CN114028336B - Preparation method of cefotaxime sodium for injection - Google Patents

Preparation method of cefotaxime sodium for injection Download PDF

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CN114028336B
CN114028336B CN202111219123.0A CN202111219123A CN114028336B CN 114028336 B CN114028336 B CN 114028336B CN 202111219123 A CN202111219123 A CN 202111219123A CN 114028336 B CN114028336 B CN 114028336B
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cefotaxime
sodium
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CN114028336A (en
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贾全
任峰
胡利敏
孙玉双
田洪年
刘树斌
张建丽
魏宝军
贺娇
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Ncpc Hebei Huamin Pharmaceutical Co ltd
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P31/04—Antibacterial agents
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    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract

The invention discloses a preparation method of cefotaxime sodium for injection, belonging to the field of pharmaceutical chemicals, wherein a mixed solution of sodium chloride solution and cefotaxime sodium seed crystal is used as an initial base material, an alcohol solution of sodium acetate trihydrate and an acetone solution of cefotaxime acid are added at the same time, the stirring speed and the crystallization temperature during crystallization are controlled, and all quality indexes of the obtained cefotaxime sodium for injection meet the quality requirements of EP10.0 edition pharmacopoeia, and the cefotaxime sodium for injection has high stability and can meet the requirements of clinical medication.

Description

Preparation method of cefotaxime sodium for injection
Technical Field
The invention relates to the field of pharmaceutical chemicals, and particularly relates to a preparation method of cefotaxime sodium for injection.
Background
Cefotaxime sodium (Cefotaxime sodium) is a third-generation cephalosporin semisynthetic broad-spectrum antibiotic, and a product of the Cefotaxime sodium is white, quasi-white or light yellow white crystal, and has no odor or slightly special odor. Is soluble in water, slightly soluble in methanol, ethanol, and acetone, and insoluble in chloroform, n-hexane, dichloromethane, diethyl ether, and ethyl acetate. The molecular formula is as follows: c 16 H 16 N 5 O 7 S 2 Na, molecular weight: 477.44, molecular formula as follows:
Figure GDA0004077865450000011
the existing crystallization method of cefotaxime sodium is divided into a three-water system crystallization method and a water-containing system crystallization method.
CN101486719A discloses a crystallization method using acetone aqueous solution as a solvent system, which solves the problem of poor clarity of the product solution prepared by a three-water system crystallization method, but the stability of the product prepared by the method is poor. This is because cefotaxime sodium has poor stability in the presence of water molecules, and the amide side chain, lactam ring and acetyl group of cefotaxime sodium are likely to be degraded, and can be hydrolyzed under the conditions of acid, alkali and temperature rise.
Cefotaxime sodium for injection has poor stability, cannot meet the requirement of the current consistency evaluation, and brings potential safety hazard to the administration of patients.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method of cefotaxime sodium for injection, which can effectively improve the stability of product quality, is easy to split-package powder injection preparations, has simple operation in the preparation process, and is suitable for industrial production.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a preparation method of cefotaxime sodium for injection takes cefotaxime acid as a starting raw material, and is characterized by comprising the following operation steps:
(a) Taking a sodium chloride solution and a cefotaxime sodium seed crystal mixed solution as an initial substrate;
(b) Adding cefotaxime acid into the alcohol reagent, and uniformly stirring to obtain a first mixed solution;
(c) Adding sodium acetate trihydrate into the alcohol reagent, and uniformly stirring to obtain a second mixed solution;
(d) Simultaneously adding the first mixed solution and the second mixed solution obtained in the steps (b) and (c) into the initial base material obtained in the step (a);
(e) Adding an acetone reagent into the crystallization liquid obtained in the step (d) in a flowing manner, and growing crystals;
(f) After the feeding is finished, filtering, and washing a filter cake by using an alcohol atomization reagent;
(g) Washing the filter cake obtained in the step (f) with acetone, and drying;
(h) Subpackaging the preparation to obtain the cefotaxime sodium hydrochloride product for injection.
The technical scheme of the invention is further improved as follows: in the step a, the cefotaxime sodium seed crystal accounts for 0.5 to 1 percent of the weight of the cefotaxime acid; the mass fraction of sodium chloride in the sodium chloride solution is 26.5 percent, and the volume weight ratio (mL/g) of the sodium chloride solution to the cefotaxime acid is (2-3): 4.
The technical scheme of the invention is further improved as follows: and the alcohol reagent in the steps b, c and f is one of methanol, ethanol and isopropanol.
The technical scheme of the invention is further improved as follows: in the step b, the volume-weight ratio (mL/g) of the alcohol reagent to the cefotaxime acid is (2-3) to 4.
