Calcium dobesilate crystals having high tap and loose densities and their use

Abstract

This invention belongs to the field of chemical engineering and pharmaceutical crystallization technology, and relates to calcium dobesilate crystals with high tap density and loose density and their applications, particularly to a rod-shaped or plate-shaped calcium dobesilate crystal and its application as a seed crystal in a crystallization process to improve the tap density, loose density, and yield of calcium dobesilate. The calcium dobesilate crystals of this invention exhibit diffraction peaks at approximately 6.8, 10.9, 13.7, 19.7, 20.6, 27.1, and 27.4 degrees Celsius in X-ray powder diffraction at a 2θ angle, with an error range of ±0.2. The rod-shaped or plate-shaped crystals of this invention have high tap density (≥1.1 g / ml) and loose density (≥0.7 g / ml), are not prone to agglomeration, do not easily trap mother liquor, and are easy to wash. When using the rod-shaped or thick-plate crystals as seed crystals, not only can products with higher tap density and loose density be obtained, but also the yield of single-batch concentrated crystallization can be significantly improved, the number of times calcium dobesilate mother liquor is concentrated can be reduced, and the overall yield can be further improved while improving product quality.

Description

Technical Field

[0001] This invention belongs to the field of chemical engineering and pharmaceutical crystallization technology, and relates to calcium dobesilate crystals with high tap density and loose density and their applications, especially to a calcium dobesilate crystal with rod-shaped or thick plate-shaped morphology and its application as a seed crystal in crystallization processes to improve the tap density, loose density and yield of calcium dobesilate. Background Technology

[0002] Calcium dobesilate, with the molecular formula C 12 H 10 CaO 10 S2 has the chemical structure shown in Formula I and a molecular weight of 418.41.

[0003]

[0004] Calcium dobesilate is a drug that acts on the capillary endothelial cell layer and basal layer, regulating and improving capillary permeability and flexibility, increasing capillary wall resistance, reducing permeability, activating the lymphatic circulation system, reducing blood and plasma viscosity, correcting the albumin / globulin ratio, reducing platelet aggregation, and decreasing plasma viscosity, thereby preventing thrombosis. In the production of calcium dobesilate, different dosage forms and formulations have different requirements for the physical properties of the active pharmaceutical ingredient (API). For example, in the preparation of calcium dobesilate capsules, if the tap density and loose density of the API are low, capsule shell breakage or the dissolution rate of the formulation may be affected. Therefore, most pharmaceutical manufacturers require the tap density of calcium dobesilate API to be >1.1 g / ml or the loose density to be >0.7 g / ml, i.e., calcium dobesilate heavy powder.

[0005] Existing calcium dobesilate crystals have various morphologies, among which needle-like, flake-like, or powdery crystals are more common. These crystal morphologies generally have low tap density (<1.0 g / ml) and low bulk density (<0.7 g / ml), are prone to clumping, easily trap mother liquor, are difficult to wash, and have low yields from single-batch concentration and crystallization. To improve the overall yield, multiple concentration and crystallization processes are required.

[0006] There are few reports on improving the tap density or loose density and yield of calcium dobesilate crystals at present. However, this is one of the problems that the industry urgently needs to solve. There are currently no literature reports on methods to control crystal morphology by optimizing the crystallization process and using them to improve the tap density or loose density and crystallization yield of calcium dobesilate. Summary of the Invention

[0007] The present invention aims to provide a novel calcium dobesilate crystal, which may have a rod-shaped or sheet-like morphology, and also relates to a crystallization process for improving the tap density, bulk density and yield of calcium dobesilate by using the calcium dobesilate crystal as a seed crystal.

[0008] This invention is achieved through the following technical solution:

[0009] The present invention first provides a calcium dobesilate crystal, wherein the calcium dobesilate crystal has a rod-shaped or thick sheet-like morphology.

[0010] Furthermore, the calcium dobesilate crystal of the present invention, when subjected to Cu-Kα radiation, exhibits diffraction peaks at approximately 6.8, 10.9, 13.7, 19.7, 20.6, 27.1, and 27.4 degrees of light using X-ray powder diffraction at an angle of 2θ, with an error range of ±0.2.

[0011] Furthermore, X-ray powder diffraction, expressed in 2θ angles, shows diffraction peaks at approximately 6.8, 10.0, 10.9, 13.7, 16.3, 17.7, 19.7, 20.6, 21.1, 22.8, 27.1, 27.4, 29.4, 32.9, 36.0, and 42.3, with an error range of ±0.2.

