A crystal of tebuconazole and a continuous crystallization method and application thereof

Abstract

The present application provides a kind of tebuconazole crystal and its continuous crystallization method and application, comprising: (1) under the condition of stirring, tebuconazole mother liquor with temperature of 65-75 ℃ is added into crystallization kettle, is cooled to 60-65 ℃, tebuconazole crystal seed is added, and is cooled to 50-60 ℃ to grow crystal, and then crystal slurry enters secondary crystallization kettle;(2) after entering secondary crystallization kettle, under the condition of stirring, it is cooled to 40-50 ℃, and grows crystal, and then crystal slurry enters tertiary crystallization kettle;(3) after entering tertiary crystallization kettle, under the condition of stirring, it is cooled to 20-30 ℃, and grows crystal, to obtain the tebuconazole crystal;According to the method obtained tebuconazole crystal, particle size distribution is narrow, the main particle size of product after process improvement can reach 400 μm, D50 is 300-360 μm, D90 is 650-680 μm, has good anti-caking performance, and process is simple, can realize industrialization.

Description

Technical Field

[0001] This invention belongs to the field of chemical engineering industrial crystallization technology, specifically relating to a tebuconazole crystal, its continuous crystallization method, and its application. Background Technology

[0002] Tebuconazole (CAS: 107534-96-3), chemically named 4,4-dimethyl-3-(1H-1,2,4-triazol-1-ylmethyl)-1-(4-chlorophenyl)-3-pentanol, has the molecular formula C1. 16 H 22 ClN3O is a highly effective, broad-spectrum, systemic triazole fungicide with protective, curative, and eradicative functions. It boasts a broad fungicidal spectrum and long-lasting effect. Used worldwide as a seed treatment and foliar spray, it offers a wide-spectrum fungicidal activity and long-lasting effect. Tebuconazole is primarily used to control various fungal diseases on crops such as wheat, rice, peanuts, vegetables, bananas, apples, pears, and corn and sorghum. It is registered and widely used on over 60 crops in more than 50 countries globally. When used to control sclerotinia stem rot in rapeseed, it not only provides good control but also exhibits lodging resistance and significant yield-increasing effects. Its mechanism of action against the pathogen involves inhibiting the demethylation of ergosterol on the cell membrane, preventing the pathogen from forming a cell membrane and thus killing it.

[0003] Traditional tebuconazole crystallization processes produce rod-shaped crystals with a particle size between 20 and 30 μm, which is generally too small. This results in severe crystal agglomeration and poor anti-caking properties. CN102659696A describes a method to improve the particle size of tebuconazole crystals through cooling crystallization, thereby enhancing its anti-caking properties. The tebuconazole crystals obtained using this method have a D90 of 280-300 μm. However, both the particle size and anti-caking properties of the tebuconazole crystals obtained by this method require further improvement.

[0004] Therefore, it is essential to find a crystallization method that can further increase the particle size of tebuconazole crystals, reduce crystal aggregation, and improve its anti-caking ability. Summary of the Invention

[0005] The purpose of this invention is to overcome the problems of small particle size, poor anti-caking properties, and severe agglomeration of existing tebuconazole products, and to provide a method that improves the particle size resistance of tebuconazole, makes the resulting product less prone to agglomeration, has strong anti-caking properties, requires less seed crystals in the process, and is conducive to scale-up.

[0006] A continuous crystallization method for tebuconazole crystals, the continuous crystallization method comprising the following steps:

[0007] (1) Under stirring conditions, the tebuconazole mother liquor at a temperature of 65-75℃ is added to the primary crystallization vessel, cooled to 60-65℃, tebuconazole seed crystals are added, and the temperature is lowered to 50-60℃ to grow crystals. Then the crystal slurry enters the secondary crystallization vessel.

[0008] (2) After the crystal slurry enters the secondary crystallization kettle, it is cooled to 40-50°C under stirring conditions to grow crystals, and then the crystal slurry enters the tertiary crystallization kettle;

[0009] (3) After the crystal slurry enters the three-stage crystallization kettle, it is cooled to 20-30°C under stirring conditions to grow crystals and obtain the tebuconazole crystals.

