Crystal form of fosfomycin sodium, preparation method and application thereof

Abstract

The present invention belongs to the field of pharmaceutical synthesis technology, and in particular to a new crystal form of fosfomycin sodium and its preparation method and application. The X-ray powder diffraction pattern of the new crystal form of fosfomycin sodium has characteristic peaks at the following 2θ angle positions: 6.59 ± 0.2°, 6.90 ± 0.2°, 15.88 ± 0.2°, 18.43 ± 0.2°, 18.72 ± 0.2°, 20.94 ± 0.2° and 30.65 ± 0.2°. Its preparation method includes: fosfomycin left phosphorus right amine salt is dissolved in sodium hydroxide aqueous solution, liquid separation, water layer is added to alcohol solvent and stirred for crystallization, filter cake is washed after filtration, filter cake is passed through saturated water nitrogen and purged to the filter cake surface to appear molten state, vacuum drying, obtains fosfomycin sodium new crystal form. Fosfomycin sodium provided by the present invention is a hemihydrate crystal form, and its hygroscopicity is low, which is more conducive to subpackaging and mixing in production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a new crystal form of fosfomycin sodium and a preparation method and application thereof. Background Art

[0002] Fosfomycin is a new broad-spectrum antibiotic structurally classified as a phosphate derivative. It inhibits early bacterial cell wall synthesis, hindering cell wall synthesis and leading to bacterial death. It exhibits moderate antibacterial activity against Gram-positive bacteria such as Staphylococci, Streptococci, and Enterococcus faecalis, as well as Gram-negative bacteria such as Escherichia coli, Serratia, Shigella, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Currently, there are four main types of fosfomycin: fosfomycin sodium salt, fosfomycin calcium salt, fosfomycin tromethamine salt, and fosfomycin benzylamine salt.

[0003] Fosfomycin sodium, chemical name is (1R, 2S)-1,2-epoxypropylphosphonic acid disodium salt, molecular formula is Na2C3H5O4P, molecular weight is 182.02, and molecular structure is shown in Formula I.

[0004]

[0005] Ⅰ.

[0006] Fosfomycin sodium binds to a bacterial cell wall synthase, hindering the first step in the bacterial cell wall synthesis process, thereby exerting a bactericidal effect. It has antibacterial activity against Staphylococci, Streptococcus pneumoniae, Escherichia coli, Neisseria gonorrhoeae, Proteus mirabilis, Salmonella typhi, Serratia marcescens, most Pseudomonas aeruginosa, Streptococcus pyogenes, Streptococcus faecalis, some indole-positive Proteus, and certain Klebsiella and Enterobacter species. Fosfomycin sodium is primarily used clinically to treat infections of the urinary tract, urinary system, skin and soft tissue, respiratory tract, and intestinal tract caused by susceptible Gram-negative bacteria. It can also be used in combination with other antibiotics to treat severe infections caused by susceptible bacteria, such as sepsis, lung and meningeal infections, peritonitis, adnexitis, intrauterine infections, pelvic inflammatory disease, and osteomyelitis. It can also be used in combination with vancomycin to treat methicillin-resistant Staphylococcus aureus (MRSA) infections.

[0007] Patent CN118290481A discloses a method for crystallizing fosfomycin sodium, comprising: reacting fosfomycin fosfomycin amine salt with sodium hydroxide in water to release fosfomycin sodium, followed by phase separation to obtain a fosfomycin sodium aqueous solution; then, using a high-pressure pump, spray-crystallize the fosfomycin sodium aqueous solution with ethanol, followed by filtration, washing, and drying to obtain white fosfomycin sodium crystals. This invention utilizes spray-crystallization and segmented crystallization to control the crystallization rate and ensure complete crystal growth.

[0008] Fosfomycin sodium prepared in existing public materials is highly hygroscopic and easily deliquesces in air. This places very high demands on the environmental conditions of production processes such as granulation, packaging, sampling, and testing, requiring strict humidity control. Otherwise, deliquesce is easily caused by air humidity. Therefore, developing a new crystalline form of fosfomycin sodium with low hygroscopicity is an urgent issue to be addressed. Summary of the Invention

[0009] In view of this, one of the objects of the present invention is to provide a new crystal form of fosfomycin sodium, which has low hygroscopicity and good stability.

