New sulfamonomethoxine sodium crystal form and preparation method thereof

Abstract

The invention provides an ethanol solvate of sulfamonomethoxine and a method for preparing the ethanol solvate of sulfamonomethoxine. The invention relates to a sulfamonomethoxine sodium crystal, in particular to an ethanol solvate of 4-amino-N-(2, 6-dimethoxy-4-pyrimidine) benzenesulfonamide monosodium salt, the crystal serving as a seed crystal can improve the crystallization process of sulfamonomethoxine sodium and has good fluidity, the obtained material has no obvious hygroscopicity, the preparation process is simple and easy to implement, and the crystal is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a new crystal form of sulfamethoxazole sodium and a preparation method thereof. Background Art

[0002] Sulfonamide antibiotics are available in many varieties and in large quantities. They are effective broad-spectrum synthetic antibiotics that are highly sensitive to streptococci, pneumococci, salmonella, and Corynebacterium pyogenes. They have significant therapeutic effects on certain infectious diseases including epidemic meningitis and plague.

[0003] Sulfadimethoxine sodium, chemical name is 4-amino-N-(2,6-dimethoxy-4-pyrimidine)benzenesulfonamide monosodium salt, its structural formula is as follows:

[0004]

[0005] Many documents have reported on the pharmacological effects of sulfamethoxazole sodium, such as the Japanese Journal of Veterinary Science, 1964, 26(2). It reported the changes in drug concentration in hens after oral administration of sulfamethoxazole sodium.

[0006] Sulfadimethoxine is a poorly water-soluble substance. After being prepared as sodium sulfadimethoxine, it exhibits good solubility in water. However, existing processes for the crystallization of sodium sulfadimethoxine result in a long induction period, resulting in very fine crystals that are difficult to stir, absorb water, and filter. Therefore, research into improving the crystallization process of sulfadimethoxine using a seeding method is of great significance. Summary of the Invention

[0007] In order to solve the above technical problems, the present invention provides a new crystal form of sulfamethoxazole sodium and a preparation method thereof.

[0008] First, the present invention provides a new crystal form of sulfamethoxazole sodium, which is an ethanol solvate of sulfamethoxazole sodium, characterized by having an X-ray diffraction pattern with characteristic peaks at 5.78, 9.15, 10.20, 15.74, 17.40, 20.73 and 24.13°2θ±0.20°.

[0009] The above-mentioned new crystal form of sulfamethoxazole sodium has X-ray diffraction patterns at 5.78, 9.15, 10.20, 11.53, 11.64, 12.34, 15.74, 16.08, 16.96, 17.40, 17.85, 18.63, 18.90, 19.61, 20.07, 21.24, 21.60, 22.12, 23.14, 23.14, 23.51, 24.13, 24.80 , 25.00, 25.39, 26.20, 26.42, 26.98, 27.19, 27.55, 27.84, 28.07, 28.83, 29.20, 29.83, 30.37, 31.10, 31.67, 31.90, 32.30, 32.91, 33.66, 34.36, 35.00, 36.63, 37.13, 38.50, and 39.38 ± 0.2 degrees 2θ.

[0010] The gas phase detection residual solvent of the new crystal form of sulfamethoxazole sodium contains about 60,000 ppm of ethanol.

[0011] Sulfadimethoxine type Ethanol residue / ppm Existing process 890 Solvent compounds 63450

[0012] The moisture content of the new crystalline form of sulfamethoxazole sodium increased by 0.08% after being sealed and stored without nitrogen protection for 14 days.

[0013] During the production process, sulfadimethoxine sodium prepared by the existing process will deliquesce when stored without nitrogen protection.

[0014]

[0015] Secondly, the present invention provides a method for preparing sulfamethoxazole sodium alcohol solvate, comprising the following steps:

[0016] (1) dissolving the solid base in an alcohol solvent, and adding sulfadimethoxine to the alcohol solvent containing the base;

[0017] (2) cooling and adding crystalline sulfadimethoxine to induce crystallization;

[0018] (3) Heating and heat preservation;

[0019] (4) Slowly cool down, filter, and store after vacuum drying.

[0020] Among them, preferably, the base is NaOH and the alcohol reagent is ethanol.

[0021] Wherein, the mass ratio of the solid base to the alcohol solvent in the above step (1) is in the range of 0.004:1 to 0.005:1.

[0022] Wherein, the water content of the alcohol solvent in the above step (1) is 4-6%.

[0023] Wherein, the solid dissolving temperature in the above step (1) is 50-80°C.

