Preparation technology of ceftazidime avibactam sodium for injection

Abstract

The present invention relates to the field of preparation of compound powder injection, and specifically discloses a preparation process of ceftazidime avibactam sodium for injection, comprising the following steps: S1, ceftazidime and avibactam sodium are refined respectively; S11, dissolving: ceftazidime and avibactam sodium are dissolved respectively to obtain ceftazidime solution and avibactam sodium solution; S12, impurity removal; S13, crystallization: vitamin E and sodium sulfate are first added to the solution and stirred evenly, and then the temperature is lowered for crystallization; S14, powderization: the solution after crystallization is filtered and dried in sequence to obtain ceftazidime powder and avibactam sodium powder; S2, the ceftazidime obtained in step S1 is mixed evenly with sodium carbonate in a prescribed ratio; S3, the avibactam sodium obtained in step S1 and the ceftazidime containing sodium carbonate obtained in step S2 are mixed in a prescribed ratio. The present invention can improve the uniformity of the mixing of ceftazidime and avibactam sodium, and can improve the stability of the drug.

Description

Technical Field

[0001] The invention relates to the field of preparation of compound powder injections, and in particular to a preparation process of ceftazidime avibactam sodium for injection. Background Art

[0002] Ceftazidime avibactam sodium for injection is a compound powder injection, which is prepared by mixing ceftazidime (containing sodium carbonate) and avibactam sodium in a prescribed proportion.

[0003] The existing process flow for preparing ceftazidime avibactam sodium for injection is: powder mixing preparation (sterilization of raw materials and mixing equipment) - mixing - packaging preparation (sterilization of packaging equipment) - aseptic packaging - nitrogen filling - capping - packaging.

[0004] Since ceftazidime avibactam sodium for injection is a compound powder injection, in order to reduce the quality difference of bottled products in the same batch, the uniformity of the mixing of ceftazidime and avibactam sodium should be improved. In order to improve the uniformity of the mixing of ceftazidime and avibactam sodium, the mixing equipment and mixing process are mainly considered, for example, by improving the addition amount and addition order of ceftazidime and avibactam sodium during mixing, or providing a more uniform mixing equipment.

[0005] However, existing methods for improving mixing uniformity usually result in large differences in the quality of bottled products in the same batch. Summary of the invention

[0006] The purpose of the present invention is to provide a preparation process of ceftazidime avibactam sodium for injection, so as to improve the uniformity of mixing ceftazidime and avibactam sodium and improve the stability of the drug.

[0007] The present invention is achieved through the following technical solutions:

[0008] The preparation process of ceftazidime avibactam sodium for injection comprises the following steps:

[0009] S1. Refining ceftazidime and avibactam sodium respectively;

[0010] S11, dissolving: dissolving ceftazidime and avibactam sodium respectively to obtain a ceftazidime solution and an avibactam sodium solution;

[0011] S12, removing impurities;

[0012] S13, crystallization: first add vitamin E and sodium sulfate to the solution and stir evenly, then cool and crystallize;

[0013] S14, powdering: filtering and drying the solution after crystallization in sequence to obtain ceftazidime powder and avibactam sodium powder;

[0014] S2, mixing the ceftazidime obtained in step S1 and sodium carbonate in a prescribed ratio;

[0015] S3. Mix the avibactam sodium obtained in step S1 and the ceftazidime containing sodium carbonate obtained in step S2 according to a prescribed ratio.

[0016] The invention can improve the purity of ceftazidime powder crystals and avibactam sodium powder crystals and reduce the impurities of ceftazidime avibactam sodium for injection by refining ceftazidime and avibactam sodium, that is, recrystallizing ceftazidime and avibactam sodium.

[0017] The present invention can improve the surface smoothness of the sucked-out crystals by adding vitamin E and sodium sulfate into the solution during crystallization, and improve the uniformity of mixing by improving the surface smoothness of the crystals.

[0018] Furthermore, the vitamin E of the present invention is beneficial to maintaining the ceftazidime avibactam sodium dry, thereby preventing it from being affected by moisture in the environment and thus reducing its stability.