[0010] Preferably, the solute of the tebuconazole mother liquor in step (1) is tebuconazole, and the solution is cyclohexane;

[0011] The concentration of the solute in the tebuconazole mother liquor in step (1) is 8–20 wt%.

[0012] Preferably, the particle size of the tebuconazole seed crystals in step (1) is 500-1300 mesh;

[0013] The amount of tebuconazole seed crystals added in step (1) is 1-8 wt% of the tebuconazole crystals.

[0014] Preferably, the stirring rate in step (1) is 150–300 r / min;

[0015] The tebuconazole mother liquor in step (1) is added to the primary crystallization vessel by dropping at a rate of 1-8 ml / min.

[0016] The cooling rate for step (1) to reduce the temperature to 50-60℃ is 5-15℃ / h;

[0017] The crystal growth time in step (1) is 0.5 to 2 hours.

[0018] Preferably, the rate at which the crystal slurry enters the secondary crystallization vessel in step (2) is 1–8 ml / min;

[0019] The stirring rate in step (2) is 150–300 r / min;

[0020] The cooling rate for step (2) to cool to 40-50°C is 5-15°C / h;

[0021] The crystal growth time in step (2) is 0.5 to 2.5 hours.

[0022] Preferably, the rate at which the crystal slurry enters the three-stage crystallization vessel in step (3) is 1–8 ml / min;

[0023] The stirring rate in step (3) is 150–300 r / min;

[0024] The cooling rate for step (3) to cool down to 20-30°C is 5-15°C / h;

[0025] The crystal growth time in step (3) is 0.5 to 2.5 hours.

[0026] Preferably, step (3) further includes solid-liquid separation and drying of the mixture obtained after crystal growth;

[0027] The solid-liquid separation method is filtration;

[0028] The drying temperature is 50 degrees Celsius, the drying time is 24 hours, and the drying is carried out under normal pressure.

[0029] A tebuconazole crystal, which is a tebuconazole crystal prepared according to a continuous crystallization method for a tebuconazole crystal.

[0030] Preferably, the main particle size of the tebuconazole crystal product reaches 400 μm, the D50 is 300-360 μm, and the D90 is 650-680 μm.

[0031] An application of tebuconazole crystals, specifically the application of tebuconazole crystals in the preparation of pesticides.

[0032] Technical features and beneficial effects of the present invention:

[0033] 1. This invention uses a cooling crystallization technique to prepare tebuconazole crystals, which does not require multiple reheating processes, making the process simple and low-cost, and the resulting product has a particle size much larger than that obtained by traditional processes;

[0034] 2. This invention employs continuous crystallization, enabling continuous crystallization operations, which is easy to implement in engineering. At the same time, adjusting the addition of seed crystals and the stirring rate can control the range of crystal particle size distribution, achieving precise control over the particle size distribution of the product.

[0035] 3. Based on the molecular thermodynamics and crystal growth kinetics parameters of tebuconazole, this invention designs different cooling rates in different temperature ranges. In the higher temperature range (above 50°C), nucleation of tebuconazole is significantly inhibited, while growth is enhanced. At a reasonable cooling rate, adding a trace amount of seed crystals can suppress secondary nucleation. Below 50°C, although nucleation is enhanced, the system is more prone to nucleation under the same supersaturation. However, the seed crystals added in the early stage have already grown significantly, and more crystal faces can absorb the supersaturation consumption. Therefore, the cooling rate can be gradually accelerated. By reasonably designing the cooling curve, the wide particle size distribution caused by secondary nucleation can be significantly suppressed.

