Preparation method of potassium clavulanate
By using potassium citrate or potassium gluconate solvents combined with organic solvents for cooling crystallization, the problem of low purity of potassium clavulanate was solved, achieving the preparation of high-purity and high-quality potassium clavulanate, which is suitable for industrial production.
Patent Information
- Application Number
- CN202511996676.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-27
- Publication Date
- 2026-02-13
AI Technical Summary
In existing technologies, potassium clavulanate has insufficient purity and excessive use of organic solvents, resulting in unstable quality.
Potassium citrate or potassium gluconate was used as a solvent to prepare potassium clavulanate by adding an organic solvent to an aqueous solution and then cooling and crystallizing. The pH value was controlled and the organic solvent was added in batches or at a constant rate to reduce the use of organic solvent.
It improves the purity and quality of potassium clavulanate, reduces the amount of organic solvents used, enhances safety, and is suitable for industrial production.
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical preparation technology, specifically to a method for preparing potassium clavulanate. Background Technology
[0002] Clavulanate potassium is one of the most widely used β-lactamase inhibitors in the world. Beecham first isolated clavulanate from *Streptomyces rodentata* in 1976. Clavulanate binds firmly to enzymes, rendering them inactive, and its activity is not reactivated by the removal of potassium clavulanate. Clavulanate potassium alone has little clinical significance and is usually used in combination with other β-lactam antibiotics. It is commonly prepared as a combination with amoxicillin sodium or ticarcillin sodium.
[0003] Currently, the potassium clavulanate prepared by the methods disclosed in the literature does not have high purity, uses a lot of organic solvents, and has unstable quality. Summary of the Invention
[0004] In view of the above-mentioned deficiencies in the prior art, the object of the present invention is to provide a method for preparing potassium clavulanate, comprising the following steps, 1) Prepare a clavulanic acid ammonium salt solution, wherein the solvent comprises water and an organic solvent; 2) Prepare an aqueous solution of potassium citrate or potassium gluconate; 3) Add potassium clavulanate ammonium salt to an aqueous solution of potassium citrate or potassium gluconate; 4) Add an organic solvent to step 3, then cool to 0~5℃ to allow potassium clavulanate to crystallize; 5) Filter out the crystals from step 4, wash them, and dry them; The order of steps 1 and 2 above is not fixed.
[0005] Compared with the prior art, the present invention has the following beneficial effects: This invention uses potassium citrate or potassium gluconate, which is biofriendly even if residues remain.
[0006] The present invention obtains a purer product by adding an organic solvent to the system and then cooling and crystallizing. Detailed Implementation
[0007] The following specific embodiments illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.
[0008] Furthermore, it should be understood that the one or more method steps mentioned in this invention do not preclude the existence of other method steps before or after the combined steps, or the insertion of other method steps between these explicitly mentioned steps, unless otherwise stated; moreover, unless otherwise stated, the numbering of each method step is merely a convenient tool for identifying each method step, and not for limiting the order of the method steps or limiting the scope of the invention. Changes or adjustments to their relative relationships, without substantially altering the technical content, should also be considered as within the scope of the invention.
[0009] This invention provides a method for preparing potassium clavulanate, comprising the following steps: 1) Prepare a clavulanic acid ammonium salt solution, wherein the solvent comprises water and an organic solvent; activated carbon may be added during the preparation process and then removed by filtration; 2) Prepare an aqueous solution of potassium citrate or potassium gluconate; 3) Add potassium clavulanate ammonium salt solution to potassium citrate or potassium gluconate aqueous solution; the addition shall not be a one-time addition, but shall be made in batches or by uniform dripping. 4) Add an organic solvent to step 3), then cool to 0~5℃ to allow potassium clavulanate to crystallize; 5) Filter out the crystals from step 4), wash them, and dry them; The order of steps 1) and 2) above is not fixed.
[0010] In an optional embodiment of the present invention, the clavulanic acid amine salt may be selected as tert-butyl clavulanic acid or tert-octyl clavulanic acid.
[0011] In an optional embodiment of the present invention, the organic solvent in step 1) is selected from alcohol solvents, such as ethanol, propanol, n-butanol, isopropanol, etc.
[0012] In an optional embodiment of the present invention, the pH of step 1) is controlled between 5.0 and 7.0; preferably, acetic acid is used to adjust the pH.
[0013] In an optional embodiment of the present invention, step 3) potassium clavulanate ammonium salt is added to an aqueous solution of potassium citrate or potassium gluconate by a uniform dropwise addition method; preferably, the temperature is controlled at 20~30 degrees Celsius.
[0014] In an optional embodiment of the present invention, the molar ratio of potassium clavulanate ammonium salt to potassium citrate or potassium gluconate in step 3) is 1:1.01 to 1:2.0; preferably 1:1.01 to 1:1.5.
[0015] In an optional embodiment of the present invention, the organic solvent in step 4) is selected from alcohol-based organic solvents, such as ethanol, propanol, n-butanol, isopropanol, etc.
[0016] In an optional embodiment of the present invention, step 4) cooling is performed by slow cooling.
[0017] In an optional embodiment of the present invention, step 5) washing is performed using an alcoholic organic solvent, such as ethanol, propanol, n-butanol, isopropanol, etc.
[0018] In an optional embodiment of the present invention, the washing temperature in step 5) is selected from 0 to 5 degrees Celsius.
[0019] In an optional embodiment of the present invention, the drying temperature in step 5) is 20~30 degrees Celsius.