[0010] To achieve the above object, the present invention adopts the following technical solutions:

[0011] A new crystal form of fosfomycin sodium, wherein the X-ray powder diffraction pattern of the new crystal form has characteristic peaks at the following 2θ angle positions: 6.59±0.2°, 6.90±0.2°, 15.88±0.2°, 18.43±0.2°, 18.72±0.2°, 20.94±0.2° and 30.65±0.2°.

[0012] The new crystal form is fosfomycin sodium hemihydrate crystal form.

[0013] Preferably, the X-ray powder diffraction pattern of the new crystal form has characteristic peaks at the following 2θ angle positions: 6.59±0.2°, 6.90±0.2°, 12.01±0.2°, 13.89±0.2°, 15.88±0.2°, 18.43±0.2°, 18.72±0.2°, 19.98±0.2°, 20.94±0.2°, 23.42±0.2°, 24.23±0.2°, 25.24±0.2°, 25.64 ±0.2°, 26.74±0.2°, 28.29±0.2°, 29.14±0.2°, 30.65±0.2°, 31.62±0.2°, 32.19±0.2°, 33.99±0.2°, 34.47±0.2°, 35.43±0.2°, 36.74±0.2°, 37.44±0.2°, 38.73±0.2°, 39.59±0.2°, 40.29±0.2°, 40.69±0.2°, 42.19±0.2°, 43.34±0.2°, 43.86±0.2°, 44.52±0.2°, 45.27±0.2°, 45.71±0.2°, 46.26±0.2°, 47.04±0.2°, 47.97±0.2°, 49.29±0.2°, 52.03±0.2°, 52.56±0.2°, 52.92±0.2°, 53.99±0.2°, 54.53±0.2°, 55.56 ±0.2°, 56.69±0.2°, 59.04±0.2°, 59.71±0.2°, 60.51±0.2°, 61.64±0.2°, 62.49±0.2°, 62.89±0.2°, 63.93±0.2°, 65.81±0.2°, 67.27±0.2°, 68.97±0.2°, 69.58±0.2°, 73.55±0.2°, 75.19±0.2°, and 88.20±0.2°.

[0014] Preferably, the DSC spectrum of the new crystal form has a main endothermic peak at 131.82°C, and weight loss occurs at 124.60°C~142.98°C.

[0015] Preferably, the X-ray powder diffraction pattern of the new crystal form is as follows Figure 1 As shown; the DSC spectrum of the new crystal form is as shown Figure 3 shown.

[0016] A second object of the present invention is to provide a method for preparing a new crystal form of fosfomycin sodium.

[0017] To achieve the above object, the present invention adopts the following technical solutions:

[0018] The preparation method of the new crystal form of fosfomycin sodium comprises the following steps:

[0019] (1) adding fosfomycin fosfomycin amine salt to a sodium hydroxide aqueous solution, separating the liquids to obtain an aqueous layer;

[0020] (2) adding the aqueous layer obtained in step (1) into an alcohol solvent, stirring and crystallizing, filtering and washing to obtain a filter cake;

[0021] (3) The filter cake obtained in step (2) is purged with saturated water and nitrogen until a molten state appears on the surface of the filter cake, and then vacuum dried to obtain a new crystal form of fosfomycin sodium.

[0022] Preferably, the ratio of the volume of the alcohol solvent to the mass of the fosfomycin fosfomycin amine salt is 10-40:1; and the alcohol solvent is ethanol.

[0023] Preferably, the ratio of the volume of the alcohol solvent to the mass of the fosfomycin fosfomycin amine salt is 20-30:1.

[0024] Preferably, in step (1), the mass ratio of the fosfomycin fosfomycin salt to the sodium hydroxide aqueous solution is 1:1-5, more preferably 1:1.5.

[0025] Preferably, in step (1), the concentration of the sodium hydroxide aqueous solution is 20%.

[0026] Preferably, in step (2), the aqueous layer is added to an alcohol solvent at 30-70°C and stirred for crystallization; the crystallization conditions are: stirring at 30-70°C for 0.5-3h.

[0027] Preferably, in step (2), the aqueous layer is added to an alcohol solvent at 40-60°C and stirred for crystallization; the crystallization conditions are: stirring at 40-60°C for 2 hours.

[0028] Preferably, in step (2), ethanol is used for washing.

[0029] Preferably, the filter cake absorbs water during the purge with saturated water-nitrogen gas and undergoes crystal transformation to form a hemihydrate crystal form.

[0030] Preferably, in step (3), the saturated water nitrogen purge time is 1-5 hours, more preferably 2 hours.