[0036] 4. After crystallization according to the preparation method of the present invention, the obtained tebuconazole crystals have a narrow particle size distribution. The main particle size of the product after process improvement can reach about 400 μm, D50 is 300-360 μm, and D90 is between 650-680 μm, which has good anti-caking properties. Attached Figure Description

[0037] Figure 1 Optical microscope image of tebuconazole crystalloid in Experiment Example 1;

[0038] Figure 2 Optical microscope image of tebuconazole crystal using traditional techniques;

[0039] Figure 3 Crystallographic image of tebuconazole from Experiment Example 2;

[0040] Figure 4 Optical microscope image of tebuconazole crystalloid in Experiment Example 3;

[0041] Figure 5 Optical microscope image of tebuconazole crystalloid in Experiment Example 4;

[0042] Figure 6 Optical microscope image of tebuconazole crystal in Experiment Example 5;

[0043] Figure 7 Compare with the optical microscope image of tebuconazole crystalloid in Example 1;

[0044] Figure 8 Compare with the optical microscope image of tebuconazole crystalloid in Example 2;

[0045] Figure 9 Compare with the optical microscope image of tebuconazole crystalloid in Example 3;

[0046] Figure 10 XRD patterns of tebuconazole crystals from Experiment 1 and products from the original traditional process. Detailed implementation method:

[0047] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

[0048] Example 1:

[0049] One objective of this invention is to provide a continuous crystallization method for tebuconazole crystals, the continuous crystallization method comprising the following steps:

[0050] (1) Under stirring conditions, the tebuconazole mother liquor at a temperature of 65-75℃ (e.g., 65℃, 66℃, 67℃, 68℃, 69℃, 70℃, 71℃, 72℃, 73℃, 74℃, 75℃, etc.) is added to the primary crystallization kettle, cooled to 60-65℃ (e.g., 60℃, 61℃, 62℃, 63℃, 64℃, 65℃, etc.), tebuconazole seed crystals are added, and the temperature is lowered to 50-60℃ (e.g., 50℃, 51℃, 52℃, 53℃, 54℃, 55℃, 56℃, 57℃, 58℃, 59℃, 60℃, etc.) to grow crystals, and then the crystal slurry enters the secondary crystallization kettle;

[0051] Preferably, the solute of the tebuconazole mother liquor in step (1) is tebuconazole, and the solution is cyclohexane;

[0052] Preferably, the concentration of the solute in the tebuconazole mother liquor in step (1) is 8-20 wt% (e.g., 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, etc.), and more preferably 11.5-17.5 wt%.

[0053] The particle size of the tebuconazole seed crystals in step (1) is 500-1300 mesh (e.g., 500 mesh, 600 mesh, 700 mesh, 800 mesh, 900 mesh, 1000 mesh, 1100 mesh, 1200 mesh, 1300 mesh, etc.);

[0054] Preferably, the amount of tebuconazole seed crystals added in step (1) is 1 to 8 wt% of the tebuconazole crystals (e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, etc.), and more preferably 2.5 to 5 wt%.

[0055] The stirring rate in step (1) is 150-300 r / min (e.g., 150 r / min, 170 r / min, 190 r / min, 210 r / min, 230 r / min, 250 r / min, 270 r / min, 300 rpm, etc.);

[0056] Preferably, the tebuconazole mother liquor in step (1) is added to the primary crystallization vessel by dropping, and the dropping rate is 1 to 8 ml / min (e.g., 1 ml / min, 2 ml / min, 3 ml / min, 4 ml / min, 5 ml / min, 6 ml / min, 7 ml / min, 8 ml / min, etc.).

[0057] Preferably, the cooling rate of step (1) to 50-60°C is 5-15°C / h (e.g., 5°C / h, 6°C / h, 7°C / h, 8°C / h, 9°C / h, 10°C / h, 11°C / h, 12°C / h, 13°C / h, 14°C / h, 15°C / h, etc.);

[0058] Preferably, the crystal growth time in step (1) is 0.5 to 2 hours (e.g., 0.5 hours, 0.75 hours, 1 hour, 1.25 hours, 1.5 hours, 1.75 hours, 2 hours, etc.), and more preferably 0.5 to 1.5 hours.

[0059] (2) After the crystal slurry enters the secondary crystallization kettle, it is cooled to 40-50℃ (e.g., 40℃, 41℃, 42℃, 43℃, 44℃, 45℃, 46℃, 47℃, 48℃, 49℃, 50℃, etc.) under stirring conditions to grow crystals, and then the crystal slurry enters the tertiary crystallization kettle.

