Preparation method of salbutamol sulfate, salbutamol sulfate injection and preparation method of salbutamol sulfate injection
Salbutamol sulfate was prepared using a specific solvent and recrystallization process. Citric acid and sodium citrate were used to replace disodium edetate, which solved the stability and safety issues of salbutamol sulfate injection and achieved a high-purity, high-stability disodium edetate-free formulation.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- HAINAN HUALON PHARM
- Filing Date
- 2024-11-20
- Publication Date
- 2026-05-22
Smart Images
Figure BDA0005144404370000051 
Figure BDA0005144404370000061 
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Abstract
Description
Technical Field
[0001] This invention relates to the preparation of sterile powder injections, and more particularly to a method for preparing salbutamol sulfate, a salbutamol sulfate injection solution, and the preparation method thereof. Background Technology
[0002] Salbutamol sulfate injection is a commonly used bronchodilator, primarily used to treat respiratory diseases such as bronchial asthma and wheezing bronchitis accompanied by bronchospasm. It relaxes bronchial smooth muscle by activating β2 receptors on bronchial smooth muscle cells, thereby relieving symptoms such as dyspnea. Salbutamol sulfate injection can be administered directly intravenously, subcutaneously, or intramuscularly, offering the advantage of rapid onset of action. However, current salbutamol sulfate injections require the addition of disodium edetate as a stabilizer to improve storage stability and reduce the content of related substances. However, disodium edetate is highly irritating and, after entering the body, binds to calcium and magnesium ions, leading to decreased blood calcium levels and hypocalcemia. Furthermore, some individuals are allergic to disodium edetate, experiencing allergic reactions. The stability of salbutamol sulfate prepared using disodium edetate currently requires further improvement.
[0003] Therefore, it is necessary to develop a salbutamol sulfate injection that is highly stable and free of disodium edetate. Summary of the Invention
[0004] To address the above problems, this invention provides a method for preparing salbutamol sulfate, a salbutamol sulfate injection solution, and the preparation method thereof.
[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:
[0006] A method for preparing salbutamol sulfate, wherein the preparation process of salbutamol sulfate includes the following steps:
[0007] Mix ethanol and ether in a ratio of 10:0.95 to 1.05, add salbutamol to dissolve, then add sulfuric acid aqueous solution dropwise. After the addition is complete, proceed with the reaction. After the reaction is complete, filter to obtain filtrate and the first filter cake.
[0008] After the filtrate is concentrated, diethyl ether is added, and the mixture is filtered again to obtain a second filter cake.
[0009] The first and second filter cakes were combined and recrystallized to obtain the salbutamol sulfate.
[0010] Furthermore, the recrystallization involves combining the first and second filter cakes, dissolving them by heating with ethanol to 50–55°C, maintaining the temperature at 50–55°C, adding diethyl ether dropwise until crystals precipitate, then cooling the temperature to 0–4°C at a rate of 4–6°C / h, maintaining the temperature at 0–4°C to allow crystals to precipitate, filtering, and drying to obtain the salbutamol sulfate.
[0011] Furthermore, the volume molar ratio of ethanol to salbutamol used to dissolve salbutamol is 200–210 mL: 0.1 mol.
[0012] Furthermore, the molar volume ratio of salbutamol to sulfuric acid aqueous solution is 0.1 mol: 10-11 mL;
[0013] The concentration of the sulfuric acid aqueous solution is 5 mol / L.
[0014] Furthermore, the reaction time is 2 to 3 hours.
[0015] Furthermore, the filtrate is concentrated to 1 / 3 to 1 / 2 of its original volume;
[0016] After concentration, the volume molar ratio of added diethyl ether to salbutamol is 100–105 mL: 0.1 mol.
[0017] A salbutamol sulfate injection, wherein the raw materials for preparing the effective components of the salbutamol sulfate injection, by weight, include: 0.05 parts of salbutamol sulfate prepared by the above-mentioned method, 0.85-0.9 parts of sodium chloride, 1.1-1.25 parts of citric acid monohydrate, and 0.6-0.81 parts of sodium citrate dihydrate.
[0018] A method for preparing the above-mentioned salbutamol sulfate injection, wherein the method is as follows: under nitrogen protection, water for injection is added to dissolve sodium chloride, then citric acid monohydrate and sodium citrate dihydrate are added to dissolve, the mixture is cooled, then salbutamol sulfate is added to dissolve, the volume is adjusted, filtered, filled, sealed, and sterilized to obtain the salbutamol sulfate injection.
