A method for preparing crystalline form B avibactam sodium by reactive crystallization

Abstract

The invention discloses a method for preparing crystal form B avibactam sodium by reaction crystallization, comprising: step 1, adding avibactam tetrabutylammonium salt into an ethanol aqueous solution, stirring and dissolving to obtain an avibactam tetrabutylammonium salt solution; step 2, adding the ethanol aqueous solution into sodium isooctanoate, stirring and dissolving to obtain a sodium isooctanoate solution; step 3, dripping 2% to 20% of the avibactam tetrabutylammonium salt solution prepared in step 1 into the sodium isooctanoate solution, stirring and growing crystals, and continuously dripping the remaining amount of the avibactam tetrabutylammonium salt solution, stirring and crystallizing.

Description

Technical Field

[0001] The present invention relates to the technical field of avibactam sodium production, and in particular to a method for preparing crystal form B avibactam sodium through reaction crystallization. Background Art

[0002] Avibactam Sodium is a new type of non-β-lactam β-lactamase inhibitor developed by Novexel. Avibactam Sodium belongs to the diazabicyclooctanone compound, which has no obvious antibacterial activity itself, but works by inhibiting β-lactamase. Avibactam Sodium can inhibit type A (including ESBL and KPC), some type C and some type D β-lactamases. Therefore, when used in combination with penicillin, cephalosporin and carbapenem antibiotics, it has broad-spectrum antibacterial activity, especially against Escherichia coli and Klebsiella pneumoniae containing ultra-extended-spectrum β-lactamases, Escherichia coli containing excessive AmpC enzymes, and Escherichia coli containing both AmpC and ultra-extended-spectrum β-lactamases. Avibactam Sodium has a diazabicyclooctane skeleton and is a reversible enzyme inhibitor. Its own structure can be restored by reverse reaction, so it has a long-lasting enzyme inhibitory effect. In addition, avibactam sodium itself does not have a β-lactam structure and will not induce the production of β-lactamase. Therefore, avibactam sodium is a very promising new β-lactamase inhibitor that can effectively alleviate the problem of antibiotic resistance. On February 27, 2015, Allergan's Avycaz (avibactam sodium + ceftazidime) was approved for marketing by the FDA in the form of an injection for the treatment of complicated intra-abdominal infections, complicated urinary tract infections (cUTI), kidney infections (pyelonephritis) and Gram-negative bacterial infections in adults.

[0003] Avibactam sodium is used clinically in the form of its sodium salt, and its chemical name is mono[(1R,2S,5R)-2-aminocarbonyl-7-oxo-1,6-azabicyclo[3.2.1]octan-6-yl sulfate sodium salt, and its specific structure is as follows:

[0004]

[0005] Regarding the crystalline form of avibactam sodium, CN 102834395 A discloses anhydrous form B and form D, as well as monohydrate form A and dihydrate form E. In addition, there is a fifth crystalline form C. Hydrates are prone to dehydration, for example, when placed in dry conditions and / or elevated temperatures, hydrates tend to lose their water. For example, CN 102834395 A mentions that under long-term storage and high temperatures, form E tends to lose water and tends to hydrolyze, and its stability is slightly lower (paragraph

[0098] on page 9 of the specification). It is also mentioned in the application that form E of avibactam sodium dihydrate is particularly stable at a relative humidity above 70% (paragraph

[0088] on page 8 of the specification), the relative humidity is between 0 and 70%, and in the absence of airflow, form A is a stable form (paragraph

[0099] on page 9 of the specification), indicating that the hydrate form is stable only under harsh conditions in the presence of moisture or in the absence of airflow. In addition, it was found that at temperatures above about 60°C, Form E dehydrates to a monohydrate form, and upon further temperature stress, dehydrates to an anhydrous form. The patent explicitly states that among the crystalline forms "A", "B", "D" and "E" (all more stable than the amorphous form of avibactam sodium), Form B is the most preferred form. Because specific drug processing steps such as grinding and drying usually generate heat, and thus can cause solid form transformation of thermally unstable forms. Therefore, for pharmaceutical purposes, the anhydrous form of avibactam sodium and its pharmaceutically acceptable salts is preferred over the hydrate, of which Form B is the most preferred crystalline form. The researchers conducted powder X-ray diffraction detection on the commercially available original reference preparation ceftazidime avibactam sodium for injection, in which the avibactam sodium component was anhydrous "B" crystalline form, indicating that the ceftazidime avibactam sodium for injection produced by the original product using Form B crystalline form avibactam sodium has been clinically verified for its safety, so the preparation of Form B can ensure consistency with the original crystalline form and ensure the safety of the drug.