[0019] In summary, the present invention can improve the uniformity of the mixture of ceftazidime and avibactam sodium, and can improve the stability of the medicine.

[0020] Furthermore, in step S12, the impurity removal is to decolorize the solution using a macroporous adsorption resin.

[0021] Furthermore, in step S13, the amount of vitamin E added is 3-5 mg per 1 L of solution, and the amount of sodium sulfate added is 5-10 mg per 1 L of solution.

[0022] The amount of vitamin E added and the amount of sodium sulfate added can affect the stability and mixing uniformity of the prepared ceftazidime and avibactam sodium powder injections. When the amount of vitamin E and sodium sulfate added is increased during the crystallization process, the stability is close to that of the present invention. When the amount of vitamin E and sodium sulfate added is reduced, the stability is relatively poor. Therefore, considering the cost comprehensively, in step S13, the amount of vitamin E added is 3-5 mg in 1L of solution, and the amount of sodium sulfate added is 5-10 mg in 1L of solution.

[0023] Further, in step S13, the crystallization process of the ceftazidime solution is:

[0024] Add an acidic solution to adjust the pH to 3.5-4.0, add seed crystals, and grow the crystals at -2 to 2°C for 1.5 to 2 hours.

[0025] Further, in step S13, the crystallization process of the avibactam sodium solution is:

[0026] The avibactam sodium solution was cooled to 0-30°C for 1-2 hours.

[0027] Furthermore, in step S14, the filtering process is to first remove the suspended matter in the solution and then perform suction filtration.

[0028] Removing the suspended matter first can prevent the suspended matter from adhering to the crystals during suction filtration, thereby affecting the purity of the crystals. That is, the filtration method of removing the suspended matter first and then performing suction filtration can improve the purity of the prepared ceftazidime avibactam sodium for injection.

[0029] Furthermore, in step S14, the drying process is to sequentially perform a first vacuum drying, an inert gas drying and a second vacuum drying, wherein the material is stirred during the drying process.

[0030] Conventional drying is to directly dry the crystals using a vacuum. In order to improve the smoothness of the surface of the crystal powder, the present invention arranges the drying process to sequentially perform a first vacuum drying, an inert gas drying and a second vacuum drying. Among them, the inert gas drying utilizes an inert gas to coordinate material turnover to achieve the improvement of the smoothness of the surface of the crystal powder.

[0031] Furthermore, a reducing gas is introduced into the inert gas.

[0032] Further, in step S3, the mixing process is:

[0033] First, ceftazidime powder containing sodium carbonate and avibactam sodium powder are mixed in equal proportions, and then the remaining ceftazidime powder containing sodium carbonate is added into a mixing device for mixing.

[0034] Furthermore, the method further comprises the following steps:

[0035] S4, the mixed powder obtained in step S3 is packaged, nitrogen-filled and capped in sequence.

[0036] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0037] 1. The present invention can improve the surface smoothness of the sucked crystals by adding vitamin E and sodium sulfate to the solution during crystallization, and improve the uniformity of mixing by improving the surface smoothness of the crystals; and the vitamin E of the present invention is conducive to maintaining the dryness of ceftazidime avibactam sodium, avoiding the influence of moisture in the environment and thus reducing its stability. Therefore, the vitamin E of the present invention is conducive to maintaining the dryness of ceftazidime avibactam sodium, avoiding the influence of moisture in the environment and thus reducing its stability.

[0038] 2. The drying process of the present invention is to carry out the first vacuum drying, the inert gas drying and the second vacuum drying in sequence. During the inert gas drying process, the inert gas is introduced; the stirring can not only realize the turning of the material, but also the crystal powder is in contact with the inert gas, not only the materials rub against each other, but also the gas has a certain friction with the materials, so that the surface smoothness of the ceftazidime crystal powder or the avibactam sodium crystal powder is higher, which is beneficial to the subsequent mixing of the ceftazidime crystal powder and the avibactam sodium crystal powder, and the vitamin E and sodium sulfate added during the crystallization further improve the uniformity of the mixing of materials in the same batch. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] The drawings described herein are used to provide a further understanding of the embodiments of the present invention, constitute a part of this application, and do not constitute a limitation of the embodiments of the present invention. In the drawings:

[0040] Figure 1 is a flow chart of the preparation process of the present invention;

[0041] Figure 2 It is a schematic diagram of the structure of the drying equipment used in the inert gas drying of the present invention.

