Oiling out and Polymorphism Control of Pyraclostrobin in Cooling

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Oiling Out and Polymorphism Control of Pyraclostrobin in Cooling Crystallization Kangli Li, Songgu Wu, Shijie Xu, Shichao Du, Kaifei Zhao, Lanlan Lin, Peng Yang, Bo Yu, Baohong Hou, and Jun-bo Gong Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/acs.iecr.6b03097 • Publication Date (Web): 18 Oct 2016 Downloaded from http://pubs.acs.org on October 18, 2016

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Industrial & Engineering Chemistry Research

Oiling Out and Polymorphism Control of Pyraclostrobin in Cooling Crystallization Kangli Li1, 2, Songgu Wu1, 2, Shijie Xu 1, 2, Shichao Du1, 2, Kaifei Zhao1, 2, Lanlan Lin1, 2, Peng Yang1, 2, Bo Yu1, 2, Baohong Hou1, 2, Junbo Gong1, 2* 1

School of Chemical Engineering and Technology, State Key Laboratory of

Chemical Engineering, Tianjin University, Tianjin300072, PR China; 2

Collaborative Innovation Center of Chemical Science and Engineering (Tianjin),

Tianjin300072, PR China ∗

Email: [email protected], Tel: 86-22-27405754, Fax: +86-022-27374971

ABSTRACT In this study, phase diagrams of form II (metastable form) of pyraclostrobin under different cooling rates were measured with aid of in situ tools like ATR-FTIR, FBRM and PVM. It was found that the initial concentration of pyraclostrobin corresponding to the metastable state critical oiling out point upon cooling decreases with the increase of cooling rate. Meanwhile, the seeding strategy experiments illuminated that seed loading and seed size are important factors to avoid the oiling out and to obtain form IV (stable form) of pyraclostrobin. By optimizing cooling rate and employing seeding strategy, oiling out could be eliminated and products of pure form IV of pyraclostrobin could be obtained. Keywords: pyraclostrobin, oiling out, seeding strategy, polymorphism, cooling crystallization 1. INTRODUCTION

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In cooling and/or anti-solvent processes, two coexisting liquids instead of crystals can be observed first from supersaturated solution. This phenomenon is known as oiling out or liquid–liquid phase separation (LLPS).1, 2 LLPS is well-known in protein area as well as in colloid physics area.3, 4 However, in recent years, it is increasingly interested in industrial crystallization because of its impact on the product properties such as affinity of agglomeration, product purity, crystal size distribution (CSD) and even polymorph.5- 7 According to the Ostwald rule, the new formed metastable/stable liquid phase inhibits the primary or the secondary nucleation, slows down the crystallization rate and then affects product property.8, 9 In most cases, oiling out could increase the difficulty of the optimization of crystallization process and obtain products with poor properties. So, there are some research focused on the oiling out mechanism and the method to control the oiling out. Veesler et al.5 found that oiling out hindered both primary and secondary nucleation for several hours, and the final products obtained were quasi-spherical monodispersed agglomerated particles made up of much small crystals. Lu et al.10, 11 pointed out that oiling out caused an adverse impact on the yield and purity of the product. Åke C. Rasmuson et al.12 illuminated that the CSD of the crystals was wider or more irregular in the crystallization process with oiling out. In view of the adverse impact of the oiling out, D. Duffy et al.13 used a range of in-situ tools to qualitatively describe the oiling out phenomenon as well as optimized liquid– liquid phase separation crystallization through seeding. Kai Kiesow et al.14 successfully predicted the presence or absence of oiling out for the mixture systems


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based on PC-SAFT model. The results illuminated that changing the solvents could avoid oiling out. Other methods such as decreasing initial concentration of solute, designing the profile of crystallization are also effective methods to avoid oiling out. In this paper, we report an oiling out phenomenon of Pyraclostrobin during cooling

crystallization.

