Preparation method of ceftazidime with better stability for injection

Abstract

The invention relates to a preparation method of ceftazidime for injection with better cosolvent uniformity, which is characterized in that a cosolvent is dissolved by using a mixed solvent and then is uniformly dispersed into ceftazidime, so that the content of related substances in the stability period is smaller, the crystal form stability is good, and the contents of main components and the cosolvent are stable and uniform; furthermore, visible foreign matters cannot be increased during the stability period of the preparation.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and in particular, the present invention relates to a method for preparing ceftazidime for injection with better stability. Because the cosolvent is evenly attached to the raw material, the raw and auxiliary materials will not be delaminated due to vibration during transportation or filling, which will reduce the content of the raw and auxiliary materials, thereby ensuring that the solubility problem and the appearance of visible foreign matter will not occur during the stability of the preparation due to insufficient amount of sodium carbonate. Background Art

[0002] Ceftazidime is a semi-synthetic third-generation cephalosporin. The finished product is a free acid (pentahydrate compound), and a certain amount of anhydrous sodium carbonate is added to make an injection for use. It is suitable for sepsis caused by sensitive Gram-negative bacteria, lower respiratory system infections, abdominal biliary infections, complicated urinary tract infections and severe skin and soft tissue infections. It is particularly suitable for infections in immunocompromised people caused by multiple drug-resistant Gram-negative bacteria, nosocomial infections, and central nervous system infections caused by Gram-negative bacteria or Pseudomonas aeruginosa. The antibacterial mechanism of ceftazidime is to affect the synthesis of bacterial cell walls. Similar to other cephalosporins, this product can inhibit the transpeptidase action in the last step of cross-linking in cell wall synthesis, so that cross-linking cannot be formed, thereby affecting cell wall synthesis and causing bacterial lysis and death.

[0003] Because this product is a mixture of ceftazidime and sodium carbonate, the quality of the mixing uniformity will affect the stability of the preparation. Conventional ceftazidime for injection on the market is a simple physical mixture of ceftazidime and sodium carbonate and then filled, but because the proportion of sodium carbonate is relatively low, uneven mixing often occurs. Because sodium carbonate is a stabilizer and co-solvent in this variety, the sodium carbonate is mixed unevenly, the amount of sodium bicarbonate produced by sodium carbonate and protective gas carbon dioxide is insufficient, and the solubilizing effect is poor. During the stability placement period, the raw material drug cannot be completely dissolved, and visible foreign matter will appear. Because this product is an injection solution that directly enters the blood, there is a certain safety risk if visible foreign matter appears. Therefore, solving the problem of mixing uniformity of raw and auxiliary materials is the main way to completely solve the problem of visible foreign matter caused by uneven mixing. Summary of the invention

[0004] To solve the above problems, the present invention provides a preparation prepared by obtaining a raw material drug through special processing. The raw and auxiliary materials of the preparation have good uniformity, the preparation stability is good, and no visible foreign matter will appear during the stability period, which can well ensure the safety of medication and reduce adverse reactions in patients.

[0005] The technical solution provided by the present invention is a preparation method of ceftazidime for injection: slowly add a fixed mass of ceftazidime pentahydrate to a mixture of acetone and water in which a fixed mass of sodium carbonate is dissolved at a controlled temperature of -4 to 0°C, stir for 10 minutes in a suspended state, and no sample is deposited at the bottom. Transfer the suspension to a rotary evaporator, set the temperature to 32-35°C, and evaporate under reduced pressure. Wait for the sample to have a constant weight to obtain a fixed amount of a mixture of ceftazidime pentahydrate and sodium carbonate. Accurately weigh and fill 0.5g / bottle into a 15ml medium borosilicate glass tube bottle, and 1.0g / bottle into a 20ml medium borosilicate glass tube bottle. After filling, adjust the carbon dioxide gas flow rate, fill with carbon dioxide, and after filling, press the plug and roll the cap. The uniformity of ceftazidime content and sodium carbonate in each bottle were tested, and the stability experiment confirmed that the obtained preparation had good stability. The accelerated tests of 1 month, 2 months, 3 months, 6 months and long-term tests of 18 months, 24 months and 36 months showed that the relevant substances were good, and no visible foreign matter was found under long-term conditions.

