Ceftazidime avibactam sodium for injection and preparation method thereof

Abstract

The present invention belongs to the technical field of preparation of ceftazidime avibactam sodium, and in particular to a kind of ceftazidime avibactam sodium for injection and a preparation method thereof. The preparation method of ceftazidime avibactam sodium for injection provided by the present invention comprises the following steps: avibactam sodium and ethanol aqueous solution are mixed and stirred to obtain a mixed solution, porous sodium carbonate is then added to the mixed solution to continue stirring, and the mixed material is vacuum heated after the stirring is completed, and crushed after the vacuum heating is completed to obtain a mixed powder, wherein the mass content of ethanol in the ethanol aqueous solution is 96 99%; the mixed powder and ceftazidime are mixed to obtain a mixed material; the mixed material is aseptically packaged, nitrogen-filled and rolled to obtain the ceftazidime avibactam sodium for injection. The preparation method provided by the present invention can effectively improve the stability of ceftazidime avibactam sodium.

Description

Technical Field

[0001] The invention belongs to the technical field of preparation of ceftazidime avibactam sodium, and particularly relates to ceftazidime avibactam sodium for injection and a preparation method thereof. Background Art

[0002] Ceftazidime avibactam sodium for injection is a powder injection, which is usually prepared by mixing ceftazidime and avibactam sodium in a certain ratio. In ceftazidime avibactam sodium for injection, ceftazidime is a cephalosporin antibiotic, and avibactam sodium is a β-lactamase inhibitor. The combination of the two can effectively enhance the antibacterial activity of ceftazidime and is widely used in complicated intra-abdominal infections caused by Gram-negative bacteria.

[0003] As an organic salt, avibactam sodium has poor water solubility, is sensitive to peracid environments, and has relatively poor thermal stability. Therefore, sodium carbonate is generally introduced into the preparation process of ceftazidime avibactam sodium to promote solubility on the one hand, and to adjust the pH on the other hand to improve the stability of ceftazidime avibactam sodium. The existing preparation method of ceftazidime avibactam sodium for injection generally directly mixes the three, but the effect on improving stability is limited. Summary of the invention

[0004] Therefore, the technical problem to be solved by the present invention is to overcome the defect that the existing preparation method of ceftazidime avibactam sodium for injection has limited effect on improving its stability, and further provide ceftazidime avibactam sodium for injection and a preparation method thereof.

[0005] In order to solve the above problems, the scheme of the present invention is as follows:

[0006] A method for preparing ceftazidime avibactam sodium for injection comprises the following steps:

[0007] 1) mixing avibactam sodium and an ethanol aqueous solution and stirring to obtain a mixed solution, then adding porous sodium carbonate to the mixed solution and continuing to stir, vacuum heating the mixture after the stirring is completed, and crushing the mixture after the vacuum heating is completed to obtain a mixed powder, wherein the mass content of ethanol in the ethanol aqueous solution is 96-99%;

[0008] 2) mixing the mixed powder obtained in step 1) and ceftazidime to obtain a mixed material;

[0009] 3) Aseptically packaging, nitrogen filling and capping the mixed material to obtain the ceftazidime avibactam sodium for injection.

[0010] Preferably, the mass content of avibactam sodium in the mixed solution of step 1) is 5-10%.

[0011] Preferably, the mixing speed is 100-200 rpm, and the mixing time is 20-60 min;

[0012] The stirring speed is continued to be 100-200 rpm, and the stirring time is continued to be 20-120 min.

[0013] Preferably, the vacuum heating temperature is 25-35° C., the vacuum degree is 2-5 kPa, and the vacuum heating time is 1-5 h.

[0014] The porous sodium carbonate used in the present invention can be commercially available porous sodium carbonate, or can be obtained according to a conventional preparation method in the art. Optionally, the preparation method of the porous sodium carbonate comprises the following steps:

[0015] The sodium bicarbonate particles are placed in a reaction kettle and heated to 160-190° C. under a vacuum degree of 0.1-0.5 kPa for 20-50 minutes. After the heating is completed, the temperature is lowered to room temperature to obtain porous sodium carbonate.

[0016] Preferably, the average particle size of the sodium bicarbonate particles is 120-180 μm.

[0017] Preferably, the mass ratio of ceftazidime, porous sodium carbonate and avibactam sodium is (4.1-4.2):(0.45-0.5):1.

[0018] Preferably, the average particle size of the mixed powder is 80-140 μm;

[0019] The average particle size of ceftazidime is 40-60 μm.

