Preparation method of aztreonam for injection

Abstract

The invention provides a preparation method of aztreonam for injection, which is characterized by comprising the following steps: under the conditions that the temperature is controlled at 18-26 DEG C and the relative humidity is less than or equal to 55%, feeding aztreonam and arginine into a lifting mixer according to the mass ratio of 1: (0.77-0.80) in an alternate pumping manner, and mixing. The product prepared by the method is stable and safe, and provides more reliable technical support for preparation of aztreonam for injection.

Description

Technical Field

[0001] The present invention relates to the field of drug preparation, and specifically, to a preparation method of aztreonam for injection. Background Art

[0002] When preparing aztreonam for injection using existing technologies, there are problems such as high energy consumption, complex equipment, poor preparation stability (extremely easy to delaminate), and rapid growth of impurities. Therefore, traditional aztreonam for injection often adopts the method of separately packaging aztreonam and arginine, which is complex to use and troublesome to package. Summary of the Invention

[0003] The present invention aims to overcome the above defects and provides a stable and reliable preparation method of aztreonam for injection, providing more reliable technical support for the preparation of aztreonam for injection.

[0004] The present invention provides a preparation method of aztreonam for injection, characterized in that: under the conditions of temperature controlled at 18°C to 26°C and relative humidity ≤ 55%, aztreonam and arginine are fed into a lifting mixer in a mass ratio of 1:0.75 - 0.85 in an alternating suction manner for mixing.

[0005] Further, a preparation method of aztreonam for injection provided by the present invention is further characterized in that:

[0006] The mixing time is 10 - 15 min.

[0007] Further, a preparation method of aztreonam for injection provided by the present invention is further characterized in that:

[0008] The mixing rotation speed is 8 - 15 revolutions per minute.

[0009] Further, a preparation method of aztreonam for injection provided by the present invention is further characterized in that:

[0010] The raw material particle size D(0.9) of aztreonam is selected from 150 - 350 nm.

[0011] Further, a preparation method of aztreonam for injection provided by the present invention is further characterized in that:

[0012] The mixed material after mixing is subpackaged, and the specific subpackaging method is: under the conditions of temperature controlled at 18°C to 26°C and relative humidity ≤ 50%, subpackaging is carried out in a Class A environment.

[0013] Further, a preparation method of aztreonam for injection provided by the present invention is further characterized in that:

[0014] The filling volume of subpackaging is adjusted by a screw filling machine.

[0015] Furthermore, a preparation method of aztreonam for injection provided by the present invention is further characterized in that:

[0016] The speed of the filling machine for sub-packaging is ≤ 230 bottles / min.

[0017] Furthermore, a preparation method of aztreonam for injection provided by the present invention is further characterized in that:

[0018] The sub-packaging time for a single bottle: the time from the end of sub-packaging to the end of capping is ≤ 10 min.

[0019] Functions and effects of the present invention:

[0020] Through the optimization of the process, the present invention prepares an aztreonam for injection preparation with uniform powder quality. At the same time, the process is simple, with low energy consumption, simple equipment, and the quality standard is improved. Description of the Drawings

[0021] Figure 1 Results of the moisture absorption curve of the mixed powder of aztreonam for injection; Detailed Embodiments

[0022] The present invention can implement various changes and can have various embodiments. Therefore, specific embodiments are illustrated in the drawings and described herein. However, this is not intended to limit the present invention to a specific embodiment, but should be understood to include all changes, equivalents, and alternatives that fall within the spirit and technical scope of the present invention.

[0023] The preparation process of aztreonam for injection involved in this embodiment has aztreonam and arginine in the prescription. The preparation process includes the following steps:

[0024] S1. Mixing of aztreonam and arginine

[0025] (1) Control of raw and auxiliary materials

[0026] Both aztreonam and arginine are sterile materials. The mixing process is stable and has low requirements for the particle size range of the raw materials. In this embodiment, after mixing raw materials with different particle sizes of aztreonam with D(0.9) of 155 nm, 209 nm, and 349 nm for 3 batches of verification, the content uniformity meets the requirements, and all 6 batches of process verification samples meet the quality standard requirements. This shows that the particle size range of aztreonam raw materials has little influence on the mixing process and product quality.

