A method for preparing ceftazidime avibactam sodium for injection

Abstract

The application specifically relates to a preparation method of ceftazidime and avibactam sodium for injection. The particle size of ceftazidime, avibactam sodium and sodium carbonate is controlled, specifically, the particle size of the ceftazidime raw material is controlled to be 120 mu m-140 mu m, the particle size of the sodium carbonate raw material is controlled to be 90 mu m-110 mu m, and the particle size of the avibactam sodium raw material is controlled to be 70 mu m-90 mu m, so that a remarkable mixing uniformity effect can be achieved, the content uniformity is remarkably improved, and the stability is also remarkably improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a method for preparing ceftazidime avibactam sodium for injection. Background Technology

[0002] Ceftazidime is a third-generation cephalosporin antibiotic that exerts its bactericidal effect by inhibiting bacterial cell wall synthesis. It exhibits significant activity against a variety of Gram-negative bacteria, including Pseudomonas aeruginosa. Avibactam sodium itself is not a direct-acting antibiotic; rather, it is a β-lactamase inhibitor. Many drug-resistant bacteria secrete an enzyme that destroys the structure of penicillin and cephalosporin antibiotics, rendering them ineffective. Avibactam sodium inhibits these enzymes, allowing antibiotics like ceftazidime to effectively kill bacteria. Ceftazidime / avibactam sodium for injection is a powder for injection, typically formulated by mixing ceftazidime and avibactam sodium in a specific ratio.

[0003] Avibactam sodium has poor water solubility, is unstable under acidic conditions, and has poor thermal stability. In addition, the β-lactam ring of ceftazidime is easily hydrolyzed and degraded under acidic and strongly alkaline conditions. Therefore, weakly alkaline sodium carbonate is usually added to adjust the pH during the preparation of injectable ceftazidime avibactam sodium, which can improve the stability of ceftazidime and avibactam sodium and increase water solubility.

[0004] In existing technologies, although adding sodium carbonate can increase the stability of injectable ceftazidime avibactam sodium to some extent, the effect is generally limited. Furthermore, injectable ceftazidime avibactam sodium is typically produced using a direct powder mixing process. However, due to differences in particle size, density, and flowability, it is difficult to achieve good uniformity through general mixing of ceftazidime, sodium carbonate, and avibactam sodium. Therefore, existing technologies often employ more complex mixing processes or require the addition of other substances to improve uniformity and stability. Summary of the Invention

[0005] Therefore, the technical problem to be solved by the present invention is to improve the stability of injectable ceftazidime avibactam sodium without adding other substances and with a relatively complex process, while enabling the three substances, ceftazidime, sodium carbonate, and avibactam sodium, to achieve excellent mixing uniformity under process conditions that do not require strict control of mixing conditions.

[0006] To solve this technical problem, the present invention employs the following technical solution to prepare ceftazidime avibactam sodium for injection:

[0007] Avibactam sodium with a specific particle size and sodium carbonate are mixed in a mixer. After mixing, ceftazidime sodium with a specific particle size is added for secondary mixing. The resulting powder is then aseptically dispensed, nitrogen-filled, and capped to obtain the ceftazidime sodium for injection.

[0008] Preferably, the mass ratio of ceftazidime, sodium carbonate, and avibactam sodium is (4.0-4.5):(0.4-0.5):1.

[0009] Preferably, the ceftazidime raw material is pulverized, and the particle size is controlled to be between 120µm and 140µm.

[0010] Preferably, the sodium carbonate raw material is pulverized, and the particle size is controlled between 90µm and 110µm.

[0011] Preferably, the sodium avibactam raw material is pulverized, and the particle size is controlled to be between 70µm and 90µm.

[0012] Preferably, the mixing conditions of the mixer are: a mixing speed of 16 rpm and a mixing time of 18 min.

[0013] Preferably, the sodium avibactam raw material is prepared using the following steps:

[0014] 1. Dissolve avibactam sodium in a mixed solution of water for injection and methanol, with the pH adjusted to 6.4-6.8 using sodium carbonate, wherein the volume ratio of water for injection to methanol is 1:5.

