WO2010124601A1

WO2010124601A1 - Method for producing injectable preparation containing ceftriaxone sodium and tazobactam sodium

Info

Publication number: WO2010124601A1
Application number: PCT/CN2010/072185
Authority: WO
Inventors: 韩宇东; 韩克胜; 许礼贵
Original assignee: 海口奇力制药股份有限公司
Priority date: 2009-04-30
Filing date: 2010-04-26
Publication date: 2010-11-04
Also published as: CN101537009B; RU2471484C2; CN101537009A

Abstract

A method for producing injectable preparation containing ceftriaxone sodium and tazobactam sodium, involves the steps of: (a) weighing raw materials of ceftriaxone sodium, tazobactam sodium, sterile water for injection, the mixture of ethyl acetate and isopropyl alcohol, and anhydrous ethanol with the weight ratio of 3-5: 1: 2: 5: 9, wherein the volume ratio of ethyl acetate to isopropyl alcohol is 1: 2-4; (b) dissolving ceftriaxone sodium and tazobactam sodium in sterile water for injection, then adding activated charcoal and performing filtration; (c) adding the mixture of ethyl acetate and isopropyl alcohol to the filtrate and stirring them well, then adding ceftriaxone sodium crystal seed to the solution to crystallize, and finally washing the crystal with anhydrous ethanol and drying the crystal; and (d) freeze-drying to obtain injectable preparation containing ceftriaxone sodium and tazobactam sodium. The preparation has good uniformity, high purity and safety.

Description

Production process of ceftriaxone sodium and tazobactam sodium compound preparation for injection

The present application claims priority to Chinese Patent Application No. 200910138402.7, entitled "Production Process of Ceftriaxone Sodium Citaboltam Sodium Injection for Injection", issued on April 30, 2009, The entire contents are incorporated herein by reference. Technical field

The invention relates to a production process of a compound preparation of ceftriaxone sodium and tazobactam sodium for injection. Background technique

Ceftriaxone sodium is a third-generation cephalosporin with broad-spectrum antibacterial effect. With the widespread clinical application of cephalosporin antibiotics, bacteria undergo genetic variation under the genetic pressure of antibiotics. Over the past two decades, the number of drug-resistant strains has increased, and cases of severe infections and refractory infections have increased, especially respiratory infections, which are facing severe bacterial resistance challenges. It has been developed as a compound preparation for production and use. Due to the different specific volume of the two aseptic powders, the mixing uniformity is poor; mixing uniformity is an important indicator for the quality of the product; to ensure the homogeneity of the mixing, liquid mixing is the best mixing method. Since the "clarity and color of the solution" is checked for ceftriaxone sodium in the 2005 edition of the Pharmacopoeia of the People's Republic of China, the clarity and color index of the control of sterile cephalosporin products are an important part of production. Traditional compound preparation using ceftriaxone sodium, tazobactam sodium aseptic powder mixing and sub-packaging process, wherein the clarity and color of the sterile product not only affect the clarity of the solution of the sterile product, but also further affect the The content of the bacteria product and the color grade of the solution. Summary of the invention

SUMMARY OF THE INVENTION The object of the present invention is to provide a process for producing a compound preparation of ceftriaxone sodium and tazobactam sodium for injection, which is obtained by mixing ceftriaxone sodium and tazobactam sodium in a liquid state to achieve a good uniformity of mixing.

In order to achieve the above object, the technical solution provided by the present invention is: a production process of a ceftriaxone sodium and tazobactam sodium compound preparation for injection, the production process comprising the following steps:

(1), raw materials: according to ceftriaxone sodium: tazobactam sodium: sterile water for injection: ethyl acetate and isopropyl The mixture of the alcohol and the absolute ethanol is 3 to 5 : 1 : 2 : 5 : 9, and the above raw materials are weighed separately; wherein the mixture of ethyl acetate and isopropyl alcohol is ethyl acetate and isopropanol Mix by volume ratio of 1 2~4;