[0024] Wherein, the mass ratio of sulfamethoxazole solid to alcohol solvent in the above step (1) is in the range of 1:3.0 to 1:3.05.

[0025] Wherein, the temperature after cooling in the above step (2) is 25-30°C.

[0026] Wherein, the heating temperature in the above step (3) is 70-80°C.

[0027] The heat preservation time of the above step (3) is 1 to 2 hours.

[0028] Wherein, the temperature after cooling in the above step (4) is 0-5°C.

[0029] Wherein, the vacuum drying temperature in the above step (4) is 60°C.

[0030] Furthermore, the present invention provides a process for preparing sulfamethoxazole sodium by using an alcohol solvate, comprising the following steps:

[0031] 1) dissolving the solid base in an alcohol solvent, adding sulfadimethoxine to the alcohol solvent containing the base, filtering, and rinsing with the alcohol solvent;

[0032] 2) After filtering, heating and dissolving the clear solution, adding seed crystals of sulfamethoxazole sodium alcohol solvate, and keeping the temperature to crystallize;

[0033] 3) Slowly cool and filter, and store the material after vacuum drying.

[0034] Among them, preferably, the base is NaOH and the alcohol reagent is ethanol.

[0035] Wherein, the mass ratio of the solid base to the alcohol reagent in the above step 1) is in the range of 0.004:1 to 0.005:1.

[0036] Wherein, the water content of the alcohol reagent in the above step 1) is 4-6%.

[0037] Wherein, the solid alkali dissolution temperature in the above step 1) is 50-80°C.

[0038] The mass ratio of the sulfamethoxazole solid to the eluent alcohol reagent in the above step 1) is in the range of 1:1.4 to 1:1.5.

[0039] Wherein, the mass ratio of sulfamethoxazole solid to alcohol reagent in the above step 1) is in the range of 1:3.0 to 1:3.05.

[0040] Wherein, the water content of the alcohol reagent in the eluent of step 1) is 4-6%.

[0041] The solid dissolution temperature of sulfamethoxazole in step 2) is 50-80°C.

[0042] Wherein, the crystallization temperature of the sulfamethoxazole solvent compound in the above step 2) is 50-80°C.

[0043] The technical effect of the present invention is that an ethanol solvate of sulfamethoxazole sodium is prepared during the process of studying the crystal form of sulfamethoxazole sodium. The crystal can be used as a seed crystal to improve the crystallization process of sulfamethoxazole sodium, has good fluidity, and the obtained material has no obvious hygroscopicity, thereby solving the deliquescence problem of the prior art. The preparation process is simple and easy, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 The X-ray powder diffraction (PXRD) pattern of the ethanol solvate of sulfamethoxazole sodium in Example 1 of the present invention is shown in FIG.

[0045] Figure 2 The present invention is the X-ray powder diffraction (PXRD) pattern of sulfamethoxazole sodium in the prior art.

[0046] Figure 3 The HPLC spectrum of the ethanol solvate of sulfamethoxazole sodium in Example 1 of the present invention is shown in FIG.

[0047] Figure 4 The present invention is an HPLC spectrum of sulfamethoxazole sodium in the prior art.

[0048] Figure 5 This is the infrared spectrum of the ethanol solvate of sulfamethoxazole sodium in Example 1 of the present invention.

[0049] Figure 6 The infrared spectrum of sulfamethoxazole sodium in the prior art is shown in FIG. DETAILED DESCRIPTION

[0050] To further understand the present invention, the following describes in detail a novel crystalline form of sulfamethoxazole sodium and its preparation method provided by the present invention in conjunction with the following examples. It should be understood that these examples are merely provided to further illustrate the features of the present invention and are not intended to limit the scope of the present invention or the scope of the claims.

[0051] Example 1:

[0052] Place 6.5g of flake caustic soda and 150g of ethanol in a 500ml flask, heat to 50°C, and hold for 30 minutes. Add 50g of sulfadimethoxine and stir until dissolved. Hold for at least 1 hour. Filter with suction, add 70g of ethanol to the filtrate, heat the filtrate to 50°C, and add 0.5g of seed crystals after dissolving. Maintain the internal temperature at 45-50°C and hold for 1 hour. After a large amount of material precipitates, cool to 0-5°C. Cool to 0-5°C, and hold for 1 hour. Filter with suction and rinse with the mother liquor. Dry the wet product to yield 48.10g, a 96% yield.

