Secondary Nucleation Behavior and the Mechanism in Antisolvent

Jan 28, 2016 - ... distinguish the secondary nucleation and primary nucleation over a short time. However, after crystallization, the amount of A form...
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Secondary Nucleation Behavior and the Mechanism in Antisolvent Crystallization of Thiazole Derivative Polymorphs Mitsutaka Kitamura*,†,‡ and Yasuharu Hayashi† †

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

‡

ABSTRACT: Antisolvent crystallization of a thiazole derivative, 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (BPT), was performed, and the secondary nucleation behavior and the mechanism were examined. At 313 K, the D form crystallized almost exclusively even though the A form was seeded at an initial concentration (C0) of 0.040 mol/L. The shortening of the induction period by seeding indicates that secondary nucleation occurs and that the mechanism is not microattrition. We propose that cluster A is formed in the adsorption layer on the crystal surface of seeds, and under these conditions the conformation of molecules in the adsorption layer easily converts to the more stable D form (cluster D). Cluster D will be liberated from the adsorption layer to produce the nuclei of the D form. On the other hand, at 0.024 mol/L (313 K), the amount of polymorph A increased with addition time (Ts) and amount of seeds (Sw), and the pure crystals of A form could be obtained at large Ts and Sw. The effect of Sw arises from the increase in the active surface area of the seeds. As for the difference in secondary nucleation behavior at different C0, we propose that it is caused by the difference in thickness of the adsorption layer, which increases with solute concentration, and in the conversion rate. In a thin layer (0.024 mol/L), the interaction between molecules in the adsorption layer and the crystal surface may be strong and the molecular conformation may be the same as for the A form (cluster A). This causes the secondary nucleation of the A form. However, as the solute concentration increases (0.040 mol/L), the thickness of the adsorption layer increases and the interaction between the molecules and the crystal surface weakens. Therefore, the molecular conformation in the adsorption layer or cluster near the bulk solution may be similar to the D form. Consequently, the conversion rate to D form may be large, resulting in the production of cluster D and nuclei D. The effect of Ts is consistent with this mechanism. This effect may arise from water addition decreasing the solute concentration and the decrease in the adsorption layer thickness with Ts. This may increase the production of cluster A and nuclei A. At 333 K and high C0 and W, it was difficult to distinguish the secondary nucleation and primary nucleation over a short time. However, after crystallization, the amount of A form and the solution-mediated transformation rate from BH to A form increased with Sw, indicating that seeding increased the amount of A form.

1. INTRODUCTION Polymorphic crystal seeds are frequently used to control selective crystallization of polymorphs in the pharmaceutical industry.1 Polymorphic seeding is expected for secondary nucleation of a desired polymorph. Various mechanisms have been reported for secondary nucleation in ordinary crystallization without polymorphs.2 Many studies have examined the nucleation mechanism of nuclei arising from seed crystals through contact with vessel walls, agitators, and solid objects (contact nucleation).3−5 The breakage of dendritic crystals by fluid shear was also examined as the origin of secondary nuclei.6 Denk and Botsaris7 showed that the secondary nucleation of sodium chlorate does not occur via a single mechanism, but that different secondary nucleation mechanisms can occur because of changes in the ordering of solute molecules in the liquid layer surrounding the crystal. Among these secondary nucleation mechanisms, contact nucleation is the best understood, especially in agitated crystallizers.3−5 Cui and Myerson8 recently examined whether contact secondary nuclei originate from parent crystals via the mechanism of microattrition or from semiordered solute clusters at the interface of parent crystals by using a steel rod and a single crystal of γ-glycine. They concluded that the mechanism of secondary nucleation changed with the magnitude of the contact force. © 2016 American Chemical Society

The mechanism of secondary nucleation in polymorphic crystallization has not been well investigated. The secondary nucleation behavior of polymorphs has been reported mainly for cooling crystallization. For example, Beckmann9 reported a method of adding polymorphic seeds during cooling crystallization in relation to the metastable zone width. Al-Zoubi and Malmataris10 reported the effects of initial concentration and the seeding procedure on the polymorphic crystallization of paracetamol. Tao et al.11 reported the cross-nucleation of Dmannitol polymorphs in seeded crystallization. These papers showed that the concomitant or cross nucleation of the polymorphs is caused by the epitaxial growth of a different polymorph on the seed. Ni and Liao12 reported the effect of polymorphic seeding with other effects, such as mixing, on the nucleation behavior of L-glutamic acid polymorphs. Previously, we reported that adding a polymorphic seed crystal can cause the secondary nucleation of a different polymorph. For example, in the crystallization of a nickel complex clathrate13 (cocrystal), the form different from the Received: Revised: Accepted: Published: 1413