[0019] Furthermore, before adding salbutamol sulfate and after dissolving it with citric acid monohydrate and sodium citrate dihydrate, the temperature after cooling is below 10°C.
[0020] The beneficial effects of the preparation method of salbutamol sulfate, the salbutamol sulfate injection solution, and the preparation method of the present invention are as follows:
[0021] This invention utilizes a specific ratio of ethanol and diethyl ether mixture as a solvent and a specific process to prepare salbutamol sulfate, which can effectively improve the yield and purity of salbutamol sulfate. The improved purity of salbutamol sulfate can further improve the stability of salbutamol sulfate injection.
[0022] This invention simplifies the formulation and reduces the amount and types of excipients by adding specific amounts of citric acid and sodium citrate, thereby reducing adverse reactions and improving safety.
[0023] This invention improves the stability of salbutamol sulfate injection by adding specific amounts of citric acid and sodium citrate as pH adjusters, which helps maintain the pH of the salbutamol sulfate injection.
[0024] The specific dosage of citric acid and sodium citrate in this invention can not only act as pH adjusters, but also have certain antioxidant effects, which can further prevent oxidation and free radical reactions of salbutamol sulfate during long-term storage at high temperatures, thereby improving the stability of salbutamol sulfate injection.
[0025] Furthermore, the specific dosage of citric acid and sodium citrate in this invention, utilizing their multiple carboxyl groups, can chelate impurities such as metal ions, avoiding the need to add metal ion chelating agents such as disodium edetate as stabilizers, and can improve the stability of salbutamol sulfate injection, which is beneficial for long-term storage.
[0026] This invention uses specific doses of citric acid and sodium citrate, without the need to add disodium edetate. The citric acid and sodium citrate used are less toxic and less irritating than disodium edetate, with a lower risk of allergies, less calcium and magnesium chelation in the blood, and less impact on the balance of metal ions in the body. Detailed Implementation
[0027] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Many specific details are set forth in the following description to provide a thorough understanding of the present invention. However, the present invention may also be implemented in other ways different from those described herein. Those skilled in the art can make similar extensions without departing from the spirit of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.
[0028] Example 1: A method for preparing salbutamol sulfate, salbutamol sulfate injection and preparation method
[0029] This embodiment describes a method for preparing salbutamol sulfate, a salbutamol sulfate injection solution, and the preparation method, as detailed below:
[0030] Preparation of S1, Salbutamol Sulfate
[0031] Mix 200 mL of ethanol and 20 mL of diethyl ether, add 23.9 g (0.1 mol) of salbutamol, stir to dissolve, and then slowly add dropwise to 10.5 mL of 5 mol / L sulfuric acid aqueous solution. After the addition is complete, maintain the reaction at room temperature for 2 h. After the reaction is complete, filter to obtain filtrate and the first filter cake.
[0032] Concentrate the filtrate to half its original volume, add 100 mL of diethyl ether, stir for 10 min, and filter again to obtain a second filter cake.
[0033] The first and second filter cakes were combined and dissolved by heating with ethanol to 50°C. Diethyl ether was slowly added dropwise while maintaining the temperature at 50°C until crystals precipitated. The temperature was then lowered to 0°C at a rate of 5°C / h and maintained at 0°C for 4 hours to allow crystals to crystallize. The mixture was then filtered and dried at 50°C to obtain 55.65 g of salbutamol sulfate, labeled as M1, with a yield of 96.50% and a purity of 99.96%.
[0034] S2, Preparation of Salbutamol Sulfate Injection
[0035] Under nitrogen protection, add 0.85g sodium chloride to 80mL of water for injection and stir to dissolve. Then add 1.18g citric acid monohydrate and 0.71g sodium citrate dihydrate and stir until completely dissolved. Cool to 10℃ and then add 0.05g salbutamol sulfate M1 and stir until completely dissolved. If the pH of the resulting system exceeds 3.6-4.0, adjust the pH to 3.6-4.0 with a small amount of sulfuric acid or sodium hydroxide solution. If it does not exceed the pH, no adjustment is needed. Then bring the volume to 100mL with water for injection and filter through a 0.22μm microporous membrane. Fill and seal the filtrate in borosilicate glass ampoules. Nitrogen is purged during the sealing process to control the headspace residual oxygen content to ≤5%. Finally, sterilize at 121℃ for 15min to obtain salbutamol sulfate injection solution, labeled as N1.