[0006] Compared with the prior art, the present invention has the following beneficial effects:

[0007] The present invention provides for the first time a method of uniformly distributing sodium carbonate into a ceftazidime drug by pulping, so that no stratification occurs during the transportation of the raw material and the filling process of the preparation, thereby ensuring good uniformity of the two components in the preparation and ensuring that there are no visible foreign matter during the stability period. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 This is a crystal form diagram of commercially available ceftazidime pentahydrate;

[0009] Figure 2 This is a crystal form of ceftazidime pentahydrate obtained by reduced pressure drying;

[0010] Figure 3 This is a crystal form of ceftazidime pentahydrate obtained by spray drying;

[0011] Figure 4 This is a comparison chart of the stability crystal forms of ceftazidime pentahydrate; DETAILED DESCRIPTION

[0012] The present invention is further described below in conjunction with specific examples. These examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein may be applied to the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0013] Example 1

[0014] Measure 1000ml of acetone and place it in a 5L glass beaker. Add 100ml of distilled water under stirring. Slowly add 50.68g of sodium carbonate to the mixed solvent, stir and cool to -4~0℃; weigh 500g of ceftazidime pentahydrate and take 0.5g of sample for XRD inspection. Figure 2 As shown. Slowly add the weighed 500g of ceftazidime pentahydrate to 1100ml of mixed solvent kept at -4 to 0℃, keep warm and stir for 10-15 minutes, the suspension has no lumps and no material accumulation. Pass through a 100-mesh sieve to ensure that there are no lumps and unsoaked materials. At the same time, transfer the suspension to a 3L single-mouth flask. Connect the above-mentioned single-mouth flask to a rotary evaporator, set the water bath temperature to 32-35℃, rotary evaporate the mixed solvent, observe the solvent in the single-mouth bottle, and after no liquid drips in the waste liquid receiving bottle of the rotary evaporator, remove the single-mouth flask and weigh it every 5 minutes. After constant weight, pour out the wet product from the single-mouth bottle, place it in a vacuum oven and dry it under reduced pressure for 2-3 hours. After the material has constant weight, use a rapid moisture detector to detect that the moisture is 12.5%. Collect the material to obtain 535.25g of product with a yield of 97.20%. Take 0.5g of sample for XRD inspection, as shown in the attached Figure 2 As shown. Accurately weigh 0.5g / bottle and 1.0g / bottle and fill them into 15ml and 20ml medium borosilicate glass tube bottles respectively. After filling, adjust the carbon dioxide gas flow rate, fill with carbon dioxide, and after filling, press the plug and cap. Take 0.5g / bottle sample for XRD inspection, as shown in the attached Figure 3 shown.

[0015] Table 1 Physical properties of raw materials

[0016] Sample 1 Sample 2 Sample 3 Characteristics White crystalline powder White crystalline powder White crystalline powder <![CDATA[Bulk density (g / cm 3 )]]> 0.563 0.552 0.550 <![CDATA[Tap density (g / cm 3 )]]> 0.866 0.883 0.880 Compression (%) 35.0 37.5 37.5 Angle of repose 43.0° 43.1° 42.9° <![CDATA[Particle size (D 50 )(μm)]]> 28.0 20.7 18.1 <![CDATA[Particle size (D 90 )(μm)]]> 118 80.7 83.3

[0017] Table 2 Ceftazidime, sodium carbonate content and homogeneity test results

[0018]

[0019]

[0020] Table 3 Accelerated 6-month impurity content

[0021]

[0022] Ten bottles of 0.5 g / bottle and 1.0 g / bottle samples were taken respectively, and the ceftazidime content and sodium carbonate content were determined as shown in Table 2. The results in Table 2 show that the uniformity of the ceftazidime and sodium carbonate contents is good.

[0023] The impurity content of the samples accelerated for 6 months is shown in Table 3. The relevant substances tested for 6 months were in good condition and no visible foreign matter was found under long-term conditions.

[0024] Example 2

[0025] Measure 1000ml of acetone and place it in a 5L glass beaker. Add 100ml of distilled water under stirring conditions. Slowly add 50.68g of sodium carbonate to the mixed solvent, stir and cool to -4-0°C; slowly add 500g of ceftazidime pentahydrate weighed to 1100ml of mixed solvent kept at -4-0°C, keep warm and stir for 10-15 minutes, and the suspension has no agglomeration and no material accumulation. Pass through a 100-mesh sieve to ensure that there is no agglomeration and no unsoaked material. At the same time, transfer the suspension to the material hopper and stir. Place the above suspension on the spray dryer, turn on the vacuum pump, set the vacuum rate to 100%, adjust the air flow meter to 30 mm, set the temperature constant at 30-32°C, turn on the peristaltic pump, adjust the spray volume, insert the straw into the hopper, and start spray drying. After drying for 30-45 minutes, the moisture content was 12.5% ​​using a rapid moisture detector, and 512.23g of product was collected, with a yield of 93.09%. Accurately weigh and fill into 15ml and 20ml medium borosilicate glass tube bottles at 0.5g / bottle and 1.0g / bottle respectively. After filling, adjust the carbon dioxide gas flow rate, fill with carbon dioxide, and after filling, press the plug and cap.