October 9, 2015 December 24, 2015 December 28, 2015 January 28, 2016 DOI: 10.1021/acs.iecr.5b03730 Ind. Eng. Chem. Res. 2016, 55, 1413−1418

Article

Industrial & Engineering Chemistry Research

water volumetric fraction of 0.3−0.5, polymorph C was the stable form; however, polymorph C hardly crystallized and the other forms (A, BH, D) appeared. In this work, the antisolvent crystallization was carried out by using the same method, and the effect of seeding of A form on the polymorphic crystallization was examined. The seeds (A form) should be added under conditions where the primary nucleation of polymorph A does not occur. Previously it was observed16 that at 313 K, D form is the most stable among A, BH, and D forms and preferentially crystallized at large range of initial concentration (C0) and addition rate of antisolvent (W) (Table1). At 333 K, A form is the most stable, and with high

seed polymorph crystallized depending on the guest molecule (2-methylnaphthalene) concentrations. We also reported that in L-histidine crystallization,14 the same proportion in a mixture of the stable A form and metastable B form was nucleated by seeding with either form. In these cases, the induction time of the nucleation was shortened by seeding. This may mean that the secondary nucleation is not caused by the microattrition of the seed crystals. We proposed that the exchange of molecular conformations in clusters causes the nucleation of a form different from that of the seed crystals.1 Previously, the antisolvent crystallization of 2-(3-cyano-4isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (BPT) (Figure 1) was performed by adding water to a methanol

Table 1. Stable Form and Primary Nucleation Form16

Figure 1. BPT molecule.

solution.15,16 The addition rate of the antisolvent, initial concentration, and temperature were found to be the key factors controlling polymorphism.1 In this work, we examine the effects of the amount, addition time of the seed crystals, and other operational factors on secondary nucleation in the antisolvent crystallization of BPT. We also investigate the mechanism of the secondary nucleation of the polymorphs.

temperature [K]

C0 [mol/L]

W [mL/min]

stable form

primary nucleation form

313 313 333 333 333 333

0.024 0.040 0.055 0.055 0.079 0.079

0.25−0.70 0.25−0.70 W > 1.4 W < 1.0 W > 1.4 W < 1.0

D D A A A A

D D + (BH) BH A BH A

initial concentration and higher addition rate (W > 1.4 mL/ min) BH form crystallized; however, with decrease of addition rate (W < 1.0 mL/min), A form preferentially crystallized16 (Table 1). Therefore, in this work the experiments were carried out at 313 K (C0 = 0.024, 0.040 mol/L; W = 0.28, 0.47 mL/ min) and at 333 K with high addition rate (C0 = 0.055 mol/L, 0.079 mol/L; W = 2.8 mL/min). Before the experiments with the addition of seeds, the induction period of primary nucleation (nucleation without seeds) was measured by observing the appearance of fine crystals during the crystallization. As the factors affecting the secondary nucleation, the initial concentration, C0; addition rate of the antisolvent, W; addition time of the seeds, Ts; and amount of seeds, Sw (2−40 mg), were examined. The crystals were filtered after the crystallization, and the polymorph compositions were analyzed by XRD.

2. EXPERIMENTAL SECTION BPT (Figure 1) has five forms: three polymorphs (A, B, and C); a hydrated crystal (BH) form; and a solvated crystal with methanol (D). The typical X-ray diffraction (XRD) pattern of each polymorph is shown in Figure 2. Previously, the antisolvent crystallization of BPT was carried out by adding water (14.2 mL) dropwise to the surface of methanol−water solutions of BPT (40 mL).15,16 The water volumetric fraction increased from 0.05 to 0.3 during the crystallization. The stirring rate with glass paddle impeller was kept constant (130 rpm) throughout the crystallization. At temperatures between 303 and 333 K and

Figure 2. XRD patterns of each form (A, BH, C, and D). 1414

DOI: 10.1021/acs.iecr.5b03730 Ind. Eng. Chem. Res. 2016, 55, 1413−1418

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Industrial & Engineering Chemistry Research

3. RESULTS 3.1. Induction Time of Primary Nucleation. It was shown previously15 that in the antisolvent crystallization, primary nucleation occurs in a diffusion layer around the water droplet with addition of antisolvent because the super saturation is higher than that in bulk solution. To examine the effect of seeding on the secondary nucleation during antisolvent crystallization, the seeds must be added before primary nucleation occurs. Therefore, the induction time of the primary nucleation was measured at 313 and 333 K without seeds. Figure 3 shows the relationship between the induction time of

Figure 4. Dependence of polymorph crystallization behavior on Ts and Sw at 313 K (C0 = 0.040 mol/L, W = 0.28 mL/s).