[0031] Preferably, in step (3), the wet powder is vacuum dried at 50°C and -0.08 to -0.1 MPa for 12 h.

[0032] As a preferred solution, the preparation method of the new crystal form of fosfomycin sodium comprises the following steps:

[0033] (1) Add phospho-dextran to sodium hydroxide aqueous solution and stir to dissolve. After the solution is clear, let it stand, separate the liquids, and take the water layer.

[0034] (2) Stirring the ethanol and heating it to 40-60°C. After the temperature rises, add the ethanol to the aqueous layer obtained in step (1) while stirring, keep it at 40-60°C and stir for 1 hour, filter, wash, and obtain a filter cake;

[0035] (3) The filter cake obtained in step (2) is purged with saturated water and nitrogen for 2 h until a molten state appears on the surface of the filter cake; the wet powder is vacuum dried to obtain a new crystal form of fosfomycin sodium.

[0036] A third object of the present invention is to provide a new crystal form of fosfomycin sodium for use in the preparation of antibacterial drugs.

[0037] Preferably, the antibacterial agents include any one or more of Staphylococcus, Streptococcus pneumoniae, Escherichia coli, Neisseria gonorrhoeae, Proteus mirabilis, Salmonella typhi, Serratia marcescens, Pseudomonas aeruginosa, Streptococcus pyogenes, Streptococcus faecalis, indole-positive Proteus, Klebsiella, and Enterobacter.

[0038] The beneficial effects of the present invention are:

[0039] To overcome the problems of existing fosfomycin sodium, such as its strong hygroscopicity and easy deliquesce in air, the present invention has developed a new crystalline form of fosfomycin sodium. This new crystalline form of fosfomycin sodium is a hemihydrate, characterized by low hygroscopicity of approximately 0.8% over 12 hours and approximately 1.6% over 24 hours. This improves its stability in air and facilitates packaging and mixing during production. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 This is the XRD pattern of the fosfomycin sodium finished product prepared in Example 1.

[0041] Figure 2 This is the XRD pattern of the fosfomycin sodium finished product prepared in Comparative Example 1.

[0042] Figure 3 This is the DSC diagram of the fosfomycin sodium finished product prepared in Example 1.

[0043] Figure 4 The liquid chromatogram of the fosfomycin sodium finished product prepared in Example 1. DETAILED DESCRIPTION

[0044] The technical solutions of the present invention will be further described in detail below with reference to specific embodiments. Obviously, the embodiments described are only some of the embodiments of the present invention, not all of them. Therefore, all other embodiments derived by those skilled in the art based on the embodiments of the present invention without inventive effort are intended to fall within the scope of protection of the present invention.

[0045] In the examples of the present invention, if no specific techniques or conditions are specified, the techniques or conditions described in the literature in this field or the product instructions are used. If the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be purchased commercially.

[0046] In the embodiments of the present invention, the temperature is room temperature (15-35° C.) unless otherwise specified.

[0047] In the embodiment of the present invention, the conditions of the X-ray diffractometer are as follows: the instrument model is MiniFlex600, the manufacturer is Rigaku, Japan, the voltage is 40 kV, the current is 15 mA, the scanning range (2θ): 3-90°, and the step size is 0.02°.

[0048] Example 1. Preparation of a new crystalline form of fosfomycin sodium

[0049] (1) Add 10g of phospho-2-aminobenzylamine salt to 15g of sodium hydroxide aqueous solution (20%) and stir to dissolve. After the solution is clear, let it stand and separate the liquids to take the water layer.

[0050] (2) Stir 300 ml of ethanol and heat it to 40°C. After the temperature rises to 40°C, add the ethanol to the aqueous layer obtained in step (1) with stirring, and keep stirring at 40°C for 1 hour.

[0051] (3) Filtration, washing the filter cake with ethanol (20 ml), and blowing saturated water nitrogen into the filter cake for 2 h until the surface of the filter cake is molten; the wet powder is dried at 50 ° C under vacuum (-0.08 ~ -0.1 MPa) for 12 h to obtain 6.1 g of fosfomycin sodium finished product; its moisture content is 4.82%, the yield is 92.92%, and the purity is 99.8%.

