Control of Crystal Aspect Ratio and Size by Changing Solvent

Nov 10, 2015 - Department of Applied Chemistry and Bioengineering, Graduate School of Engineering, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-...
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Control of Crystal Aspect Ratio and Size by Changing Solvent Composition in Oiling Out Crystallization of an Active Pharmaceutical Ingredient Masahiro Takasuga*,†,‡ and Hiroshi Ooshima‡ †

Chemical Development Laboratories, CMC Center, Takeda Pharmaceutical Company Limited, 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka, 532-8686, Japan ‡ Department of Applied Chemistry and Bioengineering, Graduate School of Engineering, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan ABSTRACT: Oiling out crystallization of an active pharmaceutical ingredient, API-T, was carried out under agitation using a mixed solvent (acetone/water) system, and the effects of oiling out (liquid [oily droplet phase]/liquid [continuous phase] separation) on the aspect ratio and size of crystals were investigated. Acetone composition of the oil phase and API-T distribution to the oil phase increased with a decrease in charged acetone composition, and both decreased in the continuous phase. By utilizing this relationship, API-T crystals with small aspect ratios were produced under a low charged composition of acetone, at which a high recovery of product crystals could be expected. Furthermore, large crystals were obtained in the oiling-out crystallization. Such performance was never achieved in normal single-phase crystallization, and thus an advantage of oiling out crystallization was shown. tends to be avoided. In our previous work, 4 it was demonstrated in an oiling out crystallization that crystal size was controllable by changing the oil droplet size, even when it was hard to control in the normal single-phase crystallization. Namely, the miniaturization of oil droplets by high-speed agitation was shown to induce the suppression of nucleation, resulting in the production of large crystals. Thus, it was a demonstration of an advantage of oiling out crystallization. Crystal shape plays an important role in the efficacy of medicines as well their production. For example, spherical large crystals can be expected to have good filterability and, on the contrary, fine needle crystals will hinder the filtration. The crystal shape may be affected by the kind of solvent and/or solvent composition.5 In oiling out crystallizations, each phase is different in solvent composition and it depends on the initial composition before phase separation.6,7 As crystals appear from each phase, the difference in the solvent composition between the oil and continuous phases will affect the shape of the product crystals. A few papers have been reported with respect to the change of crystal morphology in oiling out crystallization,8,9 but the situation still remains unclear with regard to industrial crystallizations.

1. INTRODUCTION It is crucial to control the crystal size of active pharmaceutical ingredients (APIs) to ensure the efficacy of medicines. There have been many papers published with regard to the control of crystal size in crystallization operations.1 However, few papers have been published regarding oiling out crystallization, which involves liquid−liquid phase separation in a mixture of an organic compound (solute) and a mixed solvent. In oiling out crystallization, liquid−liquid phase separation occurs during the cooling and/or the change of the composition of the mixed solvent. In batch crystallization with agitation, one phase appears as numerous numbers of droplets, and the other phase is a continuous phase that suspends the droplets. The former is called the oil phase, but strictly speaking it is a phase that looks like an oil. The solute concentration and the composition of the mixed solvent in each phase changes from the charged condition, as the solute concentration increases in the oil phase and decreases in the continuous phase. The supersaturation ratios in both phases may also change. The primary nucleation rate becomes slower than that expected from an increase of the solute concentration in the oil phase.2,3 Therefore, it is important in oiling out crystallization to consider the effects of the composition change through the phase separation on the characteristics of crystals, for instance, size and size distribution. An oft-expressed problem in oiling out crystallization is that it brings negative effects, such as adhesion of an oily product to the agitator or inner wall of the crystallizer, and therefore it © XXXX American Chemical Society

Received: August 19, 2015 Revised: November 4, 2015

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DOI: 10.1021/acs.cgd.5b01192 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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Figure 1. Solubility (solid line) and cloud points (dotted line) of API-T in an acetone/water system at 20 °C, (a) charged compositions (cross) and the compositions of the continuous phase (filled circle) after phase separation and (b) the compositions of the oil phase (filled circle). by centrifugation, and then each phase was weighed. The acetone composition of each phase was analyzed by a gas chromatograph, GC2014, Shimadzu Co., Ltd. A decrease in the amount of the oil phase during crystallization was tracked by the weight ratio of oil phase to both phases. 2.5. Characteristics of Crystals. The crystals were observed by a digital microscope, VHX-600, Keyence Corp., after the API-T concentration reached the solubility for the acetone composition. The lengths and breadths of plate-like crystals were measured for more than 600 crystals. The average aspect ratio of crystals was calculated from the length and breadth data for all sampled crystals. To express the size with an equivalent volume diameter, the relationship between a representative thickness and breadth of crystals was determined by using a scanning electron microscope, VE-9800, Keyence Corp., and the volume of a crystal was calculated as a product of length, breadth, and thickness estimated from breadth. The crystal size distribution was determined from the equivalent volume diameter, and the size distribution was deconvoluted in order to discuss the birth-phase of fine crystals and large crystals.

