Preparation intermediate containing fosfomycin and method

Abstract

The invention relates to the field of medicines, and also relates to a fosfomycin-containing preparation intermediate and a use method thereof. According to the preparation intermediate obtained by the invention, the brittleness of the material can be reduced, the plasticity of the material can be improved, a product with uniform particle size distribution of the material is obtained, and samples with different particle size distribution ranges can be obtained by adjusting spray drying parameters or pulverizer parameters according to requirements. Meanwhile, in research, unexpected discovery shows that the impurity level of the sample prepared by the technical scheme provided by the invention is lower, and particularly, the impurity level is basically not increased in a long-time crushing treatment process by adopting a crusher.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, and further relates to a fosfomycin-containing preparation intermediate and a method. BACKGROUND

[0002] Fosfomycin was isolated from the filtrate of actinomycete culture in 1967. It is a small-molecule organic compound with simple chemical structure and small relative molecular mass, and is a broad-spectrum antibiotic. The mechanism of action of fosfomycin is to prevent the synthesis of the early stage of bacterial cell wall, thus it has killing effect on both gram-positive bacteria and gram-negative bacteria. The drug is mainly used for respiratory tract infection, urinary tract infection, skin and soft tissue infection, etc. caused by sensitive bacteria. Since it has small relative molecular mass and no antigenicity, no cross-resistance with other antibacterial drugs has been found so far. Therefore, it can also be used in combination with other antibiotics for the treatment of severe infections such as septicemia, peritonitis, osteomyelitis, etc. caused by sensitive bacteria. Fosfomycin sodium is a disodium salt of (1R, 2S)-1, 2-epoxypropylphosphonic acid. The epoxy ring belongs to a high-tension structure, and is prone to hydrolysis and ring opening to generate 1, 2-dihydroxypropylphosphonic acid (diol impurity) when heated or during long-term storage. The impurity not only reduces the content of the main drug and weakens the efficacy, but also increases the risk of adverse reactions when used for a long time or in large doses.

[0003] At present, there are many reports on the existing technology of fosfomycin sodium, as shown below: CN201010194112A discloses a new method for preparing fosfomycin sodium for injection. In the method, sodium hydroxide is added to distilled water under stirring, and then left to stand while continuing to stir. The left lower sodium salt solution is collected, and a saturated solution of citric acid is added dropwise to the sodium salt solution. Activated carbon is added and stirred, and then filtered to remove the carbon. The filtrate is added dropwise to anhydrous ethanol, and left to stand. Crystals are separated out, and the solid-liquid mixture is separated by filtration. The filter cake is washed, and the wet product is dried to constant weight to obtain the fosfomycin sodium for injection. The patent improves the resource utilization rate and reduces the production cost through the improvement of the preparation method.

[0004] CN201310074587A discloses a fosfomycin sodium pharmaceutical composition and a preparation method thereof. The pharmaceutical composition comprises fosfomycin sodium and metronidazole lipid microspheres. Metronidazole adopts the lipid microsphere technology, and the combination of drugs reduces the complex infection and improves the drug resistance of fosfomycin sodium.

[0005] CN201310482173A discloses a fosfomycin sodium composition lyophilized powder for injection. Fosfomycin sodium and chitosan nanoparticles are compounded to improve the antibacterial effect of the lyophilized powder.

[0006] The above prior art does not involve how to solve the problems of particle size distribution and stability of sodium fosfomycin, which limits the application of sodium fosfomycin in clinic. Therefore, it is necessary to find a suitable particle size distribution and improve the stability of sodium fosfomycin. In addition, sodium fosfomycin is unstable to heat and moisture, and will hydrolyze open ring and produce impurities when heated or stored for a long time. And crushing is a process with a lot of heat (spray drying also inevitably exists a wet heat process), so it will cause a sharp increase in impurity level.