[0060] Preferably, the rate at which the crystal slurry enters the secondary crystallization vessel in step (2) is 1 to 8 ml / min (e.g., 1 ml / min, 2 ml / min, 3 ml / min, 4 ml / min, 5 ml / min, 6 ml / min, 7 ml / min, 8 ml / min, etc.);

[0061] Preferably, the stirring rate in step (2) is 150-300 r / min (e.g., 150 r / min, 170 r / min, 190 r / min, 210 r / min, 230 r / min, 250 r / min, 270 r / min, 300 rpm, etc.);

[0062] Preferably, the cooling rate in step (2) to 40-50°C is 5-15°C / h;

[0063] Preferably, the crystal growth time in step (2) is 0.5 to 2.5 hours (e.g., 0.5 hours, 0.75 hours, 1 hour, 1.25 hours, 1.5 hours, 1.75 hours, 2 hours, 2.5 hours, etc.), with 0.5 to 2 hours being the most preferred.

[0064] (3) After the crystal slurry enters the three-stage crystallization kettle, it is cooled to 20-30℃ (e.g., 20℃, 21℃, 22℃, 23℃, 24℃, 25℃, 26℃, 27℃, 28℃, 29℃, 30℃, etc.) under stirring conditions to grow crystals and obtain the tebuconazole crystals.

[0065] Preferably, the rate at which the crystal slurry enters the three-stage crystallization vessel in step (3) is 1 to 8 ml / min (e.g., 1 ml / min, 2 ml / min, 3 ml / min, 4 ml / min, 5 ml / min, 6 ml / min, 7 ml / min, 8 ml / min, etc.);

[0066] Preferably, the stirring rate in step (3) is 150-300 r / min (e.g., 150 r / min, 170 r / min, 190 r / min, 210 r / min, 230 r / min, 250 r / min, 270 r / min, 300 rpm, etc.);

[0067] Preferably, the cooling rate of step (3) to 20-30°C is 5-15°C / h (e.g., 5°C / h, 6°C / h, 7°C / h, 8°C / h, 9°C / h, 10°C / h, 11°C / h, 12°C / h, 13°C / h, 14°C / h, 15°C / h, etc.);

[0068] Preferably, the crystal growth time in step (3) is 0.5 to 2.5 hours (e.g., 0.5 hours, 0.75 hours, 1 hour, 1.25 hours, 1.5 hours, 1.75 hours, 2 hours, 2.5 hours, etc.), with 0.5 to 2 hours being the most preferred.

[0069] Preferably, step (3) further includes solid-liquid separation and drying of the mixture obtained after crystal growth;

[0070] Preferably, the solid-liquid separation method is filtration;

[0071] Preferably, the drying temperature is 50 degrees Celsius, the drying time is 24 hours, and the drying is carried out under normal pressure.

[0072] The second objective of this invention is to provide a method for preparing tebuconazole crystals according to the above-mentioned continuous crystallization method for tebuconazole crystals.

[0073] Preferably, the main particle size of the tebuconazole crystal product reaches 400 μm, the D50 is 300-360 μm, and the D90 is 650-680 μm.

[0074] A third objective of this invention is to provide an application of the tebuconazole crystals in the preparation of pesticides.

[0075] In this invention, solution crystallization is an effective method for obtaining the target crystal form, crystal habit, particle size, and particle size distribution. Solubility data and thermodynamic properties of tebuconazole are essential for controlling its crystal form, crystal habit, and particle size distribution. Solid-liquid equilibrium data are also fundamental data for the industrial design and scale-up of continuous crystallization.