[0006] Regarding the preparation of crystal form B, the method reported in the literature is mainly crystallized by adding seed crystals, for example, after adding additional seed crystals, crystallization is simultaneously carried out by sodium isooctanoate salt conversion reaction. The preparation product of avibactam sodium is a sterile product for injection obtained by aseptic packaging of sterile raw materials, so it is necessary to ensure that the raw material avibactam sodium crystal form B is sterile. In aseptic production, it is very difficult to obtain its sterile crystal seeds, there is no effective method to obtain, and the conditions are harsh, and it is not easy to stably amplify. CN102834395A discloses that it is difficult to prepare anhydrous form B in the absence of seed crystals (page 9 of the specification,

[0102] -

[0104] paragraphs). In view of the above problems, how to prepare a pharmaceutically preferred crystalline form B avibactam sodium product by reaction crystallization without seed crystals has become a difficult point in the field of pharmaceutical synthesis research. Summary of the invention

[0007] The present invention provides a method for preparing crystalline form B avibactam sodium by reactive crystallization. The method does not require the addition of seed crystals, is easy to operate, and is more in line with industrial production requirements.

[0008] A method for preparing avibactam sodium crystal form B comprises the following steps:

[0009] Step 1, adding avibactam tetrabutylammonium salt into an ethanol aqueous solution, stirring and dissolving to obtain an avibactam tetrabutylammonium salt solution;

[0010] Step 2, adding ethanol aqueous solution to sodium isooctanoate, stirring and dissolving to obtain a sodium isooctanoate solution;

[0011] Step 3, dropwise adding 2% to 20% of the total amount of the avibactam tetrabutylammonium salt solution prepared in step 1 into the sodium isooctanoate solution, stirring to grow crystals, and continuing to dropwise add the remaining amount of the avibactam tetrabutylammonium salt solution, stirring to crystallize.

[0012] In some embodiments, the mass percentage of ethanol in the ethanol aqueous solution in step 1 is 94-98%, preferably 95-97.5%.

[0013] In some embodiments, the mass percentage of ethanol in the ethanol aqueous solution in step 2 is 94-98%, preferably 95-97.5%.

[0014] In some embodiments, the dropping temperature in step 3 is 20°C to 40°C, preferably 25°C to 35°C.

[0015] In some embodiments, in step 3, the crystal is grown with stirring at a temperature of 20°C to 40°C; preferably, the crystal is grown with stirring at a temperature of 25°C to 35°C.

[0016] In some embodiments, in step 3, the crystallization is carried out by stirring at a temperature of 20°C to 40°C, preferably, the crystallization is carried out by stirring at a temperature of 25°C to 35°C.

[0017] In some embodiments, in step 3, the stirring time for growing the crystal is 1 h to 5 h, preferably 1 h to 2 h.

[0018] In some embodiments, in step 3, the stirring crystallization time is 1 h to 20 h, preferably 14 h to 16 h.

[0019] In some embodiments, in step 1, the mass volume ratio of the avibactam tetrabutylammonium salt to the ethanol aqueous solution, in grams per milliliter, is 1:(5-50), preferably 1:(8-20), and more preferably 1:(10-12).

[0020] In some embodiments, in step 3, the equivalent ratio of sodium isooctanoate to avibactam tetrabutylammonium salt is (1-5):1, preferably 2:1.

[0021] In some embodiments, in step 2, the amount of the ethanol aqueous solution is such that the mass volume ratio of avibactam tetrabutylammonium salt to the ethanol aqueous solution, in grams per milliliter, is 1:(5-50), preferably 1:(8-20), and more preferably 1:(10-12).

[0022] In some embodiments, in step 3, 5% to 10% of the total amount of the avibactam tetrabutylammonium salt solution prepared in step 1 is added dropwise to the sodium isooctanoate solution, stirred to grow crystals, and the remaining amount of the avibactam tetrabutylammonium salt solution is continued to be added dropwise, and stirred to crystallize.

[0023] In some embodiments, step 3 also includes the steps of filtering, washing and drying the product after crystallization, the washing detergent is an alcohol poor solvent, and the mass volume ratio of the avibactam tetrabutylammonium salt to the detergent, in grams per milliliter, is 1: (1 to 3), preferably 1: 2.