In the present work, an oiling out crystallization was quantitatively investigated, and the effect of the oiling out on the aspect ratio of crystals was revealed.

2. EXPERIMENTAL SECTION 2.1. Materials. A pharmaceutical compound, named API-T in this study, was produced by Takeda Pharmaceutical Co., Ltd. and had a purity of 99.0 wt %. Reagent grade acetone and distilled water were obtained from Wako Pure Chemical Industries. 2.2. Solubility and Cloud Point. The solubility of API-T in an acetone/water mixed solvent was measured at 20 °C using a Chemistation, Tokyo Rikakikai Co., Ltd., with five flasks, a temperature control unit and a magnetic stirrer for each flask. The solubility was measured by dissolving as much as possible an excess amount of API-T. The API-T concentration was analyzed using a high performance liquid chromatograph (HPLC), LC-2010, Shimadzu Co., Ltd. The cloud points, representing liquid/liquid separation points, were determined from the relationship of the API-T concentration vs temperature at a given acetone composition of mixed solvent, using the Chemistation. A given concentration of API-T solution was prepared with a mixed solvent of a given acetone composition, and the solution was gradually cooled until liquid−liquid phase separation was observed. The same experiments were carried out by changing the API-T concentration, and the acetone composition in the range of 0.014−1.05 g/g-solvent and 45−75 wt %, respectively. The cloud point data thus obtained as a function of temperature were rearranged as a function of acetone composition at 20 °C. 2.3. Crystallization Procedure. All experiments were performed using a 100 mL three-necked/semiellipse-bottomed glass crystallizer equipped with a three-retreating-blades agitator and a temperature probe. The crystallizer was immersed in a thermostatic bath. A given amount of API-T was placed in the crystallizer and dissolved with a given amount of acetone at 20 °C. When a given amount of water preadjusted to 20 °C was added to the solution under agitation at 200 rpm, the solution instantaneously oiled out prior to crystallization if it was above the cloud point, which is the phase separation point determined by temperature and the charged solvent composition and solute concentration. Then the crystallization started spontaneously in both phases, as each phase was in a supersaturated condition, to give hemihydrate crystals that were recovered. The crystallization was carried out with an API-T concentration of 0.07 g/g-solvent as the charged concentration and a charged acetone composition in the range of 47.0−51.5 wt %. As a control experiment, single-phase crystallization was conducted at 20 °C by changing the API-T concentration and the acetone composition in the range of 0.01−0.68 g/g-solvent and 45.1−70.8 wt %, respectively. The initial API-T concentration was adjusted to just below the cloud point, considering the relationship between the cloud point and acetone composition of the water/acetone mixed solvent. 2.4. Change of Weight Ratio of Oil/Continuous Phase during Crystallization. A sample solution containing both the oil and continuous phases was withdrawn from the crystallization mixture before nucleation and was separated into the oil and continuous phase

3. RESULTS AND DISCUSSION 3.1. Phase Diagram of Oiling Out Crystallization. Figure 1 shows the solubility and the cloud point of API-T in an acetone/water system. The filled circles in Figure 1a show the continuous phase compositions with respect to API-T and acetone after phase separation, and the filled circles in Figure 1b show the oil phase compositions, all of which completely overlapped the cloud points. The API-T concentration increased for the oil phase and decreased for the continuous phase, compared to the charged composition. 3.2. Concentration Tracking. The API-T concentration in the continuous phase and the weight of oil phase were tracked during the oiling out crystallization (Figure 2). The

Figure 2. Trend of the API-T concentration in the continuous phase (filled circle) and the percentage of oil phase weight to the total weight (open circle) during oiling out crystallization for Run 2. B