[0052] The XRD pattern of the fosfomycin sodium product obtained in this example is as follows: Figure 1 As shown, the specific data are shown in Table 1; its liquid phase spectrum is as follows Figure 4 The specific data are shown in Table 2; its DSC spectrum is shown in Figure 3 As shown, there is a major endothermic peak at 131.82°C, and a weight loss of 4.5285% occurs between 124.60°C and 142.98°C. The weight loss is 4.82% based on the moisture content. This weight loss is water of crystallization. Based on the moisture content and weight loss, the crystal contains 0.5 units of water of crystallization, indicating that this crystal form is fosfomycin sodium hemihydrate. The original fosfomycin sodium crystal form is an anhydrous form.

[0053] Table 1. Characteristic peak data of X-ray powder diffraction of fosfomycin sodium crystal form

[0054]

[0055] Table 2. Figure 4 Points results table

[0056]

[0057] Example 2. Preparation method of a new crystal form of fosfomycin sodium

[0058] (1) Add 10g of phospho-2-aminobenzylamine salt to 15g of sodium hydroxide aqueous solution (20%) and stir to dissolve. After the solution is clear, let it stand and separate the liquids to take the water layer.

[0059] (2) Stir 200 ml of ethanol and heat it to 60°C. After the temperature rises to , add the ethanol to the aqueous layer obtained in step (1) while stirring, and keep stirring at 60°C for 1 hour.

[0060] (3) Filtration, washing the filter cake with ethanol (20 ml), and blowing saturated water nitrogen into the filter cake for 2 h until the surface of the filter cake is molten; the wet powder is dried at 50 ° C in a vacuum (-0.08 ~ -0.1 MPa) for 12 h to obtain 5.9 g of fosfomycin sodium finished product; its moisture content is 4.66%, the yield is 89.87%, and the purity is 99.8%.

[0061] After testing, the XRD pattern of the fosfomycin sodium finished product obtained in this embodiment is consistent with Figure 1 Basically the same.

[0062] Comparative Example 1

[0063] (1) Add 10g of phospho-2-aminobenzylamine salt to 15g of sodium hydroxide aqueous solution (20%) and stir to dissolve. After the solution is clear, let it stand and separate the liquids to take the water layer.

[0064] (2) Stir 200 ml of anhydrous ethanol and heat it to 60°C. Then, add the aqueous layer obtained in step (1) dropwise to the anhydrous ethanol for crystallization. Keep stirring at 60°C for 1 hour.

[0065] (3) Filter and wash the filter cake with anhydrous ethanol (20 ml); dry the wet powder at 50 ° C under vacuum (-0.08 ~ -0.1 MPa) for 12 h to obtain 5.46 g of fosfomycin sodium finished product with a moisture content of 0.38%, a yield of 83.17%, and a purity of 99.8%. Its XRD pattern is as follows Figure 2 shown.

[0066] Comparative Example 2

[0067] (1) Add 10g of phospho-2-aminobenzylamine salt to 15g of sodium hydroxide aqueous solution (20%) and stir to dissolve. After the solution is clear, let it stand and separate the liquids to take the water layer.

[0068] (2) Stir 200 ml of anhydrous ethanol and heat it to 60°C. Then add the ethanol to the aqueous layer obtained in step (1) while stirring, and keep stirring at 60°C for 1 hour.

[0069] (3) Filter and wash the filter cake with anhydrous ethanol (20 ml); dry the wet powder at 50 ° C under vacuum (-0.08 ~ -0.1 MPa) for 12 h to obtain 5.52 g of fosfomycin sodium product; its moisture content is 0.44%, the yield is 84.08%, and the purity is 99.8%.

[0070] After testing, the XRD pattern of the fosfomycin sodium finished product obtained in this comparative example is Figure 2 Basically the same.

[0071] Example 3. Product Moisture and Hygroscopicity Test

[0072] The products obtained from the above examples and comparative examples were tested for moisture and hygroscopicity.

[0073] (1) Moisture content was measured using a Karl Fischer moisture analyzer (Mettler-Toledo, model V20S).

[0074] (2) X-ray diffractometer conditions: The instrument model is MiniFlex600, manufactured by Rigaku Corporation, Japan, voltage 40 kV, current 15 mA, scanning range (2θ): 3-90°, step size 0.02°.

[0075] (3) Hygroscopicity test method: Place a certain mass of the sample to be tested in an open bottle, and then place the open bottle in a constant temperature dryer filled with a saturated ammonium chloride aqueous solution. After placing it at 25±1℃ for 24 hours, weigh the weight of the sample after absorbing moisture in the constant temperature dryer.

