Mechanism of Solvent Effect in Polymorphic Crystallization of BPT

Article pubs.acs.org/IECR

Mechanism of Solvent Effect in Polymorphic Crystallization of BPT Mitsutaka Kitamura,*,†,‡ Emi Umeda,† and Kenichi Miki† †

Department of Mechanical and System Engineering, University of Hyogo, 2167 Shosha, Himeji, 671-2201, Japan Laboratory for Control of Polymorphism, 665-7, Matsuyama City, 790-0924, Japan

‡

ABSTRACT: The effect of solvent on the crystallization behavior of the polymorphs of 2-(3-cyano-4-isobutyloxyphenyl)-4methyl-5-thiazolecarboxylic acid (BPT) was investigated under rapid cooling. From methanol (MeOH) and ethanol (EtOH) solutions, only the solvated crystals of the D forms of methanol (D(MeOH)) and ethanol (D(EtOH)) crystallized. Both D forms are stable and have similar crystal structures. However, the solubility of the D(EtOH) form is 1.5 times higher than that of the D(MeOH) form. With the release of alcohol molecules, both D forms transformed to the C form with an increase in temperature for the DSC measurement. After that, the C form transformed to the A form via a melt-mediated mechanism. The release temperature of alcohol was higher for D(EtOH) than for D(MeOH). When the crystallization was performed in 1-propanol (1PrOH) and 2-propanol (2-PrOH), the metastable A form preferentially crystallized. On the other hand, in acetonitrile (MeCN) solutions the stable C form was selectively obtained. These crystallization behaviors in each solvent did not depend on supersaturation in solutions. The FTIR spectra of BPT in EtOH and 1-PrOH suggested that BPT molecules in solution take a conformation similar to that in each crystal. These results suggest that the solvent effect is controlled by the thermodynamic equilibrium properties such as the conformation of the solute and the solute−solvent interactions rather than the crystallization kinetics of the polymorphs. Furthermore, the solution-mediated transformation rate from the A form to the C form is higher in MeCN than those in 1-PrOH and 2-PrOH. In the mixed solvents of 1-PrOH and MeCN with water, the same polymorphs crystallized as those obtained in pure solvents in the water volume fraction up to the range of 0.1. However, the hydrated crystals (BH form) predominantly crystallized with further addition of water. Solubility measurements suggested that such behavior is related to the solvated structure surrounding the BPT molecule.

1. INTRODUCTION The formation of polymorphs and solvated crystals is an important problem in pharmaceutical industries, because bioavailability and other properties depend on polymorphs.1 It is known that solvents have an influence on polymorphism1−4 especially in the crystallization of pharmaceutical compounds. In polymorphic crystallization behavior, thermodynamic equilibrium properties such as the conformation of the solute in solution and the solute−solvent interactions may have an influence on the polymorphic crystallization. On the other hand, the polymorphic crystallization process is composed of the relative nucleation and growth of the polymorphs, and transformation between the polymorphs.1 Therefore both factors of thermodynamic equilibrium and the crystallization kinetics should be considered to analyze the polymorphic crystallization process.1 Blagden et al.5 related the solvent dependence of the polymorphic appearance of sulfathiazole with the hydrogen-bonding motifs of each form. Weissbuch et al.6 discussed the growth kinetics of different polymorphs in terms of crystal structure, and solvent−surface, solute−solvent, and solute−solute interactions. Stoica et al.7 studied the crystal habit of polymorphs in different solvents by MD simulations. Using calorimetric and structural analysis techniques to study the crystallization process of 2,4,6-trinitrotoluene, Vercelj et al.8 concluded that the crystallization behavior of the polymorphs is attributable to kinetics in solution rather than structural control. Previously, we reported9 the relative stability of polymorphs of BPT (2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid) (Figure 1) and the transformation behavior by a solution-mediated mechanism10 in a mixed solvent of methanol © 2012 American Chemical Society

Figure 1. BPT molecule.

