Treatment method of unqualified hydrocortisone sodium succinate

Abstract

The invention relates to the technical field of chemical medicine preparation, in particular to a treatment method of unqualified hydrocortisone sodium succinate. Comprising the following steps: S1, in a nitrogen atmosphere, adding water into unqualified hydrocortisone sodium succinate, uniformly stirring, dropwise adding an alkaline solution at 3-5 DEG C, stirring, and hydrolyzing the hydrocortisone sodium succinate into hydrocortisone; s2, adding an acidic solvent into the reacted system to adjust the pH value of the system to 8-8.5, collecting an intermediate product, washing with water until the intermediate product is neutral, and removing the impurity 17-hydrocortisone sodium succinate to obtain a hydrocortisone crude product; and S3, carrying out reflux decoloration on the hydrocortisone crude product, filtering after decoloration, carrying out vacuum concentration, cooling, collecting the product, cleaning, and drying to obtain the hydrocortisone product. According to the method, the unqualified hydrocortisone sodium succinate is dissolved with water and then is hydrolyzed into the hydrocortisone by adding alkali, so that the economic and effective treatment of the unqualified hydrocortisone sodium succinate is realized for the first time.

Description

Technical Field

[0001] This invention relates to the field of chemical drug preparation technology, and in particular to a method for treating substandard hydrocortisone sodium succinate. Background Technology

[0002] The chemical name of hydrocortisone sodium succinate is 11β,17α-dihydroxy-21-(3-carboxy-1-hydroxypropoxy)pregn-4-ene-3,20-dione-sodium salt. It is a glucocorticoid drug used to treat critically ill patients with conditions such as toxic infections, anaphylactic shock, severe adrenocortical insufficiency, connective tissue diseases, and severe bronchial asthma. It can also be used to prevent and treat acute transplant rejection. Hydrocortisone, with the chemical name 11β,17α,21-trihydroxypregn-4-ene-3,20-dione, is also a glucocorticoid drug with various pharmacological effects, including anti-inflammatory, immunosuppressive, antitoxin, and anti-shock properties.

[0003] Sources of substandard hydrocortisone sodium succinate: Due to its product characteristics, hydrocortisone sodium succinate is heat-sensitive and highly soluble in solvents. Therefore, the final salt formation is carried out by spray drying or freeze drying, resulting in a short shelf life (2 years). During storage, impurities of hydrocortisone and 17-hydrocortisone sodium succinate gradually increase. If it cannot be sold in time after production, it will become substandard hydrocortisone sodium succinate; or substandard hydrocortisone sodium succinate may be produced due to other reasons.

[0004] The structural formulas of hydrocortisone sodium succinate, 17-hydrocortisone sodium succinate, and hydrocortisone are as follows:

[0005] As society becomes more aware of pharmaceutical quality, many customers require that supplied hydrocortisone sodium succinate products meet the quality requirements of ≤0.5% hydrocortisone and ≤0.5% 17-hydrocortisone sodium succinate. However, due to the characteristics of hydrocortisone sodium succinate, it cannot be obtained by solvent recrystallization. Therefore, substandard hydrocortisone sodium succinate cannot be purified by solvent recrystallization. Lacking suitable disposal methods, most substandard hydrocortisone sodium succinate is treated as hazardous waste, resulting in both waste and environmental pollution.

[0006] Because sodium hydrocortisone succinate is heat-sensitive, approximately 0.35% of 17-hydrocortisone succinate and approximately 0.35% of hydrocortisone impurities are easily generated during the spray drying and vacuum drying processes of the sodium hydrocortisone succinate salt solution. Therefore, the starting material hydrocortisone succinate for sodium hydrocortisone succinate needs to meet the requirements of HPLC purity above 99.5%, 17-hydrocortisone succinate impurity ≤ 0.1%, and hydrocortisone impurity ≤ 0.1%.