Figure 3. Relationship between the induction time, τp, and the addition rate of water, W, at 313 K.

the primary nucleation after the start of water addition (τp) and the addition rate of water (W = 0.25−0.70 mL/s) at the initial concentrations (C0) of 0.024 and 0.040 mol/L (313 K). The value of τp decreases with W and C0. Based on these results, the polymorph A seeds were added before the primary nucleation occurred (Ts < τp) with various seed addition times (Ts) and amounts of seeds (Sw). At 333 K, experiments were performed at high initial concentrations (0.055 and 0.079 mol/L) with a high W of 0.28 mL/s. The primary nucleation of the BH form happened16 at the end of water addition. Therefore, in the experiments at 333 K, the seeds were added 2 min before the end of water addition. 3.2. Effect of Seeding on Polymorphic Nucleation at 313 K. Previously,16 it was observed that in the antisolvent crystallization at 313 K with C0 of 0.024 and 0.040 mol/L without seeds, the stable solvated D form preferentially crystallized at W between 0.25 and 0.70 mL/s (Table1). However, at low C0 (0.024 mol/L), sometimes the BH form appeared with the D form, and the BH form transformed to the D form.16 The induction time (τp) of the primary nucleation under these conditions is shown in Figure 3. In this work, when the seeds of polymorph A were added under the same conditions, the nucleation happened instantly just after seeding. This shortening of the induction period indicates that the secondary nucleation happened through seeding. However, at 0.040 mol/L, mainly D form was crystallized by seeding, and only a small amount of A form was included. In Figures 4 and 5 the crystallization behaviors at W of 0.28 and 0.47 mL/s (C0 = 0.04 mol/L) are shown on the map with the coordinates of Ts and Sw, respectively. Each point represents the results of several runs. At 0.28 mL/s (Figure 4), the contamination of polymorph A in D form crystals was observed at Sw > 40 mg and Ts > 20

Figure 5. Dependence of polymorphic crystallization behavior on Ts and Sw at 313 K (C0 = 0.040 mol/L, W = 0.47 mL/s).

min. At 0.47 mL/s (Figure 5), a similar trend was observed, and the contamination of D form with polymorph A occurred at Sw > 20 mg and Ts > 14 min.These results indicate that at 0.04 mol/L D form preferentially nucleates and A form is included only at high Sw and Ts. In Figures 6 and 7, the effect of the seeds on the crystallization behavior at C0 of 0.024 mol/L and W of 0.28 and 0.47 mL/min is shown. It can be seen in Figure 6 that a much larger amount of A form crystallized than that at 0.04 moL/L (Figure 4). Furthermore, pure A form could be obtained, for Ts > 40 min and Sw > 10 mg. These are critical values for obtaining pure polymorph A. As Ts and Sw decreased, the amount of A form (effect of seeding) decreased and the contamination with BH or D forms increased. A similar trend was observed at W of 0.47 mL/s (Figure 7); with increase of Ts and Sw, the contamination of D form decreased, and pure A form was obtained when Ts > 25 min and Sw > 25 mg. These results show that increasing Ts and Sw accelerate the secondary nucleation of A form. Furthermore, it was found from Figures 4−7 that the effect of the seeding is clearly larger for lower C0. 3.3. Effect of Seeding on Polymorphic Nucleation at 333 K. At 333 K, A form is more stable than D and BH forms, 1415

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Figure 6. Dependence of polymorphic crystallization behavior on Ts and Sw at 313 K (C0 = 0.024 mol/L, W = 0.28 mL/s).

Figure 8. Effect of Sw on the transformation from the BH to A form at 333 K after the crystallization (C0 = 0.055 mol/L).