The technical scheme of the invention is further improved as follows: in the step c, the molar ratio of the sodium acetate trihydrate to the cefotaxime acid is (1.05-1.1) to 1; the volume weight ratio (mL/g) of the alcohol reagent, the water and the sodium acetate trihydrate is (10-15): 12.
The technical scheme of the invention is further improved as follows: and d, uniformly adding the first mixed solution and the second mixed solution in the step d within 30 min.
The technical scheme of the invention is further improved as follows: in the step e, the volume-weight ratio (mL/g) of the acetone to the cefotaxime acid is (10-15) to 1.
The technical scheme of the invention is further improved as follows: in the step f, the alcohol atomization reagent adopts a high-speed gasification nozzle to form atomized liquid drops with the diameter of 1-2 mu m, and the volume-weight ratio (mL/g) of the washing dosage to the cefotaxime acid is (1-2): 20.
due to the adoption of the technical scheme, the invention has the technical progress that:
the process for preparing cefotaxime sodium for injection by the method is energy-saving and environment-friendly, the used solvent can be recycled, the crystallization process is simple to operate, the prepared cefotaxime sodium for injection has the advantages of good quality, low impurity content and good product stability, and the sample has good uniformity and stability, especially good absorbance quality index. The problem of poor stability of cefotaxime sodium is solved, the quality stability of a preparation product is consistent with that of an original product, and the stability, safety, uniformity and consistency of the product are improved to a certain extent.
Detailed Description
The present invention will be described in further detail with reference to the following examples:
a preparation method of cefotaxime sodium for injection takes cefotaxime acid as a starting raw material, and is characterized by comprising the following operation steps:
(a) Taking 20-30mL of a sodium chloride solution with the mass fraction of 26.5% and 0.2-0.4g of cefotaxime sodium seed crystal mixed solution as initial bottom materials;
(b) Adding 40g of cefotaxime acid into methanol, ethanol or isopropanol, and uniformly stirring for 20-30mL to obtain a first mixed solution;
(c) Adding 12.5-13.15g of sodium acetate trihydrate into 10-15mL of methanol, ethanol or isopropanol and 10-15mL of water, and uniformly stirring to obtain a second mixed solution;
(d) Simultaneously adding the first mixed solution and the second mixed solution into the initial base material, and finishing adding at a constant speed within 30 min;
(e) And (d) adding 400-600mL of acetone reagent into the crystallization liquid.
(f) After the feeding is finished, filtering, atomizing 2-4 mL of methanol, ethanol or isopropanol by adopting a high-speed gasification nozzle to form atomized liquid drops with the diameter of 1-2 mu m, and washing a filter cake.
(g) Washing the filter cake obtained in the step (f) with acetone, and drying;
(h) Subpackaging the preparation to obtain the cefotaxime sodium hydrochloride product for injection.
Example 1
(a) Taking 20mL of a sodium chloride solution with the mass fraction of 26.5% and 0.2g of cefotaxime sodium seed crystal mixed solution as an initial substrate;
(b) Adding 40g of cefotaxime acid into methanol, and uniformly stirring for 20mL to obtain a first mixed solution;
(c) Adding 12.5g of sodium acetate trihydrate into 10mL of methanol and 10mL of water, and uniformly stirring to obtain a second mixed solution;
(d) Simultaneously adding the first mixed solution and the second mixed solution into the initial base material, and finishing adding at a constant speed within 30 min;
(e) 400mL of acetone reagent was added to the crystallized solution of step (d).
(f) After the feeding is finished, filtering and atomizing the reagent by using methanol; atomizing 2mL of methanol by using a high-speed gasification nozzle to form atomized liquid drops with the diameter of 1 mu m, and washing a filter cake.
(g) And (f) washing the filter cake in the step (f) with acetone, and drying to obtain 40.5g of cefotaxime sodium.
(h) Subpackaging the preparation to obtain the cefotaxime sodium hydrochloride product for injection.
Example 2
(a) Taking 30mL of a sodium chloride solution with the mass fraction of 26.5% and 0.4g of cefotaxime sodium seed crystal mixed solution as an initial substrate;
(b) Adding 40g of cefotaxime acid into methanol, and uniformly stirring for 30mL to obtain a first mixed solution;
(c) Adding 13.15g of sodium acetate trihydrate into 15mL of methanol and 15mL of water, and uniformly stirring to obtain a second mixed solution;
(d) Simultaneously adding the first mixed solution and the second mixed solution into the initial base material, and finishing adding at a constant speed within 30 min;
(e) 600mL of acetone reagent was added to the crystallized solution of step (d).
(f) After the feeding is finished, filtering and atomizing the reagent by using methanol; 4mL of methanol is atomized by a high-speed gasification nozzle to form atomized liquid drops with the diameter of 2 mu m, and a filter cake is washed.