(2), Dissolution and filtration: Add sterile water for injection in the dissolution tank, 8 ° C ~ 12 ° C, then add ceftriaxone sodium, tazobactam sodium and stir to dissolve, add activated carbon, add the amount of liquid in the tank 0.2%, stirred for 30 min, filtered, and the filtrate was obtained;

( Crystallization and washing: Add the filtrate to the crystallization tank, add the mixture of ethyl acetate and isopropyl alcohol and stir well, add 1-5 g of ceftriaxone sodium seed crystals in the mixture to crystallize and raise the crystal for at least 5 hours. After washing three times with three times the amount of absolute ethanol, it is dried;

(4), freeze-dried:

(4.1) Pre-freezing: After the temperature in the drying cabinet is lowered to -28 ° C, it is kept for 2.5 hours;

(4.2) Sublimation drying: When the vacuum in the drying box reaches 30 Pa or less, the heating system is started, and the temperature is controlled at -15 ° C ~ -20 ° C, sublimated and dried;

(4.3) Re-drying: heat up to 20 ° C ~ 30 ° C, hold for 3 hours;

(4.4) The high-purity nitrogen gas filtered through the 0.22μηι filter was passed and returned to normal pressure to obtain a compound preparation of ceftriaxone sodium and tazobactam sodium for injection.

The filtration in the step (2) is: the mixed solution is sequentially subjected to ultrafiltration through a 0.45 μm titanium rod filter, a 0.22 μηι and a 0.01 μm filter element.

The crystallization tank in the step (3) is Α grade sterilized.

In the step (the drying is as follows: purifying compressed hot air by sterilization filtration, the wind speed is 2 m/s, the temperature is 45 ° C ~ 50 ° C, and the drying time is 4 ~ 5 hours.

The volume ratio of ethyl acetate to isopropanol in the step (1) is 1:3.

In the step (1), ceftriaxone sodium: tazobactam sodium: sterilized water for injection: a mixture of ethyl acetate and isopropyl alcohol: anhydrous ethanol in a weight ratio of 3:1:2:5:9.

The invention has the advantages that: the invention is suitable for the preparation of ceftriaxone sodium and tazobactam sodium for injection of ceftriaxone and tazobactam in a ratio of 3:1 to 5:1; using liquid-liquid mixing, The mixing homogeneity is good; the invention can ensure that ceftriaxone sodium: tazobactam sodium is always crystallized according to 3 to 5:1, which solves the difference in solubility of ceftriaxone sodium and tazobactam sodium, resulting in analysis Different crystallinity results in the final product not meeting the requirements of ceftriaxone sodium: tazobactam sodium is 3 ~ 5: 1; The purity of the high preparation further ensures the advantage of high safety in clinical use. detailed description

The invention will be further described in detail below with reference to the drawings and specific embodiments, but the invention is not limited to the illustrated embodiments.

Example 1

A production process of a ceftriaxone sodium and tazobactam sodium compound preparation for injection, the production process comprising the following steps:

First, the choice of prescription

Prescription 1, and ratio: Specifications l .Og

The name of the material is 89 匕匕 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 Propanol mixture (1: 2) 1250 5 absolute ethanol 2250 9

Co-made 1000 bottles

Prescription 2, and ratio: Specifications l .Og

The name of the material is 89 匕匕 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 Propanol mixture (1: 3) 1250 5

Anhydrous ethanol 2250 9

Co-made 1000 bottles

Prescription 3, and ratio: Specifications l .Og

The name of the material was pre-treated with ceftriaxone sodium 894.0g (equivalent to 750g ceftriaxone). 3 He was sitting on Batona 294.0g (equivalent to 250g tazobactam) 1 Sterilized water for injection 500 g 2 mixture of ethyl acetate and isopropyl alcohol (1: 4) 1250 5 anhydrous ethanol 2250 9 1000 bottles

