Method for recovering effective components from oxacillin sodium mother liquor

Abstract

A method for recovering effective components from oxacillin sodium mother liquor belongs to the technical field of medicine manufacturing, and comprises the following steps: S1, heating the oxacillin sodium mother liquor, and carrying out reduced pressure distillation; adding water into the kettle residue, stirring, standing for layering, and obtaining a water phase for later use; s2, activating anion exchange resin; s3, adding the water phase obtained in the step S1 into the anion exchange resin treated in the step S2, starting adsorption, washing with water to be neutral after adsorption is completed, eluting with 1%-5% sodium hydroxide, and collecting liquid which is an oxacillin sodium water solution; s4, heating the oxacillin sodium aqueous solution to 40 DEG C, adding hydrochloric acid, adjusting the pH value to 3.0-4.0, and preserving heat and growing crystals for 1 hour; dropwise adding hydrochloric acid, adjusting the pH value to 1.5-2.5, cooling and growing crystals for 2 hours, and drying to obtain oxacillin acid solid; s5, dissolving the oxacillin acid solid in a 95% alcohol solvent, dropwise adding a sodium isooctanoate solution, and crystallizing after dropwise adding; cooling and growing crystals for 2 hours, filtering to obtain a wet material, and drying to obtain oxacillin sodium. The method is easy to implement, and the product quality is stable.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical manufacturing technology, specifically relating to a method for recovering the active ingredient from oxacillin sodium mother liquor. Background Technology

[0002] Oxacillin sodium is used to treat various infections caused by penicillin-resistant Staphylococcus, including sepsis, respiratory infections, meningitis, and soft tissue infections. It can also be used for mixed infections caused by Streptococcus pyogenes or Pneumococcus and penicillin-resistant Staphylococcus.

[0003] The solvent used in the preparation of oxacillin sodium is usually a mixture of alcohol and butyl acetate. The preparation involves reacting oxacillin acid with sodium isooctanoate and then cooling and crystallizing to obtain oxacillin sodium. This method produces oxacillin sodium mother liquor, which contains about 10%-15% oxacillin sodium, resulting in yield loss. If it is not recovered, it will not only cause waste and increase production costs, but also increase the difficulty of waste liquid treatment. Summary of the Invention

[0004] The purpose of this invention is to provide a method for recovering the active ingredient from oxacillin sodium mother liquor. The recovery method provided by this invention is easy to implement, has a high yield, and produces stable product quality.

[0005] The technical solution adopted by this invention to achieve its purpose is as follows: A method for recovering the active ingredient from oxacillin sodium mother liquor includes the following steps: S1. Heat the oxacillin sodium mother liquor, distill under reduced pressure to remove excess alcohols; add water to the residue, stir, let stand to separate the layers, discard the organic phase, and keep the aqueous phase for later use; S2. Activate the anion exchange resin with 1%-5% hydrochloric acid, and elute with water until the liquid is neutral; then activate with 1%-5% sodium hydroxide, and elute with water until the liquid is neutral; finally activate with 1-5% sodium chloride, and elute with water. S3. Add the aqueous phase obtained in step S1 to the anion exchange resin treated in step S2 to start adsorption. After adsorption is complete, wash with water until neutral, elute with 1%-5% sodium hydroxide, and collect the liquid. This liquid is an aqueous solution of oxacillin sodium. S4. Heat the oxacillin sodium aqueous solution to 40℃, add hydrochloric acid, adjust the pH to 3.0-4.0, and keep it at this temperature for 1 hour to grow crystals; add hydrochloric acid dropwise, adjust the pH to 1.5-2.5, cool down and grow crystals for 2 hours, and dry to obtain solid oxacillin acid; S5. Oxychlornic acid solid was dissolved in 95% alcohol solvent, and sodium isooctanoate solution was added dropwise. After the addition was completed, crystals were formed. The solution was cooled and allowed to grow crystals for 2 hours. The mixture was then filtered to obtain a wet material, which was dried to obtain sodium oxychlornic acid.