[0007] CN118319850A discloses a sodium fosfomycin injection, which adds an ether substance in the prescription to increase the stability of the product. Although this method can improve the stability of the product to a certain extent, ether substances as a high-risk excipient in pharmaceutical preparations have been rarely used in modern preparations. The main reason is that if the structure is modified or the purity control is unreasonable, the following risks are likely to occur: Ether substances can destroy red blood cells and cause hemolytic reaction, leading to anemia, jaundice, etc. They can stimulate histamine release and cause severe anaphylactoid reactions such as skin rash, itching, dyspnea, and even shock. They can cause strong irritation to the skin, mucous membrane and blood vessels, which may cause pain, phlebitis and tissue necrosis at the injection site. Ether substances can inhibit the central nervous system and cause dizziness, drowsiness, loss of consciousness, and respiratory depression. Long-term or large-scale exposure may cause toxic damage to the liver and kidneys, leading to hepatitis, nephritis and renal failure.

[0008] CN118290481A discloses a crystallization technical solution: in water, phosphomycin levomycin salt reacts with sodium hydroxide, and sodium fosfomycin is released, then phase separation is carried out to obtain a sodium fosfomycin aqueous solution; the sodium fosfomycin aqueous solution is subjected to high-pressure pump counter-jet crystallization with ethanol, and then white crystalline sodium fosfomycin is obtained by filtration, washing and drying.

[0009] Although this technical solution can obtain sodium fosfomycin with narrow particle size distribution, the preparation process is complicated, the process control is difficult, the crystallization period is long, and the particle size range value obtained by preparation is single, which cannot meet the flexible adjustment according to the particle size distribution quality standards of different pharmaceutical production enterprises, and is not conducive to commercialization. SUMMARY

[0010] In addition to the above problems, the present inventors, based on the production line of the preparation industry, found that the strong brittleness of fosfomycin varieties leads to poor control of particle size distribution, more fine powder, pollution of the preparation production environment, and influence on production efficiency. When applied to preparation production, it often leads to uneven quality within the batch, and even affects the production of preparation finished products. In the face of this pain point, the inventors have carried out a series of scientific researches, and through a large number of trial attempts, it is found that the addition of soluble cellulose or plasticizer in the preparation of fosfomycin raw materials can solve the problem. In a large number of test processes, the inventors found through comparative study that a certain proportion of soluble fiber and plasticizer can greatly enhance the effect by using a specific freeze-drying curve or spray drying process, and unexpectedly found that it can also significantly reduce the related substance level. Through the technical scheme of the present application, a product with uniform and controllable particle size can be obtained, which is easy to mix evenly in the preparation production mixing step, ensuring the uniformity of the whole batch of preparation product quality. At the same time, when used for aseptic packaging, because of the change of the material properties, the fine powder is reduced, and the preparation clean room environment is no longer challenged by the material in the prior art, such as exceeding the standard of planktonic particles, which seriously affects the production efficiency and increases the cost.

[0011] The technical scheme provided by the present application is as follows: The present application provides a fosfomycin-containing preparation intermediate, which is composed of fosfomycin salt, plasticizer and soluble cellulose substance.

[0012] In one aspect of the present application, a fosfomycin-containing preparation intermediate is provided, which is composed of fosfomycin salt, plasticizer and soluble cellulose substance.

[0013] Further, the fosfomycin salt is sodium fosfomycin, calcium fosfomycin or fosfomycin trometamol salt.

[0014] Further, the plasticizer is one of mannitol, sorbitol, trehalose and sucrose.

[0015] Further, the soluble cellulose substance is one of methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethylmethyl cellulose, hydroxybutylmethyl cellulose and low-substituted-hydroxypropyl cellulose.