Prescription 4, and ratio: Specifications l.Og

Prescription 5, and ratio: Specifications l.Og

Prescription 6, and ratio: Specifications l.Og

The name of the material is 89 匕匕 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 89 Propanol mixture (1: 3) 1250 5 Anhydrous ethanol 2250 10 Manufacture 1000 bottles Prescription 7, and ratio: Specifications l .Og

among them:

1. Prescription 1, 2, 3 to evaluate the effect of the mixture of different ratios of ethyl acetate and isopropanol on the yield of ceftriaxone sodium and tazobactam sodium, and the clarity and color;

2, prescription 4, 5, 6 to assess the different ratio of anhydrous ethanol and ceftriaxone sodium and tazobactam sodium, the effect on the yield of precipitation and clarity and color; 3, prescription 7, 8, 9 to assess the different ratio of ethyl acetate and isopropyl alcohol mixture (1: 3) and ceftriaxone sodium, tazobactam sodium, the effect of precipitation on the yield and clarity and colour;

4. Mix with traditional ceftriaxone sodium and tazobactam sodium at 3:1 (product is the prescription number:

10-1, 10-2, 10-3, 10-4, 10-5, 10-6), product uniformity, clarity comparison;

5. Results:

Experiments show that:

1. The ratio of ethyl acetate and isopropyl alcohol (1:3) to tazobactam sodium is 1:5, and the ratio of absolute ethanol to tazobactam sodium is 1:9, and the yield is greater than 93%. Clarity and color (clarification,

<6# (yellow-green)) are better than the 2005 edition of the Chinese Pharmacopoeia standard;

2. According to the experimental results, we use the following production prescriptions:

The name of the material was pre-treated with ceftriaxone sodium 894.0g (equivalent to 750g ceftriaxone). 3 He was sitting on Batona 294.0g (equivalent to 250g tazobactam) 1 Sterilized water for injection 500 g 2 mixture of ethyl acetate and isopropanol (1 : 3 ) 1250 5

Anhydrous ethanol 2250 9

Co-made 1000 bottles

Second, dissolution filtration

1. Cool to 10 by adding sterile water for injection in the dissolution tank. C±2, the prescribed amount of ceftriaxone sodium and tazobactam sodium were stirred and dissolved, stirred with 0.2% activated carbon and filtered in 30 min;

2. The filtration method is as follows: The mixed solution with activated carbon in the dissolution tank is passed through the sterilized pipeline through the infusion pump, and then filtered through a 0.45 micron titanium rod filter, 0.22μηι and 0.01 micron filter, and then filtered. The bacteria-grade area is cleaned and dried in the crystallization tank; the filtrate is sent to the quality inspection department to detect the content, endotoxin, pH and other items. Third, crystallization, crystal washing

1. Add 5 times the mixture of ethyl acetate and isopropyl alcohol (1:3) to the crystallizing tank of ceftriaxone sodium and tazobactam sodium mixture, and add 5g of ceftriaxone sodium seed crystal to the mixture. Crystallization in the liquid, crystal growth for 5 hours, aseptically in the three-in-one aseptic dryer with cleaning and disinfection by infusion pump, and then washed three times with three times the amount of absolute ethanol, and then dried;

2, drying with steam heating and sterilization filtration purification hot air control hot air inlet air temperature

The refined ceftriaxone sodium tazobactam sodium mixed powder was dried for 45 hours between 45 °C for about 4 hours.

Four, freeze-dried

1. Pre-freeze: Reduce the shelf to -45 °C and keep it for 2.5 hours after the temperature drops to -28 °C.

2. Sublimation drying: When the vacuum in the drying box reaches 30Pa or less, the heating system is started, and the temperature is controlled below -20 °C, and sublimation is dried.