(g) And (f) washing the filter cake obtained in the step (f) with acetone, and drying to obtain 40.3g of cefotaxime sodium.
(h) Subpackaging the preparation to obtain the cefotaxime sodium hydrochloride product for injection.
Example 3
(a) Taking 25mL of a mixed solution of 26.5 mass percent sodium chloride solution and 0.3g of cefotaxime sodium seed crystal as an initial substrate;
(b) Adding 40g of cefotaxime acid into methanol, and uniformly stirring for 25mL to obtain a first mixed solution;
(c) Adding 12.75g of sodium acetate trihydrate into 10-15mL of methanol and 12.5mL of water, and uniformly stirring to obtain a second mixed solution;
(d) Simultaneously adding the first mixed solution and the second mixed solution into the initial base material, and finishing adding at a constant speed within 30 min;
(e) 500mL of acetone reagent was added to the crystallized solution of step (d).
(f) After the feeding is finished, filtering and atomizing the reagent by using methanol; 3mL of methanol is atomized by a high-speed gasification nozzle to form atomized liquid drops with the diameter of 1 mu m, and a filter cake is washed.
(g) And (f) washing the filter cake obtained in the step (f) with acetone, and drying to obtain 40.4g of cefotaxime sodium.
(h) Subpackaging the preparation to obtain a cefotaxime sodium hydrochloride product for injection.
Example 4
(a) Taking 25mL of a sodium chloride solution with the mass fraction of 26.5% and 0.3g of cefotaxime sodium seed crystal mixed solution as an initial substrate;
(b) Adding 40g of cefotaxime acid into ethanol, and uniformly stirring for 25mL to obtain a first mixed solution;
(c) Adding 12.75g of sodium acetate trihydrate into 10-15mL of ethanol and 12.5mL of water, and uniformly stirring to obtain a second mixed solution;
(d) Simultaneously adding the first mixed solution and the second mixed solution into the initial base material, and finishing adding at a constant speed within 30 min;
(e) 500mL of acetone reagent was added to the crystallized solution of step (d).
(f) After the feeding, filtering, atomizing 3mL of ethanol by using a high-speed gasification nozzle to form atomized liquid drops with the diameter of 1 mu m, and washing a filter cake.
(g) And (f) washing the filter cake in the step (f) with acetone, and drying to obtain 40.2g of cefotaxime sodium.
(h) Subpackaging the preparation to obtain the cefotaxime sodium hydrochloride product for injection.
Example 5
(a) Taking 25mL of a sodium chloride solution with the mass fraction of 26.5% and 0.3g of cefotaxime sodium seed crystal mixed solution as an initial substrate;
(b) Adding 40g of cefotaxime acid into isopropanol, and uniformly stirring for 25mL to obtain a first mixed solution;
(c) Adding 12.75g of sodium acetate trihydrate into 12.5mL of water containing 12.5mL of isopropanol, and uniformly stirring to obtain a second mixed solution;
(d) Simultaneously adding the first mixed solution and the second mixed solution into the initial base material, and finishing adding at a constant speed within 30 min;
(e) 500mL of acetone reagent was added to the crystallized solution of step (d).
(f) After the feeding is finished, filtering, atomizing 3mL of isopropanol by adopting a high-speed gasification nozzle to form atomized liquid drops with the diameter of 1 mu m, and washing a filter cake.
(g) And (f) washing the filter cake in the step (f) with acetone, and drying to obtain 40.2g of cefotaxime sodium.
(h) Subpackaging the preparation to obtain the cefotaxime sodium hydrochloride product for injection.
Comparative examples 1 to 3
Comparative example 1
(a) Taking 50mL of a sodium chloride solution with the mass fraction of 10% and 0.05g of cefotaxime sodium seed crystal mixed solution as an initial substrate;
(b) Adding 40g of cefotaxime acid into methanol, and uniformly stirring for 50mL to obtain a first mixed solution;
(c) Adding 14g of sodium acetate trihydrate into 10mL of 20mL of methanol, and uniformly stirring to obtain a second mixed solution;
(d) Simultaneously adding the first mixed solution and the second mixed solution into the initial base material, and finishing adding at a constant speed within 30 min;
(e) 600mL of acetone reagent was added to the crystallized solution of step (d).
(f) After the feeding is finished, filtering and atomizing the reagent by using methanol; 5mL of methanol is atomized by a high-speed gasification nozzle to form atomized liquid drops with the diameter of 5 mu m, and a filter cake is washed.
(g) And (f) washing the filter cake obtained in the step (f) with acetone, and drying to obtain 39.1g of cefotaxime sodium.