[0026] Table 4 Physical properties of raw materials

[0027] Sample 1 Sample 2 Sample 3 Characteristics White crystalline powder White crystalline powder White crystalline powder <![CDATA[Bulk density (g / cm 3 )]]> 0.563 0.552 0.550 <![CDATA[Tap density (g / cm 3 )]]> 0.866 0.883 0.880 Compression (%) 35.0 37.5 37.5 Angle of repose 43.0° 43.1° 42.9° <![CDATA[Particle size (D 50 )(μm)]]> 28.0 20.7 18.1 <![CDATA[Particle size (D 90 )(μm)]]> 118 80.7 83.3

[0028] Table 5 Ceftazidime, sodium carbonate content and homogeneity test results

[0029]

[0030] Table 6 Impurity content after 6 months of acceleration

[0031]

[0032]

[0033] Ten bottles of 0.5 g / bottle and 1.0 g / bottle samples were taken respectively, and the ceftazidime content and sodium carbonate content were determined as shown in Table 5. The results in Table 5 show that the uniformity of the ceftazidime and sodium carbonate contents is good.

[0034] The impurity content of the samples accelerated for 6 months is shown in Table 6. The relevant substances tested for 6 months were in good condition and no visible foreign matter was found under long-term conditions.

[0035] Comparative Example 1

[0036] Accurately weigh 500g of ceftazidime and 50.68g of sodium carbonate. Place the two materials weighed above in the hopper of a three-dimensional mixer, lock the hopper cover, turn on the switch of the mixer, start the equipment, adjust the speed and rotation angle of the mixer, mix the materials thoroughly, stir for 5 minutes, and shut down. Accurately weigh and fill 15ml and 20ml borosilicate glass tube bottles at 0.5g / bottle and 1.0g / bottle respectively. After filling, adjust the carbon dioxide gas flow rate, fill carbon dioxide, fill, and press the plug to roll the cap. Take a sample from the upper, middle and lower parts of the material for testing. The mixing uniformity of the mixed material is shown in Table 7. The average value is taken. The mixing uniformity is good after mixing for 25-30 minutes. After mixing for more than 40 minutes, the uniformity of excessive mixing tends to deteriorate. As the mixing time increases, a poor regularity is shown.

[0037] Table 7 Mixing uniformity of ceftazidime and sodium carbonate

[0038] Sampling time point Ceftazidime content (calculated as ceftazidime) Sodium carbonate content 25 minutes 78.90％ 9.21％ 30 minutes 78.45％ 9.20％ 40 minutes 85.30％ 2.2％ 60 minutes 83.2％ 4.2％

[0039] The mixed powder raw material drug mixed for 30 minutes in Comparative Example 1 and the raw materials prepared in Examples 1 and 2 were simulated for transportation and static storage. After two repeated cycles, the contents of ceftazidime and sodium carbonate were detected as shown in Table 8. The mixed powder raw material sample of Comparative Example 1 showed slight stratification, resulting in changes in the contents of ceftazidime and sodium carbonate before and after transportation; the raw materials prepared in Examples 1 and 2 had good uniformity and did not show stratification or changes in content during transportation and storage.

[0040] Table 8 Contents of ceftazidime and sodium carbonate after simulated transportation and static storage

[0041]

[0042] The stability of the raw material obtained in Comparative Example 1 was tested for long-term stability for 12 months, 18 months, and 24 months. It was found that white particles appeared after some samples dissolved for 18 months, and they could only be dissolved after repeated shaking. The samples prepared by the methods of Examples 1 and 2 had good solubility and no visible foreign matter appeared.

Claims

1. A method for preparing ceftazidime for injection with better stability, characterized in that: The preparation method is as follows: dissolving a cosolvent into a mixed solvent; dissolving ceftazidime pentahydrate into the mixed solvent containing the cosolvent at a certain temperature, stirring for a period of time in a suspended state until no sediment is deposited at the bottom; and drying the suspension to obtain a mixture of ceftazidime pentahydrate and the cosolvent; The ceftazidime for injection with better stability can be obtained by filling the bottles.

2. The method for preparing ceftazidime for injection with better stability according to claim 1, characterized in that: The co-solvent is sodium carbonate, sodium bicarbonate, sodium carbonate monohydrate or a mixture of sodium carbonate and sodium bicarbonate.

3. The method for preparing ceftazidime for injection with better stability according to claim 1, characterized in that: The mixed solvent is a mixture of water and acetone.

4. A method for preparing ceftazidime for injection with better stability according to claim 1 or 3, characterized in that: The volume ratio of the mixed solvent water to acetone is 1:10-1:

20.

5. The method for preparing ceftazidime for injection with better stability according to claim 1, characterized in that: The drying is performed under reduced pressure or by spray drying.

6. The method for preparing ceftazidime for injection with better stability according to claim 1, characterized in that: The temperature is -4-0°C.

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