Pyraclostrobin

N-[2-[[[1-(4-chlorophenyl)-1H-pyrazol-3-yl]

oxy]

(carbamic methyl]

acid,

phenyl]-N-methoxy-,

methyl ester, C19H18ClN3O4, CAS NO.175013-18-0, Figure 1) is a strobilurin fungicide with a broad spectrum, high efficiency and low toxicity developed by BASF in the 1990s. Pyraclostrobin is classified as a “reduced risk candidate” by the United States Environmental Protection Agency, because of its environmentally friendly and extensive applications.15, 16 Pyraclostrobin molecules are capable of forming several different polymorphs.17 It means that pyraclostrobin would have a prosperous market, however, several problems need to be solved in its preparation. One problem is that oiling out always happens in several solvent mixtures. Another problem is that metastable crystal form instead of stable form is often obtained in the crystallization process with oiling out. Moreover, crystals obtained from the crystallization process with oiling out showed poor properties such as low yield, low purity and high degree of agglomeration. However, the oiling out phenomenon of pyraclostrobin has never been reported in previous studies. It is necessary for us to investigate this phenomenon and find an effective way to avoid oiling out. In this contribution, a range of in-situ tools like ATR-FTIR, FBRM and PVM were used to monitor and analyze the phase separation (LLPS and solid-liquid



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separation) in cooling process. The phase diagram of pyraclostrobin at a cooling rate of 0.1 K/min in isopropanol/cyclohexane solvent mixtures was experimentally measured. Oiling out points at different cooling rate were determined and analyzed to show the effect of cooling rate on oiling out. Seeding strategy was also designed to avoid oiling out and to obtain the desired polymorph. Crystals acquired from experiments were compared and analyzed by the differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and optical microscope. 2. MATERIALS AND METHODS 2.1 Materials Form IV of pyraclostrobin was provided by Shandong Sino-Agri United Biotechnology Co., Ltd. (Jinan, China) and used to prepare form II. Form II of pyraclostrobin was prepared by cooling crystallization in isopropanol/cyclohexane solvent mixtures (mass fraction of isopropanol is 0.10) as follow: adding 5 g form IV of pyraclostrobin into 100 g solvent mixtures and heating up the slurry to 313.15 K, then allowed 30 min at this temperature to make solute dissolve completely. After that the solution was cooled to 278.15 K under the cooling rate of 0.1 K/min. The mass fraction purity of pyraclostrobin is higher than 0.99 determined HPLC (Agilent 1100, Agilent Technologies, USA). Isopropanol and cyclohexane are analytical grade with mass fraction purity higher than 0.995 and were purchased from Tianjin Kewei Chemical Co., Ltd. of China. The above-mentioned reagents were used without further purification. The detailed information of the above-mentioned materials is listed in Table 1.


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2.2 Characterization of form II and form IV of pyraclostrobin Form IV of pyraclostrobin is the stable polymorph, and form II is the metastable polymorph. It is necessary to determine the crystal polymorph in the process of the experiment. Thus, form IV and form II of pyraclostrobin were characterized by the powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). PXRD was used to identify the polymorphic purity for two forms of pyraclostrobin. The experiment was measured on Rigaku D/max-2500 (Rigaku, Japan) using Cu-Kα radiation (1.5405 Å) over the 2-theta range from 2° to 50° with the scanning rate of 8°min-1. The patterns of two forms of pyraclostrobin were shown in Figure 2. In view of the difference of the melting temperature of different polymorphs, the melting temperature Tm of the two forms of pyraclostrobin were obtained by DSC (1/500, Mettler-Toledo, Switzerland) under a nitrogen atmosphere. Approximately 5 mg was put into a standard DSC aluminum pan and heated from 298.15 K to 358.15 K at the rate of 2 K/min. Each sample was measured three times and the result was given in Figure 3. The data of melting temperature (the onset temperature) is consistent with previous literature.17 2.3 Measurement and Monitoring of Phase Separation. Solubility of form II of pyraclostrobin. The solubility of form II of pyraclostrobin in 10 % by weight isopropanol (on solute-free basis) in isopropanol/cyclohexane solvent mixtures from 278.15 K to 308.15 K was measured by a synthetic method.18 The experiments were carried out in a 50 mL jacketed



