Method for preparing disodium 5 '-adenylate

Abstract

The invention discloses a method for preparing disodium 5 '-adenosine monophosphate, and belongs to the technical field of nucleotide sodium salt preparation. The method comprises the following steps: adding an organic solvent and 5 '-adenosine monophosphate into a converter provided with an ultrasonic device, starting stirring, controlling the temperature at 5-25 DEG C, starting ultrasonic to form a uniform suspension system, dropwise adding a sodium-containing alkaline aqueous solution into the converter, carrying out a heat preservation reaction for 10-30 min after dropwise adding, collecting a solid product, putting the solid product into 95% ethanol for immersion cleaning, and collecting the solid product to obtain the 5'-adenosine monophosphate. 5 '-adenosine monophosphate is directly converted into the disodium 5'-adenosine monophosphate in a suspension system, the preparation process is simple and easy to operate, the yield is larger than 95.6%, the purity can reach 99%, the particle size is uniform, the bulk density is 0.60 g / ml or above, and the method has excellent stability and very excellent application prospects.

Description

Technical Field

[0001] The present invention belongs to the technical field of the preparation of sodium nucleoside salts, and particularly relates to a method for preparing disodium 5'-adenylate. Background Art

[0002] Adenylate is a class of important bioactive molecules, composed of adenine, ribose, and phosphate groups. It is a key participant in various metabolic processes within cells, including energy conversion, signal transduction, and nucleic acid synthesis. Adenylate has multiple important physiological functions in organisms. For example, as a component of the energy molecule ATP, it provides energy for the normal physiological activities of cells. At the same time, adenylate is also a precursor substance for nucleic acid synthesis, participating in gene transcription and expression, which is crucial for maintaining the normal growth and development of cells.

[0003] Currently, the main methods for preparing adenylate are chemical synthesis and biological methods. The chemical synthesis method uses adenine as a raw material, a phosphorylation reagent to introduce a phosphate group, and then through steps such as hydrolysis, extraction, decolorization, and crystallization to obtain it. However, this method has many drawbacks: the reagents are highly toxic, posing great hazards to the health of operators and the environment; the process conditions are harsh, difficult to control, the subsequent extraction process is complex, and a large amount of three wastes are generated, which is not conducive to industrial production. The biological method uses yeast as a strain, extracts yeast RNA through fermentation culture, then enzymatically liberates adenylate, and finally separates and crystallizes it. The adenylate prepared by the biological method has extremely high safety, high product purity, fewer by-products, mild production conditions, less pollution, is easy to produce on a large scale, and has a lower cost.

[0004] In practical applications, adenylate and its derivative disodium 5'-adenylate have a wide range of uses. Disodium 5'-adenylate is an important chemical substance, presenting as colorless to white crystals. In the pharmaceutical field, it is an important raw material for synthesizing complex nucleotide drugs and can be used to treat various diseases. In addition, adenylate is also widely used in cosmetics moisturizing, agricultural growth regulators, etc. Therefore, high-quality disodium 5'-adenylate products have a great market demand and have important economic value and application prospects.

[0005] The existing method for preparing disodium 5'-adenylate is mainly by dissolving adenylate in an aqueous solution and adding an alkali solution to adjust the pH, but this method has the following problems: First, the aqueous solution of disodium 5'-adenylate is extremely prone to intermolecular association, unable to nucleate regularly, and the crystallization is prone to oil separation, often resulting in abnormal crystallization. Second, the yield is extremely low and urgently needs to be improved. Summary of the Invention

[0006] To solve the problems existing in the background art, the object of the present invention is to provide a method for preparing disodium 5'-adenylate. In the present invention, 5'-adenylic acid is dispersed in an organic solvent to form a suspension system, and an alkaline solution is added dropwise under ultrasonic conditions, and 5'-adenylic acid is directly converted into disodium 5'-adenylate in the suspension system, avoiding the industry bottleneck of first preparing an adenylic acid disodium solution and then crystallizing in the prior art, which results in the inability to prepare a product with qualified particle size and bulk density. The disodium 5'-adenylate prepared by the method of the present invention has uniform particle size, high bulk density, excellent stability, and the yield is also significantly improved.