[0012] The present invention preferably uses the following rod-shaped calcium dobesilate crystals: X-ray powder diffraction with an angle of 2θ as shown in the figure. Figure 1 As shown.

[0013] The present invention preferably uses the following thick, sheet-like calcium dobesilate crystals: X-ray powder diffraction with an angle of 2θ as shown in the figure. Figure 2 As shown.

[0014] One objective of this invention is to provide a crystallization process for the aforementioned rod-shaped or sheet-shaped calcium dobesilate crystals, comprising the following steps:

[0015] 1) Dissolve crude calcium dobesilate in purified water to obtain a clear solution A;

[0016] 2) Vacuum concentrate solution A to a certain specific gravity, control the temperature to the crystallization temperature, control the stirring speed, and start crystallization. When the system is completely transformed into a clear crystalline suspension solution, stop stirring, let stand for 10-30 seconds, pour out the supernatant, add an appropriate amount of purified water (the amount of water should just submerge the solid crystals), and filter to obtain calcium hydroxybenzenesulfonate crystals with the target morphology.

[0017] In step 1), the ratio of calcium dobesilate to purified water and the dissolution temperature are not specifically specified, as long as a clear aqueous solution of calcium dobesilate can be obtained. Obviously, if the dissolution temperature is too low, more purified water is required, the solution concentration is low, and the time to concentrate to the required specific gravity is longer.

[0018] Preferably, the vacuum concentration temperature in step 2) is 70–80°C.

[0019] Preferably, the vacuum degree of solution concentration in step 2) is -0.065 to -0.075 MPa.

[0020] Preferably, in step 2), the calcium hydroxybenzenesulfonate solution is concentrated to a specific gravity of 1.43-1.45.

[0021] Preferably, the temperature range for calcium hydroxybenzenesulfonate crystallization in step 2) is 60–72°C.

[0022] Preferably, the stirring speed in step 2) is 180-220 rpm.

[0023] The product obtained in step 2) has a tapped density ≥ 1.1 g / ml and a loose density ≥ 0.7 g / ml;

[0024] Among them, when the crystallization temperature range of calcium dobesilate is 60-65℃, its crystals are rod-shaped, and the resulting product has a tap density ≥1.12g / ml and a loose density ≥0.7g / ml;

[0025] When calcium dobesilate crystallizes at a temperature range of 68–72°C, the crystals are in the form of thick flakes, and the resulting product has a tap density ≥1.1 g / ml and a loose density ≥0.7 g / ml.

[0026] Preferably, when the vacuum concentration temperature in step (2) is 70-75℃, the solution concentration vacuum degree is -0.07~-0.075Mpa, the concentration specific gravity is 1.43-1.44, the crystallization temperature range of calcium dobesilate is 60~68℃, and the stirring speed is 180~200rpm, the obtained calcium dobesilate has a tap density ≥1.15g / ml, a loose density ≥0.7g / ml, and its crystals are rod-shaped or thick sheet-shaped.

[0027] Furthermore, when the vacuum concentration temperature in step (2) is 70-75℃, the solution concentration vacuum degree is -0.07~-0.075Mpa, the concentration specific gravity is 1.43-1.44, the temperature range for calcium dobesilate crystallization is 60~62℃, and the stirring speed is 180~200rpm, the obtained calcium dobesilate has a tap density ≥1.18g / ml, a loose density ≥0.75g / ml, and its crystals are rod-shaped.

[0028] Another object of the present invention is to provide the application of the calcium dobesilate crystals in increasing the tap density or loose density of calcium dobesilate.

[0029] Another object of the present invention is to provide a crystallization process for improving the tap density, bulk density and yield of calcium dobesilate, comprising the following steps:

[0030] 1) Dissolve crude calcium dobesilate in purified water to obtain a clear solution B;

[0031] 2) Vacuum concentrate solution B to a certain specific gravity, control the temperature to the crystallization temperature, add seed crystals, control the stirring speed, and start crystallization. When the system is completely transformed into a clear crystalline suspension solution, continue vacuum concentration for 1.0h to 2.0h. After the concentration is completed, cool down to below 50℃ and filter to obtain a refined calcium dobesilate product with improved tap density, loose density, and yield.

[0032] In step 1), the ratio of calcium dobesilate to purified water and the dissolution temperature are not specifically specified, as long as a clear aqueous solution of calcium dobesilate can be obtained. Obviously, if the dissolution temperature is too low, more purified water is required, the solution concentration is low, and the time to concentrate to the required specific gravity is longer.