[0042] Marks and corresponding parts names in the attached drawings:

[0043] 1- horizontal drum; 2- rotating shaft; 3- stirring blades; 4- air inlet pipe; 5- exhaust pipe; 6- branch pipe; 7- feed pipe. DETAILED DESCRIPTION

[0044] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with embodiments and drawings. The exemplary embodiments of the present invention and their description are only used to explain the present invention and are not intended to limit the present invention.

[0045] Embodiment 1:

[0046] like Figure 1 As shown, the preparation process of ceftazidime avibactam sodium for injection comprises the following steps:

[0047] S1. Refining ceftazidime and avibactam sodium respectively;

[0048] S11, dissolving: dissolving ceftazidime and avibactam sodium respectively to obtain a ceftazidime solution and an avibactam sodium solution;

[0049] Among them, the dissolution process of ceftazidime is:

[0050] The crude ceftazidime was dissolved in sterile water for injection at 50°C, and the mass ratio of ceftazidime to sterile water for injection was 1:60.

[0051] Among them, the dissolution process of avibactam sodium is:

[0052] The crude avibactam sodium is dissolved in a hot mixed solvent of methanol and water, wherein the volume ratio of methanol to water is 3:2, and the mass volume ratio of the crude avibactam sodium to the mixed solvent of methanol and water is 1:25 in g / ml; the temperature of the hot mixed solvent is 65°C.

[0053] S12, impurity removal:

[0054] D280 macroporous adsorption resin is added to the ceftazidime solution and the avibactam sodium solution respectively for decolorization; sterile injection water is added for stirring and adsorption decolorization, and the volume of the sterile injection water added is 150 times that of the ceftazidime solution or the avibactam sodium solution; and then the filtered liquid is placed in a crystallization device for crystallization.

[0055] S13, crystallization: first add vitamin E and sodium sulfate to the solution and stir evenly, then cool and crystallize;

[0056] The crystallization process of ceftazidime solution is as follows:

[0057] First, add vitamin E and sodium sulfate to the ceftazidime solution and stir evenly. The amount of vitamin E added is 3 mg per 1L solution, and the amount of sodium sulfate added is 5 mg per 1L solution. Then, hydrochloric acid is added to adjust the pH to 3.5-4.0, and then seed crystals are added. The crystals are grown at a temperature of -1 to 0°C for 2 hours to precipitate ceftazidime crystals.

[0058] The crystallization process of avibactam sodium solution is:

[0059] First, vitamin E and sodium sulfate were added to the avibactam sodium solution and stirred evenly. The amount of vitamin E added was 3 mg per 1 L of solution, and the amount of sodium sulfate added was 5 mg per 1 L of solution. Then, the avibactam sodium solution was cooled to 10° C. and stirred for 2 h to precipitate avibactam sodium crystals.

[0060] S14, powdering: filtering and drying the solution after crystallization in sequence to obtain ceftazidime powder and avibactam sodium powder;

[0061] The filtering process is to first remove the suspended matter in the solution and then perform suction filtration; specifically, the suspended matter can be discharged through the upper overflow port.