[0076] The calculation formula of hygroscopicity is: (weight of sample after absorbing moisture in the constant temperature dryer - weight of sample before absorbing moisture in the constant temperature dryer) ÷ weight of sample before absorbing moisture in the constant temperature dryer × 100%.

[0077] The test results of moisture and hygroscopicity are shown in Table 3. As can be seen from Table 3, compared with the comparative example product, the new crystal form of fosfomycin sodium prepared by the method of the present invention has lower hygroscopicity and better stability. The preparation method of the present invention is characterized in that the filter cake absorbs water during the saturated water-nitrogen purge process and undergoes crystal transformation to form a hemihydrate crystal form.

[0078] Table 3. Moisture and moisture absorption test results

[0079]

Claims

1. A crystalline form of fosfomycin sodium, characterized in that: The X-ray powder diffraction pattern of the crystal form has characteristic peaks at the following 2θ angle positions: 6.59±0.2°, 6.90±0.2°, 15.88±0.2°, 18.43±0.2°, 18.72±0.2°, 20.94±0.2° and 30.65±0.2°; the crystal form is a hemihydrate crystal form.

2. The crystal form according to claim 1, characterized in that The X-ray powder diffraction pattern of the crystalline form has characteristic peaks at the following 2θ angle positions: 6.59±0.2°, 6.90±0.2°, 12.01±0.2°, 13.89±0.2°, 15.88±0.2°, 18.43±0.2°, 18.72±0.2°, 19.98±0.2°, 20.94±0.2°, 23.42±0.2°, 24.23±0.2°, 25.24±0.2°, 25.64±0.2 °, 26.74±0.2°, 28.29±0.2°, 29.14±0.2°, 30.65±0.2°, 31.62±0.2°, 32.19±0.2°, 33.99±0.2°, 34.47±0.2°, 35.43±0.2°, 36.74±0.2°, 37.44±0.2°, 38.73±0.2°, 39.59±0.2°, 40.29±0.2°, 40.69±0.2°, 42 .19±0.2°, 43.34±0.2°, 43.86±0.2°, 44.52±0.2°, 45.27±0.2°, 45.71±0.2°, 46.26±0.2°, 47.04±0.2°, 47.97±0.2°, 49.29±0.2°, 52.03±0.2°, 52.56±0.2°, 52.92±0.2°, 53.99±0.2°, 54.53±0.2°, 55.56± 0.2°, 56.69±0.2°, 59.04±0.2°, 59.71±0.2°, 60.51±0.2°, 61.64±0.2°, 62.49±0.2°, 62.89±0.2°, 63.93±0.2°, 65.81±0.2°, 67.27±0.2°, 68.97±0.2°, 69.58±0.2°, 73.55±0.2°, 75.19±0.2°, and 88.20±0.2°.

3. The crystal form according to claim 1, characterized in that The DSC spectrum of the crystal form has a main endothermic peak at 131.82°C, and weight loss occurs at 124.60°C~142.98°C.

4. The crystal form according to claim 1, characterized in that The X-ray powder diffraction pattern of the crystal form is shown in FIG1 ; the DSC spectrum of the crystal form is shown in FIG3 .

5. The method for preparing the crystal form according to any one of claims 1 to 4, characterized in that: The steps include: (1) adding fosfomycin fosfomycin amine salt to a sodium hydroxide aqueous solution, separating the liquids to obtain an aqueous layer; (2) adding the aqueous layer obtained in step (1) into an alcohol solvent, stirring and crystallizing, filtering and washing to obtain a filter cake; (3) The filter cake obtained in step (2) is purged with saturated water and nitrogen until a molten state appears on the surface of the filter cake, and then vacuum dried to obtain a crystalline form of fosfomycin sodium.

6. The preparation method according to claim 5, characterized in that The ratio of the volume of the alcohol solvent to the mass of the fosfomycin fosfomycin amine salt is 10-40:1; and the alcohol solvent is ethanol.

7. The preparation method according to claim 5, characterized in that In step (2), the aqueous layer is added to an alcohol solvent at 30-70°C and stirred for crystallization; the crystallization conditions are: stirring at 30-70°C for 0.5-3h.

8. The preparation method according to claim 5, characterized in that The filter cake absorbs water and undergoes crystallization during the purge process using saturated water nitrogen to form a hemihydrate crystal form.

9. The preparation method according to claim 5, characterized in that In step (3), the saturated water nitrogen purge time is 1-5h.

10. Use of the crystal form of fosfomycin sodium according to any one of claims 1 to 4 in the preparation of antibacterial drugs.

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