[0015] 2. Add anhydrous ethanol dropwise to the solution in step 1, add seed crystals, grow crystals for 1 hour, cool down, and stir to precipitate crystals for 1 hour;

[0016] 3. Filter the crystals obtained in step 2, wash the filter cake twice with anhydrous ethanol, then vacuum dry and pulverize to obtain sodium avibactam crystal raw material.

[0017] Preferably, in step 1, the weight ratio of avibactam sodium to the mixed solution of water for injection and methanol is avibactam sodium: water for injection and methanol = 1:30, and the dissolution temperature is 55°C.

[0018] Preferably, the amount of anhydrous ethanol added in step 2 is 3 times the total volume of the mixed solution of water for injection and methanol in step 1, and the temperature is lowered to 15°C.

[0019] Preferably, the vacuum drying conditions in step 3 are: 42°C, vacuum degree -0.09MPa, drying for 12 hours, and the particle size of the pulverized sodium avibactam is controlled at 70µm-90µm.

[0020] The technical solution of the present invention has the following technical features: under the formulation specifications of ceftazidime and avibactam sodium for injection, the mass ratio of ceftazidime to avibactam sodium is generally 4:1. A small amount of sodium carbonate is generally added to increase stability and solubility. Sodium carbonate is used in the smallest amount among the three. Meanwhile, injectable ceftazidime avibactam sodium is usually produced using a direct powder mixing process. However, due to differences in particle size, density, flowability, and other physical properties, it is difficult to achieve good uniformity in general mixing of ceftazidime, sodium carbonate, and avibactam sodium. This invention improves the mixing uniformity by controlling the particle size of the three substances. The difference in particle size will significantly affect the mixing effect. In injectable ceftazidime avibactam sodium, ceftazidime is the most abundant and belongs to the mixed powder skeleton, while the amount of avibactam sodium is between the three. This invention constructs a bridging scheme for avibactam sodium, in which avibactam sodium is both the dispersed phase of ceftazidime and the dispersion medium of sodium carbonate. The technical solution is to first mix avibactam sodium and sodium carbonate with a specific particle size, and then mix them with ceftazidime.

[0021] Further research revealed that the crystal structure and smoothness of sodium avibactam also significantly affect particle mixing. The inventors further investigated the crystallization method of sodium avibactam and obtained a crystallization method that can further improve the mixing uniformity. Detailed Implementation

[0022] The following embodiments are provided to further understand the present invention and are not limited to the preferred embodiments described herein. The scope of protection of the present invention is not limited by the specific embodiments.

[0023] Example 1: The preparation method of ceftazidime avibactam sodium for injection includes the following steps;

[0024] S1. Sterile ceftazidime, avibactam sodium, and sodium carbonate raw materials are pulverized separately using an air jet mill under sterile conditions. The particle size of ceftazidime is controlled at 120µm-140µm; the particle size of avibactam sodium is controlled at 70µm-90µm; and the particle size of sodium carbonate is controlled at 90µm-110µm.

[0025] S2. Take 1 kg of pulverized sodium avibactam and 0.4 kg of sodium carbonate and add them to a single-arm mixer. Start the single-arm mixer and control the mixing speed to 16 rpm and the mixing time to 18 min.

[0026] S3. After mixing, add 4 kg of pulverized ceftazidime, start the single-arm mixer, control the mixing speed at 16 rpm, and the mixing time at 18 min.

[0027] S4. After mixing, the content uniformity of the mixed powder obtained in S3 is checked. If it passes the test, the mixed powder is aseptically dispensed, filled with nitrogen, and capped to obtain the ceftazidime avibactam sodium for injection.

[0028] Content uniformity test results: Ceftazidime RSD=1.3%; Avibactam sodium RSD=1.7%.