[0053] Example 2:

[0054] Place 7g of flake caustic soda and 150g of ethanol in a 500ml flask, heat to 50°C and hold for 40 minutes. Add 50g of sulfadimethoxine and stir until dissolved. Hold for at least 1 hour. Filter with suction, add 70g of ethanol to the filtrate, heat the filtrate to 50°C and dissolve until clear, then add 0.6g of seed crystals. Maintain the internal temperature at 50-55°C and hold for 1 hour. After a large amount of material precipitates, cool to 0-5°C. Cool to 0-5°C and hold for 1 hour. Filter with suction and rinse with the mother liquor. Dry the wet product to yield 47.65g, a 95.3% yield.

[0055] Example 3:

[0056] In a 500ml flask, place 6.5g of caustic soda flakes, 145g of ethanol, and 5g of water. Heat to 50°C and hold for 30 minutes. Add 50g of sulfadimethoxine and stir until dissolved. Hold for at least 1 hour. Filter with suction, add 70g of ethanol to the filtrate, heat the filtrate to 50°C, and after dissolving, add 0.6g of seed crystals. Maintain the internal temperature at 50-55°C and hold for 1 hour. After a large amount of material precipitates, cool to 0-5°C. Cool to 0-5°C and hold for 1 hour. Filter with suction and rinse with the mother liquor. Dry the wet product to yield 45.60g, a yield of 91.2%.

Claims

1. A new crystal form of sulfamethoxazole sodium, which is an ethanol solvate of sulfamethoxazole sodium, characterized in that It has an X-ray diffraction pattern with characteristic peaks at 5.78, 9.15, 10.20, 15.74, 17.40, 20.73 and 24.13° 2θ±0.20°.

2. The new crystal form of sulfadimethoxine sodium according to claim 1, characterized in that It has an X-ray diffraction pattern shown in FIG1 .

3. A method for preparing sulfamethoxazole sodium alcohol solvate, comprising the following steps: (1) dissolving the solid base in an alcohol solvent, and adding sulfadimethoxine to the alcohol solvent containing the base; (2) cooling and adding crystalline sulfadimethoxine to induce crystallization; (3) Heating and heat preservation; (4) Slowly cool down, filter, and store after vacuum drying.

4. The method for preparing sulfamethoxazole sodium alcohol solvate according to claim 3, wherein: The above-mentioned base is NaOH, and the alcohol reagent is ethanol.

5. The method for preparing sulfamethoxazole sodium alcohol solvate according to claim 3, wherein: The mass ratio of the solid base to the alcohol solvent in the above step (1) is in the range of 0.004:1 to 0.005:1, and the mass ratio of the sulfamethoxazole solid to the alcohol solvent in the step (1) is in the range of 1:3.0 to 1:3.

05.

6. The method for preparing sulfamethoxazole sodium alcohol solvate according to claim 3, wherein: The solid dissolving temperature in the above step (1) is 50-80°C.

7. The method for preparing sulfamethoxazole sodium alcohol solvate according to claim 3, wherein: After cooling in step (2), the temperature is 25-30°C.

8. The method for preparing sulfamethoxazole sodium alcohol solvate according to claim 3, wherein: The heating temperature in the above step (3) is 70-80° C. and the holding time is 1-2 h.

9. The method for preparing sulfamethoxazole sodium alcohol solvate according to claim 3, wherein: The temperature after cooling in the above step (4) is 0-5°C, and the vacuum drying temperature in step (4) is 60°C.

10. An improved process for preparing sulfamethoxazole sodium by using an alcohol solvate, comprising the following steps: 1) dissolving the solid base in an alcohol solvent, adding sulfadimethoxine to the alcohol solvent containing the base, filtering, and rinsing with the alcohol solvent; 2) After filtering, heating and dissolving the clear solution, adding seed crystals of sulfamethoxazole sodium alcohol solvate, and keeping the temperature to crystallize; 3) Slowly cool and filter, and store the material after vacuum drying.

11. The process according to claim 10, characterized in that: The above-mentioned base is NaOH, and the alcohol reagent is ethanol.

12. The process according to claim 10, characterized in that: The mass ratio of the solid base to the alcohol solvent in the above step 1) is in the range of 0.004:1 to 0.005:1, the mass ratio of the sulfamethoxazole solid to the alcohol solvent in the step 1) is in the range of 1:3.0 to 1:3.05, and the mass ratio of the sulfamethoxazole solid to the eluent in the step 1) is in the range of 1:1.4 to 1:1.

5.

13. The process according to claim 10, characterized in that: The solid dissolving temperature in the above steps 1) and 2) is 50-80°C.

14. The process according to claim 10, characterized in that: The water content of the alcohol solvent in the eluent in step 2) is 4-6%.

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