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crystallizer. A thermostat baths (CF41, Julabo) was used to control the experimental temperature, and the equilibrium temperature was determined by PT100 with an accuracy of ± 0.01 K that was inserted into the inner chamber of the crystallizer. The solubility of solute was measured by a laser monitoring system which was the same as that described in the literature.19 The measurement principle is based on the relationship between the penetrating intensity of the laser beam and the solute dissolved in the solvent. The intensity of the laser beam penetrating the crystallizer reaches the maximum when the solution is clear, and the value decreases once the solute suspends in the solution. During the experiments, predetermined amounts (20 g) of the solvent were placed in the crystallizer and kept at equilibrium temperature. Continuous agitation was achieved by a magnetic stir bar. A predetermined mass of solid solute was added to the crystallizer step by step as far as the penetrating intensity of the laser beam reaches the maximum. The mass of solute added was no more than 0.001 g, once the solution under determination was close to its equilibrium state. This process was repeated until the intensity of the laser beam penetrating the vessel could not return to the maximum value and remained constant for about two hours. The total amount of solute consumed was recorded. And each measuring point was repeated three times. The mass of the solute and solvents was weighed by an analytical balance (Mettler Toledo AB204-N, Switzerland) with a standard uncertainty of 0.0001 g during the experiment. Liquid−liquid phase separation curves. A predetermined mass of solution which initial pyraclostrobin concentration was increased from 5 g/100g solvent, 6.25g/100g solvent, 7.5g/100g solvent to 55 g/100g solvent at 2.5 g/100g solvent intervals was placed in the crystallizer with jacket and heated up to a temperature


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which was 5 K higher than its saturation temperature. After maintaining this temperature for 30 min, the solution was cooled down at a rate of 0.1 K/min with magnetic stirring (300 rpm) until 278.15 K to make sure the supersolubility point can be obtained. FBRM, ATR-FTIR and PVM were used to measure the liquid−liquid phase separation curves during the experiment. The FBRM (model G400, Mettler Toledo) was used to characterise particle dimension by the chord length distribution (CLD) data. The measurement duration was set at 10 s. ATR-FTIR (ReactIR 45m, Mettler-Toledo) spectra were collected from 648 to 2800 cm-1, and the measurement duration was set at 1min. LLPS and crystallization can be measured by the change of the total counts shown by the FBRM and the intensity of the IR peak. In addition, PVM (model V819, Mettler-Toledo) was used to take images of the formation of the oil out and the crystallization. The steady state critical oiling-out point upon heating20 at given solvent composition was also measured. According to the result of the preliminary experiment, excess solid form II of pyraclostrobin was added in the crystallizer and the suspending solutions was heated slowly at a rate of 0.1 K/min from 298.15 K until oiling-out occurred. The critical temperature of oiling-out is the temperature at which oiling out happened. What’s more, in order to understand the influence of cooling rate on the cooling crystallization process, the supersolubility points without oiling out and cloud points under cooling rates of 0.5 K/min and 1 K/min were measured by the method used above. The initial pyraclostrobin concentration was increased from 5 g/100g solvent



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to 55 g/100g solvent at 2.5 g/100g solvent intervals. And each measuring point was repeated three times. 2.4 Seeding strategy to control oiling out and the polymorph The cooling rate has a significant influence on oiling out during cooling crystallization, but at high initial concentration, the cooling rate has no effect on controlling oiling out. So, a series of experiments were carried out to study the effect of seeding on the cooling crystallization process. The purpose of seeding is not only to avoid oiling out in cooling process but also to obtain crystals of form IV directly. A solution of pyraclostrobin at the initial concentration of 20g/100g solvent was held at the isolation temperature of 323.15 K for 30 min to make sure that the pyraclostrobin had completely dissolved. The solution was kept under agitation 300 rpm. Different sieve fraction of the pure form IV of pyraclostrobin including 200-300 µm, 100-125 µm, < 97 µm were used as seed. Different seed loadings were investigated: 7 %, 5 % and 3% of the solids loaded in the saturated solution. Linear cooling rate of 0.1 K/min and 0.5 K/min was applied for seeded crystallization. Dry seed crystals of the form IV were added just at the moment when the temperature reached 306.15 K (a temperature between the cloud point curve and the solubility curve). Then, the solution was continued cooled down to 283.15 K and held for 30 min before filtering. Crystal products were filtered and collected for further characterization by using PXRD and DSC. 3. RESULTS AND DISCUSSION 3.1 In-situ analysis of oiling out formation