[0076] The solubility data of tebuconazole were determined as follows:

[0077] Temperature (°C) Concentration (g / 100g solution) Crystallization amount (g / 100g solvent) 25 0.60 0.61 30 0.99 1.00 35 1.32 1.33 40 1.58 1.61 45 2.30 2.35 50 3.37 3.49 55 5.53 5.85 60 8.44 9.22 65 13.50 15.61 70 19.91 24.86

[0078] A solution containing more solute than saturates in its metastable region is called a supersaturated solution. The limiting solubility of the solute in a supersaturated solution that is poised to spontaneously form crystal nuclei is called its supersolubility. The region between the solubility curve and the supersolubility curve is the metastable region of the solute. In a given solution system, the solubility curve remains constant, while the supersolubility curve varies with conditions, its position depending on factors such as the cooling rate, stirring intensity, and the presence of impurities.

[0079] The metastable region width refers to the distance between the supersolubility and solubility of a solute, usually expressed as limiting supersaturation or limiting supercooling. A wider metastable region indicates a more stable supersaturated solution and a lower likelihood of crystallization. However, a wider metastable region can also lead to severe burst nucleation. When the solution is in the metastable region, adding seed crystals or slowly cooling to promote primary nucleation can yield crystals with good morphology and uniform particle size. Therefore, measuring the metastable region of a crystalline substance is of great significance for crystallization operations. During crystallization, it is generally desirable to control the crystallization process within the metastable region to promote crystal growth, inhibit secondary nucleation, reduce the formation of fine particles, and obtain a product with large and uniform particle size.

[0080] The metastable region data, as determined, are as follows:

[0081]

[0082] By measuring these fundamental data, we can see that the solubility of tebuconazole in cyclohexane is significantly affected by temperature, especially in the high-temperature region where its solubility increases rapidly with increasing temperature. As the temperature decreases, the effect of temperature on the solubility of tebuconazole gradually diminishes, primarily manifested in its lower solubility at low temperatures. Therefore, controlling tebuconazole crystallization in the high-temperature region is crucial. Furthermore, by measuring the nucleation metastable region of tebuconazole, the temperature difference between the saturation temperature and crystallization temperature at different concentrations is between 12 and 18°C, indicating that the metastable region is stable and relatively wide at different temperatures. Therefore, by adding seed crystals and controlling the cooling rate, the crystallization process can be controlled within the nucleation metastable region, inhibiting nucleation and promoting growth to obtain a product with large and uniform particle size.

[0083] Experimental Example 1:

[0084] (1) Add 13.5% tebuconazole mother liquor at 70℃ to the crystallization vessel at a time of 4 ml / min, cool to 65℃, add seed crystals with a particle size of 450 mesh at 2.5% of the product mass, and grow crystals for 0.5 hours. Cool the crystallization vessel at a rate of 10℃ / h to 60℃, with a rotation speed of 250 r / min.

[0085] (2) Add the crystal slurry from step (1) to the secondary crystallization vessel at a rate of 4 ml / min. Cool the secondary crystallization vessel to 50°C at a rate of 10°C / h. After crystallization for 1 hour, add the slurry to the tertiary crystallization vessel at a rate of 4 ml / min.

[0086] (3) The three-stage reactor is cooled to 25°C at a cooling rate of 10°C / h, and crystallization is carried out for 1 hour at a rotation speed of 250r / min to finally obtain a crystalline mixture.

[0087] (4) The crystalline mixture obtained in step (3) is filtered to obtain a solid, which is then washed and dried to obtain tebuconazole crystals.

[0088] The particle size distribution of the tebuconazole crystals obtained in this experiment was tested (using a Malvern MS3000 laser particle size analyzer), and the D90 of the obtained tebuconazole crystals was found to be 653 μm.

[0089] See the image of the product's stereoscopic optical microscope. Figure 1 The original traditional craft product image (see image) Figure 2 As can be seen, the aggregation of crystal products has slowed down significantly.

[0090] Experimental Example 2:

[0091] The only difference from Experimental Example 1 is that the mass fraction of the tebuconazole mother liquor is 17.5%, the added seed crystals are about 800 mesh and their mass is 5% of the product mass, and the rest of the preparation methods are the same as those in Experimental Example 1.

[0092] The tebuconazole crystals obtained in this experiment were tested using the same method as in Experiment 1, and it was found that the D90 of the obtained tebuconazole crystals was 658 μm.