[0027] The aztreonam raw material, arginine auxiliary material, and 3 batches of process verification samples of aztreonam for injection are compared with the reference preparation by X-ray diffraction. The crystal forms of aztreonam for injection and the reference preparation are consistent.

[0028] (2) The temperature is controlled at 18°C to 26°C, and the relative humidity is ≤ 55%.

[0029] (3) The ratio of the two raw materials will affect the mixing effect. Comparative experiments show that the optimal ratio of aztreonam to arginine is 1:0.78, and the sub-optimal ratios are 1:0.75, 1:0.80, and 1:0.85, where slight instability and poor mixing homogeneity occur, affecting the results to a certain extent. When the ratio exceeds 1:0.85, such as 1:0.9 or 1:1, layering and instability occur after mixing, resulting in unqualified content.

[0030] (4) Aztreonam and arginine are alternately pumped into a fully automatic lifting mixer. (Alternate pumping means sending aztreonam to the feeding point, opening the inner cover, and pumping the sterile powder of aztreonam into the fully automatic lifting mixer. After the pumping is completed, send arginine to the feeding point, open the inner cover, and pump the sterile powder of arginine into the fully automatic lifting mixer. Repeat the above operations to alternately pump aztreonam and arginine into the fully automatic lifting mixer.)

[0031] Under the same other conditions, it is easy to layer when using a non-alternate process.

[0032] (5) The mixing time is 15 minutes and the mixing speed is 10 revolutions per minute.

[0033] Under the same other conditions, the mixing times of 5min, 10min, 15min, 20min, 30min, and 60min were studied. When the time is less than 15min, aztreonam and arginine are not evenly mixed, the content homogeneity is poor, and the RSD is large. When the mixing time ≥ 15min, the mixing is uniform and the RSD is less than 2%. Considering energy conservation, etc., the mixing time of 15min is selected. S2. Sub-packaging of aztreonam (containing) arginine

[0034] (1) The temperature is controlled at 18°C - 26°C and the relative humidity ≤ 55%.

[0035] According to the hygroscopic curve results of the mixed powder of aztreonam for injection ( Figure 1 ), the critical relative humidity of the mixed powder of aztreonam for injection is about 65%; considering the tightness and production duration in the mixing and sub-packaging stages, it is recommended to control the humidity below 55% in the sub-packaging stage.

[0036] (2) Sub-packaging is carried out in a Class A environment, and the product filling volume is adjusted by a screw filling machine. The difference in the single-bottle filling volume of the product affects the effectiveness of the drug and is a key process parameter. Therefore, the filling volume is randomly inspected at the pre-production, in-production, and post-production stages. The filling volume of the sub-packaging can be controlled within ±2%, and the filling volume range is much lower than the quality standard requirements (±5%), with higher safety. The process is stable, and the summary table of the filling volume inspection is shown in Table 1.

[0037] (3) The speed of the filling machine ≤ 230 bottles / min.

[0038] (4) The time for single vial filling and the time from the end of filling to the end of capping ≤ 10 min.

[0039] (5) The filling time ≤ 12 h, which is much less than the freeze-drying time.

[0040] In this method, aztreonam (containing) arginine is filled into vials, and after plugging, capping, visual inspection, labeling, and packaging, the products to be inspected are obtained. After inspection, qualified products are obtained and warehoused. The above preparation process has the advantages of simple method, short cycle, low energy consumption, and low cost, and is suitable for industrial production.

[0041] Table 1 Summary Table of Fill Volume Inspection

[0042]

[0043]

[0044] Process comparison:

[0045] Current production process:

[0046] Aztreonam and arginine are first mixed and then filled according to the ratio to obtain the preparation aztreonam for injection.