[0020] Preferably, in step 2), the mixing speed is 1500-2000 rpm and the mixing time is 20-60 min.

[0021] The present invention also provides ceftazidime avibactam sodium for injection, which is prepared by the above-mentioned preparation method.

[0022] The technical solution of the present invention has the following advantages:

[0023] The preparation method of ceftazidime avibactam sodium for injection provided by the present invention, first introduces porous sodium carbonate, then prepares a mixed solution of avibactam sodium and ethanol aqueous solution, and the porous sodium carbonate and the mixed solution are mixed again, and a mixed powder is obtained through vacuum drying, and finally the mixed powder and ceftazidime are mixed, and the obtained mixed material is aseptically packaged, nitrogen-filled and rolled to obtain the ceftazidime avibactam sodium for injection. The present invention first introduces porous sodium carbonate, and then porous sodium carbonate and a mixed solution (by avibactam sodium and ethanol aqueous solution) are mixed, and avibactam sodium will enter the porous sodium carbonate pores with the solution during the mixing process, and ethanol and a small amount of water are subsequently removed by vacuum heating, and avibactam sodium is doped in the internal pores of porous sodium carbonate and is tightly attached to the surface, and is subsequently mixed with ceftazidime after crushing, and it can effectively improve the stability of ceftazidime avibactam sodium.

[0024] In addition, the present invention uses an ethanol aqueous solution of a specific concentration to prepare a mixed solution with avibactam sodium, and unexpectedly found that it is beneficial to improve the stability of ceftazidime avibactam sodium. The inventor speculates that the introduction of a small amount of water is beneficial to a faster and tighter combination of avibactam sodium and porous sodium carbonate, thereby improving the stability of ceftazidime avibactam sodium. DETAILED DESCRIPTION

[0025] The following examples are provided for further understanding of the present invention, but are not intended to limit the best mode of implementation and do not limit the scope of protection of the present invention.

[0026] The experimental steps or conditions not specified in the following embodiments of the present invention can be implemented according to the conventional experimental steps and conditions used in the existing literature in the field. The reagents or instruments used without specifying the manufacturer are all conventional reagents or instruments that can be purchased commercially.

[0027] Example 1

[0028] This embodiment provides a method for preparing ceftazidime avibactam sodium for injection, comprising the following steps:

[0029] 1) placing sodium bicarbonate particles with an average particle size of 150 μm in a reaction kettle and heating them to 180° C. under a vacuum degree of 0.2 kPa for 20 min, and cooling them to room temperature after the heating to obtain porous sodium carbonate;

[0030] 2) Avibactam sodium and an ethanol aqueous solution (the mass content of ethanol in the ethanol aqueous solution is 98%) are mixed and stirred at a mixing and stirring speed of 100 rpm for 20 min to obtain a mixed solution, in which the mass content of avibactam sodium in the mixed solution is 8%, and then porous sodium carbonate is added to the mixed solution and continued to stir, the mass ratio of porous sodium carbonate to avibactam sodium is 0.47:1, the stirring speed is continued at 150 rpm, and the stirring time is continued for 30 min. After the stirring is completed, the mixture is vacuum heated to remove ethanol and water, the vacuum heating temperature is 30° C., the vacuum degree is 4 kPa, and the vacuum heating time is 2 h. After the vacuum heating is completed, the mixture is crushed to obtain a mixed powder (the average particle size of the mixed powder is 100 μm);

[0031] 3) placing the mixed powder obtained in step 2) and ceftazidime (average particle size of 50 μm) in a mixer for mixing, wherein the mass ratio of ceftazidime to avibactam sodium is 4.15:1, the mixing speed is 1800 rpm, and the mixing time is 40 min to obtain a mixed material;

[0032] 4) The mixed material is aseptically packaged, nitrogen-filled and capped to obtain the ceftazidime avibactam sodium for injection.

[0033] Example 2

[0034] This embodiment provides a method for preparing ceftazidime avibactam sodium for injection, comprising the following steps:

[0035] 1) placing sodium bicarbonate particles with an average particle size of 160 μm in a reaction kettle and heating them to 185° C. under a vacuum degree of 0.2 kPa for 30 min, and cooling them to room temperature after heating to obtain porous sodium carbonate;