[0036] Examples 2-5: Preparation method of salbutamol sulfate, salbutamol sulfate injection and its preparation method
[0037] Examples 2-5 are methods for preparing salbutamol sulfate, salbutamol sulfate injection, and their preparation methods, respectively. Their steps are basically the same as in Example 1, differing only in the amount of raw materials and process parameters. See Table 1 for details.
[0038] Table 1. Summary of process parameters in Examples 2-5
[0039]
[0040]
[0041] The contents of other parts of Examples 2 to 5 are the same as those of Example 1.
[0042] Comparative Example 1: Preparation of Salbutamol Sulfate
[0043] Mix 200 mL of ethanol and 5 mL of diethyl ether, add 23.9 g (0.1 mol) of salbutamol, stir to dissolve, and then slowly add dropwise to 10.5 mL of 5 mol / L sulfuric acid aqueous solution. After the addition is complete, maintain the reaction at room temperature for 2 h. After the reaction is complete, filter to obtain filtrate and the first filter cake.
[0044] Concentrate the filtrate to half its original volume, add 100 mL of diethyl ether, stir for 10 min, and filter again to obtain a second filter cake.
[0045] The first and second filter cakes were combined and dissolved by heating with ethanol to 50°C. Ether was slowly added dropwise while maintaining the temperature at 50°C until crystals precipitated. The temperature was then lowered to 0°C at a rate of 5°C / h and maintained at 0°C for 4 hours to allow crystals to crystallize. The mixture was then filtered and dried at 50°C to obtain 53.32 g of salbutamol sulfate, with a yield of 92.46% and a purity of 99.63%.
[0046] It is evident that reducing the amount of diethyl ether used in the reaction process leads to more side reactions, which in turn reduces the purity and yield of the prepared salbutamol sulfate product.
[0047] Comparative Example 2: Preparation of Salbutamol Sulfate
[0048] Mix 200 mL of ethanol and 50 mL of diethyl ether, add 23.9 g (0.1 mol) of salbutamol, stir, but cannot completely dissolve, slowly add dropwise to 10.5 mL of 5 mol / L sulfuric acid aqueous solution, after the addition is complete, maintain the reaction at room temperature for 2 h, after the reaction is complete, filter to obtain filtrate and the first filter cake;
[0049] Concentrate the filtrate to half its original volume, add 100 mL of diethyl ether, stir for 10 min, and filter again to obtain a second filter cake.
[0050] The first and second filter cakes were combined and dissolved by heating with ethanol to 50°C. Diethyl ether was slowly added dropwise while maintaining the temperature at 50°C until crystals precipitated. The temperature was then lowered to 0°C at a rate of 5°C / h and maintained at 0°C for 4 hours to allow crystals to crystallize. The mixture was then filtered and dried at 50°C to obtain 48.71 g of salbutamol sulfate, with a yield of 84.46% and a purity of 98.93%.
[0051] It is evident that increasing the amount of diethyl ether used in the reaction process leads to a decrease in the solubility of salbutamol, which in turn results in a reduction in both the purity and yield of the prepared salbutamol sulfate product.
[0052] Comparative Example 3: Preparation of Salbutamol Sulfate
[0053] Mix 100 mL of ethanol and 10 mL of diethyl ether, add 23.9 g (0.1 mol) of salbutamol, stir, but cannot completely dissolve, slowly add dropwise to 10.5 mL of 5 mol / L sulfuric acid aqueous solution, after the addition is complete, maintain the reaction at room temperature for 2 h, after the reaction is complete, filter to obtain filtrate and the first filter cake;
[0054] Concentrate the filtrate to half its original volume, add 100 mL of diethyl ether, stir for 10 min, and filter again to obtain a second filter cake.
[0055] The first and second filter cakes were combined and dissolved by heating with ethanol to 50°C. Ether was slowly added dropwise while maintaining the temperature at 50°C until crystals precipitated. The temperature was then lowered to 0°C at a rate of 5°C / h and maintained at 0°C for 4 hours to allow crystals to crystallize. The mixture was then filtered and dried at 50°C to obtain 44.37 g of salbutamol sulfate, with a yield of 76.94% and a purity of 95.12%.