[0047] Original production process:

[0048] In the injection water of the prescription amount, a certain ratio of aztreonam and arginine is added, and the stirred and dissolved solution is sterilized and filtered through two 0.20 μm polyethersulfone pleated filters. After measuring the content, the filling volume is calculated. It is filled into sterilized and dried glass bottles in the A-level RABS under the B-level background. The rubber stoppers after semi-plugging and sterilization and drying are automatically sorted and framed and enter the freeze-drying chamber. It is frozen under normal pressure and enters the primary drying within a certain vacuum range. A large amount of water existing in the form of ice is discharged by sublimation. In the desorption drying, the remaining small amount of water is continuously discharged to obtain the freeze-dried powder injection. After fully covering the stoppers in the freeze-drying chamber, it is pushed out of the freeze-drying chamber and automatically unframed. It is sealed with an aluminum cap in the A-level RABS under the C-level background. After visual inspection of the appearance quality, the bottle stickers are pasted in the general production area and packaged.

[0049] A. Quality comparison:

[0050] As shown in Table 2, when using the optimized preparation process to produce aztreonam for injection, the related substances of the prepared samples are significantly reduced, the maximum single impurity content is less than 0.1%, the quality is controllable, indicating the safety and reliability of the current filling process. The clarity of the solution ≤ No. 0.5; the color of the solution ≤ Y-2 or YG-2, with better stability; the quality standard is improved.

[0051] Table 2 Key Quality Comparison Table before and after Process Optimization

[0052]

[0053] *For the solution of the present invention

[0054] B. Comparison of mixing uniformity

[0055] Meanwhile, the mixing uniformity of the preparation was investigated, and the results are shown in Table 3. The results show that all 6 batches of the preparation can be mixed evenly, with stable quality and reliable process, effectively solving the problem that aztreonam and arginine are difficult to be mixed evenly during the production of traditional aseptic process, and the phenomenon of layering is likely to occur during the sub-packaging process.

[0056] Table 3 Investigation table of mixing uniformity

[0057]

[0058]

[0059] C. Comparison of finished product rate:

[0060] Before the process optimization, the finished product rate of this product was in the range of 92.00%-98.00%. After the process optimization, the finished product rate of this product remained at about 99%. The results are shown in Table 4, and the yield of aztreonam for injection has been improved compared with the prior art.

[0061] Table 4 Summary table of material balance

[0062]

[0063] Thus, through the optimization of the process, the present invention prepares an aztreonam for injection preparation with uniform powder quality. Meanwhile, the process is simple, with low energy consumption, simple equipment, and the quality standard has been improved.

[0064] Although the above has been described centering around the embodiments, this is only an illustration and does not limit the present invention. Those of ordinary skill in the art understand that various deformations and applications not illustrated above can be made without departing from the essential characteristics of this embodiment. For example, each constituent element specifically shown in the embodiment

[0065] can be implemented after being deformed. Moreover, various differences related to such deformations and applications should be interpreted as being included in the scope of the present invention defined in the appended claims.

Claims

1. A preparation method of aztreonam for injection, characterized in that Under the conditions that the temperature is controlled at 18°C to 26°C and the relative humidity is ≤55%, aztreonam and arginine are fed into a lifting mixer in a mass ratio of 1:0.75 - 0.85 in an alternating suction manner for mixing.

2. The preparation method of aztreonam for injection according to claim 1, characterized in that : The mixing time is 10 - 15 min.

3. The preparation method of aztreonam for injection according to claim 1, characterized in that : The mixing speed is 8 - 15 revolutions per minute.

4. The preparation method of aztreonam for injection according to claim 1, characterized in that : The raw material particle size D(0.9) of aztreonam is selected from 150 - 350 nm.

5. The preparation method of aztreonam for injection according to claim 1, characterized in that : The mixed material after mixing is sub-packed. The specific sub-packing method is: under the conditions that the temperature is controlled at 18°C to 26°C and the relative humidity is ≤50%, sub-packing is carried out in a Class A environment.

6. The preparation method of aztreonam for injection according to claim 5, characterized in that : The filling volume of sub-packing is adjusted by a screw filling machine.

7. The preparation method of aztreonam for injection according to claim 5, characterized in that : The speed of the filling machine for sub-packing is ≤230 bottles per minute.

8. The preparation method of aztreonam for injection according to claim 5, characterized in that : The sub-packing time for a single bottle: the time from the end of sub-packing to the end of capping is ≤10 min.

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