[0036] 2) Avibactam sodium and an ethanol aqueous solution (the mass content of ethanol in the ethanol aqueous solution is 97%) are mixed and stirred at a mixing and stirring speed of 150 rpm for 20 min to obtain a mixed solution, in which the mass content of avibactam sodium in the mixed solution is 10%, and then porous sodium carbonate is added to the mixed solution and continued to stir, the mass ratio of porous sodium carbonate to avibactam sodium is 0.47:1, the stirring speed is continued at 150 rpm, and the stirring time is continued for 30 min. After the stirring is completed, the mixture is vacuum heated to remove ethanol and water, the vacuum heating temperature is 30° C., the vacuum degree is 3 kPa, the vacuum heating time is 2 h, and after the vacuum heating is completed, the mixture is crushed to obtain a mixed powder (the average particle size of the mixed powder is 100 μm);

[0037] 3) placing the mixed powder obtained in step 2) and ceftazidime (average particle size of 50 μm) in a mixer for mixing, wherein the mass ratio of ceftazidime to avibactam sodium is 4.15:1, the mixing speed is 1800 rpm, and the mixing time is 40 min to obtain a mixed material;

[0038] 4) The mixed material is aseptically packaged, nitrogen-filled and capped to obtain the ceftazidime avibactam sodium for injection.

[0039] Example 3

[0040] This embodiment provides a method for preparing ceftazidime avibactam sodium for injection, comprising the following steps:

[0041] 1) placing sodium bicarbonate particles with an average particle size of 160 μm in a reaction kettle and heating them to 190° C. under a vacuum degree of 0.2 kPa for 40 min, and cooling them to room temperature after the heating to obtain porous sodium carbonate;

[0042] 2) Avibactam sodium and an ethanol aqueous solution (the mass content of ethanol in the ethanol aqueous solution is 97%) are mixed and stirred at a mixing and stirring speed of 150 rpm for 20 min to obtain a mixed solution, in which the mass content of avibactam sodium in the mixed solution is 10%, and then porous sodium carbonate is added to the mixed solution and continued to stir, the mass ratio of porous sodium carbonate to avibactam sodium is 0.47:1, the stirring speed is continued at 150 rpm, and the stirring time is continued for 50 min. After the stirring is completed, the mixture is vacuum heated to remove ethanol and water, the vacuum heating temperature is 30° C., the vacuum degree is 3 kPa, and the vacuum heating time is 2.5 h. After the vacuum heating is completed, the mixture is crushed to obtain a mixed powder (the average particle size of the mixed powder is 100 μm);

[0043] 3) placing the mixed powder obtained in step 2) and ceftazidime (average particle size of 50 μm) in a mixer for mixing, wherein the mass ratio of ceftazidime to avibactam sodium is 4.15:1, the mixing speed is 1800 rpm, and the mixing time is 40 min to obtain a mixed material;

[0044] 4) The mixed material is aseptically packaged, nitrogen-filled and capped to obtain the ceftazidime avibactam sodium for injection.

[0045] Example 4

[0046] This embodiment provides a method for preparing ceftazidime avibactam sodium for injection, comprising the following steps:

[0047] 1) placing sodium bicarbonate particles with an average particle size of 160 μm in a reaction kettle and heating them to 190° C. under a vacuum degree of 0.2 kPa for 50 min, and cooling them to room temperature after heating to obtain porous sodium carbonate;

[0048] 2) Avibactam sodium and an ethanol aqueous solution (the mass content of ethanol in the ethanol aqueous solution is 97%) are mixed and stirred at a mixing and stirring speed of 150 rpm for 30 min to obtain a mixed solution, in which the mass content of avibactam sodium in the mixed solution is 7%, and then porous sodium carbonate is added to the mixed solution and continued to stir, the mass ratio of porous sodium carbonate to avibactam sodium is 0.47:1, the stirring speed is continued at 150 rpm, and the stirring time is continued for 60 min. After the stirring is completed, the mixture is vacuum heated to remove ethanol and water, the vacuum heating temperature is 30° C., the vacuum degree is 3 kPa, and the vacuum heating time is 3 h. After the vacuum heating is completed, the mixture is crushed to obtain a mixed powder (the average particle size of the mixed powder is 100 μm);

[0049] 3) placing the mixed powder obtained in step 2) and ceftazidime (average particle size of 50 μm) in a mixer for mixing, wherein the mass ratio of ceftazidime to avibactam sodium is 4.15:1, the mixing speed is 1800 rpm, and the mixing time is 40 min to obtain a mixed material;

[0050] 4) The mixed material is aseptically packaged, nitrogen-filled and capped to obtain the ceftazidime avibactam sodium for injection.