[0056] It is evident that reducing the amount of ethanol and diethyl ether used in the reaction process leads to a decrease in the solubility of salbutamol, which in turn results in a reduction in both the purity and yield of the prepared salbutamol sulfate product.
[0057] Comparative Example 4: Preparation of Salbutamol Sulfate
[0058] Mix 300 mL of ethanol and 30 mL of diethyl ether, add 23.9 g (0.1 mol) of salbutamol, stir, but cannot completely dissolve, slowly add dropwise to 10.5 mL of 5 mol / L sulfuric acid aqueous solution, after the addition is complete, maintain the reaction at room temperature for 2 h, after the reaction is complete, filter to obtain filtrate and the first filter cake;
[0059] Concentrate the filtrate to half its original volume, add 100 mL of diethyl ether, stir for 10 min, and filter again to obtain a second filter cake.
[0060] The first and second filter cakes were combined and dissolved by heating with ethanol to 50°C. Ether was slowly added dropwise while maintaining the temperature at 50°C until crystals precipitated. The temperature was then lowered to 0°C at a rate of 5°C / h and maintained at 0°C for 4 hours to allow crystals to crystallize. The mixture was then filtered and dried at 50°C to obtain 42.73 g of salbutamol sulfate, with a yield of 74.09% and a purity of 99.96%.
[0061] It is evident that increasing the amount of ethanol and diethyl ether used in the reaction process leads to a decrease in the yield of the prepared salbutamol sulfate product.
[0062] Comparative Example 5: Preparation of Salbutamol Sulfate
[0063] Mix 200 mL of ethanol and 20 mL of diethyl ether, add 23.9 g (0.1 mol) of salbutamol, stir, but cannot completely dissolve, slowly add dropwise to 10.5 mL of 5 mol / L sulfuric acid aqueous solution, after the addition is complete, maintain the reaction at room temperature for 2 h, after the reaction is complete, filter to obtain filtrate and the first filter cake;
[0064] Concentrate the filtrate to half its original volume, add 100 mL of diethyl ether, stir for 10 min, and filter again to obtain a second filter cake.
[0065] The first and second filter cakes were combined and dissolved by heating with ethanol to 50°C. Diethyl ether was slowly added dropwise while maintaining the temperature at 50°C until crystals precipitated. The temperature was then lowered to 0°C at a rate of 15°C / h and maintained at 0°C for 4 hours to allow crystals to crystallize. The mixture was then filtered and dried at 50°C to obtain 54.42 g of salbutamol sulfate, with a yield of 94.36% and a purity of 99.95%.
[0066] It is evident that increasing the cooling rate during recrystallization leads to a decrease in the yield of the prepared salbutamol sulfate product.
[0067] Experiment 1: Performance Testing of Salbutamol Sulfate Injection
[0068] Comparative Examples 6-9 are comparative experiments on the preparation process of salbutamol sulfate injection in Example 1, and all use salbutamol sulfate M1 as raw material, with the only difference being:
[0069] In Comparative Example 6, only 0.5 g of citric acid monohydrate was added, while the amounts of other raw materials, process steps, and parameters remained unchanged. The resulting salbutamol sulfate injection was labeled as DN1.
[0070] In Comparative Example 7, only 2g of citric acid monohydrate was added, while the amounts of other raw materials, process steps, and parameters remained unchanged. The resulting salbutamol sulfate injection was labeled as DN2.
[0071] In Comparative Example 8, only 0.2g of sodium citrate dihydrate was added, while the amounts of other raw materials, process steps, and parameters remained unchanged. The resulting salbutamol sulfate injection was labeled as DN3.
[0072] In Comparative Example 9, only 1.5g of sodium citrate dihydrate was added, while the amounts of other raw materials, process steps, and parameters remained unchanged. The resulting salbutamol sulfate injection was labeled DN4.