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In order to further understand the phenomenon of oiling out of pyraclostrobin in the cooling process, the ATR-FTIR, FBRM and PVM were used to monitor the cooling process. In this study, it is necessary to select a proper IR peak height which presents a reflection of absorbed energy which corresponds to the vibration and rotation of chemical bonds.21 IR spectra of solvent and solution in Figure 4 indicated that pyraclostrobin showed a distinct IR fingerprint, and the peak at 1550 cm-1 (N-H) could be chosen to record changes of the composition and oiling out formation. An agitated solution of the pyraclostrobin (concentration is 50 g pyraclostrobin / 100g solvent) in isopropanol/cyclohexane solvent mixtures was cooling linearly from 323.15 K to 298.15 K at a rate of 0.1 K/min. During the cooling down process, as is shown in Figure 5, the intensity of the IR peak and total counts/s shown by the FBRM in pyraclostrobin solution maintained nearly constant until the temperature was cooled down to 312.9 K, then a sharp increase in the peak height with a corresponding increase in the total counts/s. The increase of IR curve can be explained by the redistribution of pyraclostrobin in the oil phase and the continuous phase once LLPS was occurred. The increase in the total counts/s can be further verified with the PVM image shown in Figure 6a. Upon further cooling after oiling out, the curve of the total counts/s showed a tendency that increased firstly, then decreased subsequently. This tendency can be explained by the fact that as the temperature decreased, small oil droplets would coalesce to big oil droplets. Figure 6b showed this coalescence. After constant temperature, the curve of FBRM had an extremely sharp decrease. Meanwhile, the intensity of the IR peak had a sudden



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increase and then a very sharp decrease. With the aid of PVM (Figure 6c), we can conclude that the changes in these data are due to the nucleation of pyraclostrobin. This sharp decrease of total counts/s is combined action of nucleation and the settlement of oil layer. In crystallization process, the composition in the oil phase and that in the continuous phase tends to be similar, and when the composition in the oil phase reaches the same composition as the continuous phase the oiling phase will disappear. Therefore, the fluctuation of the IR curve may be ascribed to the balance of the nucleation and the transfer of composition from the oil phase to the continuous phase.22 Finally, the intensity of IR peak was gradually constant with the constant temperature. Figure 6d is a good example to illustrate the agglomeration of pyraclostrobin. In conclusion, the phase separation of pyraclostrobin solution in cooling process includes three main phenomena: (a) LLPS; (b) coalescence of oil droplets; (c) nucleation and crystal growth. 3.2 Investigation of Phase Diagram The solubility of form II of pyraclostrobin in 10 % by weight isopropanol (on solute-free basis) in isopropanol/cyclohexane solvent mixtures was showed in Figure 7. The solubility of form II of pyraclostrobin increased with the increase of temperature. In order to further understand the crystallization process of pyraclostrobin, the phase diagram of pyraclostrobin in 10 wt % isopropanol/cyclohexane mixing solvents was measured experimentally and presented in Figure 8. The phase diagram includes


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the solubility curve of form II of pyraclostrobin, the cloud point curve, the oiling out curve and two supersolubility curves. During the cooling process, FBRM was used to determine the cloud point and the spontaneous nucleation point at a cooling rate of 0.1 K/min. There are two curves about spontaneous nucleation points, which represent different phenomena of spontaneous nucleation, mainly affected by the concentration. Below 12.5 g/100g solvent, there was no LLPS before the spontaneous nucleation, which meant that the solvent experienced a normal single-phase crystallization. This curve was represented by the olive-green triangles. On the other hand, when the concentration was higher than 12.5 g/100g solvent, the solution will undergo LLPS before spontaneous nucleation occurs in the cooling process. This form of crystallization experienced at concentrations higher than 12.5 g/100g solvent was known as oiling-out crystallization.22 This curve was represented by the blue rhombuses. The dividing point A at about (295.15 K, 12.5 g/100 g solvent) was defined as the metastable state critical oiling out point upon cooling. According to the determination method of the critical temperature of oiling out upon heating,23 the critical temperature of oiling out during heating in the given isopropanol/cyclohexane solvent mixtures was 311.65 K (Point B). The oiling out curve was also determined on the basis of the definition of the critical temperature of oiling out upon heating. 3.3 Effect of cooling profiles on the oiling out Considering the influence of cooling rate on oiling out, cloud point curves under different cooling rates were measured, and the results were showed in Figure 9. The cooling rate contributed to the metastable state critical oiling out point upon cooling.



