Spherical potassium clavulanate, its preparation method and compound preparation

Abstract

The application provides a spherical potassium clavulanate, a preparation method thereof and a compound preparation. The spherical potassium clavulanate has a spherical diameter of 25-150 microns. The preparation method of the spherical potassium clavulanate is as follows: 1. Dissolving a tertiary butylamine salt in an organic solvent to obtain an amine salt solution; 2. Preparing a potassium isooctanoate solution by dissolving potassium isooctanoate in an appropriate amount of organic solvent; 3. Removing carbon in the solution by adding activated carbon into the amine salt solution, stirring, filtering and washing the carbon with a small amount of organic solvent; 4. Crystallizing by controlling the temperature of the crystallization solution at 16-20 DEG C, stirring and adding the potassium isooctanoate solution at a constant speed; after the addition is completed, the temperature is lowered to 2-6 DEG C, and the stirring and heat preservation are performed for greater than or equal to 2 hours; 5. Filtering, washing and drying by filtering the crystallization solution, washing the solution with a solvent at 2-6 DEG C for 3-4 times, and vacuum drying the wet powder by cold pumping for 1 hour and drying at 35 DEG C for 6 hours. The spherical potassium clavulanate prepared by the method has uniform particle size distribution, good fluidity, easy dispensing and quality meeting the standard of the 2020 edition of the Chinese Pharmacopoeia.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a spherical potassium clavulanate, its preparation method, and a compound formulation thereof. Background Technology

[0002] Potassium clavulanate is (Z)-(2S,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylic acid potassium. On anhydrous basis, it contains 81.0%–85.6% clavulanic acid (C8H9NO5). It is a white to slightly yellow crystalline powder; slightly odorous; extremely hygroscopic.

[0003] 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.

[0004] Potassium clavulanate can be prepared by reaction crystallization, dissolution crystallization, and reverse-flow dissolution crystallization. Reaction crystallization is the most widely used method, and it typically involves two steps. The first step is the preparation of a clavulanate amine salt intermediate, commonly using tert-butylamine, tert-octylamine, or polyamines. The second step is an ion exchange salt formation reaction, usually using potassium isooctanoate as the salt-forming agent.

[0005] Currently, the form of potassium clavulanate reported in domestic and international literature and patents is mainly rod-shaped, hence the name "potassium clavulanate". Potassium clavulanate produced by pharmaceutical companies is also rod-shaped.

[0006] Chinese patent CN 109535184 B discloses a method for preparing potassium clavulanate from tert-octyl clavulanate. The method includes: (1) dissolving and filtering tert-octyl clavulanate; (2) dissolving and filtering a salt-forming agent; and (3) crystallizing tert-octyl clavulanate with potassium isooctanoate. This patent obtains high-quality, high-purity potassium clavulanate through optimized process methods, but the potassium clavulanate prepared according to this method has a rod-like structure.

[0007] Chinese patent application CN104910194A discloses a method for preparing potassium clavulanate and its compound formulation. The method involves first filtering the fermentation broth of *Streptomyces rod-shaped*; after decolorizing the filtrate, adding an extractant, transferring it to a pressure-resistant container, removing air bubbles, sealing and shaking, and freezing under controlled temperature until the aqueous phase is frozen. The aqueous phase is then removed to obtain the extract. Potassium carbonate solution is added to the extract while stirring, transferred to a pressure-resistant container, removing air bubbles, sealing and shaking, freezing under controlled temperature, removing the organic phase, and after the solid melts, slowly adding acetone while stirring. The mixture is then filtered, washed, and dried to obtain potassium clavulanate. Potassium clavulanate is then aseptically mixed with amoxicillin or with ticarcillin. The preparation method disclosed in this patent application is simple, low-cost, and produces a product with low impurity content and high purity.

[0008] Currently, there are relatively few patents on the preparation of potassium clavulanate alone, while there are relatively more patents on the preparation of compound formulations. Summary of the Invention

[0009] The purpose of this invention is to provide a spherical potassium clavulanate, its preparation method and compound formulation. This invention prepares potassium clavulanate with a novel structure, and the obtained spherical potassium clavulanate has uniform particle size and good flowability.

[0010] This invention is implemented as follows:

[0011] The spherical potassium clavulanate provided by the present invention has a spherical structure with a diameter of 25-150 μm.