DOI: 10.1021/acs.cgd.5b01192 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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crystallization was found to occur in the oil phase first, because the oil phase weight decreased at the initial stage of crystallization when the concentration in the continuous phase was constant for 20 min. If the oil droplet composition reaches the same composition as the continuous phase it will disappear. Thus, the volume (weight) of oil phase was gradually decreased after 20 min elapsed. On the other hand, the concentration in the continuous phase fluctuated during crystallization from 20 to 70 min, which could be explained as follows. Nucleation and crystal growth in the continuous phase occurred and the API-T concentration in the continuous phase decreased. The crystallization in the continuous phase may also be affected by crystals generated in the oil phase. In addition, API-T molecules in the continuous phase will be replenished from the disappeared oil phase. Thus, the fluctuation was attributed to the balance of the rate of crystallization in the continuous phase, and the transfer rate of API-T molecules from the disappeared oil phase to the continuous phase. With regard to the acetone composition, the compositions of the oil and continuous phases both become close to 50 wt %, which is the initial charged composition (Run 2) during the crystallization. As long as the oil phase exists, the concentration in the oil phase should track the cloud point, because phase separation cannot occur in the region under the cloud point. As the acetone composition of the oil phase becomes 50 wt % (Run 2) and the concentration decreases below the cloud point, the oil cannot exist and disappears as shown in Figure 2. Figure 3 shows how the composition of both phases would vary according to the cloud point if the crystallization in the continuous phase did not occur until the oil phase disappeared.

3.3. Comparison of the Aspect Ratio of Crystals obtained by Oiling Out Crystallization and Normal Single-phase Crystallization. Table 1 presents the average aspect ratio of crystals obtained in the oiling out crystallization (Runs 1−5). In Table 1, the results obtained in a normal singlephase crystallization are also tabulated for comparison (Runs 6−9). The average aspect ratio of crystals obtained in the oiling out crystallization increased with an increase in the charged acetone composition. On the other hand, in the single-phase crystallization, it decreased with an increase in the acetone composition. The changes in aspect ratio may often be explained by a change of crystal polymorphs, an effect of initial supersaturation ratio. However, the change of aspect ratio observed in the present study should be attributed to the third effect, that is, a solvent effect on growth of a specific crystal face. The crystals obtained in all experiments were confirmed to be the same crystal form by their XRD patterns. Furthermore, it was hard to explain the aspect ratio change with changes in the supersaturation ratio, because as shown in Table 1 the initial supersaturation ratios were almost the same in all cases. The result of the single-phase crystallization indicates that acetone acts as a reagent to reduce the aspect ratio. A possible mechanism explaining the effect of acetone on the shape change is discussed as follows. Acetone will interact with the face of the long axis direction, and since the API-T molecule has a carboxyl group, it can be assumed that a hydrogen bond will be formed between acetone and the hydroxyl group of APIT. Such hydrogen bonding between API-T molecules and acetone must then inhibit the formation of hydrogen bonds between API-T molecules and water molecules that are required for formation of the hemihydrate crystals of API-T. As a result, the crystal growth to the long axis direction will be suppressed, and this is why the crystal shape depends on acetone composition of the mixed solvent. Accordingly, the aspect ratio shown in Table 1 can be reasonably explained as follows. In Run 1, 81.6% of API-T was distributed into the oil phase, and the acetone composition of the oil phase was 72.9% as shown in Figure 1b. Namely, the small aspect ratio of 1.7 can be explained by the distribution of the large portion of API-T into the oil phase with a high acetone composition. This result can be compared with the small aspect ratio of 1.6 obtained by the single-phase crystallization, Run 9, conducted under 70.8% acetone composition. In Run 5, a significant portion of API-T, 69.7%, was distributed in the continuous phase. The acetone composition of the continuous phase was 50.8%, as shown in Figure 1a, which is close to the acetone composition adopted in

Figure 3. Assumed track of the API-T concentration, supposing the crystallization in the continuous phase did not occur until the oil phase disappeared, (a) in the continuous phase and (b) in the oil phase for Run 2.