[0006] Furthermore, in step S1, the temperature of vacuum distillation is ≤50℃ and the vacuum degree is ≤-0.08MP.

[0007] Furthermore, in step S1, the amount of water added is based on a mass ratio of water to mother liquor of 0.2-0.4.

[0008] Furthermore, in step S2, the amount of 1%-5% hydrochloric acid used is 2-3 BV, the amount of 1%-5% sodium hydroxide solution is 2-3 BV, and the amount of 1-5% sodium chloride solution is 2-3 BV.

[0009] Furthermore, during the resin elution process in step S3, the 1-5% sodium chloride solution is 2-3 BV.

[0010] Furthermore, in step S4, the concentration of hydrochloric acid used for crystallization is 10%-30%.

[0011] Furthermore, in step S4, the temperature for cooling and crystal growth is 0-10℃.

[0012] Further, in step S5, the sodium isooctanoate solution is added at a temperature of 25-45℃. The sodium isooctanoate solution is prepared by mixing sodium isooctanoate with a 95% alcohol solvent; m(sodium isooctanoate):V(95% alcohol) = 0.1-0.2. The alcohol used to dissolve the oxacillin acid solid has a ratio of m(oxacillin acid):V(95% alcohol) = 0.1-0.25; the molar ratio of sodium isooctanoate to oxacillin acid is 1.0-1.1.

[0013] Furthermore, the drying temperature in steps S4 and S5 is 30-50℃, and the drying time is 1-5h.

[0014] Furthermore, the 95% alcohol solvent is one or more of ethanol, isopropanol, n-propanol, and n-butanol.

[0015] The beneficial effects of this invention are: The oxacillin sodium product recovered by the method of this invention is of high quality and easy to industrialize and promote. Attached Figure Description

[0016] Figure 1 This is a liquid chromatogram of the oxacillin sodium recovered in Example 1 of the present invention.

[0017] Figure 2 This is a liquid chromatogram of oxacillin sodium recovered in Example 2 of the present invention.

[0018] Figure 3 This is a liquid chromatogram of the oxacillin sodium recovered in Example 3 of the present invention. Detailed Implementation

[0019] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of the present invention.

[0020] Example 1 A method for recovering the active ingredient from oxacillin sodium mother liquor includes the following steps: S1. Heat 1.5L of oxacillin sodium mother liquor (oxacillin sodium content: 38.2mg / mL), distill under reduced pressure to remove excess alcohols. The temperature of the reduced pressure distillation is ≤50℃ and the vacuum degree is ≤-0.08MP. Add 450mL of water to the residue in the reactor, stir, let stand to separate the layers, discard the organic phase, and keep the aqueous phase for later use. S2. The anion exchange resin is activated with 2% hydrochloric acid at a volume of 3 BV, and eluted with water until the liquid is neutral; then activated with 2% sodium hydroxide at a volume of 3 BV, and eluted with water until the liquid is neutral; finally activated with 5% sodium chloride at a volume of 3 BV, and eluted with water. S3. Add the aqueous phase obtained in step S1 to the anion exchange resin treated in step S2 to start adsorption. After adsorption is complete, wash with water until neutral, elute with 2% sodium hydroxide at a volume of 3 BV, and collect the liquid. This liquid is an aqueous solution of oxacillin sodium. S4. Heat the oxacillin sodium aqueous solution to 40℃, add 10% hydrochloric acid, adjust the pH to 3.5, and keep it at this temperature for 1 hour to grow crystals; add 10% hydrochloric acid dropwise, adjust the pH to 1.9, cool down to grow crystals for 2 hours, and dry at 40℃ for 5 hours to obtain 47.6g of oxacillin acid solid. S5. Oxacillin solid was dissolved in 250 mL of 95% ethanol. At 45°C, sodium isooctanoate solution (prepared by mixing 21.0 g of sodium isooctanoate with 200 mL of 95% ethanol) was added dropwise. After the addition was complete, crystals were formed. The solution was cooled to 0°C and allowed to crystallize for 2 hours. After filtration, a wet material was obtained and dried at 40°C for 5 hours to obtain sodium oxacillin. The yield was 35.2 g, with a yield of 61.43% and a purity of 99.57%.