[0012] Furthermore, the angle of repose of this spherical potassium clavulanate is 20°–30°.

[0013] Furthermore, the preparation process of the spherical potassium clavulanate is as follows: First, an amine salt is dissolved in an organic solvent to prepare an amine salt solution; then, potassium isooctanoate is dissolved in an organic solvent to prepare a potassium isooctanoate solution; next, the amine salt solution is decarbonized, and then the potassium isooctanoate solution is added to crystallize; finally, the solution is filtered, washed, and dried.

[0014] This invention provides a method for preparing spherical potassium clavulanate with uniform particle size and good flowability. The specific preparation method is as follows: First, an amine salt solution is prepared using tert-butylamine clavulanate. Only organic solvents are used in the preparation of the amine salt solution; water is not used. The organic solvents are at least two of ethanol, isopropanol, and ethyl acetate. The prepared amine salt solution is decarbonized and filtered. A potassium isooctanoate solution is prepared, using the same organic solvent as that used in the preparation of the amine salt solution. The filtered amine salt solution is kept at 16-20°C, and potassium isooctanoate is added for crystallization. After crystallization, the system is cooled to 3-5°C and kept at this temperature for 2 hours. The crystallized solution is filtered and washed 3-4 times with isopropanol at 2-6°C. The wet powder is then vacuum dried, first by cold suction for 1 hour, and then by drying at 35°C for 6 hours.

[0015] The method for preparing spherical potassium clavulanate provided by this invention comprises the following specific steps:

[0016] (1) Amine salt dissolution stage: Add 85 mL of ethanol and 32.5 mL of isopropanol to 5 g of clavulanic acid tert-butylamine salt, stir and dissolve at 22-26℃, pH≥7.0, slowly add glacial acetic acid (about 0.5-1.2 mL) to the solution, and adjust the pH to 6.00.

[0017] (2) Preparation of KEE solution: Add 4g of potassium isooctanoate to 25mL of isopropanol and 25mL of ethanol and stir until completely dissolved to obtain KEE solution.

[0018] (3) Decarbonization of the solution: Add 1.3g of activated carbon to the amine salt solution obtained in step (1), stir for 30min and then filter, and wash the carbon with a small amount of isopropanol.

[0019] (4) Crystallization: The crystallization solution is kept at a temperature of 16-20℃, stirred, and KEE solution is added at a constant rate over a period of 30 minutes. After the addition is completed, the temperature is lowered to 2-6℃ and stirred and kept at that temperature for ≥2 hours.

[0020] (5) Filtration, washing and drying: Filter the crystallization liquid and wash it 3-4 times with isopropanol at 2-6℃. Vacuum dry the wet powder, first cold-pump for 1 hour, then dry at 35℃ for 6 hours.

[0021] The organic solvents (ethanol and isopropanol) used in steps (1) and (2) above can be replaced with a mixed solvent of ethanol and ethyl acetate, or a mixed solvent of isopropanol and ethyl acetate, or a mixed solvent of ethanol, isopropanol and ethyl acetate.

[0022] The present invention also provides a compound formulation made from the above-mentioned spherical potassium clavulanate and amoxicillin sodium, ticarcillin sodium or amoxicillin.

[0023] The innovative aspects and advantages of this invention are as follows:

[0024] This invention employs a solvent method to prepare potassium clavulanate, using a mixture of two or three of ethyl acetate, isopropanol, and ethanol as a composite solvent. No water is added to the composite solvent. Specific process parameters are then used to influence the crystal conformation, thermodynamic state, and solubility of potassium clavulanate, resulting in spherical potassium clavulanate with uniform particle size distribution, good flowability, and easy packaging. The obtained spherical potassium clavulanate can be combined with amoxicillin sodium, ticarcillin sodium, or amoxicillin to prepare compound formulations. Attached Figure Description

[0025] Figure 1 Images of rod-shaped potassium clavulanate crystals prepared in Comparative Example 1 are shown. The left image corresponds to 100X magnification, and the right image corresponds to 400X magnification.

[0026] Figure 2 These are images of the spherical potassium clavulanate crystals prepared in Example 1. The left image corresponds to 100X magnification, and the right image corresponds to 400X magnification.