[0093] See the image of the product's stereoscopic optical microscope. Figure 3 The aggregation of crystal products has been significantly reduced.

[0094] Experimental Example 3:

[0095] (1) Add 20% tebuconazole mother liquor at 75℃ to the crystallization vessel at a time of 8 ml / min, cool to 63℃, add seed crystals with a particle size of 1300 mesh at 8% of the product mass, and grow crystals for 0.5 hours. Cool the crystallization vessel at a rate of 15℃ / h to 55℃, with a rotation speed of 300 r / min.

[0096] (2) Add the crystal slurry from step (1) to the secondary crystallization vessel at a rate of 8 ml / min. Cool the secondary crystallization vessel to 45°C at a rate of 15°C / h. After growing the crystals for 2.5 hours, add the slurry to the tertiary crystallization vessel at a rate of 8 ml / min.

[0097] (3) The three-stage reactor is cooled to 30°C at a cooling rate of 15°C / h, and crystallization is carried out for 2.5 hours at a rotation speed of 300r / min to finally obtain a crystalline mixture.

[0098] (4) The crystalline mixture obtained in step (3) is filtered to obtain a solid, which is then washed and dried to obtain tebuconazole crystals.

[0099] The particle size distribution of the tebuconazole crystals obtained in this experiment was tested (using a Malvern MS3000 laser particle size analyzer), and the D90 of the obtained tebuconazole crystals was found to be 651 μm.

[0100] See the image of the product's stereoscopic optical microscope. Figure 4 The aggregation of crystal products has been significantly reduced.

[0101] Experiment Example 4:

[0102] (1) Add 8% tebuconazole mother liquor at 65℃ to the crystallization vessel at a time of 2ml / min, cool to 60℃, add seed crystals of 1% of the product mass and 800 mesh size, and grow crystals for 1 hour. Cool the crystallization vessel at a rate of 5℃ / h to 50℃, with a rotation speed of 150r / min.

[0103] (2) Add the crystal slurry from step (1) to the secondary crystallization vessel at a rate of 2 ml / min. Cool the secondary crystallization vessel to 40°C at a rate of 5°C / h. After crystallization for 1 hour, add the slurry to the tertiary crystallization vessel at a rate of 2 ml / min.

[0104] (3) The three-stage reactor is cooled to 20°C at a cooling rate of 5°C / h, and crystallization is carried out for 1 hour at a rotation speed of 150r / min to finally obtain a crystalline mixture.

[0105] (4) The crystalline mixture obtained in step (3) is filtered to obtain a solid, which is then washed and dried to obtain tebuconazole crystals.

[0106] The particle size distribution of the tebuconazole crystals obtained in this experiment was tested (using a Malvern MS3000 laser particle size analyzer), and the D90 of the obtained tebuconazole crystals was found to be 660 μm.

[0107] See the image of the product's stereoscopic optical microscope. Figure 5 The aggregation of crystal products has been significantly reduced.

[0108] Experimental Example 5:

[0109] (1) Add 11.5% tebuconazole mother liquor at 70℃ to the crystallization vessel at a time of 5 ml / min, cool to 63℃, add seed crystals with a particle size of 800 mesh at 5% of the product mass, and grow crystals for 1.5 hours. Cool the crystallization vessel at a rate of 10℃ / h to 60℃, with a rotation speed of 250 r / min.

[0110] (2) Add the crystal slurry from step (1) to the secondary crystallization vessel at a rate of 5 ml / min. Cool the secondary crystallization vessel to 50°C at a rate of 10°C / h. After 2 hours of crystal growth, add the slurry to the tertiary crystallization vessel at a rate of 5 ml / min.

[0111] (3) The three-stage reactor is cooled to 30°C at a cooling rate of 10°C / h, and crystallization is carried out for 2 hours at a rotation speed of 250r / min to finally obtain a crystalline mixture.

[0112] (4) The crystalline mixture obtained in step (3) is filtered to obtain a solid, which is then washed and dried to obtain tebuconazole crystals.