[0033] Preferably, the vacuum concentration temperature in step 2) is 70–80°C.

[0034] Preferably, the vacuum degree of solution concentration in step 2) is -0.065 to -0.075 MPa.

[0035] Preferably, in step 2), the calcium dobesilate solution is concentrated to a specific gravity of 1.44-1.46.

[0036] Preferably, the seed crystal in step 2) is the aforementioned rod-shaped or sheet-shaped crystal.

[0037] Preferably, the amount of seed crystals added in step 2) is 0.5 to 1 wt% of the amount of crude calcium dobesilate added in step 1).

[0038] Preferably, the crystallization temperature in step 2) is controlled at 66–70°C.

[0039] Preferably, the stirring speed in step 2) is 180-220 rpm.

[0040] Preferably, the vacuum concentration time in step 2) is 1.0 to 2.0 hours.

[0041] The product obtained in step 2) has a tap density ≥ 1.1 g / ml and a loose density ≥ 0.7 g / ml; the single-batch concentration crystallization yield is ≥ 60%; meeting the requirements of most pharmaceutical manufacturers.

[0042] The beneficial effects of this invention are:

[0043] 1. This invention optimizes the crystallization process of calcium dobesilate to obtain a rod-shaped or thick-plate-shaped crystal. Compared with crystals obtained by existing crystallization processes, this morphology has a larger particle size, effectively reducing the contact area between particles, thereby reducing or preventing the agglomeration of calcium dobesilate crystals. Furthermore, the rod-shaped or thick-plate-shaped crystals have higher tap density (≥1.1 g / ml) and bulk density (≥0.7 g / ml), are less prone to agglomeration, less likely to trap mother liquor, and are easier to wash. In pharmaceutical production, increased tap density or bulk density facilitates the mixing of active pharmaceutical ingredients and excipients, and is beneficial for subsequent processes such as tableting, granulation, or capsule filling. When using the rod-shaped or thick-plate-shaped crystals of this invention as seed crystals, not only can products with higher tap density and bulk density be obtained, but the yield of single-batch concentration crystallization can also be significantly improved, reducing the number of times calcium dobesilate mother liquor is concentrated, further increasing the overall yield while improving product quality.

[0044] 2. The crystallization process of the present invention is simple to operate, the conditions are controllable, the morphology of the obtained crystals is reproducible, it has a significant effect as a seed crystal to induce crystallization, the results are reliable, and it is easy to realize industrial production. Attached Figure Description

[0045] Figure 1 XRD pattern of calcium dobesilate rod-shaped crystals prepared in Example 1;

[0046] Figure 2 XRD pattern of calcium dobesilate thick-plate crystals prepared in Example 2;

[0047] Figure 3 Visual view of the rod-shaped crystals (wet) of calcium dobesilate prepared in Example 1;

[0048] Figure 4 Visual view of the rod-shaped crystals (dry product) of calcium dobesilate prepared in Example 1;

[0049] Figure 5 Visual view of the thick, sheet-like crystals (wet product) of calcium dobesilate prepared in Example 2;

[0050] Figure 6 Visual view of the thick, sheet-like crystals (dry product) of calcium dobesilate prepared in Example 2;

[0051] Figure 7 The image shows the XRD pattern of calcium hydroxybenzenesulfonate powder crystals prepared in Example 3. Detailed Implementation

[0052] The following examples further illustrate the present invention in detail. It should also be understood that the following examples are only for further explanation of the present invention and should not be construed as limiting the scope of protection of the present invention. Any non-essential improvements and adjustments made by those skilled in the art based on the principles described herein fall within the scope of protection of the present invention. The specific process parameters, etc., in the following examples are merely examples within a suitable range; that is, those skilled in the art can make selections within a suitable range based on the description herein, and are not intended to be limited to the specific data in the examples below.

[0053] Example 1: Preparation of rod-shaped calcium dobesilate crystals

[0054] Option 1: A crystallization process for rod-shaped calcium dobesilate crystals, comprising the following steps:

[0055] 1) Take 200g of crude calcium dobesilate and 100mL of purified water and add them to a reaction flask. Heat at 75℃ to dissolve and clarify to obtain solution A;

[0056] 2) Concentrate solution A under vacuum at 70℃ and -0.075 MPa until the specific gravity is 1.44. Then, control the system temperature at 62℃ and crystallize under stirring at 200 rpm. Stop stirring when the system is completely transformed into a clear crystalline suspension. Let it stand for 10-30 seconds, pour off the supernatant, add an appropriate amount of purified water (the amount of water should just submerge the solid crystals), and filter to obtain rod-shaped calcium dobesilate crystals (wet product). Take a portion of the sample and vacuum dry it at 60℃ for 12 hours to obtain rod-shaped crystals (dry product). The sample is pulverized and passed through an 80-mesh sieve. According to the Chinese Pharmacopoeia 2020 edition, Part IV, 0993, the tap density is 1.18 g / ml and the loose density is 0.75 g / ml.