[0062] The drying treatment is to sequentially perform the first vacuum drying, the inert gas drying and the second vacuum drying, wherein vitamin E is introduced into the inert gas during the inert gas drying, and the material is stirred during the drying process; the method of introducing vitamin E into the inert gas is:

[0063] The vitamin E is sprayed and atomized to the inert gas outlet by high-pressure spraying;

[0064] Drying equipment used in inert gas drying such as Figure 2 As shown, it includes a horizontal drum 1, on which a feed pipe 7 is arranged. Since the horizontal drum 1 can rotate, the feed pipe 7 can be used for both feeding and discharging. A rotating shaft 2 is passed through the horizontal drum 1, and both ends of the rotating shaft 2 protrude from the horizontal drum 1 and are fixedly connected to both ends of the horizontal drum 1. The rotating shaft 2 is connected to a power output shaft of a motor, and the rotating shaft 2 is driven by the motor to rotate to realize the rotation of the horizontal drum 1. A stirring blade 3 is arranged on the part of the rotating shaft 2 placed in the horizontal drum 1. The horizontal drum The two ends of 1 are respectively connected to form an intake pipe 4 and an exhaust pipe 5 through sealed bearings. The intake pipe 4 is used to introduce an inert gas containing vitamin E spray into the horizontal drum 1. The inert gas can be nitrogen, argon, etc., preferably nitrogen. The exhaust pipe 5 is used to discharge the gas in the horizontal drum 1; a branch pipe 6 is provided at the outlet of the intake pipe 4. The branch pipe 6 is used to introduce a reducing gas into the intake pipe 4. The branch pipe 6 is connected to a storage tank storing the reducing gas through a pipeline. The reducing gas can be hydrogen.

[0065] In this embodiment, inert gas drying is performed. During the inert gas drying process, not only inert gas is introduced, but also the horizontal drum 1 is driven by a motor to rotate, so that the material is turned over in the horizontal drum 1 and contacts with the gas at the same time. Not only the materials rub against each other, but the gas also has a certain friction with the materials, so that the surface smoothness of the ceftazidime crystalline powder or the avibactam sodium crystalline powder is higher, which is beneficial to the subsequent mixing of the ceftazidime crystalline powder and the avibactam sodium crystalline powder, and can improve the uniformity of the mixing of materials in the same batch to a certain extent.

[0066] S2, the ceftazidime obtained in step S1 is mixed with sodium carbonate in a prescribed ratio, and the weight ratio of sodium carbonate in the ceftazidime mixed powder containing sodium carbonate is about 10%. Since the content of sodium carbonate is relatively low, the powder surface smoothness can be improved without inert gas drying.

[0067] S3, the avibactam sodium obtained in step S1 and the ceftazidime containing sodium carbonate obtained in step S2 are mixed according to a prescribed ratio, the mass ratio of the ceftazidime crystalline powder mixed with sodium carbonate to the avibactam sodium crystalline powder is 4:1, specifically, the theoretical dosage per 20,000 bottles of batch: 40 kg of ceftazidime crystalline powder (containing sodium carbonate), i.e. 36 kg of ceftazidime, 4 kg of sodium carbonate, and 10 kg of avibactam sodium crystalline powder; the specific mixing process is:

[0068] Mixed powder preparation: after unpacking and sterilization, the raw materials, aluminum barrels and accessories are moved to the online electronic scale through the laminar flow vehicle with sterile docking protection;

[0069] Mixing: First, mix the ceftazidime crystalline powder containing sodium carbonate and the avibactam sodium crystalline powder in equal proportions for 20 minutes, and then add the remaining ceftazidime powder containing sodium carbonate into a mixing device and mix for 60 minutes at a mixing and stirring speed of 80 rpm.

[0070] S4, the mixed powder obtained in step S3 is packaged, nitrogen-filled and capped in sequence:

[0071] Preparation for subpackaging: clean, sterilize and dry the borosilicate tube bottles, rubber stoppers and aluminum-plastic combination caps for injection and set them aside;

[0072] Aseptic filling: Set the filling speed at 80 bottles / minute and the filling volume at ±4% on the filling line, and detect the filling volume difference in a timely manner;

[0073] Nitrogen filling: After the sub-packaging is qualified, set the nitrogen filling speed and pressure that match the sub-packaging machine, and measure the residual oxygen content after the stopper operation;

[0074] Capping: After stoppering, the injection bottles are capped on the capping machine, and the edges are checked to see if they are flat and smooth;

[0075] Packaging: Samples that pass the light inspection will be labeled and boxed, and finally packed.