and water. Furthermore, the antisolvent crystallization of BPT was carried out by adding water to methanol solutions, and it was found that the addition rate of the antisolvent, initial concentration, and temperature are the key controlling factors of polymorphism.11 It was considered that the complicated crystallization and the transformation behavior of the BPT polymorphs is due to the change of the thermodynamic stability during the antisolvent crystallization.1 On the other hand, we also examined the polymorphic crystallization process of various BPT esters at constant temperature by a rapid cooling method.12,13 The results showed that the polymorphic crystallization behavior is related to the molecular structure12 and in the case of propyland butyl-ester of BPT the metastable form appeared only at a high concentration of BPT in ethanol solutions,13 i.e., the Oswald step rule14 was observed to be established. In the present research, the crystallization of BPT was carried out using a rapid cooling method in various pure solvents and in mixed solvents Received: Revised: Accepted: Published: 12814

June 17, 2012 August 22, 2012 September 4, 2012 September 4, 2012 dx.doi.org/10.1021/ie300418q | Ind. Eng. Chem. Res. 2012, 51, 12814−12820

Industrial & Engineering Chemistry Research

Article

Figure 2. XRD patterns of polymorphs: (a) A form, (b) BH form, (c) C form, and (d) D form(MeOH).

for each deuterated solvent with tetramethylsilane as the internal reference. The concentration change in the solutions was measured for about 24 h, even after the end of the crystallization, and the solubility was determined from the constant steady-state value. To the solvents mixed with various volumetric fractions of water, excess amounts of each polymorph were added to the solutions and the solubility was measured by analyzing the concentration of the supernatant solutions at equilibrium. The polymorph was also determined by XRD analysis after the solubility measurement.

with water, and the mechanism of the solvent effect on the polymorphic crystallization behavior was further investigated.

2. EXPERIMENTAL SECTION BPT (Figure 1) has three polymorphs (A, B, and C), a hydrated crystal (BH), and a solvated crystal with methanol (D(MeOH). The typical XRD pattern of each polymorph is shown in Figure 2. It is reported that the polymorphic crystallization behavior usually depends on the cooling rate.15 In this work, the crystallization was carried out by “ rapid cooling method”. BPT was dissolved in each solvent at 318−323 K, and the solution was rapidly cooled to the crystallization temperature (298 K) by changing the thermostatically controlled water circulating in the jacket of the crystallizer. The cooling time is very short (within 5−7 min), and the nucleation occurs after the temperature reached 298 K. We consider that the initial supersaturation is important for the nucleation of polymorphs. In this “rapid cooling method” the polymorphs nucleate and grow at constant initial supersaturation and temperature. The solvents used for the crystallization were methanol (MeOH), ethanol (EtOH), 1propanol (1-PrOH), 2-propanol (2-PrOH), and acetonitrile (MeCN). The effect of antisolvent (water) on polymorphic crystallization was also examined by the same method in mixed solvents with MeOH, 1-PrOH, and MeCN. The range of the initial concentration for the crystallization was determined by measuring the induction period for the nucleation of BPT crystals at various concentrations of BPT in each solvent. The concentration change during the course of crystallization was measured by UV spectroscopy (Shimadzu) at a wavelength of 254 nm. Crystals precipitated from solution were filtered and the polymorphic composition was determined by Xray diffraction (XRD) (RINT2200, Rigaku). Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) measurements were carried out at a rate of temperature increase of 5 K/min, and the solid-state transformation mechanism was examined. FTIR spectroscopy (Spectra BXII, Perkin-Elmer) was carried out on the supersaturated solutions of BPT (MeOH: 2.6 × 10−2 mol/L; EtOH: 5.3 × 10−2 mol/L; PrOH: 8.0 × 10−2 mol/ L; 2-PrOH: 8.0 × 10−2 mol/L) for each solvent, respectively, using a thin layer cell (0.5−1 mm) at 298 K. 1H NMR spectra were measured on a JEOL JNM AL-400 system (399.65 MHz)

3. RESULTS AND DISCUSSIONS 3.1. Crystallization Behavior in Methanol and Ethanol Solvents. The induction period (τ) for BPT solutions with MeOH as a solvent was measured as shown in Figure 3. The range of the initial BPT concentration (Co) for nucleation was determined to be 0.03−0.04 mol/L (moles per liter of solution) using the results shown in Figure 3. The concentration (C)

Figure 3. Relationship between the induction period (τ) and BPT concentration in MeOH solutions. 12815

dx.doi.org/10.1021/ie300418q | Ind. Eng. Chem. Res. 2012, 51, 12814−12820


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change during crystallization in MeOH for various initial concentrations (Co) is shown in Figure 4a. When the metastable

Figure 5. TGA patterns of crystals obtained in each solvent.