[0016] Further, the intermediate composition is as follows: (1) methyl cellulose: mannitol = 1:5-50; (2) methyl cellulose: sorbitol = 1:5-50; (3) methyl cellulose: trehalose = 1:5-50; (4) methyl cellulose: sucrose = 1:5-50; (5) Hydroxypropyl cellulose: mannitol = 1 : 5 - 50; (6) Hydroxypropyl cellulose: sorbitol = 1 : 5 - 50; (7) Hydroxypropyl cellulose: trehalose = 1 : 5 - 50; (8) Hydroxypropyl cellulose: sucrose = 1 : 5 - 50; (9) Hydroxypropylmethyl cellulose: mannitol = 1 : 5 - 50; (10) Hydroxypropylmethyl cellulose: sorbitol = 1 : 5 - 50; (11) Hydroxypropylmethyl cellulose: trehalose = 1 : 5 - 50; (12) Hydroxypropylmethyl cellulose: sucrose = 1 : 5 - 50; (13) Hydroxyethylmethyl cellulose: mannitol = 1 : 5 - 50; (14) Hydroxyethylmethyl cellulose: sorbitol = 1 : 5 - 50; (15) Hydroxyethylmethyl cellulose: trehalose = 1 : 5 - 50; (16) Hydroxyethylmethyl cellulose: sucrose = 1 : 5 - 50; (17) Hydroxybutylmethyl cellulose: mannitol = 1 : 5 - 50; (18) Hydroxybutylmethyl cellulose: sorbitol = 1 : 5 - 50; (19) Hydroxybutylmethyl cellulose: trehalose = 1 : 5 - 50; (20) Hydroxybutylmethyl cellulose: sucrose = 1 : 5 - 50; (21) Low-substitution-hydroxypropyl cellulose: mannitol = 1 : 5 - 50; (22) Low-substitution-hydroxypropyl cellulose: sorbitol = 1 : 5 - 50; (23) Low-substitution-hydroxypropyl cellulose: trehalose = 1 : 5 - 50; (24) Low-substitution-hydroxypropyl cellulose: sucrose = 1 : 5 - 50.

[0017] In a second aspect, the preparation process of the intermediate of the preparation is as follows: a. Dissolve soluble cellulose in water for injection or pure water, slowly heat to 50-70°C, swell for 1-2 hours until completely dissolved and clear, to obtain solution a; add a heat-stable agent (one of mannitol, sorbitol, trehalose, and sucrose) to solution a, stir until completely dissolved to obtain solution b; b. Slowly add phosphomycin salt to solution b to obtain solution c, which is the intermediate of the preparation.

[0018] In a third aspect, the present application provides a method for preparing sodium phosphomycin using the intermediate of the preparation, comprising the following steps: a, connect solution c, i.e. the preparation intermediate, to the spray dryer, set the air inlet volume to 50-200 m3 / hour, the air inlet temperature to 50-80℃, the liquid inlet speed to 2-10 m3 / hour, the spray nozzle aperture to 0.5-3.0 mm, and the atomization pressure to 1.0-3.0 Mpa; b, set the recovery bin pressure to -10--100 Pa, to obtain the phosphomycin salt.

[0019] In a fourth aspect, the preparation process of sodium phosphomycin can also be: a, pass the solution c preparation intermediate through a three-stage filter with a sterilizing filter element, then inject it into a freeze dryer for large-plate freeze drying, and the freeze drying curve is: ; After freeze drying, break the vacuum and collect the material; b, crush the freeze-dried material using a hammer crusher, and select the screen aperture to be φ 0.6-4.0 mm, and the crushing knife to be blunt or knife face, and the cutting knife speed to be 3000-20000 rpm, to obtain the product.