[0027] Figure 3 These are images of the spherical potassium clavulanate crystals prepared in Example 2. The left image corresponds to 100X magnification, and the right image corresponds to 400X magnification.

[0028] Figure 4 These are images of the spherical potassium clavulanate crystals prepared in Example 3. The left image corresponds to 100X magnification, and the right image corresponds to 400X magnification.

[0029] Figure 5 These are images of the spherical potassium clavulanate crystals prepared in Example 4. The left image corresponds to 100X magnification, and the right image corresponds to 400X magnification.

[0030] Figure 6 These are images of the spherical potassium clavulanate crystals prepared in Example 5. The left image corresponds to 100X magnification, and the right image corresponds to 400X magnification.

[0031] Figure 7 Images of rod-shaped potassium clavulanate crystals prepared in Comparative Example 2 are shown. The left image corresponds to 100X magnification, and the right image corresponds to 400X magnification. Detailed Implementation

[0032] The preparation method of spherical potassium clavulanate in this invention will be described in detail below with reference to specific embodiments.

[0033] Comparative Example 1: Preparation method of rod-shaped potassium clavulanate.

[0034] The inventor prepared rod-shaped potassium clavulanate according to the current preparation process of his pharmaceutical factory, as follows:

[0035] (1) Amine salt dissolution stage: Add 10g of clavulanic acid tert-butylamine salt to 130mL of isopropanol and 5mL of purified water, and stir to dissolve at 22-26℃. Moisture content: 4.1%-4.8%, pH≥7.0. Slowly add glacial acetic acid (about 0.5-1.2mL) to the solution to adjust the pH to 5.4-6.5.

[0036] (2) Preparation of KEE solution: Add 8g of potassium isooctanoate to 100mL of isopropanol and stir until completely dissolved to obtain KEE solution.

[0037] (3) Decarbonization of the solution: Add about 8 mL of KEE solution to the amine salt solution obtained in step (1), stir evenly, control the temperature at 16-20℃, add 1.3 g of activated carbon, stir for 30 min, filter, and wash the carbon with a small amount of isopropanol.

[0038] (4) Crystallization: The crystallization solution is kept at a temperature of 16-20℃, stirred, and the remaining KEE solution is added at a constant rate over a period of 30 minutes. After the addition is completed, the temperature is lowered to 2-6℃ and stirred and kept at that temperature for ≥2 hours.

[0039] (5) Filtration, washing and drying: Filter the crystallization liquid and wash it 3-4 times with isopropanol at 2-6℃. Vacuum dry the wet powder, first cold-pump for 1 hour, then dry at 35℃ for 6 hours.

[0040] The samples prepared in this comparative example were observed under a microscope, and the results are as follows: Figure 1 As shown. Figure 1 In the image, the left image is magnified 100 times, and the right image is magnified 400 times. Figure 1 It can be seen that the prepared potassium clavulanate has a rod-like structure.

[0041] Example 1: Preparation method of spherical potassium clavulanate.

[0042] (1) Amine salt dissolution stage: Add 170 mL of ethanol and 65 mL of isopropanol to 10 g of clavulanic acid tert-butylamine salt, stir and dissolve at 22-26℃, pH≥7.0, slowly add glacial acetic acid (about 1-2.4 mL) to the solution, and adjust the pH to 6.00.

[0043] (2) Preparation of KEE solution: Add 8g of potassium isooctanoate to 50mL of isopropanol and 50mL of ethanol and stir until completely dissolved to obtain KEE solution.

[0044] (3) Decarbonization of the solution: Add 2.6g of activated carbon to the amine salt solution obtained in step (1), stir for 30min and then filter, and wash the carbon with a small amount of isopropanol.

[0045] (4) Crystallization: The crystallization solution is kept at a temperature of 16-20℃, stirred, and KEE solution is added at a constant rate over a period of 30 minutes. After the addition is completed, the temperature is lowered to 2-6℃ and stirred and kept at that temperature for ≥2 hours.

[0046] (5) Filtration, washing and drying: Filter the crystallization liquid and wash it 3-4 times with isopropanol at 2-6℃. Vacuum dry the wet powder, first cold-pump for 1 hour, then dry at 35℃ for 6 hours.

[0047] The sample prepared in this embodiment was observed under a microscope, and the results are as follows: Figure 2 As shown. Figure 2 In the image, the left image is magnified 100 times, and the right image is magnified 400 times. Figure 2 It can be seen that the prepared potassium clavulanate has a spherical structure.