Figure 4. (a) Concentration change with time for crystallization in MeOH. (b) Concentration change with time for crystallization in EtOH.

Figure 6. DSC curves of BPT polymorphs.

form crystallizes and the transformation occurs through the solution-mediated mechanism, a two-step concentration decrease is expected.9,12 In Figure 4a the concentration decreases simply after nucleation and attained the same concentration for each initial supersaturation. This result suggests that the same form crystallizes regardless of supersaturation and that no transformation occurs. The XRD patterns of the crystals obtained after the crystallization were the same as that of the D form (Figure 2d). The D form is the methanol solvate, and the result of the TGA measurement is shown in Figure 5. The weight loss (9.2%) at about 370 K due to the escape of MeOH molecules indicates that the molar ratio of BPT to MeOH is 1.0. In the DSC curves of the D form(MeOH) shown in Figure 6, the endothermic peak appears at about 370 K, which corresponds to the weight loss due to the escape of methanol molecules (Figure 5). Two endothermic peaks are also observed near 474 K and 482 K, and between them a small exothermic peak appears. From the concentration attained in Figure 4a, the solubility of the D form in MeOH at 298 K is estimated as C* = 2.03 × 10−2 mol/L. It was clarified previously9,11 that the stability of the D form increases with a decrease in temperature at the methanol volume fraction 0.7 in a water and methanol mixture. In this case, no transformation was observed in the MeOH solutions at 298 K, indicating that the D form is the most stable form.

In the case of EtOH, the concentration change also simply decreased and reached a constant value in the same manner as MeOH (Figure 4b). The XRD patterns of crystals obtained at each supersaturated solution are the same (Figure 7), meaning that only the stable form crystallized. The molar ratio of EtOH and BPT in this crystal was determined to be 1.0 from the weight loss (12.6%) at about 350 K in the TGA measurement in Figure

Figure 7. X-ray diffraction pattern of crystals obtained from an EtOH solution. 12816



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5. Furthermore, the XRD pattern of this crystal (Figure 7) appeared to be very similar to that of the crystal obtained in MeOH (Figure 2d). This may indicate that the crystal structure is close to the D form in the case of MeOH (D(MeOH)); therefore, MeOH may be replaced with EtOH in this crystal. Consequently, we denote this crystal as the D(EtOH) form. The solubility of the D(EtOH) form in EtOH at 298 K was determined to be C* = 3.40 × 10−2 mol/L from Figure 4b, which is 1.5 times higher than that of the D(MeOH) form. Furthermore, the results of the DSC measurements (Figure 6) show that the escape temperature of EtOH from crystals is 350 K, which is 20 K lower than that of MeOH. This means that the intermolecular force between BPT and MeOH molecules, where hydrogen bonding may be predominant, is higher than that between BPT and EtOH molecules. The transformation rate from the D(EtOH) form to the BH form in the atmosphere was much higher than that for the D(MeOH) form, indicating that the D(EtOH) form loses ethanol molecules and absorbs water molecules from the atmosphere (BH form) more easily than the D(MeOH) form. This behavior corresponds to the difference in the intermolecular force between BPT and each alcohol. It is also noted that the same two endothermic peaks in the DSC curves shown in Figure 6 for the D(EtOH) form can be seen for the D(MeOH) form. 3.2. The Solid-State Transformation Mechanism of Polymorphs. The DSC curves for the A and C forms are shown in Figure 6. In the DSC curve for the A form, a single endothermic peak due to melting can be observed (the melting point was estimated as 482 K). On the other hand, in the case of the C form, small endothermic and exothermic peaks appear before a large endothermic peak that corresponds to melting. Because the temperature of the large endothermic peak coincides with the melting point of the A form, the small endothermic and exothermic peaks in the case of the C form may be due to meltmediated transformation of the C form to the A form; in other words, the C form initially melts and the A form crystallizes in the melt, and thereafter the A form melts. This indicates that the A form is the stable form at higher temperatures. Furthermore, for both the D(MeOH) and the D(EtOH) forms, the DSC curves similar to that for the C form can be seen at temperatures near the melting point. It is considered that both D forms transform to the same C form by releasing alcohol molecules from the crystals; following this, the C form transforms to the A form. 3.3. Crystallization Behavior for 1-PrOH, 2-PrOH, and MeCN Solvents and the Solvent Effect Mechanism. The concentration change during crystallization in 1-PrOH solutions is shown in Figure 8a. The concentration decreased with time in a single step and attained the same value for each initial concentration. The XRD patterns of the crystals formed were the same as that of the A form (Figure 2a). In the 2-PrOH solutions, a simple decreasing concentration curve was also observed (Figure 8b), and furthermore only the A form preferentially crystallized. In these solvents, the C form is the most stable form.9 However, no transformation of the A form was observed after at least several days in both 1-PrOH and 2PrOH solvents. This indicates that nucleation of the C form is disfavored and that the nucleation rate is very slow in these solvents, whereas the nucleation of the metastable A form is favored. From Figure 8a and 8b, it appears that the solubility of the A form in 1-PrOH (C* = 5.05 × 10−2 mol/L) at 298 K is slightly higher than that in 2-PrOH (C* = 4.50 × 10−2 mol/L). When the crystallization was performed in MeCN, the BPT concentration simply decreased; however, it attained two