3. Re-drying: The temperature control product is below 30 ° C in the drying stage, and the drying time is 3 hours. 4. After lyophilization, use a high-purity nitrogen gas sterilized by 0.22μηι filter to break the vacuum, return to normal pressure, and then pressurize the out of the box to obtain a combination preparation of ceftriaxone sodium and tazobactam sodium for injection. Example 2

(1), raw materials: according to ceftriaxone sodium: tazobactam sodium: sterile water for injection: ethyl acetate and isopropyl alcohol mixture: anhydrous ethanol in a weight ratio of 5: 1 : 2 : 5 : 9, Weigh the above raw materials separately;

Wherein, the mixture of ethyl acetate and isopropyl alcohol is ethyl acetate and isopropyl alcohol mixed in a volume ratio of 1: 2;

(2), Dissolution and filtration: Add sterile water for injection in the dissolution tank, 8 ° C ~ 12 ° C, then add ceftriaxone sodium, tazobactam sodium and stir to dissolve, add activated carbon, add the amount of liquid in the tank 0.2%, stirred for 30 min, and then filtered: the mixed solution was sequentially subjected to ultrafiltration through a 0.45 μm titanium rod filter, 0.22 μηι, and a 0.01 μm filter element to obtain a filtrate;

( Crystallization and washing: Add the filtrate to the crystallization tank, add the mixture of ethyl acetate and isopropyl alcohol, stir well, add lg ceftriaxone sodium seed crystals in the mixture, crystallize and crystallize for at least 5 hours, then After washing three times with three times the amount of absolute ethanol, drying: Purifying compressed hot air by sterilization filtration, wind speed 2m/s, temperature 45 ° C, drying time 5 hours;

(4), freeze-dried:

(4.2) Sublimation drying: When the vacuum degree in the drying box reaches 30 Pa or less, the heating system is started, the temperature is controlled at -15 ° C, and sublimation is dried;

(4.3) Re-drying: heat up to 20 ° C for 3 hours;

(4.4) The high-purity nitrogen gas filtered through the 0.22μηι filter was passed and returned to normal pressure to obtain a compound preparation of ceftriaxone sodium and tazobactam sodium for injection. Example 3 A production process of a combination preparation of ceftriaxone sodium and tazobactam sodium for injection, the production process comprising the following steps:

Wherein, the mixture of ethyl acetate and isopropyl alcohol is ethyl acetate and isopropyl alcohol in a volume ratio of 1:

4 mix;

(2), Dissolution and filtration: Add sterile water for injection in the dissolution tank, 8 ° C ~ 12 ° C, then add ceftriaxone sodium, tazobactam sodium and stir to dissolve, add activated carbon, add the amount of liquid in the tank 0.2%, stirred for 30 min, and then filtered: the mixed solution was sequentially subjected to ultrafiltration through a 0.45 μm titanium rod filter, 0.22 μηι, and a 0.01 m filter to obtain a filtrate;

( Crystallization and washing: Add the filtrate to the crystallization tank, add the mixture of ethyl acetate and isopropyl alcohol, stir well, add 3g of ceftriaxone sodium seed crystals in the mixture, crystallize and crystallize for at least 5 hours, then After washing three times with three times the amount of absolute ethanol, drying: Purifying compressed hot air by sterilization filtration, wind speed 2m / s, temperature 50 ° C, drying time is 5 hours;

(4), freeze-dried:

(4.3) Re-drying: heat up to 20 ° C for 3 hours;

(4.4) The high-purity nitrogen gas filtered through the 0.22μηι filter was passed and returned to normal pressure to obtain a compound preparation of ceftriaxone sodium and tazobactam sodium for injection. Stability test: A stability test was carried out on the preparation obtained according to the above method.

1, method:

The sample lot numbers are: Example 1 (080501), Example 2 (080502), and Example 3 (080503). Investigation items: appearance traits, content, clarity, related substances, moisture, etc.