[0073] The preparation method of Comparative Example 10 is as follows:
[0074] Under nitrogen protection, 80 mL of water for injection was mixed with 0.85 g of sodium chloride and 0.05 g of disodium edetate, stirred until dissolved, and then sulfuric acid was added to adjust the pH to 3.8. The mixture was cooled to 10 °C, and then 0.05 g of salbutamol sulfate M1 was added and stirred until completely dissolved. If the pH of the resulting system exceeded 3.6–4.0, a small amount of sulfuric acid or sodium hydroxide solution was used to adjust the pH to 3.6–4.0. If the pH did not exceed this range, no adjustment was necessary. The solution was then brought to a final volume of 100 mL using water for injection and filtered through a 0.22 μm microporous membrane. The filtrate was filled and sealed in borosilicate glass ampoules. Nitrogen was used during the sealing process to control the headspace residual oxygen level to ≤5%. Finally, the solution was sterilized at 121 °C for 15 min to obtain salbutamol sulfate injection solution, labeled DN5.
[0075] Take the salbutamol sulfate injection solutions N1 and DN1 to DN5 prepared in Examples 1 and Comparative Examples 6 to 9, and place them at 60±2℃ and RH 75±5% for 56 days. During this period, samples were taken on days 0, 7, 14, 28 and 56, and tested according to the stability test items. The results were compared with the data from day 0.
[0076] The clarity, color, visible foreign matter, and sediment were observed. Specific test results are shown in the table below:
[0077] Table 2 Summary of Test Results
[0078]
[0079]
[0080] As can be seen from Table 2, the salbutamol sulfate injection prepared by this invention does not require the addition of stabilizers and still has good stability. Moreover, it produces almost no impurities during storage, which is beneficial for long-term storage.
[0081] Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.
Claims
1. A method for preparing salbutamol sulfate, characterized in that, The preparation process of the salbutamol sulfate includes the following steps: Mix ethanol and ether in a ratio of 10:0.95 to 1.05, add salbutamol to dissolve, then add sulfuric acid aqueous solution dropwise. After the addition is complete, proceed with the reaction. After the reaction is complete, filter to obtain filtrate and the first filter cake. After the filtrate is concentrated, diethyl ether is added, and the mixture is filtered again to obtain a second filter cake. The first and second filter cakes were combined and recrystallized to obtain the salbutamol sulfate.
2. The method for preparing salbutamol sulfate according to claim 1, characterized in that, The recrystallization process involves combining the first and second filter cakes, dissolving them by heating with ethanol to 50–55°C, maintaining the temperature at 50–55°C, adding diethyl ether dropwise until crystals precipitate, then cooling the temperature to 0–4°C at a rate of 4–6°C / h, maintaining the temperature at 0–4°C to allow crystals to precipitate, filtering, and drying to obtain the salbutamol sulfate.
3. The method for preparing salbutamol sulfate according to claim 1 or 2, characterized in that, The volume molar ratio of ethanol to salbutamol used to dissolve salbutamol is 200–210 mL: 0.1 mol.
4. The method for preparing salbutamol sulfate according to claim 1 or 2, characterized in that, The molar volume ratio of salbutamol to sulfuric acid aqueous solution is 0.1 mol: 10-11 mL; The concentration of the sulfuric acid aqueous solution is 5 mol / L.
5. The method for preparing salbutamol sulfate according to claim 1 or 2, characterized in that, The reaction time is 2 to 3 hours.
6. The method for preparing salbutamol sulfate according to claim 1 or 2, characterized in that, The filtrate is concentrated to 1 / 3 to 1 / 2 of its original volume; After concentration, the volume molar ratio of added diethyl ether to salbutamol is 100–105 mL: 0.1 mol.
7. A salbutamol sulfate injection solution, characterized in that, The raw materials for preparing the active ingredient of the salbutamol sulfate injection, by weight, include: 0.05 parts of salbutamol sulfate prepared by the method of any one of claims 1-6, 0.85-0.9 parts of sodium chloride, 1.1-1.25 parts of citric acid monohydrate, and 0.6-0.81 parts of sodium citrate dihydrate.
8. The method for preparing the salbutamol sulfate injection according to claim 7, characterized in that, The preparation method of the salbutamol sulfate injection is as follows: under nitrogen protection, water for injection is added to dissolve sodium chloride, then citric acid monohydrate and sodium citrate dihydrate are added to dissolve, the mixture is cooled, then salbutamol sulfate is added to dissolve, the volume is adjusted, filtered, filled, sealed, and sterilized to obtain the salbutamol sulfate injection.
9. The method for preparing salbutamol sulfate injection according to claim 8, characterized in that, Before adding salbutamol sulfate and after dissolving it with citric acid monohydrate and sodium citrate dihydrate, the temperature after cooling is below 10℃.