Figure 8. (a) Concentration change with time for crystallization in 1PrOH. (b) Concentration change with time for crystallization in 2PrOH. (c) Concentration change with time for crystallization in MeCN.

different concentrations (Figure 8c). In most cases the attained concentration was 8.0 × 10−3 mol/L, and the XRD measurement revealed that the stable C form (XRD pattern shown in Figure 2c) predominantly crystallizes. On the other hand, when the 12817



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Figure 9. (a) FTIR spectra of BPT in MeOH and EtOH solutions. (b) FTIR spectra of BPT in 1-PrOH and 2-PrOH solutions.

attained concentration was higher (1.2 × 10−2 mol/L), the metastable A form crystallized. In this case, the A form transformed to the C form within about 20 h. It can be seen that the crystallization behavior in 1-PrOH, 2PrOH, and MeCN solutions are very different from those in methanol and ethanol solutions, where the D form is obtained.

These behaviors did not depend on the initial supersaturation in the experiments. It is presumed that the solute−solvent intermolecular force is not so strong in the 1-PrOH, 2-PrOH, and MeCN solutions, and the unsolvated polymorphs (the A and C forms) crystallize. In MeOH and EtOH solutions the solute− solvent interaction may be relatively large and the solvated D 12818



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3.5.2. Crystallization from Mixed Solvents of 1-PrOH and Water. When water was added to 1-Pr-OH at Vw of 0.05−0.1, the A form crystallized in the same way as in pure solutions. However, with a further increase in Vw to greater than 0.1, the BH form crystallized predominantly. The crystallization of the hydrated crystal (BH) may be due to the increase of water activity in solutions by the addition of a small amount of water in 1-PrOH solutions.16 The solubility of the A form was measured at temperatures between 298 K and 318 K in the different solvent compositions, and the results are shown in Figure 10a. It can be seen that at each temperature the solubility of the A form initially increases with an increase in Vw; however, with a further increase in Vw to greater than 0.1, the solubility begins to decrease. We speculate that such solubility may reflect the solvated structure surrounding the BPT molecule. At Vw values less than 0.1, BPT