[0024] In some embodiments, the washing solvent is ethanol, and more preferably the washing solvent is anhydrous ethanol.

[0025] The "good solvent" and "poor solvent" described in this application are relative to the solute to be dissolved. "Good solvent" refers to: a solvent with a strong solubility for the solute, and an interaction parameter χ with the solute is less than 0.5; on the contrary, "poor solvent" refers to: a solvent with a weak solubility for the solute, and an interaction parameter χ with the solute is greater than 0.5. For different solutes, the "good solvent" or "poor solvent" is different. A "good solvent" used for one solute may be a "poor solvent" for another solute; a "poor solvent" used for one solute may be a "good solvent" for another solute. For example, ethanol, the "poor solvent" used for avibactam sodium in this application, is a "good solvent" for the solute biphenyl.

[0026] The present invention stably prepares avibactam sodium crystal form B by reaction crystallization, wherein a portion of avibactam tetrabutylammonium salt solution is added dropwise to sodium isooctanoate ethanol aqueous solution, and the solution is stirred to grow crystals, a small amount of seed crystals are generated in situ in the system, and then the remaining amount of avibactam tetrabutylammonium salt solution is added, and the solution is stirred to crystallize, thereby obtaining avibactam sodium crystal form B. Experimental studies have shown that the avibactam sodium crystal form B is prepared by the method of the present invention with high yield, high purity, and good reproducibility, and the preparation method has simple operation steps, especially the preparation process does not require seed crystals, overcomes the defect that the traditional reaction crystallization preparation method needs to add additional sterile seed crystals, is easy to large-scale industrial production, and is especially conducive to the aseptic amplification production of the variety, and has broad market prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The XRPD pattern of avibactam sodium prepared in Example 1;

[0028] Figure 2 This is the XRPD pattern of avibactam sodium prepared in Example 2. DETAILED DESCRIPTION

[0029] In order to facilitate the understanding of the present invention, the present invention will be described more fully below with reference to the relevant drawings. The preferred embodiments of the present invention are given in the drawings. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0031] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0032] Powder X-ray diffraction (XRPD) conditions:

[0033] A θ / θ coupled goniometer with transmission geometry and a Cu-Kα 1,2 Powder X-ray diffraction was performed using a solid-state Rigaku Smartlab (9kw) diffractometer with a 40kV tube voltage and a 150mA tube current, with a step size of 0.02°2θ, at 15° / min, in an angular range of 3° to 40°2θ. The diffraction pattern was recorded at room temperature. The typical accuracy of the 2θ value is ±0.2°2θ. Therefore, for example, the diffraction peak of the crystalline form of avibactam of the present invention that appears at 17.2°2θ can appear at 17.0 to 17.4°2θ on most X-ray diffractometers under standard conditions.

[0034] In the preparation method provided in the present application, the avibactam tetrabutylammonium salt can be purchased commercially or prepared by a known method, for example, by the method described in patent CN103649051A.

[0035] The avibactam tetrabutylammonium salt used in the following examples was prepared according to the method described in Example 4a of the specification of Chinese patent CN103649051A.

[0036] Example 1

[0037] Step (1): adding 200 mL of 97.5% ethanol aqueous solution to 20 g of avibactam tetrabutylammonium salt, stirring to dissolve;

[0038] Step (2): add 200 mL of 97.5% ethanol aqueous solution to 6.56 g of sodium isooctanoate (1 eq), and stir to dissolve;

[0039] Step (3): controlling the temperature at 25-30° C., adding a portion (5% of the total amount) of the avibactam tetrabutylammonium salt solution to the sodium isooctanoate solution at a stirring speed of 250 rpm, growing the crystals at a stirring speed of 250 rpm for 1 hour, and continuing to add the remaining amount of the avibactam tetrabutylammonium salt solution dropwise. After the addition is completed, controlling the temperature at 25-30° C., stirring and crystallizing for 14 hours, filtering, washing with 40 mL of anhydrous ethanol, and vacuum drying for 14 hours to obtain 10.7 g of avibactam sodium (yield 94%).

[0040] The obtained avibactam sodium sample was subjected to XRPD measurement, and the result was Form B avibactam sodium. The XRPD diagram is shown in the attached Figure 1 shown.