Method of investigation: The sample content determination and related substance inspection methods from 0 months to long-term 18 months are as follows: Chromatographic conditions and system suitability test:

Detector: SPD-10AVP detector

Column: octadecylsilane bonded silica as a filler

Mobile phase: A: Water (85: 15) is the mobile phase, where A is 0.015 mol/L tetrabutylammonium phosphate (0.2 mol/L tetrabutylammonium phosphate 50 ml plus water 600 ml) - decyl alcohol-acetonitrile (650 :250:100 ), adjust the pH to 7.3 ± 0.1 with 5% phosphoric acid

Detection wavelength: 230nm

Number of theoretical plates: Calculated by ceftriaxone, the number of theoretical plates should be no less than 3000. Determination method: Weigh accurately about 100 mg of the above preparation, place it in a 50 ml volumetric flask, dissolve it with mobile phase and dilute to the mark, shake well. Take ΙΟμΙ into the liquid chromatograph, record the chromatogram; take the appropriate amount of ceftriaxone and tazobactam, accurately weighed, dissolved in the mobile phase to make each cml containing ceftriaxone 1.5mg and tazobactam Tan 0.5mg (3: 1) solution, determined by the same method, calculate the C ₁₈ H ₁₈ N ₈ 0 ₇ S ₃ and C ₁₍₎ H ₁₂ N ₄ _{5 5} S in the test sample by the external standard method. content.

Operation process: Take appropriate amount of this product, dissolve it with mobile phase and make 2ml solution in lml as test solution; accurately measure lml, put it in 100ml volumetric flask, dilute to the mark with mobile phase, shake well, As a control solution. According to the chromatographic conditions under the content determination, take the control solution ΙΟμΙ, inject the liquid chromatograph, adjust the detection sensitivity, so that the peak height of the ceftriaxone peak is about 20% of the full scale of the recorder; The two solutions were each ΙΟμΙ, respectively injected into the liquid chromatograph, recording the chromatogram to the retention time of the main component peak of ceftriaxone 3.5 times. If there is impurity peak in the chromatogram of the test solution, the single impurity peak area should not be larger than the control. The sum of the main peak areas of ceftriaxone and tazobactam in the solution (1.0%), and the sum of the area of each impurity peak should not be greater than 4 times (4.0%) of the sum of the areas of the two main peaks in the control solution.

2, test results

2.1 Accelerated test

Take 300 samples of each of the three batches, set at 40 ± 2 ° C, place RH75 ± 5% for 6 months and sample at the end of the first, second, third and sixth months of the experiment, according to the above investigation items and investigation methods. The results are shown in Table 1. Accelerated test results for three batches of 080501, 080502 and 08050

2.2 Long-term test

Take 1400 samples of each of the three batches, place the sample at 25 ± 2 °C, RH60 ± 14%, and take samples at the end of the 3rd, 6th, 9th, 12th, 18th, and 24th month of the experiment, according to the above inspection method. Investigate and compare the results with 0 months to determine whether clinical studies can be concluded. The results are shown in Table 2.

Table 2 Long-term test results of batch samples 080501, 080502 and 080503

Test results

Test related substance Marking amount (%)

Batch number alkali water

Appearance traits aseptic clarity

Degree maximum sum ceftriaxone

080501 White powder 6.5 Compliance Compliance 8.0 0.1 0.3 103.2 101.5

0 080502 White powder 6.5 Compliance Compliance 7.8 0.1 0.3 105.6 103.6

080503 White powder 6.4 Compliance Compliance 7.8 0.1 0.3 101.0 100.1

March 080501 White powder 6.5 Compliance Compliance 8.0 0.1 0.3 103.1 101.2

080502 White powder 6.5 Compliance with regulations 7.8 0.1 0.3 105.1 103.2 080503 White powder 6.4 Compliance with regulations 7.8 0.1 0.3 100.8 99.8