[0007] To achieve the above object, the present invention provides the following technical solutions:

[0008] The present invention provides a method for preparing disodium 5'-adenylate, comprising the following steps:

[0009] (1) Add an organic solvent and 5'-adenylic acid to a converter equipped with an ultrasonic device, start stirring, and control the temperature at 5-25 °C;

[0010] (2) Turn on the ultrasonic device. After forming a uniform suspension system, add a sodium-containing alkaline aqueous solution dropwise to the converter. After the addition is completed, keep the temperature for reaction for 10-30 min;

[0011] (3) Collect the solid product in the reaction solution of step (2) to obtain a wet material of primary disodium 5'-adenylate, put it into 95% ethanol for washing, collect the solid product, and obtain a wet material of secondary disodium 5'-adenylate;

[0012] (4) Dry the wet material of secondary disodium 5'-adenylate obtained in step (3) to obtain a disodium 5'-adenylate product.

[0013] Based on the above technical solution, further, the particle size of the adenylic acid in step (1) is controlled at 80-200 mesh, preferably 120-150 mesh.

[0014] Based on the above technical solution, further, the temperature in step (1) is controlled at 5-20 °C.

[0015] Based on the above technical solution, further, the organic solvent in step (1) is one or a mixture of two or more of methanol, ethanol, and isopropanol; the mass ratio of the 5'-adenylic acid to the organic solvent is 1:5-30, preferably 1:8-1:15.

[0016] Based on the above technical solution, further, the rotation speed of the stirring in step (1) is 100-300 r / min.

[0017] Based on the above technical solution, further, the frequency of the ultrasonic wave in step (2) is 20-100 KHz, and the power is 20-100 W.

[0018] Based on the above technical solution, further, the solute of the sodium-containing alkaline aqueous solution in step (2) is one or a combination of two or more of food-grade sodium hydroxide, sodium carbonate or sodium bicarbonate, and the mass percentage concentration of the sodium-containing alkaline aqueous solution is 10-40%, preferably 10-30%.

[0019] Based on the above technical solution, further, the molar amount of the solute in the sodium-containing alkaline aqueous solution added dropwise in step (2) is 2-3 times the molar amount of 5'-adenylic acid; the dropping time is controlled within 60-150 min, preferably 90-120 min.

[0020] Based on the above technical solution, further, the collection method in step (3) includes suction filtration and centrifugation; before collection, the reaction solution is cooled to 5-10 °C.

[0021] Based on the above technical solution, further, the usage amount of 95% ethanol in step (3) is 2-5 times the weight of the wet material of disodium 5'-adenylate; the immersion washing time is 10-60 min.

[0022] Based on the above technical solution, further, the drying method in step (4) is fluidized drying or vacuum drying.

[0023] Based on the above technical solution, further, the specific process of vacuum drying is as follows: the vacuum degree ≤ -0.10 MPa, dynamic gradient drying is implemented, drying is carried out at 40-49 °C for 0.2-1 h, at 50-69 °C for 0.2-1 h, and at 60-69 °C for 0.5-2 h.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] (1) The preparation process of the present invention is simple and easy to operate, the reaction conditions are mild, the organic solvent can be reused, the energy consumption is low, which conforms to the concept of green production and is easy to scale up to industrial batch production.

[0026] (2) The method of the present invention uses 5'-adenylic acid prepared by a biological method as a substrate, which is green and safe. The purity of the prepared disodium 5'-adenylate is as high as over 99%, and the yield can reach 95.6%, significantly reducing the production cost.

[0027] (3) The disodium 5'-adenylate prepared by the method of the present invention is a granular product with uniform particle size, does not caking after long-term placement, and the stability is significantly improved.

[0028] (4) The bulk density of the disodium 5'-adenylate prepared by the method of the present invention is increased to more than 0.6 g / ml, overcoming the problem of uneven mixing caused by large differences in bulk density during the use of compounding materials. Description of the Drawings

[0029] To more clearly illustrate the embodiments of the present invention, the accompanying drawings related to the embodiments will be briefly introduced below.

[0030] Figure 1 High performance liquid chromatography (HPLC) chromatogram of disodium 5'-adenylate prepared in Example 2.

[0031] Figure 2 Particle size distribution diagram of disodium 5'-adenylate prepared in Example 2.

[0032] Figure 3 Microscopic image of disodium 5'-adenylate prepared in Example 2.