[0020] Example 1 1) Clavulanic acid tert-octylamine salt solution: 10g clavulanic acid tert-octylamine, 10mL water, 10mL isopropanol, 2g activated carbon, acetic acid adjusted to pH 6.0. Further filtration removes the activated carbon; 2) Potassium citrate solution: 15g potassium citrate, 15mL water; 3) Add clavulanic acid tert-octylamine salt solution dropwise to potassium citrate aqueous solution; add at a uniform rate over 30 minutes; maintain the temperature at 25 degrees Celsius. 4) Slowly add 50 mL of isopropanol to step 3) over 30 minutes; then slowly cool to 0°C over 30 minutes to allow potassium clavulanate to crystallize. 5) Filter out the crystals from step 4), wash with isopropanol at 0 degrees Celsius, and dry at 25 degrees Celsius for 2 hours to obtain white crystals with a purity of 99.92% (0.08% impurities).
[0021] Example 2 1) Clavulanic acid tert-octylamine salt solution: 10g clavulanic acid tert-octylamine, 10mL water, 10mL isopropanol, 2g activated carbon, acetic acid adjusted to pH 6.0. Further filtration removes the activated carbon; 2) Potassium citrate solution: 18g potassium citrate, 15mL water; 3) Add clavulanic acid tert-octylamine salt solution dropwise to potassium citrate aqueous solution; add at a uniform rate over 30 minutes; maintain the temperature at 25 degrees Celsius. 4) Slowly add 50 mL of isopropanol to step 3) over 30 minutes; then slowly cool to 0°C over 30 minutes to allow potassium clavulanate to crystallize. 5) Filter out the crystals from step 4), wash with isopropanol at 0 degrees Celsius, and dry at 25 degrees Celsius for 2 hours to obtain white crystals with a purity of 99.86% (0.14% impurities).
[0022] Comparative Example 1 1) Clavulanic acid tert-octylamine salt solution: 10g clavulanic acid tert-octylamine, 10mL water, 10mL isopropanol, 2g activated carbon, acetic acid adjusted to pH 6.0. Further filtration removes the activated carbon; 2) Potassium isooctanoate solution: 8.5g potassium isooctanoate, 15mL water; 3) Add clavulanic acid tert-octylamine salt solution dropwise to potassium isooctanoate aqueous solution; add at a uniform rate, complete the addition over 30 minutes; control the temperature at 25 degrees Celsius; 4) Slowly add 50 mL of isopropanol to step 3) over 30 minutes; then slowly cool to 0°C over 30 minutes to allow potassium clavulanate to crystallize. 5) Filter out the crystals from step 4), wash with isopropanol at 0 degrees Celsius, and dry at 25 degrees Celsius for 2 hours to obtain white crystals with a purity of 99.77% (0.23% impurities).
[0023] Comparative Example 2 1) Clavulanic acid tert-octylamine salt solution: 10g clavulanic acid tert-octylamine, 10mL water, 10mL isopropanol, 2g activated carbon, acetic acid adjusted to pH 6.0. Further filtration removes the activated carbon; 2) Potassium isooctanoate solution: 8.5g potassium isooctanoate, 15mL isopropanol; 3) Add clavulanic acid tert-octylamine salt solution dropwise to potassium isooctanoate solution; add at a uniform rate over 30 minutes; maintain the temperature at 25 degrees Celsius. 4) Slowly add 50 mL of isopropanol to step 3) over 30 minutes; then slowly cool to 0°C over 30 minutes to allow potassium clavulanate to crystallize. 5) Filter out the crystals from step 4), wash with isopropanol at 0 degrees Celsius, and dry at 25 degrees Celsius for 2 hours to obtain a slightly yellow crystal with a purity of 99.70% (0.30% impurities).
[0024] The potassium clavulanate product prepared by this invention has high purity and high quality, avoids the use of large amounts of organic solvents, is safer, and is suitable for industrial production.
[0025] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by those skilled in the art without departing from the spirit and technical concept disclosed in the present invention should still be covered by the claims of the present invention.
Claims
1. A method for preparing potassium clavulanate, characterized in that, Includes the following steps, 1) Prepare a clavulanic acid ammonium salt solution, the solvent of which includes water and an organic solvent; 2) Prepare an aqueous solution of potassium citrate or potassium gluconate; 3) Add potassium clavulanate ammonium salt solution to potassium citrate or potassium gluconate aqueous solution; 4) Add an organic solvent to step 3), then cool to 0~5℃ to allow potassium clavulanate to crystallize; 5) Filter out the crystals from step 4), wash them, and dry them; The order of steps 1) and 2) above is not fixed.
2. The method for preparing potassium clavulanate according to claim 1, characterized in that... Clavulanic acid ammonium salt can be selected as tert-butyl clavulanic acid or tert-octyl clavulanic acid.
3. The method for preparing potassium clavulanate according to claim 1, characterized in that... The organic solvent in step 1) is selected from alcohol solvents.
4. The method for preparing potassium clavulanate according to claim 1, characterized in that... The pH of step 1) should be controlled between 5.0 and 7.
0.
5. The method for preparing potassium clavulanate according to claim 4, characterized in that... Adjust the pH with acetic acid.
6. The method for preparing potassium clavulanate according to claim 1, characterized in that... Step 3) Add potassium clavulanate ammonium salt to an aqueous solution of potassium citrate or potassium gluconate by a uniform dripping method; preferably, the temperature is controlled at 20~30 degrees Celsius.
7. The method for preparing potassium clavulanate according to claim 1, characterized in that... Step 4) The organic solvent is selected from alcohol-based organic solvents.
8. The method for preparing potassium clavulanate according to claim 1, characterized in that... Step 4) Cooling down is done by slow cooling.
9. The method for preparing potassium clavulanate according to claim 1, characterized in that... Step 5) Washing is performed using alcohol-based organic solvents.
10. The method for preparing potassium clavulanate according to claim 1, characterized in that, Step 5) The washing temperature is selected from 0 to 5 degrees Celsius.