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The concentration that related to the oiling out point decreased with the increasing cooling rate. In other words, the cooling rate had a striking influence on the crystallization process under lower concentrations of pyraclostrobin. 3.4 Seeding strategy to control oiling out and the polymorph By analyzing the phase diagrams we built in this work, we can draw a conclusion that cooling rate can inhibit oiling out at relatively low concentrations, but at high concentrations like 20 g/100 g solvent, it is no longer work without other effect. Moreover, the metastable polymorphism, form II was always obtained firstly whether oiling out occurs or not in the cooling crystallization. Taking into account the important role of seeding in the crystallization process23, a series of experiments were performed to avoid oiling out and control the polymorph outcome. All the results are shown in Table 2, Figure 10, Figure 11 and Figure 12. According to the phase graph we built, a point of seeding at 306.15 K was chosen at which the solution was supersaturated but without oiling out. The results of the addition of seed of form IV indicated that the seed size, mass of seed and cooling rate had influence on oiling out and polymorph. Supersaturation has been known as an extremely important element for oiling out and crystallization. The presence of an available surface of seeds can reduce the supersaturation due to the growth of seeds added.21, 24 As is shown in Table 2, Figure 10 and Figure 11, experiments of 1, 2 and 3 were good examples to show the influence of mass of seeds of form IV (mseed/msolute % ) on oiling out and polymorph. The more mass of seed with same seed size we added, the bigger available surface area can be obtained, hence, the oiling out in cooling crystallization


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may be eliminated and primary and secondary nucleation could also be suppressed, If enough quantity of seeds was added to the saturated solution such as experiment 3, crystals of form IV could be obtained in the cooling process without oiling out. Similarly, compared to experiments of 3, 4 and 5, we can draw a conclusion that seed size is a factor of controlling oiling out and polymorph. In addition, as results of experiments 3, 6 and Figure12 showed, slow cooling rate could be an essential condition to control oiling out and polymorph. Moreover, Figure12 indicated that oiling out has shown a significant effect on affinity of agglomeration. 4. CONCLUSION In this contribution, the LLPS of pyraclostrobin was investigated in isopropanol/cyclohexane mixing solvents system during cooling crystallization. Based on the data obtained from in situ tools, this cooling crystallization process can be divided into three phenomena: (a) LLPS; (b) coalescence of oil droplets; (c) nucleation and crystal growth. As is shown in the phase diagram of pyraclostrobin at a cooling rate of 0.1 K/min, a normal single-phase crystallization would change to an oiling-out crystallization once the concentration of pyraclostrobin exceeded a certain value. Contrasting with cloud point curves of different cooling rates, it is obvious that the cooling rate has a significant effect on the metastable state critical oiling out point upon cooling. The concentration corresponded to the metastable state critical oiling out point upon cooling decreases with the increase of the cooling rate. The results of the seeding of form IV indicated that decreasing the seeds size,



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increasing mass of seeds and slowing down the cooling rate in the cooling process would eliminate oiling out and obtain stable polymorph of pyraclostrobin. Furthermore, slow cooling could restrain the degree of agglormeration of the product. So, high quality final crystal products can be obtained by designing a seeding strategy and a route of cooling crystallization according to the phase diagram.


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ACKNOWLEDGEMENTS The authors are grateful to the financial support of National Natural Science Foundation of China (NNSFC 21176173 and NNSFC 21376164) and Major National Scientific Instrument Development Project 21527812.



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cooling crystallization. Org. Process Res. Dev. 2011, 15, 681-687.



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Figure captions: Figure 1. Chemical structure of pyraclostrobin Figure 2. X-ray power diffraction patterns of pyraclostrobin Figure 3. DSC curves of pyraclostrobin of different forms Figure 4. IR spectra taken at 298.15 K to identify the absorption fingerprint of the pyraclostrobin Figure 5. Change of ATR-FTIR and FBRM data with temperature at the initial concentration of 50 g pyraclostrobin /100 g solvent Figure 6. PVM images of pyraclostrobin in the cooling process corresponding to the process of Figure 5 (a - oiling out at 10000s, b - coalescence of oil droplets at 13000s, c - nucleation of pyraclostrobin at 17500s, d - agglomeration of pyraclostrobin at 21180s) Figure 7. The solubility of pyraclostrobin of form II as function of temperature in 10wt% isopropanol/cyclohexane solvent mixture Figure 8. Phase diagram of pyraclostrobin of form II under cooling rate of 0.1 K/min in 10wt% isopropanol/cyclohexane solvent mixture (point A - the metastable state critical oiling out point upon cooling; point B - the critical temperature of oiling out upon heating) Figure 9. Phase diagrams of pyraclostrobin of form II under cooling rate of 0.5 K/min (a) and 1 K/min (b) in 10 wt% isopropanol/cyclohexane solvent mixture: ▲ supersolubility without oiling out; ■ solubility; ● cloud point; ◆ the metastable state critical oiling out point upon cooling