Table 1. Aspect Ratio and the Distribution of API-T in Each Phase distribution of API-T (supersaturation ratio) crystallization

entry

oiling out

Run Run Run Run Run Run Run Run Run

single-phase

1 2 3 4 5 6 7 8 9

charged composition of acetone [wt %]

API-T concentration [g/g-solvent]

continuous [wt %]

47.0 50.0 50.5 51.0 51.5 45.1 52.0 60.0 70.8

0.07 0.07 0.07 0.07 0.07 0.01 0.07 0.25 0.68

18.4 (2.2) 36.8 (2.2) 47.3 (2.4) 57.5 (2.5) 69.7 (2.6) (2.2) (3.0) (2.5) (2.2)

C

oil [wt %] 81.6 63.2 52.7 42.5 30.3

(2.3) (2.2) (2.1) (2.2) (2.2)

average aspect ratio [−] 1.7 1.9 2.5 2.8 3.1 3.5 3.3 2.9 1.6

DOI: 10.1021/acs.cgd.5b01192 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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Figure 4. Dependence of aspect ratio on the crystal size obtained by (a) the single-phase crystallization and (b) the oiling out crystallization.

size: 29 μm). Figure 5b presents API-T crystals obtained by a single-phase crystallization (Run 6). The former are clearly larger than the latter. The difference in size was not caused by a difference in the working initial supersaturation ratio, because the supersaturation ratios were the same for the two experiments, as shown in Table 1. The formation of large crystals is an advantage of oiling out crystallization. In our previous work dealing with the oiling out crystallization of APIT,4 the oiling out crystallization was found to be appropriate to produce large crystals. The nucleation rate, that is, the frequency of nucleation, in oiling out crystallization was found to depend on the oil droplet size.4 The smaller the size the oil-droplets are, the lower the frequency of nucleation becomes, which suggests that the number of crystals can be suppressed by making the oil-droplet size smaller. The fine crystals generated in small droplets grow large through collision with small oil droplets remaining without nucleation and the absorption of the API-T in them.4 Since the droplet size depends on agitation speed, the average crystal size in the oiling out crystallization increases with an increase in agitation speed, and the crystals presented in Figure 5a were thus obtained. Meanwhile, the nucleation rate in the single-phase crystallization was faster, and the crystal size was small as represented in panel (b). This result was not affected by agitation in the range from 50 to 200 rpm.4 The partition ratio of API-T between oil and continuous phases, as well as the size of the oil droplets, must affect the size distribution of crystals, because crystals generated in the oil phase grow large. It can be expected that the larger the partition ratio of API-T to the oil phase, the larger the average size of the crystals will become. Figure 6 shows the crystal size distribution for the oiling out crystallization (Runs 1−5) and a single-phase crystallization (Run 7) that was conducted at the same API-T concentration as the oiling out crystallization. The largest crystals were obtained in the oiling out crystallization of Run 1 that was conducted under the largest partition of API-T to the oil phase. The smaller the distribution of API-T to the oil phase became, the size distribution moved to the smaller direction. It was also noteworthy that the crystal size distributions of Runs 3, 4, and 5 were bimodal, and the peak of the fine part was consistent with that of Run 7. This implied that the fine crystals were generated after the number of oil droplets decreased to a level at which crystals in the continuous phase could not grow any more by using API-T supplied from oil droplets, because crystals generated in the continuous phase grow large by absorbing API-T partitioned in the oil phase when a sufficient amount of oil droplets is remained. This is the reason why the crystal size of fine crystals was consistent with that obtained in

the single-phase crystallization of Run 7. This is the reason why a large aspect ratio of 3.1 was obtained in Run 5. Thus, the aspect ratio in oiling out crystallization was found to depend on the acetone composition of the phase in which a large portion of API-T was distributed. Figure 4a presents the crystal-size dependence of the aspect ratio in the single-phase crystallization. The aspect ratio was dependent on the acetone composition of solvent as mentioned above, but independent of the crystal size. In the oiling out crystallization, as shown in Figure 4b, the aspect ratio decreased with an increase in the crystal size. The change of the aspect ratio depending on the crystal size was due to the difference in the phase, namely, the oil phase or the continuous phase, where the crystals grew, as described later. Since the recovery rate of crystals is important in the industrial production of crystalline products, the crystallization is often conducted at a low solubility condition. In the case of API-T, for instance, the crystallization can be conducted in a solvent with a low acetone composition, as adopted in Runs 1 and 6. If a small aspect ratio is desired under the conditions with such a low acetone composition, the oiling out crystallization process is a good choice as shown in Panel (a) of Figure 5. The oiling out crystallization is a favorable operation with respect to the control of aspect ratio.

Figure 5. Micrographs of the crystals obtained from (a) the oiling out crystallization, Run 1 and (b) the single-phase crystallization, Run 6.