[0057] By changing the crystallization parameters, rod-shaped calcium dobesilate crystals under different crystallization conditions were obtained for schemes 2 and 3, respectively. The crystallization conditions and properties of schemes 1-3 are shown in Table 1. Taking the crystal of scheme 1 as an example, its crystallization XRD pattern is shown in... Figure 1 .

[0058] The peak values ​​of its main diffraction peaks are as follows:

[0059]

[0060] Example 2: Preparation of thick-sheet calcium dobesilate crystals

[0061] Option 4: A crystallization process for thick, sheet-like calcium dobesilate crystals, comprising the following steps:

[0062] 1) Take 200g of crude calcium dobesilate and 100mL of purified water and add them to a reaction flask. Heat at 75℃ to dissolve and clarify to obtain solution A;

[0063] 2) Concentrate solution A under vacuum at 75℃ and -0.070 MPa until the specific gravity is 1.44. Then, control the system temperature at 68℃ and crystallize under stirring at 200 rpm. Stop stirring when the system is completely transformed into a clear crystalline suspension. Let it stand for 10-30 seconds, pour off the supernatant, add an appropriate amount of purified water (the amount of water should just submerge the solid crystals), and filter to obtain rod-shaped calcium dobesilate crystals (wet product). Take a portion of the sample and vacuum dry it at 60℃ for 12 hours to obtain rod-shaped crystals (dry product). The sample is pulverized and passed through an 80-mesh sieve. According to the Chinese Pharmacopoeia 2020 edition, Part IV, 0993, the tap density is 1.15 g / ml and the loose density is 0.73 g / ml.

[0064] By changing the crystallization parameters, thick-plate calcium dobesilate crystals under different crystallization conditions were obtained for schemes 5 and 6, respectively. The crystallization conditions and properties of schemes 4-6 are shown in Table 1. Taking the crystal of scheme 4 as an example, its crystallization XRD pattern is shown in... Figure 2 .

[0065] The peak values ​​of its main diffraction peaks are as follows:

[0066]

[0067] Example 3: Preparation of powdered or flake-shaped calcium dobesilate crystals (Comparative Example)

[0068] Option 7: A crystallization process for powdered calcium dobesilate crystals, comprising the following steps:

[0069] 1) Take 200g of crude calcium dobesilate and 100mL of purified water and add them to a reaction flask. Heat at 75℃ to dissolve and clarify to obtain solution A;

[0070] 2) Vacuum concentrate solution A, controlling the temperature at 80℃ and the vacuum degree at -0.065Mpa, until the specific gravity is 1.42. Then, control the system temperature at 55℃ and crystallize under stirring at 150rpm. Stop stirring when the system is completely transformed into a clear crystalline suspension. Let it stand for 10-30s, pour off the supernatant, add an appropriate amount of purified water (the amount of water should just submerge the solid crystals), and filter to obtain powdered calcium dobesilate crystals (wet product). Take a portion of the sample and vacuum dry it at 60℃ for 12h to obtain powdered crystals (dry product). The sample is pulverized and passed through an 80-mesh sieve. According to the Chinese Pharmacopoeia 2020 edition, Part IV, 0993, the tap density is 0.90g / ml and the loose density is 0.62g / ml.

[0071] By changing the crystallization parameters, long, plate-like calcium dobesilate crystals were obtained under different crystallization conditions in Scheme 8. The crystallization conditions and properties of Schemes 7-8 are shown in Table 1. Taking the crystal from Scheme 7 as an example, its crystallization XRD pattern is shown in... Figure 7 .

[0072] Table 1: Properties of calcium dobesilate crystals prepared with different crystallization parameters

[0073]

[0074]

[0075] Example 4 uses the rod-shaped calcium dobesilate crystals prepared in Example 1 as seed crystals to prepare high-quality calcium dobesilate.