[0029] Content uniformity determination method: After the powder mixing is completed, the mixing uniformity is determined by a 10-point sampling method using a sterile sampler. Ten different sampling points are set for each example or comparative example. Three samples are taken from each sampling point, for a total of 30 samples to detect the content of ceftazidime and avibactam sodium. The test results are statistically analyzed, and the overall relative standard deviation (RSD) is calculated.

[0030] Example 2

[0031] The steps for preparing avibactam sodium for injection in this embodiment are basically the same as in Example 1, except that the avibactam sodium raw material before pulverization is treated as follows:

[0032] S1. Mix water for injection and methanol at a volume ratio of 1:5, heat to 55°C, adjust the pH to 6.4 with sodium carbonate, and then add avibactam sodium and stir to dissolve; wherein the weight ratio of avibactam sodium to the water for injection and methanol mixture is avibactam sodium : water for injection and methanol mixture = 1:30.

[0033] S2. Add ethanol dropwise to the solution in S1 in a volume equal to 3 times the volume of the mixed solution of water for injection and methanol in S1. Add sodium avibactam in S1 in a weight equal to 0.02 times the weight of sodium avibactam in S1 as seed crystals. Grow crystals for 1 hour, cool to 15°C, and stir to precipitate crystals for 1 hour.

[0034] S3. Filter the crystals obtained in S2, wash the filter cake twice with anhydrous ethanol, and then vacuum dry it for 12 hours at 42℃ and a vacuum degree of -0.09MPa to obtain the final product.

[0035] All other steps were performed in accordance with the method described in Example 1 to prepare ceftazidime avibactam sodium for injection.

[0036] Content uniformity test results: ceftazidime RSD=0.20%; avibactam sodium RSD=0.35%.

[0037] Example 3

[0038] The steps for preparing ceftazidime avibactam sodium for injection in this embodiment are basically the same as those in Example 2, except that the pH is adjusted to 6.8 with sodium carbonate compared to step S1 in Example 2.

[0039] All other steps were prepared according to the method in Example 2 to prepare ceftazidime avibactam sodium for injection.

[0040] Content uniformity test results: ceftazidime RSD=0.22%; avibactam sodium RSD=0.34%.

[0041] Example 4

[0042] The steps for preparing ceftazidime avibactam sodium for injection in this embodiment are basically the same as those in Example 2, except that the pH is adjusted to 6.6 with sodium carbonate compared to step S1 in Example 2.

[0043] All other steps were prepared according to the method in Example 2 to prepare ceftazidime avibactam sodium for injection.

[0044] Content uniformity test results: Ceftazidime RSD=0.21%; Avibactam sodium RSD=0.37%.

[0045] Example 5

[0046] The steps for preparing ceftazidime avibactam sodium for injection in this embodiment are basically the same as those in Example 2, except that 1 kg of pulverized avibactam sodium, 0.5 kg of sodium carbonate, and 4.5 kg of pulverized ceftazidime are used.

[0047] All other steps were prepared according to the method in Example 2 to prepare ceftazidime avibactam sodium for injection.

[0048] Content uniformity test results: ceftazidime RSD=0.25%; avibactam sodium RSD=0.33%.

[0049] Comparative Example 1

[0050] The difference between this comparative example and Example 1 is that the mixing order of the pulverized ceftazidime, avibactam sodium, and sodium carbonate raw materials is different; the three are directly mixed. The preparation method includes the following steps;

[0051] S1. Sterile ceftazidime, avibactam sodium, and sodium carbonate raw materials are pulverized separately using an air jet mill under sterile conditions. The particle size of ceftazidime is controlled at 120µm-140µm; the particle size of avibactam sodium is controlled at 70µm-90µm; and the particle size of sodium carbonate is controlled at 90µm-110µm.

[0052] S2. Take 1 kg of pulverized avibactam sodium, 0.4 kg of sodium carbonate, and 4 kg of ceftazidime and add them to a single-arm mixer. Start the single-arm mixer and control the mixing speed to 16 rpm and the mixing time to 18 min.

[0053] S3. After mixing, the content uniformity of the mixed powder obtained in S2 is checked. If it passes the test, the mixed powder is aseptically dispensed, filled with nitrogen, and capped to obtain the ceftazidime avibactam sodium for injection.