One may choose a single-phase crystallization using a solvent with a high acetone composition at the expense of a reduced crystal recovery rate. However, it should be noted that in the oiling out crystallization larger crystals can be obtained, as described later and shown by comparison of Figure 5a,b. 3.4. Crystal Size Distribution. The API-T crystals shown in Figure 5a were obtained by an oiling out crystallization (Run 1) conducted under agitation at 200 rpm (average oil droplet D

DOI: 10.1021/acs.cgd.5b01192 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

continuous phase, compared to the charged concentration, respectively. A small aspect ratio of crystals was obtained by the crystallization under high acetone composition of mixed solvent in a single-phase crystallization. That operation, however, inevitably leads to low recovery of crystals because of the high solubility of the API-T. On the other hand, the oiling out crystallization was found to have a favorable effect on making the aspect ratio smaller. The oiling-out crystallization made it possible to get crystals with a small aspect ratio under a region of low acetone composition of mixed solvent, where a high recovery of crystals could be expected, due to the low solubility of API-T. The crystallization kinetics was found to differ before and after the oil phase disappearance. Crystals grew large by increasing the distribution of the charged API-T into the oil phase, although the crystals grown in the continuous phase were small. In conclusion, large size crystals and a large amount of crystals with small aspect ratios could be obtained by an oiling out crystallization, whereas the same performance could not be achieved in a single-phase crystallization.

Figure 6. Crystal size distribution obtained from oiling out crystallization (Runs 1−5) and from single-phase crystallization (Run 7).

Run 7 of the single-phase crystallization. This effect appeared in the crystal size distributions of Runs 1 and 2, where little fine crystals can be observed, and it is due to the originally small percentage of API-T partitioned in the continuous phase in Runs 1 and 2. In order to simplify the discussion, the amount of crystals generated after the disappearance of oil droplets was estimated from the concentration of API-T remaining at that time, and the result is presented in Figure 7. The percentage of

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AUTHOR INFORMATION

Corresponding Author

*Address: 2-17-85, Jusohonmachi, Yodogawa-ku,Osaka, 5328686, Japan. Phone: +81-3-6300-6437. Fax: +81-3-6300-6154. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to acknowledge Dr. David Cork and Mr. Koji Mukai in Chemical Development Laboratories for their advice and support during preparation of this paper.

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REFERENCES

(1) Yu, Z. Q.; Chew, J. W.; Chow, P. S.; Tan, R. B. H. Trans. IChemE., Part A, Chem. Eng. Res. Des. 2007, 85 (A7), 893−905. (2) Vivares, D.; Bonneté, F. J. Phys. Chem. B 2004, 108, 6498−6507. (3) Galkin, O.; Vekilov, P. G. J. Am. Chem. Soc. 2000, 122, 156−163. (4) Takasuga, M.; Ooshima, H. Cryst. Growth Des. 2014, 14, 6006− 6011. (5) Holmback, X.; Rasmuson, A. C. J. Cryst. Growth 1999, 198/199, 780−788. (6) Lafferrere, L.; Hoff, C.; Veesler, S. J. Cryst. Growth 2004, 269, 550−557. (7) Deneau, E.; Steele, G. Org. Process Res. Dev. 2005, 9, 943−950. (8) Veesler, S.; Revalor, E.; Bottini, O.; Hoff, C. Org. Process Res. Dev. 2006, 10, 841−845. (9) Bonnett, P. E.; Carpenter, K. J.; Dawson, S.; Davey, R. J. Chem. Commun. 2003, 698−699.

Figure 7. Relationship of the percentage of crystals obtained after the oil droplet disappearance and the percentage of the fine part for the bimodal distribution.

each of the finer parts shown in Figure 6 had a good agreement with the estimated amount of crystals generated after the oil disappearance. The result indicates that the fine crystals in Figure 6 are likely to be generated in the continuous phase after the disappearance of the oil phase. Runs 1−5 were conducted by varying the acetone composition of the mixed solvent. Therefore, it can be also concluded that the crystal size distribution can be controlled by varying the composition of the mixed solvent.

4. CONCLUSIONS The oiling out crystallization of a pharmaceutical API in acetone/water mixed solvent was investigated, comparing it with a normal single-phase crystallization. API-T was partitioned into two phases, oil phase and continuous phase, in an oiling out crystallization, and the composition of each phase was positioned on a cloud-point curve. The API-T concentration increased in the oil phase, and decreased in the E

DOI: 10.1021/acs.cgd.5b01192 Cryst. Growth Des. XXXX, XXX, XXX−XXX