[0020] Through the technical scheme of the present application, the preparation intermediate obtained reduces the brittleness of the material and improves the plasticity of the material, and a product with uniform particle size distribution is obtained. And according to requirements, the parameters of the spray drying and the parameters of the crusher can be adjusted to obtain samples with different particle size distribution ranges. At the same time in the research, unexpectedly, it is found that the technical scheme provided by the present application has lower impurity level of the prepared sample, especially in the long-time crushing process using the crusher, the impurity level is basically not increased. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 It is the particle size distribution determination spectrum of Example 1; Figure 2 It is the particle size distribution determination spectrum of Example 16; Figure 3 It is the particle size distribution determination spectrum of Comparative Example 1; Figure 4 It is the particle size distribution determination spectrum of Comparative Example 2; Figure 5 It is the HPLC related substance detection spectrum of Example 1; Figure 6 It is the HPLC related substance detection spectrum of Comparative Example 2. DETAILED DESCRIPTION

[0022] The present application will be further described below in conjunction with specific examples, it should be pointed out that the following description is only exemplary and does not limit the scope of protection.

[0023] Example 1 (spray drying method, methyl cellulose: mannitol = 1:20) A preparation intermediate of fosfomycin sodium is shown in the following table: .

[0024] Fosfomycin sodium preparation steps: 1. Methyl cellulose is added into water for injection, slowly heated to 60℃, swelled for 1.5 hours until completely dissolved and clear, obtaining solution a; then mannitol is added, stirred until completely dissolved to obtain solution b; 2. Fosfomycin sodium is slowly added into solution b to obtain solution c; 3. Solution c is connected to a spray dryer, with an inlet air flow of 100 m³ / hour, an inlet air temperature of 70℃, an inlet liquid speed of 8 m³ / hour, a spray nozzle diameter of 1.0 mm, and an atomization pressure of 2.0 Mpa; 4. The recovery bin pressure is set to -60 Pa, obtaining a preparation intermediate containing fosfomycin sodium.

[0025] Fosfomycin calcium or fosfomycin trometamol preparation only needs to replace fosfomycin sodium in step 2 with fosfomycin calcium or fosfomycin trometamol.

[0026] Examples 2, 3 (spray drying method, methyl cellulose: mannitol = 1:1 and 1:50) The preparation steps are the same as in Example 1, except that the prescription is shown in the following table: .

[0027] Examples 4-6 (spray drying method, methyl cellulose: different plasticizers = 1:25) The preparation steps are the same as in Example 1, except that the prescription is shown in the following table: .

[0028] Examples 7-11 (spray drying method, different soluble cellulose: mannitol = 1:25) The preparation steps are the same as in Example 1, except that the prescription is shown in the following table: .

[0029] Example 12 (preparation of coarse particle size material) The prescription is the same as in Example 1, and the preparation steps are basically the same as in Example 1, except that the process parameters in step 3 of the preparation are as follows: Solution c is connected to a spray dryer, with an inlet air flow of 50 m³ / hour, an inlet air temperature of 50℃, an inlet liquid speed of 2 m³ / hour, a spray nozzle diameter of 3.0 mm, and an atomization pressure of 1.0 Mpa.

[0030] Example 13 (preparation of fine particle size material) The prescription is the same as example 1, the preparation steps are basically the same as example 1, the difference is that the process parameters in preparation step 3 are as follows: The solution c is connected to the spray dryer, the air inlet is set to 200 m³ / h, the air inlet temperature is 80℃, the liquid inlet speed is 10 m³ / h, the spray nozzle diameter is 0.5 mm, and the atomizing pressure is 3.0 Mpa.

[0031] Example 14 (lyophilization process) The prescription is the same as example 1, the preparation steps are as follows: 1, slowly add methyl cellulose to water for injection, slowly heat to 55℃, swell for 1 hour to completely dissolve and clarify, get solution a; then add mannitol, stir until completely dissolved to get solution b; 2, slowly add fosfomycin salt to solution b to obtain solution c; 3, pass solution c through a three-stage filtration of a sterilizing filter, then inject it into a freeze dryer for large-plate freeze drying, and the freeze-drying curve is: ; After freeze-drying, break the vacuum and collect the material; 4, crush the freeze-dried material, use a hammer crusher, the screen mesh diameter is selected to be φ2.0 mm, and the crushing knife is a knife surface, the cutting knife speed is 12000 rpm, and it is obtained.