[0007] Due to the characteristics of hydrocortisone sodium succinate, there is currently no direct solvent purification method for substandard hydrocortisone sodium succinate. Some manufacturers use acidification and re-esterification of hydrocortisone sodium succinate, as shown in the following reaction formula: ; The impurity 17-hydrocortisone sodium succinate will undergo the following reaction: .

[0008] Because the re-esterified product contains impurities of hydrocortisone and 17-hydrocortisone succinate monoester, and 17-hydrocortisone succinate monoester is an isomer of hydrocortisone succinate monoester with similar structures and physicochemical properties, it is difficult to separate it from hydrocortisone succinate monoester. Even after multiple purification processes, it is difficult to achieve the qualified standard for hydrocortisone succinate monoester (HPLC above 99.5%, impurity 17-hydrocortisone succinate ≤0.1% and impurity hydrocortisone ≤0.1%). There is no economic value in recycling it. Therefore, no economical and effective treatment method has been found for the unqualified hydrocortisone sodium succinate. Currently, there is no publicly available information on the treatment method of unqualified hydrocortisone sodium succinate, either domestically or internationally.

[0009] Therefore, this invention is proposed. Summary of the Invention

[0010] The purpose of this invention is to provide a method for processing substandard hydrocortisone sodium succinate. This method can convert substandard hydrocortisone sodium succinate into qualified hydrocortisone product with high yield and meets environmental protection requirements.

[0011] This invention provides a method for treating substandard hydrocortisone sodium succinate, comprising the following steps: S1. Under a nitrogen atmosphere, add substandard hydrocortisone sodium succinate to water and stir until homogeneous. At a temperature of 3-5℃, add alkaline solution dropwise and stir to react, hydrolyzing the hydrocortisone sodium succinate into hydrocortisone. S2. Add an acidic solvent to the system after the reaction in step S1 to adjust the pH to 8-8.5, collect the intermediate product, wash with water until neutral, remove the impurity 17-hydrocortisone sodium succinate, and obtain crude hydrocortisone. S3. Add the crude hydrocortisone to an organic solvent, add a decolorizing agent, reflux for decolorization, filter after decolorization, concentrate under reduced pressure, cool to 0-5℃, collect the product, wash, and dry to obtain the hydrocortisone product.

[0012] Furthermore, in step S1, the substandard hydrocortisone succinate contains 0.5-1% 17-hydrocortisone succinate impurity and 2-3% hydrocortisone impurity.

[0013] Furthermore, the alkaline solution in step S1 is an aqueous solution of sodium hydroxide or an aqueous solution of potassium hydroxide.

[0014] Furthermore, the mass ratio of the substandard hydrocortisone sodium succinate to the solute in the alkaline solution is 10:(1-0.8); the ratio of the substandard hydrocortisone sodium succinate to the solvent in the alkaline solution is 1:(1-1.5), wherein the substandard hydrocortisone sodium succinate is expressed in g by mass, and the solvent is water, expressed in mL.

[0015] Furthermore, the mass ratio of substandard hydrocortisone sodium succinate to sodium hydroxide is 10:1, and the mass ratio of substandard hydrocortisone sodium succinate to water is 1:1; or the mass ratio of substandard hydrocortisone sodium succinate to sodium hydroxide is 25:2, and the mass ratio of substandard hydrocortisone sodium succinate to water is 1:1.5; or the mass ratio of substandard hydrocortisone sodium succinate to potassium hydroxide is 25:2, and the mass ratio of substandard hydrocortisone sodium succinate to water is 1:1.

[0016] Furthermore, the acidic solvent in step S2 is glacial acetic acid.

[0017] Further, the organic solvent in step S3 is a mixture of acetone and water, wherein the ratio of acetone, water, and the substandard hydrocortisone sodium succinate in the mixture to that in step S1 is (20-21):(2-3):1, wherein acetone and water are expressed in mL by volume, and the substandard hydrocortisone sodium succinate is expressed in g by mass. Even further, the ratio of acetone, water, and substandard hydrocortisone sodium succinate is 20:2:1.