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Figure 10. X-ray power diffraction patterns of pyraclostrobin product obtained from different seeding experiments corresponding to Table 2 ((1) - Run 1, (2) - Run 2, (3) Run 3, (4) - Run 4, (5) - Run 5, (6) - Run 6 ) Figure 11. DSC curves of pyraclostrobin product obtained from different seeding experiments corresponding to Table 2 ((1) - Run 1, (2) - Run 2, (3) - Run 3, (4) - Run 4, (5) - Run 5, (6) - Run 6 ) Figure 12. Microscope images of pyraclostrobin product obtained from different seeding experiments ((1) - product of Run 1, (2) - product of Run 2, (3) - product of Run 3, (4) - product of Run 4)



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Figures:

Figure 1. Chemical structure of pyraclostrobin


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Figure 2. X-ray power diffraction patterns of pyraclostrobin



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Figure 3. DSC curves of pyraclostrobin of different forms


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Figure 4. IR spectra taken at 298.15 K to identify the absorption fingerprint of the pyraclostrobin



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Figure 5. Change of ATR-FTIR and FBRM data with temperature at the initial concentration of 50 g pyraclostrobin /100 g solvent


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Figure 6. PVM images of pyraclostrobin in the cooling process corresponding to the process of Figure 5 (a - oiling out at 10000s, b - coalescence of oil droplets at 13000s, c - nucleation of pyraclostrobin at 17500s, d - agglomeration of pyraclostrobin at 21180s)



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Figure 7. The solubility of pyraclostrobin of form II as function of temperature in 10wt% isopropanol/cyclohexane solvent mixture


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Figure 8. Phase diagram of pyraclostrobin of form II under cooling rate of 0.1 K/min in 10wt% isopropanol/cyclohexane solvent mixture (point A - the metastable state critical oiling out point upon cooling; point B - the critical temperature of oiling out upon heating)



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Figure 9. Phase diagrams of pyraclostrobin of form II under cooling rate of 0.5 K/min (a) and 1 K/min (b) in 10 wt% isopropanol/cyclohexane solvent mixture: ▲ supersolubility without oiling out; ■ solubility; ● cloud point; ◆ the metastable state critical oiling out point upon cooling


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Figure 10. X-ray power diffraction patterns of pyraclostrobin product obtained from different seeding experiments corresponding to Table 2 ((1) - Run 1, (2) - Run 2, (3) Run 3, (4) - Run 4, (5) - Run 5, (6) - Run 6 )



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Figure 11. DSC curves of pyraclostrobin product obtained from different seeding experiments corresponding to Table 2 ((1) - Run 1, (2) - Run 2, (3) - Run 3, (4) - Run 4, (5) - Run 5, (6) - Run 6 )


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Figure 12. Microscope images of pyraclostrobin product obtained from different seeding experiments ((1) - product of Run 1, (2) - product of Run 2, (3) - product of Run 3, (4) - product of Run 4)



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Tables Table 1. Sources and purity of the materials Analysis Chemical name

Source

Mass Purity Method

Form IV of

Shandong Sino-Agri United ≥0.990

HPLCa

Lab made

≥0.990

HPLCa

Isopropanol

Tianjin Kewei Chemical Co., Ltd

≥0.995

GCb

Cyclohexane

Tianjin Kewei Chemical Co., Ltd

≥0.995

GCb

pyraclostrobin

Biotechnology Co., Ltd.

Form II of pyraclostrobin

a

High performance liquid chromatography did by our lab. bGas chromatography did by the

supplier.


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Table 2 Comparison of powder properties obtained from the three experiments Cooling rate

Seed size

Mass of

(K/min)

(µm)

seed (wt %)

Results

Entry Oiling out

Polymorph Mixed form

Run 1

0.1

< 97

3

Much of II and IV Mixed form

Run 2

0.1

< 97

5

Less of II and IV

Run 3

0.1

< 97

7

None

Form IV Mixed form

Run 4

0.1

200-300

7


Run 5

0.1

100-125

7


Run 6

0.5

< 97

7

Much of II and IV



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For Table of Contents Only

The graphic shows the cooling crystallization processes with oiling out of pyraclostrobin. The black line represents the change of temperature. The cooling process is a linear cooling process. The red line and the blue line are the IR peak height and total counts showed by FBRM. As cooling down, oiling out appeared and followed by the coalescence of oil droplets. Finally, nucleation and growth of pyraclostrobin occurred.


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Oiling out and Polymorphism Control of Pyraclostrobin in Cooling

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