[0048] Example 2: Preparation method of spherical potassium clavulanate.

[0049] (1) Amine salt dissolution stage: Add 170 mL of ethanol and 100 mL of ethyl acetate to 10 g of clavulanic acid tert-butylamine salt, stir and dissolve at 22-26℃, pH≥7.0, slowly add glacial acetic acid (about 1-2.4 mL) to the solution, and adjust the pH to 6.00.

[0050] (2) Preparation of KEE solution: Add 8g of potassium isooctanoate to 50mL of ethyl acetate and 50mL of ethanol and stir until completely dissolved to obtain KEE solution.

[0051] (3) Decarbonization of the solution: Add 2.6g of activated carbon to the amine salt solution obtained in step (1), stir for 30min and then filter, and wash the carbon with a small amount of isopropanol.

[0052] (4) Crystallization: The crystallization solution is kept at a temperature of 16-20℃, stirred, and KEE solution is added at a constant rate over a period of 30 minutes. After the addition is completed, the temperature is lowered to 2-6℃ and stirred and kept at that temperature for ≥2 hours.

[0053] (5) Filtration, washing and drying: Filter the crystallization liquid and wash it 3-4 times with isopropanol at 2-6℃. Vacuum dry the wet powder, first cold-pump for 1 hour, then dry at 35℃ for 6 hours.

[0054] The sample prepared in this embodiment was observed under a microscope, and the results are as follows: Figure 3 As shown. Figure 3 In the image, the left image is magnified 100 times, and the right image is magnified 400 times. Figure 3 It can be seen that the prepared potassium clavulanate has a spherical structure.

[0055] Example 3: Preparation method of spherical potassium clavulanate.

[0056] (1) Amine salt dissolution stage: Add 170 mL of ethanol, 50 mL of ethyl acetate and 50 mL of isopropanol to 10 g of clavulanic acid tert-butylamine salt, stir and dissolve at 22-26℃, pH≥7.0, slowly add glacial acetic acid (about 1-2.4 mL) to the solution, and adjust the pH to 6.00.

[0057] (2) Preparation of KEE solution: Add 8g of potassium isooctanoate to 30mL of ethyl acetate, 30mL of ethanol and 30mL of ethyl acetate and stir until completely dissolved to obtain KEE solution.

[0058] (3) Decarbonization of the solution: Add 1.3g of activated carbon to the amine salt solution obtained in step (1), stir for 30min and then filter, and wash the carbon with a small amount of isopropanol.

[0059] (4) Crystallization: The crystallization solution is kept at a temperature of 16-20℃, stirred, and KEE solution is added at a constant rate over a period of 30 minutes. After the addition is completed, the temperature is lowered to 2-6℃ and stirred and kept at that temperature for ≥2 hours.

[0060] (5) Filtration, washing and drying: Filter the crystallization liquid and wash it 3-4 times with isopropanol at 2-6℃. Vacuum dry the wet powder, first cold-pump for 1 hour, then dry at 35℃ for 6 hours.

[0061] The sample prepared in this embodiment was observed under a microscope, and the results are as follows: Figure 4 As shown. Figure 4 In the image, the left image is magnified 100 times, and the right image is magnified 400 times. Figure 4 It can be seen that the prepared potassium clavulanate has a spherical structure.

[0062] Example 4: Preparation method of spherical potassium clavulanate.

[0063] (1) Amine salt dissolution stage: Add 120 mL of ethyl acetate and 80 mL of isopropanol to 10 g of clavulanic acid tert-butylamine salt, stir and dissolve at 22-26℃, pH≥7.0, slowly add glacial acetic acid (about 1-2.4 mL) to the solution, and adjust the pH to 6.00.

[0064] (2) Preparation of KEE solution: Add 8g of potassium isooctanoate to 60mL of isopropanol and 60mL of ethyl acetate and stir until completely dissolved to obtain KEE solution.

[0065] (3) Decarbonization of the solution: Add 2.6g of activated carbon to the amine salt solution obtained in step (1), stir for 30min and then filter, and wash the carbon with a small amount of isopropanol.