[0032] Example 15 (lyophilization process, coarse particle size material preparation) The prescription is the same as example 14, the preparation steps are basically the same as example 14, the difference is that the process parameters in preparation step 4 are as follows: Crush the freeze-dried material, use a hammer crusher, the screen mesh diameter is selected to be φ4.0 mm, and the crushing knife is a knife surface, the cutting knife speed is 3000 rpm, and it is obtained.

[0033] Example 16 (lyophilization process, fine particle size material preparation) The prescription is the same as example 14, the preparation steps are basically the same as example 14, the difference is that the process parameters in preparation step 4 are as follows: Crush the freeze-dried material, use a hammer crusher, the screen mesh diameter is selected to be φ0.6 mm, and the crushing knife is a blunt surface, the cutting knife speed is 20000 rpm, and it is obtained.

[0034] Example 17 The prescription is the same as example 1, the preparation steps are basically the same as example 1, the difference is that the process parameters in preparation steps 1 and 2 are as follows: Add methyl cellulose, mannitol and fosfomycin sodium to water for injection, slowly heat to 55℃, swell for 2 hours to completely dissolve and clarify, and obtain solution for standby.

[0035] Example 18

[0036] The prescription is different from that of Example 1, and the preparation steps are the same as those of Example 1. The specific prescription is shown in the following table: .

[0037] Example 19

[0038] The prescription is different from that of Example 12, and the preparation steps are the same as those of Example 12. The specific prescription is shown in the following table: .

[0039] Example 20

[0040] The prescription is different from that of Example 13, and the preparation steps are the same as those of Example 13. The specific prescription is shown in the following table: .

[0041] Comparative Example 1 Preparation of sodium fosfomycin aqueous solution In a reaction bottle, 150 mL of reverse osmosis water and 86.5 g of sodium hydroxide (2.16 mol) were added, stirred to dissolve, and a clear transparent solution was formed. At a temperature of 38-40°C, 300 g of fosfomycin levamisate monohydrate (1.08 mol) was slowly added under stirring, and the mixture was incubated and stirred for 60 min. After standing and separating the layers, the upper layer was benzylamine, and the lower layer was the sodium fosfomycin aqueous solution.

[0042] Crystallization of sodium fosfomycin Into a crystallization tank, 500 mL of anhydrous ethanol was added as a bottom liquid. At a temperature of 25°C, the sodium fosfomycin aqueous solution and anhydrous ethanol obtained in the above step were respectively sprayed from nozzles located below the ethanol liquid surface by high-pressure pumps through conduits under stirring at a speed of 40 HZ. The pressure of the high-pressure pump for spraying the sodium fosfomycin aqueous solution was controlled at 0.1 MPa, and the pressure of the high-pressure pump for spraying the anhydrous ethanol was controlled at 0.2 MPa. The nozzle for spraying the sodium fosfomycin aqueous solution and the nozzle for spraying the anhydrous ethanol were parallel and located 1 cm apart below the bottom liquid surface to form an atomization counter-spraying space. When 25% of the volume of the sodium fosfomycin aqueous solution was sprayed, the atomization spraying of the sodium fosfomycin aqueous solution and the anhydrous ethanol was stopped, and the stirring speed was adjusted to 10 HZ for 30 min. Then, the stirring speed was adjusted back to 40 HZ, and the sodium fosfomycin aqueous solution and the anhydrous ethanol were continuously atomized and sprayed in opposite directions. After the addition of the sodium fosfomycin aqueous solution and the anhydrous ethanol (total atomization spraying of the anhydrous ethanol was 6000 mL) was completed, the stirring speed was adjusted to 10 HZ, and the crystals were incubated for 2 h. After filtration, washing, and vacuum drying, 183 g of sodium fosfomycin crystals were obtained.