[0076] Option 9: A crystallization process for improving the tap density, bulk density, and yield of calcium dobesilate, comprising the following steps:

[0077] 1) Take 200g of crude calcium dobesilate and 100mL of purified water and add them to a reaction flask. Heat at 75℃ to dissolve and clarify to obtain solution B;

[0078] 2) Solution B was concentrated under vacuum at a controlled temperature of 70℃ and a vacuum degree of -0.075 MPa until the specific gravity reached 1.45. Then, the temperature was controlled at 68℃, and 2g of the above-mentioned rod-shaped calcium dobesilate crystals (wet product) from Scheme 1 were added as seed crystals. Crystallization was carried out under stirring at 200 rpm. When the system was completely transformed into a clear crystalline suspension solution, vacuum concentration was continued for 2 hours. Then, the temperature was lowered to below 50℃ and filtered. The obtained product was dried under vacuum at 60℃ for 12 hours to obtain 136.2g of calcium dobesilate, with a yield of 68.1%. After the product was pulverized and passed through an 80-mesh sieve, the tap density was determined to be 1.15g / ml and the bulk density was 0.75g / ml according to the method for determining bulk density and tapped density in Chinese Pharmacopoeia 2020, Part IV, 0993.

[0079] By changing the parameters in the crystallization process, the refined calcium dobesilate of Scheme 10 was prepared with a yield of 60.5%, a tap density of 1.12 g / ml, and a bulk density of 0.72 g / ml.

[0080] Example 5 uses the thick-sheet calcium dobesilate crystals prepared in Example 2 as seed crystals to prepare high-quality calcium dobesilate.

[0081] Option 11: A crystallization process for improving the tap density, bulk density, and yield of calcium dobesilate, comprising the following steps:

[0082] 1) Take 200g of crude calcium dobesilate and 100mL of purified water and add them to a reaction flask. Heat at 75℃ to dissolve and clarify to obtain solution B;

[0083] 2) Solution B was concentrated under vacuum at a controlled temperature of 80℃ and a vacuum degree of -0.065 MPa until the specific gravity reached 1.44. Then, the temperature was controlled at 68℃, and 2g of the above-mentioned thick sheet-like calcium dobesilate crystals (wet product) from Scheme 4 were added as seed crystals. Crystallization was carried out under stirring at 180 rpm. When the system was completely transformed into a clear crystalline suspension solution, vacuum concentration was continued for 1 hour. Then, the temperature was lowered to below 50℃ and filtered. The obtained product was dried under vacuum at 60℃ for 12 hours to obtain 130.6g of calcium dobesilate, with a yield of 65.3%. After the product was pulverized and passed through an 80-mesh sieve, the tap density was determined to be 1.13g / ml and the loose density was 0.73g / ml according to the method for determining bulk density and tap density in Chinese Pharmacopoeia 2020, Part IV, 0993.

[0084] By changing the parameters in the crystallization process, refined calcium hydroxybenzenesulfonate products Scheme 12 and 13 were prepared with yields of 62.8% and 65.1%, respectively. The tap densities of the products were 1.12 g / ml and 1.13 g / ml, and the bulk densities were 0.71 g / ml and 0.75 g / ml, respectively.

[0085] Example 6 uses the powdered calcium dobesilate crystals prepared in Example 3 as seed crystals to prepare high-quality calcium dobesilate.

[0086] Option 14:

[0087] 1) Take 200g of crude calcium dobesilate and 100mL of purified water and add them to a reaction flask. Heat at 75℃ to dissolve and clarify to obtain solution B;

[0088] 2) Solution B was concentrated under vacuum at a controlled temperature of 70℃ and a vacuum degree of -0.075 MPa until the specific gravity reached 1.44. Then, the temperature was controlled at 66℃, and 2g of the above-mentioned powdered calcium dobesilate crystals (wet product) from Scheme 7 were added as seed crystals. Crystallization was carried out under stirring at 180 rpm. When the system was completely transformed into a clear crystalline suspension solution, vacuum concentration was continued for 2 hours. Then, the temperature was lowered to below 50℃ and filtered. The obtained product was dried under vacuum at 60℃ for 12 hours to obtain 130.6g of calcium dobesilate, with a yield of 45.6%. After the product was pulverized and passed through an 80-mesh sieve, the tap density was measured to be 0.93g / ml and the loose density was 0.66g / ml according to the method for determining bulk density and tapped density in Chinese Pharmacopoeia 2020, Part IV, 0993.

[0089] By changing the parameters in the crystallization process, the refined calcium dobesilate of Scheme 15 was prepared with a yield of 40.2%, a tap density of 0.90 g / ml, and a bulk density of 0.65 g / ml.