[0033] Figure 4 Microscopic image of disodium 5'-adenylate prepared in Comparative Example 6. Detailed implementation manners

[0034] The present invention will be described in detail below in conjunction with the embodiments. However, the implementation manners of the present invention are not limited thereto. Obviously, the embodiments described below are only partial embodiments of the present invention. For those skilled in the art, without creative efforts, obtaining other similar embodiments will fall within the protection scope of the present invention.

[0035] The 5'-adenylic acid in the embodiment is prepared by enzymatic hydrolysis. The high performance liquid chromatography purity of 5'-adenylic acid is 99.8%, and the water content is less than 5%.

[0036] High performance liquid chromatography detection method for disodium 5'-adenylate: The chromatographic column is ODS-AQ 150mm×4.6mm, and the mobile phase is a mixed solution of magnesium sulfate and potassium dihydrogen phosphate (weigh 4.17g of MgSO4·7H2O and 13.68g of KH2PO4, dissolve and dilute to 1000ml with purified water, filter with a 0.45μm water-based filter membrane, and degas by ultrasonic); the flow rate is 1ml / min, the column temperature is 25°C, ultraviolet detector, and the detection wavelength is 260nm.

[0037] The particle size of the 5'-adenylic acid disodium prepared in the embodiment is analyzed by a BT-2001 type laser particle size analyzer.

[0038] The bulk density detection method for the 5'-adenylic acid disodium prepared in the embodiment is as follows: Gently pour the prepared 5'-adenylic acid disodium powder into a standard container to make it freely stack, record the mass of the poured powder, and then measure the volume of the powder to calculate the bulk density.

[0039] The pH determination process for the 5'-adenylic acid disodium prepared in the embodiment is as follows: Add the prepared 5'-adenylic acid disodium to purified water to make an aqueous solution with a mass concentration of 5%, and detect the pH of the solution with a pH detector.

[0040] The water content determination process of the disodium 5'-adenylate prepared in the examples is as follows: Take a clean flat weighing bottle, place it in a drying oven at 101°C to 105°C, with the bottle cap tilted on the edge of the bottle, dry for 1 h, take it out and cover it, place it in a desiccator to cool for 0.5 h, weigh it, and repeat drying until the mass difference between the previous and the next time does not exceed 2 mg, which is the constant weight, denoted as m1; Weigh 3 g of the prepared disodium 5'-adenylate powder and put it into this weighing bottle, with the powder thickness not exceeding 5 mm, cover it, weigh it precisely, denoted as m2, place it in a drying oven at 101°C to 105°C, with the bottle cap tilted on the edge of the bottle, after drying for 3 h, cover it and take it out, place it in a desiccator to cool for 0.5 h and then weigh it, then put it back into the drying oven at 101°C to 105°C to dry for 1 h, take it out, place it in a desiccator to cool for 0.5 h and then weigh it again, and repeat the above operations until the mass difference between the previous and the next time does not exceed 2 mg, which is the constant weight, denoted as m3. The water content is calculated by (m2 - m3) / (m2 - m1).

[0041] Example 1

[0042] Screen the 5'-adenylic acid raw material to obtain a powder with a mesh size of 120 to 150. Put 80 g of the 5'-adenylic acid powder into a converter filled with 800 ml of anhydrous methanol, stir and disperse it at 200 r / min, control the water bath temperature of the converter at 8°C to 9°C, start the ultrasonic instrument, with an ultrasonic frequency of 40 KHz and a power of 50 W. After the 5'-adenylic acid powder is dispersed to form a uniform suspension, add dropwise 63 g of a 30% food-grade sodium hydroxide aqueous solution, control the dropping time within 90 min, stop dropping, keep the temperature for conversion for 15 min, filter by suction to obtain a primary wet material; Put the above primary wet material into 300 ml of 95% ethanol for leaching for 30 min, filter by suction again to obtain a secondary wet material, transfer the above secondary wet material to a vacuum drying oven, with a vacuum degree ≤ -0.10 MPa, perform dynamic gradient drying, dry at 45°C for 0.5 h, dry at 55°C for 0.5 h, dry at 65°C for 1 h to obtain the disodium 5'-adenylate product. The performance parameters of the product are shown in Table 1.