form preferentially crystallizes. On the other hand, the transformation rate from the metastable A form to the C form is higher in MeCN than those in 1-PrOH and 2-PrOH. This corresponds to the polymorphic crystallization behavior in each solvent. Because the transformation rate of the A form via a solution-mediated mechanism1 is controlled by the nucleation and growth rate of the stable C form, the polymorphic crystallization behavior may be largely influenced by the nucleation and growth rate of the stable C form in the solvent. 3.4. Conformation of the BPT Molecule in Different Solvents (FTIR and 1H NMR measurement). In a previous paper,9 it was shown that the absorption of the carbonyl group in the aryl carboxylic acid of BPT at 1680−1750 cm−1 is clearly different among the polymorphs. The peak appears at 1678 cm−1 for crystal A; however, in the case of the C form, it shifts to a higher vibration frequency, namely, 1720 cm−1. On the other hand, peak splitting was observed in the case of BH and D forms. From these spectra it was presumed that the aryl carboxylic acid is a dimer in the case of the A form and a monomer in the case of the C form. Both BH and D forms may include both configurations of a monomer and a dimer. The FTIR spectra of MeOH, EtOH, 1-PrOH, and 2-PrOH solvents and the BPT solutions of each solvent are compared in Figure 9a and 9b. In the case of MeOH, the absorption of the solvent is very strong and discrimination of absorption by BPT is difficult. However, it can be seen that in the case of 1-PrOH and 2-PrOH the single peak of the carbonyl group is observed at about 1683 cm−1, which is near the peak observed in the spectra of the A form. On the other hand, in EtOH solution two peaks at 1687 and 1714 cm−1 can be seen. Similar peaks were observed in the spectra of the D form(MeOH); therefore, BPT molecules in EtOH solution may have a conformation similar to that in MeOH solution. It is also presumed that the solvated crystals (D form) obtained in EtOH and MeOH have a similar structure. These results indicate that the solvent effect may be controlled by the thermodynamic equilibrium properties such as the conformation of the BPT solute in solution and the solute− solvent interactions rather than the crystallization kinetics of the polymorphs.13 It is considered that the BPT conformation and the solute−solvent interaction in 1-PrOH and 2-PrOH accelerate the nucleation and growth rate of the A form; however, in MeCN the nucleation of the C form may be preferred. In MeOH and EtOH, solute−solvent interaction is strong and the nucleation and growth rate of the D form may be accelerated. The 1H NMR spectra were also measured in each deuterated solvent to distinguish the conformation. However, the difference in the chemical shift of the BPT molecules between the solvents could not be detected. 3.5. Effect of Water in Mixed Solvents on Polymorphic Crystallization Behavior. 3.5.1. Crystallization from Mixed Solvents of MeOH and Water. When water was added to the methanol solvents up to a volume fraction (Vw) of 0.3, the concentration simply decreased and the D form(MeOH) preferentially crystallized in a manner similar to that observed for pure MeOH. Near Vw of 0.3, the BH form sometimes appeared with the D form, and it transformed to the D form in several hours, indicating that the D form is the stable form. The solubilities of the D form and the BH form in the MeOH solution (Vw = 0.3) at 298 K were estimated as 1.7 × 10−3 and 2.3 × 10−3 mol/L, respectively. However, with a further increase in Vw, the BH form predominantly crystallized. Previously, we observed similar crystallization and transformation behavior in the antisolvent crystallization of a MeOH−H2O system at 313 K.9,11

Figure 10. (a) Dependence of solubility of the A form on water composition (Vw) in 1-PrOH and water mixtures at each temperature. (b) Dependence of solubility of the C form on water composition (Vw) in MeCN and water mixtures at each temperature. 12819



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solvated with 1-PrOH is more predominant than that with water molecules. However, with an increase in Vw to greater than 0.1, solvation with water may become predominant. Such solute− solvent interaction may be reflected in the nucleation behavior of the A and BH form. 3.5.3. Crystallization from Mixed Solvents of MeCN and Water. In MeCN solutions including water up to Vw of 0.1, the C form crystallized preferentially in the same manner as in pure solutions. However, when the value of Vw increased to greater than 0.1, the BH form selectively crystallized. The solubility of the C form was measured at temperatures between 298 K and 318 K in each solvent composition, and the results are shown in Figure 10b. Behavior similar to that seen in 1-PrOH was observed, that is, the peak solubility appears at almost the same solvent composition (Vw of about 0.1). In MeCN solutions, the solvent−-solute molecular interaction may also be reflected in the nucleation behavior of the C and BH form.