080501 White powder 6.6 Compliance Compliance 8.1 0.2 0.4 102.8 101.0

June 080502 White powder 6.6 Compliance Compliance 7.9 0.2 0.4 104.5 103.0

080503 White powder 6.5 Compliance Compliance 7.9 0.2 0.4 100.6 99.5

080501 White powder 6.6 Compliance Compliance 8.1 0.2 0.5 102.5 100.5

September 080502 White powder 6.7 Compliance Compliance 8.0 0.2 0.4 104.0 102.5

080503 White powder 6.6 Compliance Compliance 7.9 0.2 0.5 100.3 99.2

080501 White powder 6.6 Compliance Compliance 8.1 0.2 0.5 102.2 100.1

12

080502 White powder 6.7 Compliance Compliance 8.0 0.2 0.5 103.7 102.2 Months

080503 White powder 6.6 Compliance Compliance 7.9 0.2 0.5 100.0 99.1

080501 White powder 6.7 Compliance Compliance 8.2 0.2 0.6 102.0 99.5

18

080502 white powder 6.9 Compliance Compliance 8.3 0.2 0.7 103.2 101.6 Months

080503 White powder 6.8 Compliance Compliance 8.1 0.2 0.6 99.6 98.7

080501 White powder 6.9 Compliance Compliance 8.4 0.2 0.7 101.5 99.2

twenty four

080502 White powder 7.0 Compliance Compliance 8.5 0.2 0.8 102.7 101.1 Months

080503 White powder 6.9 Compliance Compliance 8.4 0.2 0.7 99.2 98.2

3. Conclusion:

The above results show that: The three batches of samples of l.Og specifications have passed the test for 24 months, and all the indicators are qualified. Compared with the increase of related substances, there is no significant change in other indicators. Allergic, hemolytic, vascular irritation, etc. of systemic drugs

1. Ceftriaxone sodium for injection (3:1 and 5:1) at a concentration of 150 mg/ml showed no obvious hemolysis, and the results were in accordance with the safety requirements for intravenous drug use.

Rabbits were injected with 150 mg/ml of ceftriaxone sodium and tazobactam sodium (3:1 and 5:1) 5 ml daily for 3 consecutive times. No obvious irritation was observed in the rabbits. A few injections of 150 mg/ml of ceftriaxone sodium for injection (3:1 and 5:1) showed no significant irritation, indicating that the local irritation test of the test was in compliance with the regulations.

Guinea pigs were intramuscularly injected with a concentration of 150 mg/ml per day for ceftriaxone sodium and tazobactam sodium (3:1 and 5:1) 0.5 ml for 3 consecutive times. The test group was on the 14th and 21st after the first injection. The attack was carried out and the symptoms of allergic reactions did not appear. It indicates that the test drug allergy test meets the requirements. 2. Test purpose 3: 1 and 5: 1 The ratio of ceftriaxone sodium and tazobactam sodium for injection has no hemolysis and agglutination reaction, and the safety of the drug as an intravenous drug is judged.

The rabbit ear vein and quadriceps muscle were observed to inject 3:1 and 5:1 ratios of ceftriaxone sodium for injection and stimulatory response to blood vessels and muscles after tazobactam sodium.

3. Investigate 3: 1 and 5: 1 ratio of ceftriaxone sodium and tazobactam sodium for injection.

1 hemolytic test horse

1.1 Test materials

(1) Test animals One Japanese male white rabbit, 2.3 kg, was provided by Xi'an Medical University Experimental Animal Center, and the certificate number: Shaanxi Medical Movement No. 08-018.

(2) Ceftriaxone sodium and tazobactam sodium for test drug injection, white powder, the ratio is 3:1 and 5:1, of which 3:1 ratio l.Og/bottle, containing ceftriaxone 0.75g, Tazobactam 0.25g, batch number: 010105; 5: 1 ratio 1.2 g / bottle, containing ceftriaxone l.Og, tazobactam 0.2g, batch number: 010106. Provided by Haikou Keli Pharmaceutical Co., Ltd. It is stored in cold refuse, dissolved in sterile water for injection before use, and diluted to a concentration of 150 mg of ceftriaxone sodium and tazobactam sodium per ml.

1.2 test 3 full method

(1) Preparation of 2% rabbit blood cell suspension: Take rabbit heart blood, remove fibrin with glass beads, make defibrated blood, transfer it into the centrifuge tube, add physiological saline, shake the hook, centrifuge, throw away The supernatant was washed with physiological saline until the supernatant was colorless and transparent, and then the red blood cells were diluted with physiological saline to a 2% suspension.