[0043] Comparative Examples 2-3 The sample of fosfomycin sodium obtained in Comparative Example 1 was subjected to a pulverization treatment using a hammer mill to obtain a material having a target particle size. The specific parameters are as follows: .

[0044] Test Example 1 Particle Size Study Measurement environment and inlet gas humidity requirements: ≤ 25% RH.

[0045] Dry laser particle size analyzer: Wavelength: He-Ne gas laser (red light) of 600-650 nm Power: 3-5 mW.

[0046] Measurement parameters: .

[0047] Measurement results: .

[0048] The test results described above show that the particle size distribution of each sample in the examples is concentrated, and from the particle size distribution graph, it can be clearly seen that the particle size distribution of the sample in the examples is more concentrated, and is a single peak.

[0049] Here, it should be noted that using the two different preparation methods in the technical solution of the present application, different particle size samples can be obtained using different spray drying parameters or different hammer mill parameters after freeze-drying, which is more beneficial to the commercialization of the API market enterprise's products, and different particle size products can be customized according to the needs of the preparation enterprise without the need to replace equipment, simple operation, cost reduction, and rich product particle size models.

[0050] From the detection graph, it can be clearly seen that the particle size distribution graph is a double or triple peak, and especially after the pulverization treatment of Comparative Example 2, the particle size D 10 value of the material appears a peak value, representing that the material is extremely easy to break, and in the production of preparations, with the turning of the material, the extrusion of equipment parts, etc., the material layering, environmental space dusting, low production efficiency, etc. will bring many problems, which is not conducive to commercial mass production.

[0051] Test Example 2 Related Substance Study Related substances: The related substances were determined according to the high performance liquid chromatography method. The results are recorded in the following table. The maximum single impurity refers to the maximum single impurity other than the known glycol impurity, and the total impurities refer to the sum of all impurities.

[0052] The detection method is as follows: Test solution: Take the sample of each example and comparative example, accurately weigh, add acetonitrile-10 mM ammonium acetate (1:1) to dissolve and dilute to about 15 mg of fosfomycin (C3H7O4P) per 1 mL of solution, filter, take the filtrate to obtain.

[0053] Control solution: accurately take the test solution, dilute with acetonitrile-10 mmol ammonium acetate (1:1) to about 15 μg of fosfomycin (C3H7O4P) per 1 mL of solution, shake well, and obtain.

[0054] Chromatographic conditions: octadecylsilane bonded (5um, 4.6x150mm) chromatographic column, acetonitrile as mobile phase A, 10 mM ammonium acetate as mobile phase B, linear gradient elution according to the following table; flow rate is 0.7 mL per minute; automatic sampler temperature is 5℃; atomizer temperature is 50℃; acquisition frequency is 10 Hz; temperature is 50℃; injection volume is 10 uL.

[0055] Accurately take the test solution and the control solution, respectively, inject into the liquid chromatograph, and record the chromatogram.

[0056] Gradient elution table: .

[0057] Test results are shown in the following table: .

Claims

1. An intermediate in the preparation of a phosphonium fosfomycin characterized in that, The preparation intermediate is composed of fosfomycin salt, plasticizer, soluble cellulose substance.

2. The formulation intermediate of claim 1, wherein, The fosfomycin salt is fosfomycin sodium, fosfomycin calcium or fosfomycin trometamol salt.

3. The formulation intermediate of claim 1, wherein, The plasticizer is one of mannitol, sorbitol, trehalose and sucrose.

4. The formulation intermediate of claim 1, wherein, The soluble cellulose substance is one of methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethylmethyl cellulose, hydroxybutylmethyl cellulose and low-substitution hydroxypropyl cellulose.