[0018] Further, the decolorizing agent added in step S3 is activated carbon, and the mass ratio of the activated carbon to the substandard hydrocortisone sodium succinate in step S1 is (1-2):20. Even further, the mass ratio of activated carbon to substandard hydrocortisone sodium succinate is 1:20.

[0019] Furthermore, in step S3, the reflux decolorization temperature is 55-65℃, and the time is 30-35 minutes.

[0020] Furthermore, acetone is used for cleaning in step S3.

[0021] Furthermore, the drying temperature in step S3 is 80-90℃.

[0022] This invention involves directly dissolving sodium hydrocortisone succinate in water and then hydrolyzing it with an appropriate amount of alkali to obtain hydrocortisone. Due to the significant steric hindrance of the impurity 17-hydrocortisone succinate, hydrolysis requires more alkali and a higher reaction temperature, leading to increased impurities and reduced yield. Using an appropriate amount of alkali solves the problem of impurities arising from prolonged hydrolysis of steroidal drugs in strongly alkaline conditions. It also addresses the difficulty in separating 17-hydrocortisone succinate monoester and hydrocortisone succinate monoester. A small amount of unhydrolyzed 17-hydrocortisone succinate is dissolved in water and removed; even the small amount of 17-hydrocortisone succinate hydrolyzed yields the target product, hydrocortisone. After the reaction was complete, the pH was adjusted to 8-8.5 with glacial acetic acid to create a weakly alkaline environment, preventing unreacted sodium 17-hydrocortisone succinate from being acidified into 17-hydrocortisone succinate monoester, which would become an impurity in the final product, hydrocortisone. The crude hydrocortisone was washed with water until neutral, then purified with acetone and dried to obtain hydrocortisone with an HPLC purity of over 99.5% and all impurities less than 0.1%.

[0023] In summary, compared with the prior art, the present invention has the following advantages: I. The processing method provided by this invention dissolves substandard hydrocortisone sodium succinate in water and then hydrolyzes it with alkali to obtain hydrocortisone. This is the first time that an economical and effective treatment of substandard hydrocortisone sodium succinate has been achieved, with a yield of over 67%.

[0024] II. The processing method provided by the present invention solves the problem in the prior art that the impurity 17-hydrocortisone succinate monoester and hydrocortisone succinate monoester are isomers and difficult to purify and separate. Third, the processing method provided by this invention involves low-temperature alkali hydrolysis of substandard hydrocortisone sodium succinate. It cleverly utilizes the water-soluble property of 17-hydrocortisone sodium succinate, which requires a high alkali concentration and temperature for hydrocortisone hydrolysis. Under the reaction conditions provided by this invention, hydrolysis is difficult. Even if a small amount of hydrolysis occurs, it is the target product, hydrocortisone. The impurity 17-hydrocortisone sodium succinate is then removed by washing with water. The operation is simple and easy to perform.

[0025] IV. The processing method provided by this invention uses water as the solvent for hydrolysis, which is green and environmentally friendly. It does not over-hydrolyze and produce impurities. The small amount of unreacted sodium 17-hydrocortisone succinate is dissolved in water and removed. The quality and yield are significantly competitive. Tests have shown that the hydrocortisone obtained by this method has an HPLC purity of over 99.5%, and all impurities are less than 0.10%. Moreover, the operation is simple and easy to industrialize. Attached Figure Description

[0026] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0027] Figure 1 This is the HPLC chromatogram of hydrocortisone obtained in Example 1 of the present invention; Figure 2 This is the HPLC chromatogram of hydrocortisone obtained in Example 2 of the present invention; Figure 3 This is the HPLC chromatogram of hydrocortisone obtained in Example 3 of the present invention. Detailed Implementation

[0028] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of this application. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains.