(2), hemolytic test: 3: 1 and 5: 1 ratio of ceftriaxone sodium for injection and tazobactam sodium for each tube 7, according to Table 1, 2 added various liquids, the sixth tube is not added The test solution was used as a blank control tube, and the test tube solution was not added to the seventh tube and distilled water was used instead of physiological saline as a positive control for hemolysis. Each tube was gently shaken and then incubated in a 37 ° C constant temperature water bath, observed once every lh, for 4 times. If the solution is clear red is hemolysis; if there is a brownish red or reddish brown flocculent precipitate in the solution, it means that there is red blood cell condensation. If the red blood cells are all sinking, the upper liquid is colorless and clear, and it can be judged as no hemolysis.

1.3 test results

From Tables 1 and 2, the concentration of 150 mg/ml 3:1 and 5:1 can be used for the injection of ceftriaxone sodium tazobactam sodium, in 0.1, 0.2, 0.3, 0.4, 0.5 ml tubes, 37 ° C insulation 4h, no hemolysis and agglutination reaction. The upper liquid color is colorless and clear, and the red blood cells are all sinking, indicating that 150 mg/ml 3: 1 and 5: 1 ceftridime sodium tazobactam sodium for injection has no obvious hemolysis, and meets the requirements for safety inspection for intravenous injection.

The above is only a preferred embodiment of the present invention, and it should be noted that those skilled in the art can also make several improvements and retouchings without departing from the principles of the present invention. It should be considered as the scope of protection of the present invention.

Claims

Rights request

1. A production process of a ceftriaxone sodium and tazobactam sodium compound preparation for injection, the production process comprising the following steps:

(1), raw materials: according to ceftriaxone sodium: tazobactam sodium: sterile water for injection: ethyl acetate and isopropyl alcohol mixture: absolute ethanol weight ratio of 3 ~ 5: 1: 2: 5: 9, the above raw materials are weighed separately; wherein, the mixture of ethyl acetate and isopropyl alcohol is ethyl acetate and isopropyl alcohol mixed in a volume ratio of 12 to 4;

( Crystallization and washing: Add the filtrate to the crystallization tank, add the mixture of ethyl acetate and isopropyl alcohol and stir well, add 1~5g of ceftriaxone sodium seed crystal in the mixture, crystallize, crystallize, and rotate at least After 5 hours, wash three times with three times the amount of absolute ethanol, and then dry;

(4), freeze-dried:

(4.3) Re-drying: heat up to 20 ° C ~ 30 ° C, hold for 3 hours;

The process for producing a ceftriaxone sodium and tazobactam sodium compound preparation for injection according to claim 1, wherein the filtration in the step (2) is: sequentially passing the mixed solution through a 0.45 micron titanium rod. Ultrafiltration with filter, 0.22μηι and 0.01m filter.

The process for producing a ceftriaxone sodium and tazobactam sodium compound preparation for injection according to claim 1, wherein the crystallization tank in the step (3) is 10,000-degree sterilized.

The process for producing a ceftriaxone sodium and tazobactam sodium compound preparation for injection according to claim 1, wherein the drying in the step (3) is: purifying and compressing by sterilization filtration Hot air Gas, wind speed 2m / s, temperature 45 ° C ~ 50 ° C, drying time is 4 ~ 5 hours.

The process for producing a ceftriaxone sodium and tazobactam sodium compound preparation for injection according to claim 1, wherein the volume ratio of ethyl acetate to isopropanol in the step (1) is 1: 3.

The process for producing a ceftriaxone sodium and tazobactam sodium compound preparation for injection according to claim 1, wherein: the ceftriaxone sodium in the step (1): tazobactam sodium: sterilization Water for injection: a mixture of ethyl acetate and isopropyl alcohol: anhydrous ethanol in a weight ratio of 3:1:2:5:9.