[0041] Example 2

[0042] Step (1): adding 240 mL of 95% ethanol aqueous solution to 20 g of avibactam tetrabutylammonium salt, stirring to dissolve;

[0043] Step (2): add 240 mL of 95% ethanol aqueous solution to 13.1 g of sodium isooctanoate (2 eq), and stir to dissolve;

[0044] Step (3): controlling the temperature at 30-35° C., adding a portion (10% of the total amount) of the avibactam tetrabutylammonium salt solution to the sodium isooctanoate solution at a stirring speed of 250 rpm, growing the crystals at a stirring speed of 250 rpm for 2 hours, and continuing to add the remaining avibactam tetrabutylammonium salt solution dropwise. After the addition is completed, controlling the temperature at 30-35° C., stirring and crystallizing for 16 hours, filtering, washing with 40 mL of anhydrous ethanol, and vacuum drying for 14 hours to obtain 10.4 g of avibactam sodium (yield 92%).

[0045] The obtained avibactam sodium sample was subjected to XRPD measurement, and the result was B-type avibactam sodium. The XRPD diagram is as follows: Figure 2 shown.

[0046] Table 1 shows the characteristic peak data (2θ) of the B crystal form reported in patent CN 102834395A and the crystal forms of Examples 1 to 2 of the present application.

[0047] Table 1 Characteristic peak data (2θ) of example samples and patented crystal forms

[0048]

[0049]

[0050] It can be seen from Table 1 that the characteristic peak 2θ of the crystal form of Example 1 or 2 of the present application is consistent with the main peak data of the B crystal form reported in patent CN 102834395A (consistent with the characteristic peak 2θ corresponding to the B crystal form reported on page 11 of the specification of patent CN 102834395A: 10.36, 12.97, 16.45, 17.24, 17.45, 22.29), both of which are B crystal form.

[0051] Comparative Example 1

[0052] Step (1): adding 240 mL of 95% ethanol aqueous solution to 20 g of avibactam tetrabutylammonium salt, stirring to dissolve;

[0053] Step (2): add 240 mL of 95% ethanol aqueous solution to 13.1 g of sodium isooctanoate (2 eq), and stir to dissolve;

[0054] Step (3): Control the temperature at 30-35° C., add all the avibactam tetrabutylammonium salt solution to the sodium isooctanoate solution at a stirring speed of 250 rpm, control the temperature at 30-35° C., stir and crystallize for 16 h, filter, wash with 40 mL of anhydrous ethanol, and vacuum dry for 14 hours to obtain 10.2 g of avibactam sodium (yield 90%).

[0055] The obtained avibactam sodium sample was analyzed by XRPD to be a mixed crystal form of crystal form B and crystal form A.

[0056] Comparative Example 2

[0057] Step (1): adding 240 mL of 95% ethanol aqueous solution to 20 g of avibactam tetrabutylammonium salt, stirring to dissolve;

[0058] Step (2): add 240 mL of 95% ethanol aqueous solution to 13.1 g of sodium isooctanoate (2 eq), and stir to dissolve;

[0059] Step (3): controlling the temperature at 0-5°C, adding a portion (10% of the total amount) of the avibactam tetrabutylammonium salt solution to the sodium isooctanoate solution at a stirring speed of 250 rpm, growing the crystals at a stirring speed of 250 rpm for 2 hours, and continuing to add the remaining avibactam tetrabutylammonium salt solution, controlling the temperature at 0-5°C, stirring and crystallizing for 16 hours after the addition, filtering, washing with 40 mL of anhydrous ethanol, and vacuum drying for 14 hours to obtain 9.5 g of avibactam sodium (yield 84%).

[0060] The obtained avibactam sodium sample was analyzed by XRPD to be a mixed crystalline form of Form B and Form D.

[0061] Comparative Example 3

[0062] Step (1): adding 240 mL of 95% ethanol aqueous solution to 20 g of avibactam tetrabutylammonium salt, stirring to dissolve;

[0063] Step (2): add 240 mL of 95% ethanol aqueous solution to 13.1 g of sodium isooctanoate (2 eq), and stir to dissolve;

[0064] Step (3): controlling the temperature at 45-50° C., adding a portion (10% of the total amount) of the avibactam tetrabutylammonium salt solution to the sodium isooctanoate solution at a stirring speed of 250 rpm, growing the crystals at a stirring speed of 250 rpm for 2 hours, and continuing to add the remaining avibactam tetrabutylammonium salt solution, controlling the temperature at 40-50° C., stirring and crystallizing for 16 hours after the addition, filtering, washing with 40 mL of anhydrous ethanol, and vacuum drying for 14 hours to obtain 7.9 g of avibactam sodium (yield 70%).