[0043] Example 2

[0044] Screen the 5'-adenylic acid raw material to obtain a powder with a mesh size of 120-150. Take 80 g of the 5'-adenylic acid powder and put it into a converter containing 1000 ml of absolute ethanol. Stir and disperse it at 150 r / min. Control the water bath temperature of the converter at 11-12 °C. Start the ultrasonic instrument with an ultrasonic frequency of 50 KHz and a power of 50 W. After the 5'-adenylic acid powder is dispersed to form a uniform suspension, add dropwise 65 g of a 30% food-grade sodium hydroxide aqueous solution. Control the dropping time at 95 min. Stop dropping, keep the temperature for conversion for 12 min, cool down to 8-9 °C, and perform suction filtration to obtain a primary wet material. Put the above primary wet material into 300 ml of 95% ethanol for leaching for 60 min, and perform suction filtration again to obtain a secondary wet material. Transfer the above secondary wet material to a vacuum drying oven with a vacuum degree ≤ -0.10 MPa, and perform dynamic gradient drying. Dry at 45 °C for 0.5 h, dry at 55 °C for 0.5 h, and dry at 65 °C for 1 h to obtain the 5'-adenylic acid disodium product. The performance parameters of the product are shown in Table 1.

[0045] Example 3

[0046] Screen the 5'-adenylic acid raw material to obtain a powder with a mesh size of 120-150. Take 80 g of the 5'-adenylic acid powder and put it into a converter containing 600 ml of absolute ethanol. Stir and disperse it at 300 r / min. Control the water bath temperature of the converter at 13-14 °C. Start the ultrasonic instrument with an ultrasonic frequency of 60 KHz and a power of 50 W. After the 5'-adenylic acid powder is dispersed to form a uniform suspension, add dropwise 98 g of a 20% food-grade sodium hydroxide aqueous solution. Control the dropping time at 100 min. Stop dropping, keep the temperature for conversion for 10 min, cool down to 8-9 °C, and perform suction filtration to obtain a primary wet material. Put the above primary wet material into 500 ml of 95% ethanol for leaching for 30 min, and perform suction filtration again to obtain a secondary wet material. Transfer the above secondary wet material to a vacuum drying oven with a vacuum degree ≤ -0.10 MPa, and perform dynamic gradient drying. Dry at 45 °C for 0.5 h, dry at 55 °C for 0.5 h, and dry at 65 °C for 1 h to obtain the 5'-adenylic acid disodium product. The performance parameters of the product are shown in Table 1.

[0047] Example 4

[0048] Screen the 5'-adenylic acid raw material to obtain a powder with a mesh size of 120-150. Take 80 g of the 5'-adenylic acid powder and put it into a converter containing 700 ml of absolute ethanol. Stir and disperse it at 200 r / min. Control the water bath temperature of the converter at 12-13 °C. Start the ultrasonic instrument with an ultrasonic frequency of 20 kHz and a power of 100 W. After the 5'-adenylic acid powder is dispersed to form a uniform suspension, add dropwise 133 g of a 15% food-grade sodium hydroxide aqueous solution, and control the dropping time at 105 min. Stop adding dropwise, keep the temperature for conversion for 16 min, cool down to 8-9 °C, and filter by suction to obtain a primary wet material; put the above primary wet material into 500 ml of 95% ethanol for leaching for 30 min, filter by suction again to obtain a secondary wet material, transfer the above secondary wet material to a vacuum drying oven, with a vacuum degree ≤ -0.10 MPa, perform dynamic gradient drying, dry at 45 °C for 0.5 h, dry at 55 °C for 0.5 h, and dry at 65 °C for 1 h to obtain the 5'-adenylic acid disodium product. The performance parameters of the product are shown in Table 1.

[0049] Example 5

[0050] Screen the 5'-adenylic acid raw material to obtain a powder with a mesh size of 120-150. Take 80 g of the 5'-adenylic acid powder and put it into a converter containing 700 ml of isopropanol. Stir and disperse it at 200 r / min. Control the water bath temperature of the converter at 14-15 °C. Start the ultrasonic instrument with an ultrasonic frequency of 30 kHz and a power of 80 W. After the 5'-adenylic acid powder is dispersed to form a uniform suspension, add dropwise 198 g of a 10% food-grade sodium hydroxide aqueous solution, and control the dropping time at 110 min. Stop adding dropwise, keep the temperature for conversion for 20 min, cool down to 8-9 °C, and filter by suction to obtain a primary wet material; put the above primary wet material into 500 ml of 95% ethanol for leaching for 30 min, filter by suction again to obtain a secondary wet material, transfer the above secondary wet material to a vacuum drying oven, with a vacuum degree ≤ -0.10 MPa, perform dynamic gradient drying, dry at 45 °C for 0.5 h, dry at 55 °C for 0.5 h, and dry at 65 °C for 1 h to obtain the 5'-adenylic acid disodium product. The performance parameters of the product are shown in Table 1.