5. The formulation intermediate of any one of claims 1, 3, 4, wherein, The composition is as follows in any mass ratio: (1) methyl cellulose: mannitol = 1:5-50; (2) methyl cellulose: sorbitol = 1:5-50; (3) methyl cellulose: trehalose = 1:5-50; (4) methyl cellulose: sucrose = 1:5-50; (5) hydroxypropyl cellulose: mannitol = 1:5-50; (6) hydroxypropyl cellulose: sorbitol = 1:5-50; (7) hydroxypropyl cellulose: trehalose = 1:5-50; (8) hydroxypropyl cellulose: sucrose = 1:5-50; (9) hydroxypropylmethyl cellulose: mannitol = 1:5-50; (10) hydroxypropylmethyl cellulose: sorbitol = 1:5-50; (11) hydroxypropylmethyl cellulose: trehalose = 1:5-50; (12) hydroxypropylmethyl cellulose: sucrose = 1:5-50; (13) hydroxyethylmethyl cellulose: mannitol = 1:5-50; (14) hydroxyethylmethyl cellulose: sorbitol = 1:5-50; (15) hydroxyethylmethyl cellulose: trehalose = 1:5-50; (16) hydroxyethylmethyl cellulose: sucrose = 1:5-50; (17) hydroxybutylmethyl cellulose: mannitol = 1:5-50; (18) hydroxybutylmethyl cellulose: sorbitol = 1:5-50; (19) hydroxybutylmethyl cellulose: trehalose = 1:5-50; (20) hydroxybutylmethyl cellulose: sucrose = 1:5-50; (21) low-substitution hydroxypropyl cellulose: mannitol = 1:5-50; (22) low-substitution hydroxypropyl cellulose: sorbitol = 1:5-50; (23) low-substitution hydroxypropyl cellulose: trehalose = 1:5-50; (24) low-substitution hydroxypropyl cellulose: sucrose = 1:5-50.

6. A process for the preparation of a formulation intermediate according to any one of claims 1 to 5, characterized in that, The steps include: (1) dissolving the soluble cellulose in water for injection, slowly heating to 50-70℃, swelling for 1-2 hours until completely dissolved and clear, obtaining solution a; adding the heat-stable agent to solution a, stirring until completely dissolved to obtain solution b; (2) slowly adding the fosfomycin salt to solution b to obtain solution c, i.e. the preparation intermediate.

7. A process for the preparation of fosfomycin sodium using the intermediate of any one of claims 1 to 5, characterized in that, The steps include: (1) connecting the preparation intermediate solution to the spray dryer, setting the air inlet volume to 50-200 m³ / hour, the air inlet temperature to 50-80℃, the liquid inlet speed to 2-10 m³ / hour, the spray nozzle diameter to 0.5-3.0 mm and the atomization pressure to 1.0-3.0 Mpa; (2) setting the recovery bin pressure to -10--100 Pa to obtain the fosfomycin salt-containing product.

8. A process for the preparation of fosfomycin sodium using the intermediate of any one of claims 1 to 5, characterized in that, The steps include: (1) The preparation intermediate solution is filtered through a three-stage filter, and then is injected into a freeze dryer for large-plate freeze drying. The freeze drying curve is as follows: Pre-freezing stage: temperature -35--45℃, cooling time 60 min, holding time 180-240 min; Sublimation drying stage: temperature -15--10℃, cooling time 30 min, holding time 300-360 min, 0.10-0.50 mbar; Desorption drying stage: temperature 25-60℃, cooling time 60 min, holding time 240-360 min, 0.10-0.30 mbar; Temperature -5-0℃, cooling time 30 min, holding time 60-90 min, 0.10-0.30 mbar; Temperature 25-35℃, cooling time 30 min, holding time 120-180 min, 0.05-0.15 mbar; Freeze drying is completed, the vacuum is broken, and the product is collected; (2) The freeze-dried material is crushed, a hammer crusher is used, the screen mesh aperture is selected to be φ0.6-4.0 mm, the crushing knife is a blunt surface or a knife surface, and the cutter rotating speed is 3000-20000 rpm, thereby obtaining the product.

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