[0065] The obtained avibactam sodium sample was analyzed by XRPD to be Form B.

[0066] Comparative Example 4

[0067] Step (1): adding 240 mL of 95% ethanol aqueous solution to 20 g of avibactam tetrabutylammonium salt, stirring to dissolve;

[0068] Step (2): add 240 mL of 95% ethanol aqueous solution to 13.1 g of sodium isooctanoate (2 eq), and stir to dissolve;

[0069] Step (3): controlling the temperature at 18-22° C., adding a portion (10% of the total amount) of the avibactam tetrabutylammonium salt solution to the sodium isooctanoate solution at a stirring speed of 250 rpm, growing the crystals at a stirring speed of 250 rpm for 2 hours, and continuing to add the remaining avibactam tetrabutylammonium salt solution dropwise. After the addition is completed, controlling the temperature at 18-22° C., stirring and crystallizing for 16 hours, filtering with suction, washing with 40 mL of anhydrous ethanol, and vacuum drying for 14 hours to obtain 9.6 g of avibactam sodium (yield 85%).

[0070] The obtained avibactam sodium sample was analyzed by XRPD to be a mixed crystalline form of Form B and Form D.

[0071] Comparative Example 5

[0072] Step (1): adding 240 mL of 95% by weight aqueous solution of isobutanol to 20 g of avibactam tetrabutylammonium salt, and stirring to dissolve;

[0073] Step (2): add 240 mL of 95% by weight aqueous isobutanol solution to 13.1 g of sodium isooctanoate (2 eq), and stir to dissolve;

[0074] Step (3): controlling the temperature at 30-35° C., adding a portion (10% of the total amount) of the avibactam tetrabutylammonium salt solution to the sodium isooctanoate solution at a stirring speed of 250 rpm, growing the crystals at a stirring speed of 250 rpm for 2 hours, and continuing to add the remaining avibactam tetrabutylammonium salt solution dropwise. After the addition is completed, controlling the temperature at 30-35° C., stirring and crystallizing for 16 hours, filtering with suction, washing with 40 mL of isobutanol, and vacuum drying for 14 hours to obtain 9.9 g of avibactam sodium (yield 87%).

[0075] The obtained avibactam sodium sample was analyzed by XRPD to be a mixed crystalline form of Form B and Form D.

[0076] Comparative Example 6

[0077] Step (1): adding 240 mL of 90% ethanol aqueous solution to 20 g of avibactam tetrabutylammonium salt, stirring to dissolve;

[0078] Step (2): add 240 mL of 90% ethanol aqueous solution to 13.1 g of sodium 2-ethylhexanoate (2 eq), and stir to dissolve;

[0079] Step (3): controlling the temperature at 30-35° C., adding a portion (10% of the total amount) of the avibactam tetrabutylammonium salt solution to the sodium isooctanoate solution at a stirring speed of 250 rpm, growing the crystals at a stirring speed of 250 rpm for 2 hours, and continuing to add the remaining avibactam tetrabutylammonium salt solution, controlling the temperature at 30-35° C., stirring and crystallizing for 16 hours after the addition, filtering, washing with 40 mL of anhydrous ethanol, and vacuum drying for 14 hours to obtain 9.0 g of avibactam sodium (yield 80%).

[0080] The obtained avibactam sodium sample was subjected to XRPD measurement, and the result showed that it was Form A avibactam sodium.

[0081] Table 2 Comparative Example Sample Data Summary

[0082] Comparative Example Preparation conditions The obtained crystal Yield 1 The dripping method is all dripping B, A mixed crystal 90％ 2 The temperature during the crystal growth stage is 0-5°C B, D mixed crystal 84％ 3 The temperature during the crystal growth stage is 45-50°C B crystal form 70％ 4 The temperature during the crystal growth stage is 18-22°C B, D mixed crystal 85％ 5 The solvent was replaced by isobutanol. B, D mixed crystal 87％ 6 The mass percentage of ethanol in the solvent is 90% A crystal form 80％

[0083] The present invention stably prepares the crystal form B avibactam sodium by means of reactive crystallization, which overcomes the defects of the prior art preparation method, such as the need to add additional crystal seeds, harsh conditions, and difficulty in stable amplification. The method provided by the present application does not require the addition of crystal seeds, avoids the risk of contamination caused by crystal seeds, and is more conducive to the requirements of sterile raw materials. Moreover, the operation method is simple, the yield is high, and it is easy to be industrialized on a large scale, and has broad market prospects.