[0051] Comparative Example 1

[0052] The experimental process of this comparative example is the same as that of Example 2, except that the 5'-adenylic acid raw material used is the 5'-adenylic acid raw material without screening treatment. The performance parameters of the obtained 5'-adenylic acid disodium product are shown in Table 1.

[0053] Comparative Example 2

[0054] The experimental process of this comparative example is the same as that of Example 2, except that the sodium hydroxide aqueous solution is directly poured into the converter. The performance parameters of the obtained 5'-adenylic acid disodium product are shown in Table 1.

[0055] Comparative Example 3

[0056] The experimental process of this comparative example was the same as that of Example 2, except that the conversion and heat preservation were carried out for 60 min, and the performance parameters of the disodium 5'-adenylate product obtained are shown in Table 1.

[0057] Comparative Example 4

[0058] The experimental process of this comparative example was the same as that of Example 2, except that the mass fraction of the aqueous alkali solution was 50%, the addition amount of the aqueous alkali solution was 39 g, and the performance parameters of the disodium 5'-adenylate product obtained are shown in Table 1.

[0059] Comparative Example 5

[0060] The experimental process of this comparative example was the same as that of Example 2, except that ultrasonic treatment was not used, and the performance parameters of the disodium 5'-adenylate product obtained are shown in Table 1.

[0061] Comparative Example 6

[0062] In this comparative example, disodium 5'-adenylate was prepared by the dissolution crystallization method. The specific process was as follows: 80 g of 5'-adenylic acid raw material was put into a converter containing 420 ml of pure water at normal temperature (20 - 21 °C), and a food-grade sodium hydroxide aqueous solution with a mass fraction of 30% was added to adjust to complete dissolution to form a solution system. Stirring was started at 100 r / min, and 1440 ml of 95% ethanol was added dropwise for crystallization. After the material was precipitated, the temperature was lowered to 8 - 10 °C, and suction filtration was carried out to obtain the first wet material of disodium 5'-adenylate; the above wet material was put into 200 ml of 95% ethanol for leaching, and suction filtration was carried out to obtain the second wet material of disodium 5'-adenylate; the above second wet material was transferred to a vacuum drying oven, the vacuum degree was ≤ -0.10 MPa, dynamic gradient drying was carried out, drying was carried out at 45 °C for 0.5 h, at 55 °C for 0.5 h, and at 65 °C for 1 h, and after pulverization, the disodium 5'-adenylate product was obtained, and the performance parameters of the product are shown in Table 1.

[0063] Table 1 Performance parameters of the disodium 5'-adenylate products obtained in Examples 1 - 5 and Comparative Examples 1 - 6

[0064]

[0065]

[0066] Example 6

[0067] In this example, the stabilities of the disodium 5'-adenylate products prepared in the above Examples 1 - 3 and Comparative Example 6 were investigated. The disodium 5'-adenylate product prepared in Example 1 was denoted as Sample 1, the disodium 5'-adenylate product prepared in Example 2 was denoted as Sample 2, the disodium 5'-adenylate product prepared in Example 3 was denoted as Sample 3, and the disodium 5'-adenylate product prepared in Comparative Example 6 was denoted as Sample 4.

[0068] The stability experiment is mainly an accelerated test, and the specific process is as follows:

[0069] An appropriate amount of the sample is sealed in an aluminum foil bag and placed in a thermostatic and humidostatic test chamber at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% for 6 months, and the actual temperature and humidity in the test chamber are monitored. Samples are taken once at the end of the 1st month, 2nd month, 3rd month, and 6th month during the test. After drying, the high-performance liquid chromatography content of the sample is detected, the pH of the aqueous solution with a mass concentration of 5% is measured, and at the same time, whether the color of the sample changes is recorded. The stability parameters are shown in Table 2.