[0076] Embodiment 2:

[0077] This embodiment is based on Embodiment 1, and the difference from Embodiment 1 is that:

[0078] In step S13, the amount of vitamin E added is calculated as 5 mg per 1 L of solution, and the amount of sodium sulfate added is calculated as 10 mg per 1 L of solution.

[0079] Embodiment 3:

[0080] This embodiment is based on Embodiment 1, and the difference from Embodiment 1 is that:

[0081] The drying process is directly carried out by vacuum drying.

[0082] Comparative Example 1:

[0083] This comparative example is based on Example 1, and the difference from Example 1 is that:

[0084] In step S13, the amount of vitamin E added is calculated as 1 mg per 1 L of solution, and the amount of sodium sulfate added is calculated as 3 mg per 1 L of solution.

[0085] Comparative Example 2:

[0086] This comparative example is based on Example 1, and the difference from Example 1 is that:

[0087] In step S13, the amount of vitamin E added is calculated as 8 mg per 1 L of solution, and the amount of sodium sulfate added is calculated as 15 mg per 1 L of solution.

[0088] Comparative Example 3:

[0089] This comparative example is based on Example 1, and the difference from Example 1 is that:

[0090] In step S13, vitamin E is not added.

[0091] Comparative Example 4:

[0092] This comparative example is based on Example 1, and the difference from Example 1 is that:

[0093] In step S13, no sodium sulfate is added;

[0094] Comparative Example 5:

[0095] This comparative example is based on Example 1, and the difference from Example 1 is that:

[0096] In step S13, vitamin E and sodium sulfate are not added.

[0097] Comparative Example 6:

[0098] This comparative example is based on Example 1, and the difference from Example 1 is that:

[0099] In step S13, vitamin E and sodium sulfate are not added, and the drying process is directly vacuum drying.

[0100] The ceftazidime avibactam sodium for injection prepared in Example 1 to Example 3 and Comparative Example 1 to Comparative Example 6 were subjected to a mixing uniformity test:

[0101] The specific detection process is that after the mixing in step S3 is completed, a stainless steel sterile sampler is used to perform a 10-point sampling method to determine the mixing uniformity. The measurement results are shown in Table 1:

[0102] Table 1

[0103]

[0104]

[0105] In Table 1, the calculation process of RSD of ceftazidime is: the ratio of the absolute value of the difference between the measured value and the theoretical value of ceftazidime to the theoretical value; the calculation process of RSD of avibactam sodium is: the ratio of the absolute value of the difference between the measured value and the theoretical value of avibactam sodium to the theoretical value; the calculation process of total RSD is: the ratio of the absolute value of the difference between the sum of the measured values ​​of avibactam sodium and ceftazidime and the sum of the theoretical values ​​to the difference between the sum of the theoretical values.

[0106] From the data in Table 1, we can see that:

[0107] The ceftazidime avibactam sodium for injection prepared by the invention has good uniformity, and vitamin E and sodium sulfate are added in the crystallization process, and different drying methods are adopted to uniformly affect the mixing uniformity.

[0108] The stability of ceftazidime avibactam sodium for injection prepared in Example 1 to Example 3 and Comparative Example 1 to Comparative Example 6 was tested:

[0109] The ceftazidime avibactam sodium for injection prepared in Example 1 to Example 3 and Comparative Example 1 to Comparative Example 6 were placed according to the market packaging at a temperature of 40° C. and a relative humidity of 70% for 6 months, and samples were taken at 0, 1, 3, and 6 months, respectively, to determine the contents of ceftazidime, avibactam sodium and total impurities. The results are shown in Table 2:

[0110] Table 2

[0111]

[0112]

[0113] From the data in Table 2, we can see that:

[0114] 1) From the data of Example 1 to Example 3, it can be seen that:

[0115] The ceftazidime avibactam sodium for injection prepared by the invention has good stability, and in a 6-month accelerated test, changes in ceftazidime, avibactam sodium and total impurities are small.