REFERENCES

(1) Kitamura, M. Strategy for control of crystallization of polymorphs. CrystEngComm 2009, 11, 949−964. (2) Beckmann, W. Nucleation Phenomena during the crystallization and precipitation of Abecarnil. J. Cryst. Growth 1999, 198/199, 1307− 1314. (3) Yu, L.; Rutzel-Eens, S. M.; Mitchell, C. A. Crystallization and polymorphs of conformationally flexible molecules. Org. Process Res. Dev. 2000, 4, 396−402. (4) Luisa, M; Leitao, P.; Canoyilho, J.; Ferreira, S.; Sousa, A.; Redinha, S. Effect of solvent and temperature on solution-crystallized terfenadine. Thermochim. Acta 2004, 411, 53−60. (5) Blagden, N.; Davey, R. J.; Lieberman, H. F.; Williams, L.; Payne, R.; Roberts, R.; Rowe, R.; Docherty, R. Crystal chemistry and solvent effects in polymorphic systems sulphathiazole. J. Chem. Soc., Faraday Trans. 1998, 94, 1035−1044. (6) Weissbuch, I.; Torbeev, V.Yu.; Leiserowits, L.; Lahav, M. Solvent effect on crystal polymorphism: Why addition of methanol or ethanol to aqueous solutions induces the precipitation of the least stable β form of glycine. Angew. Chem., Int. Ed. 2005, 44, 3226−3229. (7) Stoica, C.; Verwer, P.; Meekes, H.; van Hoof, P. J. C. M.; Kasperse, F. M.; Vlieg, E. Understanding the effect of a solvent on the crystal habit. Cryst. Growth Des. 2004, 4, 765−768. (8) Vrcelj, R. M.; Gallagher, H. G.; Sherwood, J. N. J. Polymorphism in 2,4,6-trinitrotoluene crystallized form solution. J. Am. Chem. Soc. 2001, 123, 2291−2295. (9) Kitamura, M.; Nakamura, K. Effect of solvent composition and temperature on polymorphism and crystallization behavior of thiazolederivative. J. Cryst. Growth 2002, 236, 676−686. (10) Li, N.; Shanks, R. A.; Murphy, D. M. Solution-mediated transformation of photographic coupler. J. Cryst. Growth 2001, 224, 128−133. (11) Kitamura, M.; Hironaka, S. Effect of temperature on anti-solvent crystallization and transformation behaviors of thiazole-derivative polymorphs. Cryst. Growth Des. 2006, 6, 1214−1218. (12) Kitamura, M.; Hara, T. Dependence of polymorphism on molecular structure of BPT esters. Cryst. Growth Des. 2007, 7, 1575− 1579. (13) Kitamura, M.; Horimoto, K. Role of kinetic process in the solvent effect on crystallization of BPT propyl ester polymorph. J. Cryst. Growth, in press. (14) Ostwald, W. Z. Phys. Chem. (Leipzig) 1899. (15) del Rio Mendez, J. R.; Rousseau, R. W. Batch and tubular-batch crystallization of paracetamol: crystal size distribution and polymorph formation. Cryst. Growth Des. 2006, 6, 1407−1414. (16) Chavez, K. J.; Rousseau, R. W. Solubility and pseudopolymorphic transitions in mixed solvents: Sodium Naproxen in methanol-water and ethanol-water solutions. Cryst. Growth Des. 2010, 10, 3802−3807.

4. CONCLUSIONS

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1. The solvated crystals of the D forms of methanol (D(MeOH)) and ethanol (D(EtOH)) crystallized from methanol (MeOH) and ethanol (EtOH) solutions. Both D forms are stable and have similar crystal structures. The solubility of the D(EtOH) form is 1.5 times higher than that of the D(MeOH) form. 2. With the release of alcohol molecules, the D forms transformed to the C form with an increase in temperature, and the C form transformed to the A form via a meltmediated mechanism. The release temperature of alcohol was higher for D(EtOH) than for D(MeOH). 3. With the crystallization in 1-propanol (1-PrOH) and 2propanol (2-PrOH), the metastable A form preferentially crystallized. On the other hand, in acetonitrile (MeCN) solutions the stable C form was selectively obtained. Such behaviors in each solvent did not depend on supersaturation. 4. The FTIR spectra of BPT in EtOH and 1-PrOH suggested that BPT molecules in solution take a conformation similar to that in each crystal. It was suggested that the solvent effect is controlled by the thermodynamic equilibrium properties such as the conformation of the solute and the solute−solvent interactions rather than the crystallization kinetics of the polymorphs. 5. The rate of the solution-mediated transformation from the A form to the C form is higher in MeCN than those in 1PrOH and 2-PrOH, corresponding to the polymorphic crystallization behavior in each solvent. 6. In the mixed solvents of 1-PrOH and MeCN with water, the same polymorphs crystallized as those obtained in pure solvents in the water volume fraction up to the range of 0.1. However, with further addition of water, the hydrated crystals (BH form) predominantly crystallized. Solubility measurements suggested that such behavior is related to the solvated structure surrounding the BPT molecule.

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Mechanism of Solvent Effect in Polymorphic Crystallization of BPT

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