[0054] Content uniformity test results: ceftazidime RSD=5.2%; avibactam sodium RSD=6.3%.

[0055] Comparative Example 2

[0056] The difference between this comparative example and Example 1 lies in the mixing order of the pulverized ceftazidime, avibactam sodium, and sodium carbonate raw materials. Ceftazidime and sodium carbonate are mixed first, followed by the addition of avibactam sodium. The preparation method includes the following steps;

[0057] S1. Sterile ceftazidime, avibactam sodium, and sodium carbonate raw materials are pulverized separately using an air jet mill under sterile conditions. The particle size of ceftazidime is controlled at 120µm-140µm; the particle size of avibactam sodium is controlled at 70µm-90µm; and the particle size of sodium carbonate is controlled at 90µm-110µm.

[0058] S2. Take 4 kg of pulverized ceftazidime and 0.4 kg of sodium carbonate and add them to a single-arm mixer. Start the single-arm mixer and control the mixing speed at 16 rpm for 18 min.

[0059] S3. After mixing, add 1 kg of pulverized sodium avibactam, start the single-arm mixer, control the mixing speed at 16 rpm, and the mixing time at 18 min.

[0060] S4. After mixing, the content uniformity of the mixed powder obtained in S3 is checked. If it passes the test, the mixed powder is aseptically dispensed, filled with nitrogen, and capped to obtain the ceftazidime avibactam sodium for injection.

[0061] Content uniformity test results: ceftazidime RSD=6.4%; avibactam sodium RSD=5.8%.

[0062] Comparative Example 3

[0063] The difference between this comparative example and Example 1 lies in the mixing order of the pulverized ceftazidime, avibactam sodium, and sodium carbonate raw materials. Ceftazidime and avibactam sodium are mixed first, followed by the addition of sodium carbonate. The preparation method includes the following steps;

[0064] S1. Sterile ceftazidime, avibactam sodium, and sodium carbonate raw materials are pulverized separately using an air jet mill under sterile conditions. The particle size of ceftazidime is controlled at 120µm-140µm; the particle size of avibactam sodium is controlled at 70µm-90µm; and the particle size of sodium carbonate is controlled at 90µm-110µm.

[0065] S2. Take 4 kg of pulverized ceftazidime and 1 kg of avibactam sodium and add them to a single-arm mixer. Start the single-arm mixer and control the mixing speed to 16 rpm and the mixing time to 18 min.

[0066] S3. After mixing, add 0.4 kg of pulverized sodium carbonate, start the single-arm mixer, control the mixing speed at 16 rpm, and the mixing time at 18 min.

[0067] S4. After mixing, the content uniformity of the mixed powder obtained in S3 is checked. If it passes the test, the mixed powder is aseptically dispensed, filled with nitrogen, and capped to obtain the ceftazidime avibactam sodium for injection.

[0068] Content uniformity test results: ceftazidime RSD=5.9%; avibactam sodium RSD=6.2%.

[0069] Comparative Example 4

[0070] The difference between this comparative example and Example 1 is that the particle size of the ceftazidime, avibactam sodium, and sodium carbonate raw materials after pulverization in step S1 is controlled to be between 120µm and 140µm.

[0071] All other steps were performed in accordance with the method described in Example 1 to prepare ceftazidime avibactam sodium for injection.

[0072] Content uniformity test results: ceftazidime RSD=5.0%; avibactam sodium RSD=4.9%.

[0073] Comparative Example 5

[0074] The difference between this comparative example and Example 1 is that the particle size of the ceftazidime, avibactam sodium, and sodium carbonate raw materials after pulverization in step S1 is controlled to be between 70µm and 90µm.

[0075] All other steps were performed in accordance with the method described in Example 1 to prepare ceftazidime avibactam sodium for injection.

[0076] Content uniformity test results: ceftazidime RSD=4.8%; avibactam sodium RSD=6.3%.