[0116] 3) From the data of Example 1, Comparative Example 1 and Comparative Example 2, it can be seen that:

[0117] When the amount of vitamin E and sodium sulfate added is increased during the crystallization process, the stability is close to that of the present invention. When the amount of vitamin E and sodium sulfate added is reduced, the stability becomes relatively poor. Therefore, considering the cost comprehensively, in step S13, the amount of vitamin E added is 3-5 mg per 1L solution, and the amount of sodium sulfate added is 5-10 mg per 1L solution.

[0118] 3) From the data of Example 1 and Comparative Examples 3-6, it can be seen that:

[0119] When vitamin E is not added in step S13, the stability of ceftazidime avibactam sodium for injection is significantly reduced.

[0120] The specific implementation methods described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above description is only a specific implementation method of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

[0121] It should be noted that the structures, proportions, sizes, etc. illustrated in the drawings of this specification are only used to match the contents disclosed in the specification for people familiar with this technology to understand and read, and are not used to limit the limiting conditions for the implementation of the present invention, so they have no substantial technical significance. Any modification of the structure, change of the proportional relationship or adjustment of the size should still fall within the scope of the technical content disclosed by the present invention without affecting the effects and purposes that can be achieved by the present invention. At the same time, the terms such as "upper", "lower", "left", "right", "middle" and the like cited in this specification are only for the convenience of description, and are not used to limit the scope of the implementation of the present invention. The change or adjustment of the relative relationship should also be regarded as the scope of the implementation of the present invention without substantially changing the technical content.

Claims

1. A process for preparing ceftazidime avibactam sodium for injection, characterized in that: The following steps are involved: S1. Refining ceftazidime and avibactam sodium respectively; S11, dissolving: dissolving ceftazidime and avibactam sodium respectively to obtain a ceftazidime solution and an avibactam sodium solution; S12, removing impurities; S13, crystallization: first add vitamin E and sodium sulfate to the solution and stir evenly, then cool and crystallize; the amount of vitamin E added is 3-5 mg per 1L solution, and the amount of sodium sulfate added is 5-10 mg per 1L solution; The crystallization process of the ceftazidime solution is as follows: adding an acidic solution to adjust the pH to 3.5-4.0, adding seed crystals, and growing the crystals at a temperature of -2 to 2°C for 1.5-2h; The crystallization process of the avibactam sodium solution is as follows: cooling the avibactam sodium solution to 0-30° C. for 1-2 hours; S14, powdering: filtering and drying the solution after crystallization in sequence to obtain ceftazidime powder and avibactam sodium powder; the drying process is to perform a first vacuum drying, an inert gas drying and a second vacuum drying in sequence, wherein the material is stirred during the drying process; S2, uniformly mixing the ceftazidime obtained in step S1 with sodium carbonate, wherein the weight proportion of the sodium carbonate is 10%; S3. Mix the avibactam sodium obtained in step S1 and the ceftazidime containing sodium carbonate obtained in step S2 in a mass ratio of 1:

4.

2. The preparation process of ceftazidime avibactam sodium for injection according to claim 1, characterized in that: In step S12, the impurity removal is to use a macroporous adsorption resin to decolorize the solution.

3. The preparation process of ceftazidime avibactam sodium for injection according to claim 1, characterized in that: In step S14, the filtering process is to first remove the suspended matter in the solution and then perform suction filtration.

4. The preparation process of ceftazidime avibactam sodium for injection according to claim 1, characterized in that: A reducing gas is introduced into the inert gas.

5. The preparation process of ceftazidime avibactam sodium for injection according to claim 1, characterized in that: In step S3, the mixing process is: firstly, the ceftazidime powder containing sodium carbonate and the avibactam sodium powder are mixed in equal proportions, and then the remaining ceftazidime powder containing sodium carbonate is added to a mixing device for mixing.

6. The preparation process of ceftazidime avibactam sodium for injection according to any one of claims 1 to 5, characterized in that: The following steps are also included: S4, the mixed powder obtained in step S3 is packaged, nitrogen-filled and capped in sequence.

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