[0021] Example 2 S1. Heat 1.5L of oxacillin sodium mother liquor (oxacillin sodium content: 37.8mg / mL), distill under reduced pressure to remove excess alcohols. The temperature of the reduced pressure distillation is ≤50℃ and the vacuum degree is ≤-0.08MP. Add 380mL of water to the residue in the reactor, stir, let stand to separate the layers, discard the organic phase, and keep the aqueous phase for later use. S2. The anion exchange resin is activated with 3% hydrochloric acid at a volume of 2.5 BV, and eluted with water until the liquid is neutral; then activated with 3% sodium hydroxide at a volume of 2.5 BV, and eluted with water until the liquid is neutral; finally activated with 3% sodium chloride at a volume of 2.5 BV, and eluted with water. S3. Add the aqueous phase obtained in step S1 to the anion exchange resin after the treatment in step S2 to start adsorption. After the adsorption is complete, wash with water until neutral, elute with 3% sodium hydroxide at a volume of 2.5 BV, and collect the liquid, which is an aqueous solution of oxacillin sodium. S4. Heat the oxacillin sodium aqueous solution to 40℃, add 10% hydrochloric acid, adjust the pH to 3.0, and keep it at this temperature for 1 hour to grow crystals; add 10% hydrochloric acid dropwise, adjust the pH to 1.8, cool down to grow crystals for 2 hours, and dry at 50℃ for 3 hours to obtain 48.4g of oxacillin acid solid; S5. Oxacillin solid was dissolved in 300 mL of 95% ethanol. At 40 °C, sodium isooctanoate solution (prepared by mixing 21.4 g of sodium isooctanoate with 200 mL of 95% ethanol) was added dropwise. After the addition was complete, crystals were formed. The solution was cooled to 0 °C and allowed to crystallize for 2 hours. After filtration, a wet material was obtained and dried at 40 °C for 5 hours to obtain sodium oxacillin. The yield was 34.9 g, with a yield of 61.55% and a purity of 99.49%.

[0022] Example 3 S1. Heat 1.6L of oxacillin sodium mother liquor (oxacillin sodium content: 36.5mg / mL), distill under reduced pressure to remove excess alcohols. The temperature of the reduced pressure distillation is ≤50℃ and the vacuum degree is ≤-0.08MP. Add 400mL of water to the residue in the reactor, stir, let stand to separate the layers, discard the organic phase, and keep the aqueous phase for later use. S2. The anion exchange resin is activated with 5% hydrochloric acid at a volume of 2 BV, and eluted with water until the liquid is neutral; then activated with 5% sodium hydroxide at a volume of 2 BV, and eluted with water until the liquid is neutral; then activated with 5% sodium chloride at a volume of 2 BV, and eluted with water. S3. Add the aqueous phase obtained in step S1 to the anion exchange resin treated in step S2 to start adsorption. After adsorption is complete, wash with water until neutral, elute with 5% sodium hydroxide at a volume of 2.5 BV, and collect the liquid, which is an aqueous solution of oxacillin sodium. S4. Heat the oxacillin sodium aqueous solution to 40℃, add 10% hydrochloric acid, adjust the pH to 3.1, and keep it at this temperature for 1 hour to grow crystals; add 10% hydrochloric acid dropwise, adjust the pH to 1.9, cool down to grow crystals for 2 hours, and dry at 40℃ for 4 hours to obtain 50.9g of oxacillin acid solid.

[0023] S5. Oxacillin solid was dissolved in 300 mL of 95% ethanol. At 40 °C, sodium isooctanoate solution (prepared by mixing 21.1 g of sodium isooctanoate with 170 mL of 95% ethanol) was added dropwise. After the addition was complete, crystals were formed. The solution was cooled to 0 °C and allowed to crystallize for 2 hours. After filtration, a wet material was obtained and dried at 40 °C for 4 hours to obtain sodium oxacillin. The yield was 37.9 g, with a yield of 64.90% and a purity of 99.52%.