[0077] Comparative Example 6

[0078] The difference between this comparative example and Example 1 is that the particle size of the ceftazidime, avibactam sodium, and sodium carbonate raw materials after pulverization in step S1 is controlled between 90µm and 110µm.

[0079] All other steps were performed in accordance with the method described in Example 1 to prepare ceftazidime avibactam sodium for injection.

[0080] Content uniformity test results: ceftazidime RSD=6.1%; avibactam sodium RSD=5.5%.

[0081] Comparative Example 7

[0082] The difference between this comparative example and Example 1 is that in step S1, the ceftazidime, avibactam sodium, and sodium carbonate raw materials are not pulverized to control particle size, but are directly mixed. The preparation method includes the following steps;

[0083] S1. Take 1 kg of sterile avibactam sodium raw material and 0.4 kg of sterile sodium carbonate raw material and add them to a single-arm mixer. Start the single-arm mixer, control the mixing speed to 16 rpm, and the mixing time to 18 min.

[0084] S2. After mixing, add 4 kg of sterile ceftazidime raw material, start the single-arm mixer, control the mixing speed at 16 rpm, and the mixing time at 18 min.

[0085] S3. After mixing, the content uniformity of the mixed powder obtained in S2 is checked. If it passes the test, the mixed powder is aseptically dispensed, filled with nitrogen, and capped to obtain the ceftazidime avibactam sodium for injection.

[0086] Content uniformity test results: Ceftazidime RSD=7.1%; Avibactam sodium RSD=8.5%.

[0087] Comparative Example 8

[0088] The difference between this comparative example and Example 2 is that in step S1, sodium carbonate is used to adjust the pH to 6.2, while the other steps are completely the same. As a result, a gel-like substance is directly precipitated, and avibactam sodium crystals cannot be precipitated.

[0089] Comparative Example 9

[0090] Compared with Example 2, the difference in this comparative example is that in step S1, water for injection and methanol are mixed at a volume ratio of 1:4. All other steps are exactly the same, and the result is that a gel-like substance is directly precipitated, and avibactam sodium crystals cannot be precipitated.

[0091] Comparative Example 10

[0092] Compared with Example 2, the difference in this comparative example is that in step S2, ethanol with a volume twice that of the mixed solution of water for injection and methanol in S1 is added dropwise to the solution in S1. All other steps are completely the same, and the result is that a gel-like substance is directly precipitated, and avibactam sodium crystals cannot be precipitated.

[0093] Comparative Example 11

[0094] The difference between this comparative example and Example 2 is that the mixing conditions of avibactam sodium and carbonic acid, as well as the subsequent mixing conditions of ceftazidime, were changed to: controlling the mixing speed at 20 rpm and the mixing time at 20 min.

[0095] All other steps were prepared according to the method in Example 2 to prepare ceftazidime avibactam sodium for injection.

[0096] Content uniformity test results: Ceftazidime RSD=0.22%; Avibactam sodium RSD=0.36%.

[0097] Comparative Example 12

[0098] The difference between this comparative example and Example 2 is that the mixing conditions of avibactam sodium and carbonic acid, as well as the subsequent mixing conditions of ceftazidime, were changed to: controlling the mixing speed at 13 rpm and the mixing time at 15 min.

[0099] All other steps were prepared according to the method in Example 2 to prepare ceftazidime avibactam sodium for injection.

[0100] Content uniformity test results: ceftazidime RSD=0.25%; avibactam sodium RSD=0.35%.

[0101] Based on the content uniformity test results of the above embodiments and comparative examples, the mixing uniformity of ceftazidime, avibactam sodium, and sodium carbonate with specific particle sizes has a significant advantage compared to the mixture without particle size control. In particular, the content uniformity of the mixed powder after avibactam crystallization treatment is even better. From the results of comparative examples 1-3, changing the mixing order has a significant impact on the content uniformity. Theoretically, the closer the particle size of the materials is, the better the mixing uniformity. However, surprisingly, from comparative examples 4-6, changing the particle size to make the three particles of ceftazidime, avibactam sodium, and sodium carbonate the same did not improve the mixing uniformity, but instead reduced the content uniformity. From the results of comparative examples 8-10, it can be seen that changing the crystallization conditions of avibactam sodium has a significant impact on the crystallization effect. However, from the results of comparative examples 11-12, changing the mixing conditions has no significant effect on the mixing uniformity. This shows that the present invention can achieve good mixing uniformity without demanding mixing conditions.

