-ray diffraction (XRD). The morphology of the crystals was examined using SEM. The concentration change during crystallization at 313 K was measured by a UV spectroscopic method. However, at 333 K it was not possible to measure because of the fast evaporation of the solvents.
3. Results and Discussion 3.1. Crystallization behavior at 333 K. The antisolvent crystallization was carried out by adding water to methanolwater mixture solutions of BPT in the same manner at 323 K.10 It appeared that at 333 K the A and BH forms preferentially crystallized. Since it was clearly shown previously9 that the C form is the most stable form at temperatures between 303 and 333 K and for methanol compositions (VMeOH) between 0.5 and 0.8, it can be said that in this case the stable form does not crystallize out. It was also clearly shown that the crystallization behavior of the polymorphs depends on the BPT initial concentration and water addition rate. In Figure 2 the crystallization behavior of A and BH is shown on the grid with the coordinates of the BPT initial concentration (C0) and the addition rate of water (W). It can be seen that when the concentration (C0) is low (0.055 mol/L), the A form preferentially crystallizes, especially at addition rates (W) lower than 1.0 mL/min. However, by increasing the addition rate (W) to more than 1.3 mL/min, the BH form precipitates. With an increase of the initial concentration (C0), the crystallization area of BH (III in Figure 2) tended to increase and that of the A form (I in Figure 2) became narrower. At 0.079 mol/L the A form crystallized only at an adding rate of less than 0.5 mL/min, and at a faster addition rate of more than 1.0 mL/min BH was obtained. In the intermediate area (II) at 0.079 and 0.158 mol/L both polymorphs precipitated. The increasing tendency of the BH form fraction with the water addition rate is the same as the result at 323 K (Figure 2 in ref 10). This may be due to an increase of the nucleation zone around the water droplet with increasing addition rate, which may accelerate nucleation of the BH form. Conversely, the results in Figure 2 show that with increasing initial concentration the BH form tends to increase and the fraction of the A form decreases. At 323 K the A form did not
Figure 3. Change of XRD pattern in the transformation from BH to A at 333 K: 5 (a), 100 (b), and 200 min (c) after the start of crystallization (W ) 2.8 mL/min; C0 ) 0.055 mol/L).
crystallize and the BH and D forms preferentially crystallized, and the increase of the initial concentration induced nucleation of the D form rather than the BH form.10 This fact indicates that the effect of the initial concentration, i.e., supersaturation, is very complicated and depends on the temperature. This temperature effect may be related to the thermodynamic stability of the crystals. In previous work9 it was shown that the thermodynamic stability of the solvated crystals of BH and D is related to the dissociation of each crystal (eqs 1 and 2).
BPT‚H2O (BH) h BPT + H2O
(1)
BPT‚CH3OH (D) h BPT + CH3OH
(2)
With an increase of the initial concentration, the water composition (ratio of water molecule to BPT molecule) in the nucleation zone may decrease.10 This will accelerate formation of the cluster and the nuclei of the A or D form rather than the BH form. Conversely, at 333 K the stability of the D form is very low due to the dissociation in eq 2, as shown in the solubility curve in the previous paper.10 This may possibly give rise to nucleation of the A form. However, with an increase of the initial concentration, the fraction of the A form inversely decreases. We presume that the nucleation process of the A form is not controlled by the dissociation equilibrium of the BH and D forms (eqs 1 and 2) and is rather controlled by the kinetic process because the A form is unsolvated. At 333 K the stability of the BH form may also be due to a lesser extent to the
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Kitamura and Hironaka
Figure 6. Dependence of the transformation rate from BH to A on water addition rate (W) at 333 K (C0 ) 0.079 mol/L).
Figure 4. SEM photographs of crystals during the transformation from BH to A: after 5 (a) and 200 min (b) (W ) 2.8 mL/min; C0 ) 0.055 mol/L). Figure 7. Crystallization behavior of polymorphs at 313 K.
Figure 5. Dependence of the transformation rate from BH to A on water addition rate (W) at 333 K (C0 ) 0.055 mol/L).