[0070] Table 2 Results of the accelerated test of disodium 5'-adenylate prepared in Examples 1-3 and Comparative Example 6

[0071]

[0072] From the above results, it can be seen that after the accelerated test of the disodium 5'-adenylate prepared in Examples 1-3, the content of disodium 5'-adenylate only decreased slightly, the color did not change significantly, and caking did not occur, which is significantly better than Sample 4 (disodium 5'-adenylate prepared in Comparative Example 6), indicating that the disodium 5'-adenylate prepared by the present invention has very excellent stability after long-term storage.

[0073] Example 7

[0074] This example examines the morphological characteristics of disodium adenylate. The disodium adenylate prepared in Example 2 is denoted as Sample A, and the disodium adenylate prepared in Comparative Example 6 is denoted as Sample B. The specific method is to use an optical microscope to magnify Sample A and Sample B by 40 times respectively to obtain the micrographs of Sample A and Sample B.

[0075] The micrograph results of Sample A are as Figure 3 shown. Sample A has good dispersibility, is in the form of uniform particles, and regular plate-like or rod-like crystal structures can be seen. Therefore, its bulk density and fluidity are good; the micrograph of Sample B is as Figure 4 shown. Sample B is extremely fine, basically in powder form and prone to agglomeration, and no regular crystal structure is seen. Its bulk density and fluidity are poor.

[0076] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present invention, and are not intended to limit them; although the present invention has been described in detail with reference to the foregoing examples, those of ordinary skill in the art should understand that they can still modify the technical solutions recorded in the foregoing examples, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the various examples of the present invention.

Claims

1. A method for preparing disodium 5'-adenylate, characterized in that, It includes the following steps: (1) Add organic solvent and 5'-adenylic acid into a converter equipped with an ultrasonic device, start stirring, and control the temperature at 5-25°C; (2) Turn on the ultrasonic device. After forming a uniform suspension system, add an aqueous alkaline solution containing sodium dropwise into the converter. After the addition is completed, keep the temperature for reaction for 10-30 min; (3) Collect the solid product in the reaction solution of step (2) to obtain the first wet material of disodium 5'-adenylate. Put it into 95% ethanol for leaching, collect the solid product, and obtain the second wet material of disodium 5'-adenylate; (4) Dry the second wet material of disodium 5'-adenylate obtained in step (3) to obtain the disodium 5'-adenylate product.

2. The method according to claim 1, characterized in that In step (1), the particle size of the adenylic acid is controlled at 80-200 mesh, preferably 120-150 mesh; the organic solvent is one or a mixture of two or more of methanol, ethanol, and isopropyl alcohol; the mass ratio of 5'-adenylic acid to the organic solvent is 1:5-30, preferably 1:8-1:

15.

3. The method according to claim 1, characterized in that, In step (1), the stirring speed is 100-300 r / min.

4. The method according to claim 1, characterized in that, In step (2), the ultrasonic frequency is 20-100 KHz, and the power is 20-100 W.

5. The method according to claim 1, wherein In step (2), the solute of the aqueous alkaline solution containing sodium is one or a combination of two or more of food-grade sodium hydroxide, sodium carbonate, and sodium bicarbonate. The mass percentage concentration of the aqueous alkaline solution containing sodium is 10-40%, preferably 10-30%.

6. The method according to claim 1, wherein In step (2), the molar amount of the solute in the aqueous alkaline solution containing sodium dropwise is 2-3 times the molar amount of 5'-adenylic acid; the dropping time is controlled at 60-150 min, preferably 90-120 min.

7. The method according to claim 1, characterized in that, In step (3), the collection method includes suction filtration and centrifugation; before collection, cool the reaction solution to 5-10°C.

8. The method according to claim 1, wherein In step (3), the usage amount of 95% ethanol is 2-5 times the weight of the wet material of disodium 5'-adenylate; the leaching time is 10-60 min.

9. The method according to any one of claims 1-8, characterized in that, The drying method in step (4) is fluidized drying or vacuum drying.

10. The method according to claim 9, characterized in that, The specific process of vacuum drying is as follows: the vacuum degree ≤ -0.10 MPa, implement dynamic gradient drying, dry at 40-49°C for 0.2-1 h, dry at 50-69°C for 0.2-1 h, and dry at 60-69°C for 0.5-2 h.

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