[0113] The particle size distribution of the tebuconazole crystals obtained in this experiment was tested (using a Malvern MS3000 laser particle size analyzer), and the D90 of the obtained tebuconazole crystals was found to be 677 μm.

[0114] See the image of the product's stereoscopic optical microscope. Figure 6 The aggregation of crystal products has been significantly reduced.

[0115] Refer to Comparative Example 1:

[0116] See CN102659696A.

[0117] The ammonium persulfate crystals obtained in this comparative example were tested using the same method as in Experimental Example 1, and the D90 of the obtained tebuconazole crystals was 291 μm.

[0118] Under a pressure of 10300 Pa and a water content of 1%, samples from Experimental Example 1 and Comparative Example 1 were placed in an agglomeration mold for 3 days to obtain two identical cylindrical agglomeration samples, A and B, with a diameter of 3.6 cm and a height of 2 cm. The agglomeration samples were then dropped freely from the same height, and the degree of breakage was compared, i.e., the agglomeration strength was tested. The test results are as follows:

[0119] experiment sample Free fall height Breakage rate 1 Experimental Example 1: Agglomerated Sample A 1m 100％ 2 Experimental Example 1: Agglomerated Sample B 2m 100％ 3 Refer to Comparative Example 1, agglomerated sample A 1m 30％ 4 Refer to Comparative Example 1, agglomerated sample B 2m 45％

[0120] Table 1 shows that, comparing experiments 1 and 3 / 4 in the agglomeration strength test, the agglomerated sample prepared from the product of Experimental Example 1 completely broke up when dropped freely from a height of 1m; while the agglomerated sample prepared from the product of Comparative Example 1 had a breakage rate of less than 50% when dropped freely from a height of 2m. The experimental results demonstrate that the anti-agglomeration performance of the tebuconazole product prepared in this invention is far superior to the product in patent CN102659696A. Comparative Example 1:

[0121] The only difference from Experimental Example 1 is that no seed crystals were added during the continuous crystallization process; the rest of the crystallization methods are the same as those in Experimental Example 1.

[0122] The tebuconazole crystals obtained in this comparative example were tested using the same method as in Experimental Example 1, and it was found that the D90 of the obtained tebuconazole crystals was 331 μm.

[0123] See the image of the product's stereoscopic optical microscope. Figure 7 As can be seen from the comparison between Experimental Example 1 and Comparative Example 1, the absence of seed crystals leads to the inability to consume supersaturation in time, resulting in a large amount of secondary nucleation. Therefore, it can be seen that the product particle size is uneven, and there are many fine particles in the product, indicating that secondary nucleation is serious during the crystallization process, and the final product has serious agglomeration.

[0124] Comparative Example 2:

[0125] The only difference from Experimental Example 1 is that the amount of seed crystals added during the process is 10% of the product mass; the rest of the preparation methods are the same as those in Experimental Example 1.

[0126] The tebuconazole crystals obtained in this comparative example were tested using the same method as in Experimental Example 1, and it was found that the D90 of the obtained tebuconazole crystals was 446 μm.

[0127] See the image of the product's stereoscopic optical microscope. Figure 8 The comparison between Experimental Example 1 and Comparative Example 2 shows that although the particle size of the product increased slightly with the addition of 10% seed crystals, it still did not meet expectations. Furthermore, the increased seed crystal amount led to significant agglomeration, resulting in lower flowability and anti-caking ability. Comparative Example 3:

[0128] The difference from Experimental Example 1 is that the amount of seed crystals added during the process is 10% of the product mass, the crystallization kettle rotation speed is 400 r / min, and the rest of the preparation methods are the same as Experimental Example 1.

[0129] The tebuconazole crystals obtained in this comparative example were tested using the same method as in Experimental Example 1. The D90 of the obtained tebuconazole crystals was 355 μm. A stereomicroscope image of the product can be found [image missing]. Figure 7 .

[0130] See the image of the product's stereoscopic optical microscope. Figure 9 As can be seen from the comparison between Experimental Example 1 and Comparative Example 3, the crystals under these conditions contain a large number of fine particles. This is because the stirring speed is too high, which breaks a large number of crystals during the crystallization process. Furthermore, the intense stirring will cause secondary nucleation of the crystals. Therefore, during the intermittent cooling crystallization process, the stirring rate increases, the crystals are broken, secondary nucleation is severe, and there are many fine particles.