[0102] Experimental example:

[0103] In accordance with the requirements for drug stability testing in Part IV and the appendix of the 2025 edition of the Chinese Pharmacopoeia, accelerated stability testing (40℃±2℃, RH 75%±5%) was conducted on Examples 1-5 and the marketed ceftazidime avibactam sodium for injection. Samples were taken and tested at 0 months and 6 months, respectively. The specific results are shown in Table 1.

[0104] Table 1. Results of accelerated stability study of ceftazidime avibactam sodium for injection.

[0105]

[0106] As can be seen from the stability results in Table 1, the ceftazidime avibactam sodium for injection prepared in this invention has extremely high stability when the mixing uniformity is very high. The possible reasons are the contact between solid particles, surface alkalinity, local microenvironment, and solid-phase interface reaction. The particle size of sodium carbonate and the mixing uniformity have a more prominent effect on the stability of the two drugs.

Claims

1. A method for preparing ceftazidime avibactam sodium for injection, characterized in that: The particle size of the three raw materials—ceftazidime, avibactam sodium, and sodium carbonate—is controlled by pulverizing, and then they are mixed in a mixer.

2. The method for preparing ceftazidime avibactam sodium for injection as described in claim 1, characterized in that: The ceftazidime has a particle size of 120µm to 140µm, the avibactam sodium has a particle size of 70µm to 90µm, and the sodium carbonate has a particle size of 90µm to 110µm.

3. The method for preparing ceftazidime avibactam sodium for injection as described in claim 1, characterized in that: The mixing conditions are a mixing speed of 16 rpm and a mixing time of 18 min.

4. The method for preparing ceftazidime avibactam sodium for injection as described in claim 1, characterized in that: The sodium avibactam raw material before pulverization is prepared by the following steps: (1) Dissolve sodium avibactam in a mixed solution of water for injection and methanol, with the pH adjusted to 6.4-6.8 by sodium carbonate, wherein the volume ratio of water for injection to methanol is 1:5; (2) Add anhydrous ethanol to the solution in step 1, add seed crystals, grow crystals for 1 hour, cool down, and stir to precipitate crystals for 1 hour; (3) Filter the crystals obtained in step 2, wash the filter cake twice with anhydrous ethanol, then vacuum dry and pulverize to obtain sodium avibactam raw material.

5. The preparation steps of the avibactam sodium raw material as described in claim 4, characterized in that: In step (1), the weight ratio of sodium avibactam to the mixed solution of water for injection and methanol is sodium avibactam: mixed solution of water for injection = 1:30, and the dissolution temperature is 55℃.

6. The preparation steps of the avibactam sodium raw material as described in claim 4, characterized in that: The amount of anhydrous ethanol added in step (2) is three times the total volume of the mixed solution of water for injection and methanol in step (1); the temperature is then lowered to 15°C.

7. The preparation steps of the avibactam sodium raw material as described in claim 4, characterized in that: The drying conditions in step (3) are 42°C, vacuum degree -0.09MPa, and drying time of 12 hours.

8. The method for preparing ceftazidime avibactam sodium for injection as described in claim 1, characterized in that: The mass ratio of ceftazidime, sodium carbonate, and avibactam sodium was (4.0-4.5):(0.4-0.5):

1.

9. The method for preparing ceftazidime avibactam sodium for injection as described in claim 1, characterized in that: First, mix avibactam sodium and sodium carbonate, then add ceftazidime and mix again.

10. The method for preparing ceftazidime avibactam sodium for injection according to any one of claims 1-9, characterized in that: The process also includes aseptic filling, nitrogen filling, and capping.

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