[0024] Finally, it should be noted that the above-described embodiments are merely specific implementations of the present invention, used to illustrate the technical solutions of the present invention, and not to limit them. The scope of protection of the present invention is not limited thereto. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that any person skilled in the art can still modify or easily conceive of changes to the technical solutions described in the foregoing embodiments within the scope of the technology disclosed in the present invention, or make equivalent substitutions for some of the technical features; and these modifications, changes, or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention, and should all be covered within the scope of protection of the present invention.

Claims

1. A method for recovering the active ingredient from oxacillin sodium mother liquor, characterized in that, Includes the following steps: S1. Heat the oxacillin sodium mother liquor, distill under reduced pressure to remove excess alcohols; add water to the residue, stir, let stand to separate the layers, discard the organic phase, and keep the aqueous phase for later use; S2. Activate the anion exchange resin with 1%-5% hydrochloric acid, and elute with water until the liquid is neutral; then activate with 1%-5% sodium hydroxide, and elute with water until the liquid is neutral; finally activate with 1-5% sodium chloride, and elute with water. S3. Add the aqueous phase obtained in step S1 to the anion exchange resin treated in step S2 to start adsorption. After adsorption is complete, wash with water until neutral, elute with 1%-5% sodium hydroxide, and collect the liquid. This liquid is an aqueous solution of oxacillin sodium. S4. Heat the oxacillin sodium aqueous solution to 40℃, add hydrochloric acid, adjust the pH to 3.0-4.0, and keep it at this temperature for 1 hour to grow crystals; add hydrochloric acid dropwise, adjust the pH to 1.5-2.5, cool down and grow crystals for 2 hours, and dry to obtain solid oxacillin acid; S5. Oxychlornic acid solid was dissolved in 95% alcohol solvent, and sodium isooctanoate solution was added dropwise. After the addition was completed, crystals were formed. The solution was cooled and allowed to grow crystals for 2 hours. The mixture was then filtered to obtain a wet material, which was dried to obtain sodium oxychlornic acid.

2. The method for recovering the active ingredient from oxacillin sodium mother liquor according to claim 1, characterized in that, In step S1, the temperature of vacuum distillation is ≤50℃ and the vacuum degree is ≤-0.08MP.

3. The method for recovering the active ingredient from oxacillin sodium mother liquor according to claim 1, characterized in that, In step S1, the amount of water added is based on a mass ratio of water to mother liquor of 0.2-0.

4.

4. The method for recovering the active ingredient from oxacillin sodium mother liquor according to claim 1, characterized in that, In step S2, the amount of 1%-5% hydrochloric acid used is 2-3 BV, the amount of 1%-5% sodium hydroxide solution is 2-3 BV, and the amount of 1-5% sodium chloride solution is 2-3 BV.

5. The method for recovering the active ingredient from oxacillin sodium mother liquor according to claim 1, characterized in that, During the resin elution process in step S3, the 1-5% sodium chloride solution is 2-3 BV.

6. The method for recovering the active ingredient from oxacillin sodium mother liquor according to claim 1, characterized in that, In step S4, the concentration of hydrochloric acid used for crystallization is 10%-30%.

7. The method for recovering the active ingredient from oxacillin sodium mother liquor according to claim 1, characterized in that, In step S4, the temperature for cooling and crystal growth is 0-10℃.

8. The method for recovering the active ingredient from oxacillin sodium mother liquor according to claim 1, characterized in that, In step S5, the sodium isooctanoate solution is added at a temperature of 25-45°C. The sodium isooctanoate solution is prepared by adding sodium isooctanoate and 95% alcohol solvent.

9. The method for recovering the active ingredient from oxacillin sodium mother liquor according to claim 1, characterized in that, In steps S4 and S5, the drying temperature is 30-50℃ and the drying time is 1-5h.

10. A method for recovering the active ingredient from oxacillin sodium mother liquor according to claim 1 or 8, characterized in that, The 95% alcohol solvent is one or more of ethanol, isopropanol, n-propanol, and n-butanol.

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