Figure 7. Dependence of polymorphic crystallization behavior on Ts and Sw at 313 K (C0 = 0.024 mol/L, W = 0.47 mL/s).

and it was observed16 that when the antisolvent crystallization was performed at high initial concentration without seeds, the A form crystallized at W lower than 1.0 mL/s (Table1). However, BH preferentially crystallized when W increased. Consequently, to examine the effect of seeding, the crystallization was carried out at high C0 of 0.055 and 0.079 mol/L and a high W of 2.8 mL/s. Under these conditions, the primary nucleation occurred near the end of water addition. Therefore, the seeds were added 2 min before the end of water addition. The discrimination between the secondary nucleation and primary nucleation was difficult over a short time; however, the nucleation seemed to happen soon after the addition of the seeds. The composition of crystals obtained just after the end of the crystallization appeared to be almost BH form, including a small amount of polymorph A. However, after the crystallization, the BH form crystals transformed to A form. Figures 8 and 9 show the changes in the polymorph A composition in crystals (XA/BH) due to the transformation with time for C0 of 0.055 and 0.079 mol/L. In these Figures, 0 min shows the end of the crystallization. It can be seen that the amount of A form and the transformation rate from BH to A form increase with amount of the seeds, Sw.

Figure 9. Effect of Sw on the transformation from the BH to A form at 333 K after the crystallization (C0 = 0.079 mol/L).

of the induction period by seeding indicates that the nucleation was caused by the secondary nucleation and that the nucleation mechanism was not microattrition. On the other hand, an adsorption layer may be present around growing crystals in a supersaturated solution.2,17 We considered that adding seeds produces semiordered A form molecules (cluster A) in the adsorption layer of solute on the crystal surface of seeds. However, under the conditions, the conformation of molecules in the adsorption layer may be easily converted to the stable D form (cluster D) (Figure 10). Then, cluster D is liberated from the adsorption layer, producing the secondary nuclei D. At 0.024 mol/L (313K) the induction period was also shortened, however, the amount of polymorph A increased with Ts and Sw, and the pure A form crystals were obtained at large Ts and Sw. These results were reproduced by many experimental runs. The effect of Sw may have been caused by the increase in the active surface area of the seeds, which accelerated the secondary nucleation. However, the difference in secondary nucleation behavior at different C0 is difficult to explain. We propose that the different effect due to different C0 is caused by the difference in thickness of the adsorption layer and in the conversion rate. The thickness of the adsorption layer is thought to increase with the solute concentration. In the

4. DISCUSSION At C0 of 0.040 mol/L (313 K), the D form crystallized almost exclusively, even though the A form was seeded. The decrease 1416

DOI: 10.1021/acs.iecr.5b03730 Ind. Eng. Chem. Res. 2016, 55, 1413−1418

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the pure crystals of A form could be obtained at large Ts and Sw. The effect of Sw is due to the increase in the active surface area of the seeds. The difference in thickness of the adsorption layer and conversion rate were proposed as the cause for the difference of the secondary nucleation behaviors between the initial concentrations (C0). In thin adsorption layer (0.024 mol/L), the interaction between molecules in the adsorption layer and the crystal surface may be strong and the molecular conformation will be the same as A form (cluster A). Then, the secondary nucleation of A is induced. However, with increase of solute concentration (0.040 mol/L), the thickness of adsorption layer increases and the molecular conformation in the adsorption layer (multilayer) or cluster near to bulk solution may become similar to D form. Under this condition, the conversion of molecular conformation to D form may be easy, resulting in the production of cluster D and nuclei D. The effect of Ts may also arise from the decrease of the solute concentration by water addition and the decrease of the adsorption layer thickness with Ts. This may increase the production of cluster A and nuclei A. At 333 K with very high C0 and W, the discrimination between the secondary nucleation and primary nucleation was difficult in the narrow time. However, after the crystallization, the amount of A form and the solution-mediated transformation rate from BH to A form were observed to increase with Sw. This fact indicates that the amount of A form was increased by seeding. These results will provide insight into the polymorphic control by seeding in other systems.