[0066] (4) Crystallization: The crystallization solution is kept at a temperature of 16-20℃, stirred, and KEE solution is added at a constant rate over a period of 30 minutes. After the addition is completed, the temperature is lowered to 2-6℃ and stirred and kept at that temperature for ≥2 hours.

[0067] (5) Filtration, washing and drying: Filter the crystallization liquid and wash it 3-4 times with isopropanol at 2-6℃. Vacuum dry the wet powder, first cold-pump for 1 hour, then dry at 35℃ for 6 hours.

[0068] The sample prepared in this embodiment appears to have a spherical structure when observed under a microscope.

[0069] Example 5: Preparation method of spherical potassium clavulanate.

[0070] (1) Amine salt dissolution stage: 10g clavulanic acid tert-butylamine salt is dissolved in 170mL ethanol, 65mL isopropanol and 2mL purified water at 22-26℃ with stirring. The pH is ≥7.0. Glacial acetic acid (about 1-2.4mL) is slowly added to the solution to adjust the pH to 6.00.

[0071] (2) Preparation of KEE solution: Add 8g of potassium isooctanoate to 50mL of isopropanol and 50mL of ethanol and stir until completely dissolved to obtain KEE solution.

[0072] (3) Decarbonization of the solution: Add 2.6g of activated carbon to the amine salt solution obtained in step (1), stir for 30min and then filter, and wash the carbon with a small amount of isopropanol.

[0073] (4) Crystallization: The crystallization solution is kept at a temperature of 16-20℃, stirred, and KEE solution is added at a constant rate over a period of 30 minutes. After the addition is completed, the temperature is lowered to 2-6℃ and stirred and kept at that temperature for ≥2 hours.

[0074] (5) Filtration, washing and drying: Filter the crystallization liquid and wash it 3-4 times with isopropanol at 2-6℃. Vacuum dry the wet powder, first cold-pump for 1 hour, then dry at 35℃ for 6 hours.

[0075] The sample prepared in this embodiment still shows a spherical structure when observed under a microscope.

[0076] Comparative Example 2: Preparation method of rod-shaped potassium clavulanate.

[0077] (1) Amine salt dissolution stage: 10g clavulanic acid tert-butylamine salt is dissolved in 170mL ethanol, 65mL isopropanol and 6mL purified water at 22-26℃ with stirring. The pH is ≥7.0. Glacial acetic acid (about 1-2.4mL) is slowly added to the solution to adjust the pH to 6.00.

[0078] (2) Preparation of KEE solution: Add 8g of potassium isooctanoate to 50mL of isopropanol and 50mL of ethanol and stir until completely dissolved to obtain KEE solution.

[0079] (3) Decarbonization of the solution: Add 2.6g of activated carbon to the amine salt solution obtained in step (1), stir for 30min and then filter, and wash the carbon with a small amount of isopropanol.

[0080] (4) Crystallization: The crystallization solution is kept at a temperature of 16-20℃, stirred, and KEE solution is added at a constant rate over a period of 30 minutes. After the addition is completed, the temperature is lowered to 2-6℃ and stirred and kept at that temperature for ≥2 hours.

[0081] (5) Filtration, washing and drying: Filter the crystallization liquid and wash it 3-4 times with isopropanol at 2-6℃. Vacuum dry the wet powder, first cold-pump for 1 hour, then dry at 35℃ for 6 hours.

[0082] The sample prepared in this comparative example showed a rod-like structure when observed under a microscope.

[0083] The inventors discovered through research that excessive water in the base solution easily forms rod-shaped potassium clavulanate particles, while adding little or no water can potentially form spherical potassium clavulanate.

[0084] Product liquidity data:

[0085] Reference standards for angle of repose testing: GB11986-89, ISO4324-1977, DIN ISO 4324-December 1983. The angle of repose of the sample is expressed in angle form.

[0086] Table 1. Results of Angle of Repose Test for Spherical and Rod-shaped Potassium Clavulanate Powder

[0087]

[0088]

[0089] As shown in Table 1, the angles of repose of the spherical potassium clavulanate prepared in Examples 1-5 were 23.3°, 26.4°, 29.5°, 21.3°, and 30.2°, respectively, while the angles of repose of the rod-shaped potassium clavulanate prepared in Comparative Examples 1 and 2 were 46.8° and 41.5°, respectively. According to the Carr flowability index evaluation table, the flowability of the spherical potassium clavulanate powder was better than that of the rod-shaped potassium clavulanate.