[0051] Comparative Example 1

[0052] This comparative example provides a method for preparing ceftazidime avibactam sodium for injection, comprising the following steps:

[0053] 1) stirring and mixing avibactam sodium and sodium carbonate, wherein the mass ratio of sodium carbonate to avibactam sodium is 0.47:1, the stirring speed is 150 rpm, and the stirring time is 30 min to obtain a mixed powder (the average particle size of the mixed powder is 100 μm);

[0054] 2) placing the mixed powder obtained in step 1) and ceftazidime (average particle size of 50 μm) in a mixer for mixing, wherein the mass ratio of ceftazidime to avibactam sodium is 4.15:1, the mixing speed is 1800 rpm, and the mixing time is 40 min to obtain a mixed material;

[0055] 3) Aseptically packaging, nitrogen filling and capping the mixed material to obtain the ceftazidime avibactam sodium for injection.

[0056] Comparative Example 2

[0057] The present comparative example provides a method for preparing ceftazidime avibactam sodium for injection, which is different from Example 1 in that in step 2), avibactam sodium and porous sodium carbonate are stirred and mixed, the mass ratio of porous sodium carbonate to avibactam sodium is 0.47:1, the stirring speed is 150 rpm, the stirring time is 30 min, and the mixture is crushed after the stirring is completed to obtain a mixed powder (the average particle size of the mixed powder is 100 μm).

[0058] Comparative Example 3

[0059] This comparative example provides a method for preparing ceftazidime avibactam sodium for injection, which is different from Example 1 in that the mass content of ethanol in the ethanol aqueous solution used in step 2) is 90%.

[0060] Comparative Example 4

[0061] This comparative example provides a method for preparing ceftazidime avibactam sodium for injection, which is different from Example 1 in that the ethanol aqueous solution used in step 2) is replaced by anhydrous ethanol.

[0062] Test Case

[0063] According to the requirements for drug stability investigation in Part IV and the appendix of the 2020 edition of the Chinese Pharmacopoeia, the stability of the ceftazidime avibactam sodium prepared in the above examples and comparative examples was tested, and the accelerated stability investigation conditions were: placed at a temperature of 40°C and a relative humidity of 75% for 6 months. The standard amount and total impurity content of ceftazidime and avibactam sodium after 6 months were investigated. The results are shown in Table 1:

[0064] Table 1

[0065]

[0066] Obviously, for ordinary technicians in the field, other modifications can be made based on the above embodiments, and the obvious modifications brought about by these modifications are still within the protection scope of the present invention.

Claims

1. A method for preparing ceftazidime avibactam sodium for injection, characterized in that: The steps include: 1) mixing avibactam sodium and an ethanol aqueous solution and stirring to obtain a mixed solution, then adding porous sodium carbonate to the mixed solution and continuing to stir, vacuum heating the mixed material after the stirring is completed, and crushing the mixed material after the vacuum heating is completed to obtain a mixed powder, wherein the mass content of ethanol in the ethanol aqueous solution is 97% or 98%; 2) mixing the mixed powder obtained in step 1) and ceftazidime to obtain a mixed material; 3) Aseptically packaging, nitrogen filling and capping the mixed material to obtain the ceftazidime avibactam sodium for injection; The preparation method of the porous sodium carbonate comprises the following steps: The sodium bicarbonate particles are placed in a reaction kettle and heated to 160-190° C. under a vacuum degree of 0.1-0.5 kPa for 20-50 minutes. After the heating is completed, the temperature is lowered to room temperature to obtain porous sodium carbonate; The average particle size of the sodium bicarbonate particles is 120-180 μm; The mass ratio of ceftazidime, porous sodium carbonate and avibactam sodium is (4.1-4.2):(0.45-0.5):

1.

2. The preparation method according to claim 1, characterized in that: Step 1) The mass content of avibactam sodium in the mixed solution is 5-10%.

3. The preparation method according to claim 1 or 2, characterized in that: The mixing speed is 100-200 rpm, and the mixing time is 20-60 min; The stirring speed is continued to be 100-200 rpm, and the stirring time is continued to be 20-120 min.

4. The preparation method according to claim 1 or 2, characterized in that: The vacuum heating temperature is 25-35°C, the vacuum degree is 2-5kPa, and the vacuum heating time is 1-5h.

5. The preparation method according to claim 1, characterized in that: The average particle size of the mixed powder is 80-140 μm; The average particle size of ceftazidime is 40-60 μm.

6. The preparation method according to claim 1 or 2, characterized in that: In step 2), the mixing speed is 1500-2000 rpm and the mixing time is 20-60 min.

7. A ceftazidime avibactam sodium for injection, characterized in that: The invention is prepared by the preparation method according to any one of claims 1 to 6.

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