Figure 10. Secondary nucleation mechanism.

thin adsorption layer (0.024 mol/L), the interaction between molecules in the adsorption layer and the crystal surface may be strong, and the molecular conformation in the adsorption layer or cluster may be the same as the A form (cluster A). This causes the secondary nucleation of A form (Figure 10). However, as the solute concentration increases (0.040 mol/L), the thickness of the adsorption layer increases (multilayer), and the interaction of the molecules in adsorption layer with crystal surface weakens. Thus, the molecular conformation in the adsorption layer or cluster near bulk solution may be similar to the D form. Therefore, the conversion of the molecular conformation to D form may be easy, resulting in the production of cluster and nuclei D. The results for the effect of Ts appear to support this assumption. This effect may arise from water addition decreasing the solute concentration and the decrease of the adsorption layer thickness with Ts. These factors may increase the production of cluster A, and the nucleation of A may be accelerated. At 333 K and high C0 and W, distinguishing the secondary nucleation and primary nucleation was difficult over a short time, and the effect of seeding with A form crystals was small. However, the amount of A form and the solution-mediated transformation rate from the BH to A form increased with the amount of seeds, Sw. This indicates that the amount of A form crystallized by seeding increased with Sw.

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AUTHOR INFORMATION

Corresponding Author

*Tel/Fax: +81 89 907 0468. E-mail: [email protected]. ne.jp. Notes

The authors declare no competing financial interest.

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REFERENCES

(1) Kitamura, M. Strategy for control of crystallization of polymorphs. CrystEngComm 2009, 11, 949−964. (2) Mullin, J. W. Crystallization; Butterworth Heinemann: Oxford, 1993. (3) Garside, J. Industrial crystallization from solution. Chem. Eng. Sci. 1985, 40, 3−26. (4) Strickland-Constable, R. F. Kinetics and Mechanism of Crystallization; Academic Press: London, 1968. (5) Wissing, R.; Elwenspoek, M.; Degens, B. In situ observation of secondary nucleation. J. Cryst. Growth 1986, 79, 614−619. (6) Garabedian, H.; Strickland-Constable, R. F. Collision Breeding of crystal Nuclei: Sodium Chlorate.I. J. Cryst. Growth 1972, 13-14, 506− 509. (7) Denk, E. G., Jr.; Botsaris, G. D. Fundamental studies in Secondary Nucleation from solution. J. Cryst. Growth 1972, 13-14, 493−499. (8) Cui, Y.; Myerson, A. S. Experimental Evaluation of Contact Secondary Nucleation Mechanisms. Cryst. Growth Des. 2014, 14, 5152−5157. (9) Beckmann, W. Seeding the desired polymorph: background, possibilities, limitations, and case studies. Org. Process Res. Dev. 2000, 4, 372−383. (10) Al-Zoubi, N.; Malamataris, S. Effects of initial concentration and seeding procedure on crystallisation of orthorhombic paracetamol from ethanolic solution. Int. J. Pharm. 2003, 260, 123−135.

5. CONCLUSIONS At 313 K almost only the D form crystallized despite seeding of A form at 0.040 mol/L of C0. The clear shortening of the induction period by seeding indicates that the secondary nucleation occurs and the mechanism is not due to microattrition. It was supposed that the cluster A is formed in the adsorption layer on the crystal surface of seeds, and under this condition the conformation of molecules in the adsorption layer easily converts to more stable D form (cluster D). The cluster D will be liberated from the adsorption layer to produce the nuclei of D form. On the other hand, at 0.024 mol/L (313 K), the amount of polymorph A increased with Ts and Sw, and 1417

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Industrial & Engineering Chemistry Research (11) Tao, J.; Jones, K. J.; Yu, L. Cross-nucleation between Dmannitol polymorphs in seeded crystallization. Cryst. Growth Des. 2007, 7, 2410−2414. (12) Ni, X.; Liao, A. Effects of mixing, seeding, material of baffles and final temperature on solution crystallization of L-glutamic acid in an oscillatory baffled crystallizer. Chem. Eng. J. 2010, 156, 226. (13) Kitamura, M.; Tanaka, T. Crystallization behavior of polymorphous Ni-complex clathrate in the presence of 2-methylnaphthalene. J. Cryst. Growth 1994, 142, 165−170. (14) Kitamura, M. Crystallization behavior and transformation kinetics of L-histidine polymorphs. J. Chem. Eng. Jpn. 1993, 26, 303−307. (15) Kitamura, M.; Sugimoto, M. Anti-solvent crystallization and transformation of thiazole-derivative polymorphs-I: effect of addition rate and initial concentrations. J. Cryst. Growth 2003, 257, 177. (16) 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. (17) Bilgram, J. H.; Steininger, R. Light scattering in crystal growth. J. Cryst. Growth 1990, 99, 30−37.

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DOI: 10.1021/acs.iecr.5b03730 Ind. Eng. Chem. Res. 2016, 55, 1413−1418