[0084] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0085] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for preparing avibactam sodium crystal form B, comprising the following steps: Step 1, adding avibactam tetrabutylammonium salt into an ethanol aqueous solution, stirring and dissolving to obtain an avibactam tetrabutylammonium salt solution; Step 2, adding ethanol aqueous solution to sodium isooctanoate, stirring and dissolving to obtain a sodium isooctanoate solution; Step 3, adding 2% to 20% of the total amount of the avibactam tetrabutylammonium salt solution prepared in step 1 to the sodium isooctanoate solution, stirring to grow crystals, and continuing to dropwise add the remaining amount of the avibactam tetrabutylammonium salt solution, stirring to crystallize; The mass percentage of ethanol in the ethanol aqueous solution in step 1 or step 2 is 94-98%; The dropping temperature in step 3 is 25°C to 40°C; and In step 3, the crystal is grown with stirring at a temperature of 25°C to 40°C, and the crystallization is stirred at a temperature of 25°C to 40°C.

2. The preparation method according to claim 1, characterized in that: The mass percentage content of ethanol in the ethanol aqueous solution in step 1 or step 2 is 95-97.5%.

3. The preparation method according to claim 1, characterized in that: The dropping temperature in step 3 is 25°C to 35°C.

4. The preparation method according to claim 1, characterized in that: In the step 3, the crystal is grown by stirring at a temperature of 25°C to 35°C.

5. The preparation method according to claim 1, characterized in that: In the step 3, the crystallization is stirred at a temperature of 25°C to 35°C.

6. The preparation method according to any one of claims 1 to 5, characterized in that: In step 3, the stirring crystal growing time is 1 h to 5 h, and the stirring crystallization time is 1 h to 20 h.

7. The preparation method according to claim 6, characterized in that: In step 3, the stirring crystal growing time is 1h to 2h, and the stirring crystallization time is 14h to 16h.

8. The preparation method according to any one of claims 1 to 5, characterized in that: In step 1, the mass volume ratio of the avibactam tetrabutylammonium salt to the ethanol aqueous solution is 1:(5-50) in g / ml.

9. The preparation method according to claim 8, characterized in that: In step 1, the mass volume ratio of the avibactam tetrabutylammonium salt to the ethanol aqueous solution is 1:(8-20) in g / ml.

10. The preparation method according to claim 8, characterized in that: In step 1, the mass volume ratio of the avibactam tetrabutylammonium salt to the ethanol aqueous solution is 1:(10-12) in g / ml.

11. The preparation method according to any one of claims 1 to 5, characterized in that: In step 3, the equivalent ratio of the sodium isooctanoate to the tetrabutylammonium salt of avibactam is (1-5):

1.

12. The preparation method according to claim 11, characterized in that: In step 3, the equivalent ratio of the sodium isooctanoate to the tetrabutylammonium salt of avibactam is 2:

1.

13. The preparation method according to any one of claims 1 to 5, characterized in that: In step 2, the amount of the ethanol aqueous solution is such that the mass volume ratio of avibactam tetrabutylammonium salt to the ethanol aqueous solution, in grams per milliliter, is 1:(5-50).

14. The preparation method according to claim 13, characterized in that: In step 2, the amount of the ethanol aqueous solution is such that the mass volume ratio of avibactam tetrabutylammonium salt to the ethanol aqueous solution, in grams per milliliter, is 1:(8-20).

15. The preparation method according to claim 13, characterized in that: In step 2, the amount of the ethanol aqueous solution is such that the mass volume ratio of avibactam tetrabutylammonium salt to the ethanol aqueous solution, in grams per milliliter, is 1:(10-12).

16. The preparation method according to any one of claims 1 to 5, characterized in that: In step 3, 5% to 10% of the total amount of the avibactam tetrabutylammonium salt solution prepared in step 1 is added dropwise to the sodium isooctanoate solution, and the mixture is stirred to grow crystals. The remaining amount of the avibactam tetrabutylammonium salt solution is continuously added dropwise, and the mixture is stirred to crystallize.

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