[0029] It should be noted that the terminology used herein is for the purpose of describing particular implementations only and is not intended to limit the exemplary implementations according to this application. As used herein, the singular form includes the plural form unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this description, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0030] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0031] Example 1 A method for treating substandard hydrocortisone sodium succinate, wherein the substandard hydrocortisone sodium succinate treated in this embodiment contains approximately 1% impurity 17-hydrocortisone sodium succinate and approximately 2% impurity hydrocortisone. The specific steps are as follows: S1. Hydrocortisone sodium succinate is hydrolyzed to hydrocortisone; Under nitrogen protection, 100g of substandard hydrocortisone sodium succinate was added to 1000mL of water. At a low temperature of 3-5℃, a sodium hydroxide aqueous solution containing 10g of sodium hydroxide and 100mL of water was added dropwise over approximately 30 minutes. The temperature was maintained at 3-5℃, and the mixture was stirred for 60 minutes. This hydrolyzed the hydrocortisone sodium succinate to hydrocortisone, with only a small amount of impurity 17-hydrocortisone sodium succinate hydrolyzing into hydrocortisone. The reaction formula is as follows: ; S2. Remove unreacted impurities: 17-hydrocortisone sodium succinate; Add an appropriate amount of glacial acetic acid to the system after the reaction in step S1 to adjust the pH of the system to 8-8.5 to prevent the acid hydrolysis of sodium 17-hydrocortisone succinate to 17-hydrocortisone succinate monoester. Collect the intermediate product, wash it with water until neutral, and remove the water-soluble impurity sodium 17-hydrocortisone succinate to obtain crude hydrocortisone. S3. Refining of hydrocortisone; Add 2000 mL of acetone, 200 mL of water, and 5 g of activated carbon to the crude hydrocortisone product. Reflux at 55-65°C for 30 minutes to decolorize. Filter the solution, concentrate the filtrate under reduced pressure until it reaches a viscous consistency, cool to 0-5°C, discharge the solution, wash with approximately 50 mL of acetone, dry under vacuum, and dry at 80-90°C to obtain 69.32 g of qualified hydrocortisone (HPLC 99.64%, HPLC chromatogram see [link]). Figure 1 All impurities <0.10%, yield 69.32%.

[0032] Example 2 A method for treating substandard hydrocortisone sodium succinate, wherein the substandard hydrocortisone sodium succinate treated in this embodiment contains approximately 0.5% impurity 17-hydrocortisone sodium succinate and approximately 2% impurity hydrocortisone. The specific steps are as follows: S1. Hydrocortisone sodium succinate is hydrolyzed to hydrocortisone; Under nitrogen protection, 100g of substandard hydrocortisone sodium succinate was added to 1000mL of water. At a low temperature of 3-5℃, sodium hydroxide aqueous solution containing 8g of sodium hydroxide and 150mL of water was added dropwise over about 30 minutes. The temperature was maintained at 3-5℃ and the mixture was stirred for 60 minutes to hydrolyze the hydrocortisone sodium succinate into hydrocortisone. Only a small amount of impurity 17-hydrocortisone sodium succinate was hydrolyzed into hydrocortisone. S2. Remove unreacted impurities: 17-hydrocortisone sodium succinate; Add an appropriate amount of glacial acetic acid to the system after the reaction in step S1 to adjust the pH of the system to 8-8.5 to prevent the acid hydrolysis of sodium 17-hydrocortisone succinate to 17-hydrocortisone succinate monoester. Collect the intermediate product, wash it with water until neutral, and remove the water-soluble impurity sodium 17-hydrocortisone succinate to obtain crude hydrocortisone. S3. Refining of hydrocortisone; Add 2000 mL of acetone, 200 mL of water, and 5 g of activated carbon to the crude hydrocortisone product. Reflux at 55-65°C for 30 minutes to decolorize. Filter the solution, concentrate the filtrate under reduced pressure until it reaches a viscous consistency, cool to 0-5°C, discharge the solution, wash with approximately 50 mL of acetone, dry under vacuum, and dry at 80-90°C to obtain 67.43 g of qualified hydrocortisone (HPLC 99.64%, HPLC chromatogram see [link]). Figure 2 All impurities <0.10%, yield 67.43%.