[0090] Example 7: Preparation of high-quality calcium dobesilate using conventional crystallization methods (without seed crystals)

[0091] Option 16:

[0092] 1) Take 200g of crude calcium dobesilate and 100mL of purified water and add them to a reaction flask. Heat at 75℃ to dissolve and clarify to obtain solution B;

[0093] 2) Solution B was concentrated under vacuum at a controlled temperature of 75℃ and a vacuum degree of -0.070 MPa until the specific gravity was 1.42. The stirring speed was 150 rpm. When the temperature was slowly lowered to 50℃, a large amount of crystals precipitated. The temperature was further lowered to 35℃ and then filtered. The product was dried under vacuum at 60℃ for 12 hours to obtain 71.4 g of calcium dobesilate, with a yield of 35.7%. After the product was pulverized and passed through an 80-mesh sieve, the tap density was determined to be 0.90 g / ml and the loose density was 0.63 g / ml according to the method for determining bulk density and tapped density in Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0094] Table 2: Properties of calcium dobesilate crystals prepared with different parameters for seed crystallization

[0095]

[0096] The results showed that, using the conventional crystallization method without adding seed crystals, the tap density of the prepared calcium dobesilate was <1.0 g / ml, and the bulk density was <0.7 g / ml. When using seed crystals, specifically powdered crystals, and varying the conditions, the tap density of the prepared calcium dobesilate was consistently <1.0 g / ml, and the bulk density was consistently <0.7 g / ml. When using rod-shaped or thick-plate-shaped crystals as seed crystals, and varying the conditions, the tap density of the prepared calcium dobesilate was consistently >1.1 g / ml, and the bulk density was consistently >0.7 g / ml, significantly improving both the tap density and bulk density of the calcium dobesilate.

Claims

1. A crystallization process for improving tap density, bulk density and yield of calcium dobesilate, characterized in that: Includes the following steps: 1) Dissolve crude calcium dobesilate in purified water to obtain clear solution B; 2) Vacuum concentrate solution B to a certain specific gravity, control the temperature to the crystallization temperature, add calcium dobesilate crystals as seed crystals, control the stirring speed, and begin crystallization. When the system is completely transformed into a clear crystalline suspension solution, continue vacuum concentration for 1.0h~2.0h. After concentration, cool to below 50℃ and filter to obtain a refined calcium dobesilate product with improved tap density, bulk density, and yield. The vacuum concentration temperature is 70~80℃, the solution concentration vacuum degree is -0.065 ~ -0.075Mpa, the calcium dobesilate solution is concentrated to a specific gravity of 1.44-1.46, the crystallization temperature is controlled at 66~70℃, and the stirring speed is 180~220rpm. The X-ray powder diffraction of the calcium hydroxybenzenesulfonate crystal used as a seed crystal in step 2) is shown in Figure 1 or 2 at a 2θ angle. The crystallization process of the seed crystal includes the following steps: Crude calcium dobesilate was dissolved in purified water to obtain a clear solution A. Solution A was concentrated under vacuum to a certain specific gravity, and the temperature was controlled to the crystallization temperature. The stirring speed was controlled to initiate crystallization. When the system was completely transformed into a clear crystalline suspension, stirring was stopped, and the solution was allowed to stand for 10-30 seconds. The supernatant was poured off, an appropriate amount of purified water was added, and the solution was filtered to obtain calcium dobesilate crystals with the target morphology. The vacuum concentration temperature was 70-80℃, the solution concentration vacuum degree was -0.065 ~ -0.075 MPa, the calcium dobesilate solution was concentrated to a specific gravity of 1.43-1.45, the crystallization temperature range was 60-72℃, and the stirring speed was 180-220 rpm.

2. The crystallization process of claim 1, characterized in that, The amount of seed crystals added is 0.5 to 1 wt% of the amount of crude calcium dobesilate.

3. The crystallization process of claim 1, characterized in that, In the crystallization process of the seed crystal, the vacuum concentration temperature is 70-75℃, the solution concentration vacuum degree is -0.07 ~ -0.075Mpa, the concentration specific gravity is 1.43-1.44, the temperature range of calcium hydroxybenzenesulfonate crystallization is 60~68℃, and the stirring speed is 180~200rpm.

4. The crystallization process of claim 1, characterized in that, In the crystallization process of the seed crystal, the vacuum concentration temperature is 70-75℃, the solution concentration vacuum degree is -0.07 ~ -0.075Mpa, the concentration specific gravity is 1.43-1.44, the crystallization temperature range of calcium dobesilate is 60~62℃, and the stirring speed is 180~200rpm.

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