dissociation (eq 1). Practically, the A form is more stable than the D and BH forms. On this account, in a slow nucleation process (low supersaturation) the unsolvated A form may preferentially nucleate. However, in a rapid nucleation process (high supersaturation) the hydrated BPT solute may crystallize directly, resulting in the appearance of the BH form. 3.2. Transformation at 333 K. It appeared that after crystallization the crystallized BH form in the II and III areas transforms to the A form by a solution-mediated mechanism.10 In Figure 3 the typical change in the XRD pattern (W ) 2.8 mL/min; C0 ) 0.055 mol/L) is shown. It can be seen that the
BH form (Figure 3a) transforms to pure A form (Figure 3c) by the mixture of the A and BH forms (Figure 3b). This fact coincides with the result of the solubility measurement, which indicates that at 333 K the BH form is more unstable than the A form.9 SEM indicated that the morphology of the BH form, which was obtained 5 min after the start of the crystallization, is very fine and fibrous (Figure 4a). However, the crystals changed to the larger pillar crystals, which is the A form obtained by the transformation (Figure 4b). Furthermore, it was found that the transformation rate of the BH form changes with the crystallization conditions. In Figure 5 the relationship between the molar fraction of A form (XA/BH) in crystals in solutions and time after the start of the crystallization in the III area in Figure 2 is shown (C0 ) 0.055 mol/L)). At the ending point of the addition of water only the BH form exists (XA ) 0). However, the fraction of the BH form decreased with time, and finally only the A form was obtained. It was found that the transformation rate of BH to A form decreases with increasing addition rate (W). The same phenomenon was observed at 323 K.10 For this reason, we suppose that even if no peak for the A form is observed in XRD measurement, a very slight amount of A form (fine crystals) may be included in BH crystals, and they act as seeds for the transformation. The amounts of A form will increase with decreasing addition rate (W). A similar trend was also observed at an initial concentration of 0.079 mol/L; however, the transformation rate seems to decrease with increasing initial concentration (C0) as shown in Figure 6. 3.3. Crystallization and Transformation behavior at 313 K. Antisolvent crystallization was carried out by adding water
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temperature to 313 K, the D form becomes much more stable than the A and BH forms. This may accelerate the preferential crystallization of the D form at this temperature. When the BH form crystallized, the BH form transformed to the D form after crystallization. Figure 8 shows the change of the XRD patterns from the mixture of the BH and D forms (at 50 min) to the pure D form (at 120 min). The SEM photographs in Figure 9 show the morphological change during the transformation. It can be seen that the fine needlelike morphology of the BH form (Figure 9a) changed to the larger pillar crystals of the D form (Figure 9b) by the solution-mediated transformation.
Figure 8. XRD patterns of crystals obtained 50 (a) and 120 (b) min after the start of crystallization (0.024 mol/L, W ) 0.28 mL/min).
at 313 K with different initial concentrations of BPT. At initial concentrations of 0.040 and 0.024 mol/L (C0), the D form tended to crystallize preferentially as shown in Figure 7. However, at low initial concentration (C0 ) 0.024 mol/L) the BH form also appeared in addition to the D form. With a decrease of the
At 313 K the concentration change could be measured at each water addition rate (W), and the results are shown in Figure 10 a and b. The half-filled marks indicate the turbidity point of the solution at each water addition rate due to nucleation in whole solutions. The filled marks show the end point of the water addition. By adding water nucleation occurred and the concentration steeply decreased due to crystallization and attained a constant value (solubility of the D form). At 0.040 mol/L the turbidity of the solution due to nucleation was observed at the same solvent composition (VMeOH) for every water addition rate. At the end of the water addition the concentration decrease ceased. At 0.024 mol/L the turbidity of the solution also occurred at the same solvent composition; however, even after the end of the water addition the concentration continuously decreased. This means that at 0.024 mol/L
Figure 9. SEM photographs of crystals 50 (a) and 120 (b) min after the start of crystallization (0.024 mol/L, W ) 0.28 mL/min).
Figure 10. Concentration change in crystallization: C0 ) (a) 0.040 and (b) 0.024 mol/L.
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the crystallization is slow and continues even after the end of water addition. 4. Conclusion The effect of temperature on the polymorphic crystallization and transformation behavior was investigated in relation to the effect of the addition rate of water and the initial concentration. In the crystallization at temperatures between 333 and 313 K the stable C form did not crystallize. At 333 K the metastable A and BH forms crystallized. At low initial concentration and slow addition rate the A form crystallized preferentially. However, at high initial concentration and high addition rate BH tended to crystallize. It was presumed that the nucleation process of the unsolvated A form is not controlled by the dissociation equilibrium of the BH and D forms but is controlled by the kinetic process. These nucleation behaviors of polymorphs at 333 K are very different from that at 323 K. After crystallization the transformation from the BH form to the A form was observed, and it was found that the transformation rate decreases with addition rate and initial concentration.
Kitamura and Hironaka
At 313 K the D form tended to crystallize preferentially. However, at low concentration the BH form also appeared with the D form and was transformed to the D form. With a decrease of the temperature to 313 K, the D form becomes much more stable than the A and BH forms. This may accelerate preferential crystallization of the D form at 313 K. References (1) Rollinger, J. M.; Gstrein, E. M.; Burger, A. Eur. J. Pharm. Biopharm. 2002, 53, 75. (2) Matsuda, Y.; Tatsumi, E. Int. J. Pharm. 1990, 60, 11. (3) Kitamura, M. J. Cryst. Growth 2002, 237-239, 2205. (4) Kitamura, M.; Ishizu, T. J. Cryst. Growth 1998, 192, 225. (5) Addadi, L.; Berkovitch-Yellin, Z.; Weissbuch, I.; Mil, J. V.; Shimon, L. J. W.; Lahav, M.; Leiserowitz, L. Angew. Chem., Int. Ed. Engl. 1985, 24, 466. (6) Threlfall, T. Org. Process Res. DeV. 2000, 4, 384. (7) Kitamura, M.; Furukawa, H. J. Cryst. Growth 1994, 141, 193-199. (8) Chen, B.-D.; et al., J. Am. Chem. Soc. 1998, 120, 1625. (9) Kitamura, M.; Sugimoto, M. J. Cryst. Growth 2003, 236. 676. (10) Kitamura, M.; Sugimoto, M. J. Cryst. Growth 2003, 257, 177.
CG050635F