[0033] Example 3 A method for treating substandard hydrocortisone sodium succinate, wherein the substandard hydrocortisone sodium succinate treated in this embodiment contains approximately 1% impurity 17-hydrocortisone sodium succinate and approximately 3% impurity hydrocortisone. The specific steps are as follows: S1. Hydrocortisone sodium succinate is hydrolyzed to hydrocortisone; Under nitrogen protection, 100g of substandard hydrocortisone sodium succinate was added to 1000mL of water. At a low temperature of 3-5℃, potassium hydroxide aqueous solution was added dropwise. The potassium hydroxide aqueous solution contained 8g of potassium hydroxide and 100mL of water. The addition was completed in about 30 minutes. The temperature was maintained at 3-5℃ and the mixture was stirred for 60 minutes to hydrolyze the hydrocortisone sodium succinate into hydrocortisone. Only a small amount of impurity 17-hydrocortisone sodium succinate was hydrolyzed into hydrocortisone. S2. Remove unreacted impurities: 17-hydrocortisone sodium succinate; Add an appropriate amount of glacial acetic acid to the system after the reaction in step S1 to adjust the pH of the system to 8-8.5 to prevent the acid hydrolysis of sodium 17-hydrocortisone succinate to 17-hydrocortisone succinate monoester. Collect the intermediate product, wash it with water until neutral, and remove the water-soluble impurity sodium 17-hydrocortisone succinate to obtain crude hydrocortisone. S3. Refining of hydrocortisone; Add 2000 mL of acetone, 200 mL of water, and 5 g of activated carbon to the crude hydrocortisone product. Recirculate the solution to 55-65°C for 30 minutes to decolorize. Filter the solution, concentrate the filtrate under reduced pressure until it reaches a viscous consistency, cool to 0-5°C, discharge the solution, wash with approximately 50 mL of acetone, dry under vacuum, and dry at 80-90°C to obtain 68.16 g of qualified hydrocortisone (HPLC 99.61%, HPLC chromatogram see [link]). Figure 3 All impurities <0.10%, yield 68.16%.

[0034] Comparative Example 1 A method for treating substandard hydrocortisone sodium succinate, wherein the substandard hydrocortisone sodium succinate treated in this comparative example contains approximately 1% impurity 17-hydrocortisone sodium succinate and approximately 2% impurity hydrocortisone. The specific steps are as follows: S1. Under nitrogen protection, 100g of substandard hydrocortisone sodium succinate was added to 1000mL of water. Sodium hydroxide aqueous solution containing 20g of sodium hydroxide and 100mL of water was added dropwise at 8-12℃. The addition was completed in about 30 minutes. The temperature was maintained at 8-12℃ and the mixture was stirred for 60 minutes to hydrolyze the hydrocortisone sodium succinate into hydrocortisone. All impurities, including 17-hydrocortisone sodium succinate, were hydrolyzed into hydrocortisone. Add an appropriate amount of glacial acetic acid to the system after the reaction in step S1 to adjust the pH of the system to neutral, wash with water to remove water-soluble inorganic salts, and obtain crude hydrocortisone. S2. Add 2000 mL of acetone, 200 mL of water, and 5 g of activated carbon to the crude hydrocortisone product. Heat to 55-65 °C and reflux for decolorization for 30 minutes. Filter, concentrate the filtrate under reduced pressure to a viscous consistency, cool to 0-5 °C, discharge, wash with about 50 mL of acetone, dry under vacuum, and dry at 80-90 °C to obtain 60.84 g of qualified hydrocortisone (HPLC 98.94%, yield 60.84%).