[0131] Crystal form refers to the arrangement of molecules within a crystal, and is an important physicochemical property of crystals. For polymorphic substances, certain physicochemical properties (such as melting point, solubility, and stability) may differ due to different crystal forms; furthermore, under different conditions, interconversion may occur between different crystal forms, resulting in crystal transformation. To verify whether there is a difference in crystal form between the tebuconazole crystals obtained from the new process and the crystals from the workshop product, XRD characterization was performed on the crystals obtained from Experimental Example 1 and the workshop product. The XRD patterns are shown below. Figure 10 As shown, according to the 2015 edition of the Chinese Pharmacopoeia, page 372, if two crystalline samples are determined to have the same crystal form, the error range of their diffraction peak positions should be within ±0.2°. Figure 10 It can be seen that the peak positions of the two different morphologies of tebuconazole crystals correspond to the same diffraction angle. Therefore, it can be considered that the tebuconazole crystals in this patent are consistent with the crystals of the products in the workshop, and no crystal transformation phenomenon occurred during the crystallization process.

[0132] The applicant declares that the above description is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention fall within the protection and disclosure scope of the present invention.

Claims

1. A method for continuous crystallization of tebuconazole crystals, characterized in that, The continuous crystallization method includes the following steps: (1) Under stirring conditions, the tebuconazole mother liquor at a temperature of 65~75℃ is added to the primary crystallization vessel, cooled to 60~65℃, tebuconazole seed crystals are added, and the temperature is lowered to 50~60℃ to grow crystals. Then the crystal slurry enters the secondary crystallization vessel. (2) After the crystal slurry enters the secondary crystallization kettle, it is cooled to 40~50℃ under stirring conditions to grow crystals, and then the crystal slurry enters the tertiary crystallization kettle; (3) After the crystal slurry enters the three-stage crystallization kettle, it is cooled to 20~30℃ under stirring to grow crystals and obtain the tebuconazole crystals; The solute in the tebuconazole mother liquor in step (1) is tebuconazole, and the solution is cyclohexane; The concentration of the solute in the tebuconazole mother liquor in step (1) is 8-20 wt%; The particle size of the tebuconazole seed crystals in step (1) is 500~1300 mesh; The amount of tebuconazole seed crystals added in step (1) is 1 to 8 wt% of the tebuconazole crystals.

2. The continuous crystallization method for tebuconazole crystals according to claim 1, characterized in that, The stirring rate in step (1) is 150~300 r / min; The tebuconazole mother liquor in step (1) is added to the primary crystallization vessel by dropping, at a rate of 1~8 ml / min; The cooling rate for step (1) to reduce the temperature to 50-60℃ is 5-15℃ / h; The crystal growth time in step (1) is 0.5~2 h.

3. The continuous crystallization method for tebuconazole crystals according to claim 1, characterized in that, In step (2), the rate at which the crystal slurry enters the secondary crystallizer is 1~8 ml / min; The stirring rate in step (2) is 150~300 r / min; The cooling rate for step (2) to cool to 40-50℃ is 5-15℃ / h; The crystal growth time in step (2) is 0.5~2.5 h.

4. The continuous crystallization method for tebuconazole crystals according to claim 1, characterized in that, In step (3), the rate at which the crystal slurry enters the three-stage crystallization vessel is 1~8 ml / min; The stirring rate in step (3) is 150~300 r / min; The cooling rate for step (3) to cool down to 20~30℃ is 5~15℃ / h; The crystal growth time in step (3) is 0.5~2.5 h.

5. The continuous crystallization method for tebuconazole crystals according to claim 1, characterized in that, Step (3) also includes solid-liquid separation and drying of the mixture obtained after crystal growth; The solid-liquid separation method is filtration; The drying temperature was 50 degrees Celsius, the drying time was 24 hours, and the drying was carried out under normal pressure.

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