[0090] Product granularity data:

[0091] Table 2. Particle size data of spherical and rod-shaped potassium clavulanate (1 cm represents 25 μm at 400x field of view)

[0092] Examples and Comparative Examples Appearance Particle size range Comparative Example 1 Rod-shaped Length: 50-250μm; Width: 12.5-50μm Example 1 spherical Sphere diameter: 50-125μm Example 2 spherical Sphere diameter: 75-125μm Example 3 spherical Sphere diameter: 75-150μm Example 4 spherical Sphere diameter: 25-100μm Example 5 spherical Sphere diameter: 75-150μm Comparative Example 2 Rod-shaped Length: 50-200μm; Width: 12.5-25μm

[0093] Based on the above-mentioned preparation of spherical potassium clavulanate, the present invention also uses the spherical potassium clavulanate to prepare potassium clavulanate compound preparations for injection or oral administration with amoxicillin sodium, ticarcillin sodium and amoxicillin respectively. The resulting compound preparations have good performance.

[0094] The above examples are only used to further illustrate the method of the present invention and do not limit the present invention in any way.

Claims

1. A spherical potassium clavulanate, characterized in that, The diameter of the spherical potassium clavulanate is 25~150 μm, and the angle of repose is 20°~30°. The method for preparing the spherical potassium clavulanate includes the following steps: (1) Preparation of amine salt solution: Clavulanic acid tert-butylamine is dissolved in at least two organic solvents selected from ethanol, isopropanol and ethyl acetate; (2) Preparation of potassium isooctanoate solution: Dissolve potassium isooctanoate in the same organic solvent as in step (1); (3) Decarbonization of amine salt solution: Add activated carbon to the amine salt solution obtained in step (1), stir and then filter; (4) Crystallization: Add the potassium isooctanoate solution obtained in step (2) to the solution obtained in step (3) at a constant rate, and cool down to crystallize after the addition is completed; (5) Filtering, washing, and drying; In step (4), the temperature of the solution obtained in step (3) is controlled at 16~20℃, and after the addition is completed, the temperature is lowered to 2~6℃ and stirred and kept warm for ≥2h.

2. A method for preparing spherical potassium clavulanate as described in claim 1, characterized in that, Includes the following steps: (1) Preparation of amine salt solution: Clavulanic acid tert-butylamine is dissolved in at least two organic solvents selected from ethanol, isopropanol and ethyl acetate; (2) Preparation of potassium isooctanoate solution: Dissolve potassium isooctanoate in the same organic solvent as in step (1); (3) Decarbonization of amine salt solution: Add activated carbon to the amine salt solution obtained in step (1), stir and then filter; (4) Crystallization: Add the potassium isooctanoate solution obtained in step (2) to the solution obtained in step (3) at a constant rate, and cool down to crystallize after the addition is completed; (5) Filtering, washing, and drying; In step (4), the temperature of the solution obtained in step (3) is controlled at 16~20℃, and after the addition is completed, the temperature is lowered to 2~6℃ and stirred and kept warm for ≥2h.

3. The method for preparing spherical potassium clavulanate according to claim 2, characterized in that, In step (4), the addition of potassium isooctanoate solution takes 30-60 minutes.

4. The method for preparing spherical potassium clavulanate according to claim 2, characterized in that, In step (1), when dissolving clavulanic acid tert-butylamine with an organic solvent, the solution is stirred at 22~26℃, pH≥7.0, and glacial acetic acid is slowly added to the solution to adjust the pH to 6.

00.

5. The method for preparing spherical potassium clavulanate according to claim 2, characterized in that, In step (3), the carbon is washed with isopropanol after filtration.

6. The method for preparing spherical potassium clavulanate according to claim 2, characterized in that, Step (5) specifically involves: filtering the crystallization liquid, washing it 3-4 times with isopropanol at 2-6°C; vacuum drying the wet powder, first cold-extracting for 1 hour, then drying at 35°C for 6 hours.

7. A compound preparation, characterized in that, The compound preparation is made from spherical potassium clavulanate and amoxicillin sodium, ticarcillin sodium or amoxicillin; wherein the spherical potassium clavulanate is the spherical potassium clavulanate as described in claim 1.

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