[0035] Comparative Example 2 A method for treating substandard hydrocortisone sodium succinate. In this comparative example, the substandard hydrocortisone sodium succinate treated contained approximately 1% impurity 17-hydrocortisone sodium succinate and approximately 2.5% impurity hydrocortisone. The specific steps are as follows: S1. Under nitrogen protection, 100g of substandard hydrocortisone sodium succinate was added to 1000mL of water. At a low temperature of 3-5℃, sodium hydroxide aqueous solution was added dropwise. The sodium hydroxide aqueous solution contained 10g of sodium hydroxide and 100mL of water. The addition was completed in about 30 minutes. The temperature was maintained at 3-5℃ and the mixture was stirred for 60 minutes to hydrolyze the hydrocortisone sodium succinate into hydrocortisone. Only a small amount of impurity 17-hydrocortisone sodium succinate was hydrolyzed into hydrocortisone. S2. Add an appropriate amount of glacial acetic acid to the system after the reaction in step S1 to adjust the pH of the system to neutral, wash with water to remove the water-soluble inorganic salts, and obtain crude hydrocortisone. S3. Add 2000 mL of acetone, 200 mL of water, and 5 g of activated carbon to the crude hydrocortisone product. Heat to 55-65 °C and reflux for decolorization for 30 minutes. Filter, concentrate the filtrate under reduced pressure to a viscous consistency, cool to 0-5 °C, discharge, wash with about 50 mL of acetone, dry under vacuum, and dry at 80-90 °C to obtain 56.98 g of qualified hydrocortisone (HPLC 99.16%, yield 56.98%).

[0036] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for treating substandard hydrocortisone sodium succinate, characterized in that, Includes the following steps: S1. Under a nitrogen atmosphere, add substandard hydrocortisone sodium succinate to water and stir until homogeneous. At a temperature of 3-5℃, add alkaline solution dropwise and stir to react, hydrolyzing the hydrocortisone sodium succinate into hydrocortisone. S2. Add an acidic solvent to the system after the reaction in step S1 to adjust the pH to 8-8.5, collect the intermediate product, wash with water until neutral, remove the impurity 17-hydrocortisone sodium succinate, and obtain crude hydrocortisone. S3. Add the crude hydrocortisone to an organic solvent, add a decolorizing agent, reflux for decolorization, filter after decolorization, concentrate under reduced pressure, cool to 0-5℃, collect the product, wash, and dry to obtain the hydrocortisone product.

2. The processing method according to claim 1, characterized in that, In step S1, the substandard hydrocortisone sodium succinate contains 0.5-1% 17-hydrocortisone sodium succinate impurity and 2-3% hydrocortisone impurity.

3. The processing method according to claim 1, characterized in that, The alkaline solution in step S1 is an aqueous solution of sodium hydroxide or potassium hydroxide.

4. The processing method according to claim 3, characterized in that, The mass ratio of the substandard hydrocortisone sodium succinate to the solute in the alkaline solution is 10:(1-0.8); the ratio of the substandard hydrocortisone sodium succinate to the solvent in the alkaline solution is 1:(1-1.5), wherein the substandard hydrocortisone sodium succinate is expressed in g by mass, and the solvent is water, expressed in mL.

5. The processing method according to claim 1, characterized in that, The acidic solvent in step S2 is glacial acetic acid.

6. The processing method according to claim 1, characterized in that, The organic solvent in step S3 is a mixture of acetone and water. The ratio of acetone, water and substandard hydrocortisone sodium succinate in the mixture to that in step S1 is (20-21):(2-3):1, where acetone and water are expressed in mL by volume and substandard hydrocortisone sodium succinate is expressed in g by mass.

7. The processing method according to claim 1, characterized in that, The decolorizing agent added in step S3 is activated carbon, and the mass ratio of the activated carbon to the unqualified hydrocortisone sodium succinate in step S1 is (1-2):

20.

8. The processing method according to claim 1, characterized in that, In step S3, the reflux decolorization temperature is 55-65℃ and the time is 30-35 minutes.

9. The processing method according to claim 1, characterized in that, In step S3, acetone is used for cleaning.

10. The processing method according to claim 1, characterized in that, The drying temperature in step S3 is 80-90℃.

Images