(h) Subpackaging the preparation to obtain the cefotaxime sodium hydrochloride product for injection.
Comparative example 2
(a) Taking 50mL of a sodium chloride solution with the mass fraction of 10% and 0.05g of cefotaxime sodium seed crystal mixed solution as an initial substrate;
(b) Adding 40g of cefotaxime acid into ethylene glycol, and uniformly stirring for 50mL to obtain a first mixed solution;
(c) Adding 14g of sodium acetate trihydrate into 10mL of 20mL of ethylene glycol, and uniformly stirring to obtain a second mixed solution;
(d) Simultaneously adding the first mixed solution and the second mixed solution into the initial base material, and finishing adding at a constant speed within 30 min;
(e) 600mL of acetone reagent was added to the crystallized solution of step (d).
(f) After the feeding is finished, filtering, and atomizing the reagent by using glycol; 5mL of ethylene glycol is atomized by a high-speed gasification nozzle to form atomized liquid drops with the diameter of 5 mu m, and a filter cake is washed.
(g) And (f) washing the filter cake obtained in the step (f) with acetone, and drying to obtain 38.5g of cefotaxime sodium.
(h) Subpackaging the preparation to obtain the cefotaxime sodium hydrochloride product for injection.
Comparative example 3
(a) Adding 40g of cefotaxime acid into ethylene glycol, and uniformly stirring for 20mL to obtain a first mixed solution;
(b) Adding 12.5g of sodium acetate trihydrate into 10mL of methanol and 10mL of water, and uniformly stirring to obtain a second mixed solution;
(c) Adding the second mixed solution into the first mixed solution at constant speed within 30 min;
(d) 400mL of acetone reagent was added to the crystallized solution of step (c).
(e) After the feeding is finished, filtering and atomizing the reagent by using methanol; atomizing 2mL of methanol by using a high-speed gasification nozzle to form atomized liquid drops with the diameter of 1 mu m, and washing a filter cake.
(f) And (f) washing the filter cake in the step (f) with acetone, and drying to obtain 39.5g of cefotaxime sodium.
(g) Subpackaging the preparation to obtain the cefotaxime sodium hydrochloride product for injection.
Comparative example 4 (CN 101486719A)
1) Adding 14.5ml of water, 60ml of acetone and 4g of anhydrous sodium acetate into a 500ml three-necked bottle, and cooling to 10 ℃;
2) Adding 20g of cefotaxime acid into the mixed solution in the step 1), and stirring until the solution is clear;
3) After clarification, 0.30g of activated carbon is added and stirred for 20 minutes at 10 ℃;
4) Filtering, washing with 15ml of 80% acetone;
5) Mixing the filtrates, controlling the temperature to 18 ℃, dropwise adding 70ml of acetone, adding seed crystals, growing the crystals and stirring for 0.5 hour;
6) Slowly dripping 240ml of acetone;
7) Cooling to 5 ℃, and growing the crystal for more than 30 minutes;
8) Filtering, soaking and washing with 100ml acetone twice,
9) Vacuum drying is carried out, and 38.1g of cefotaxime acid sodium salt conversion crystal is obtained.
10 Subpackaging the preparation to obtain the cefotaxime sodium hydrochloride product for injection.
The amount of the added crystal seeds in the step 5) is 0.03 percent of the weight of the added cefotaxime acid; the seed crystal size is picked to 80 meshes.
The dropping rate of acetone in step 6) was 240ml per 1 hour.
The vacuum drying conditions in the step 9) are as follows: the temperature of the jacket is controlled between 0 and 20 ℃; vacuum at-0.05 MPa; the drying time is more than 2 hours.
The filtration in the step 4) adopts a plate and frame filter press; the pore diameter of the filter medium is 50 μm; the filter medium is a medium material which is solvent resistant.
Comparative examples 1 to 3 were prepared similarly to example 1, except that: comparative examples 1-2 the differences from example 1 are the experimental parameters; comparative example 3 differs from example 1 in the manner of addition; comparative example 4 was run according to patent CN101486719 a.
Table 1: quality data of examples and comparative examples
Figure GDA0004077865450000081
The data in the table 1 can confirm that the product quality of the process is stable, the absorbance and the impurity level are equivalent, and the process reproducibility is good. Compared with comparative examples 1-3, the product prepared by the method has obvious advantages in content and related substance indexes; therefore, the addition amount of the sodium chloride and the feeding mode adopted by the application obviously improve the product quality.
In order to better verify the quality stability effect of cefotaxime sodium for injection prepared by the present invention, samples obtained in examples 1 to 3 and comparative examples 1 to 3 were subjected to accelerated tests under the following conditions: the temperature is 40 ℃ plus or minus 2 ℃, the relative humidity is 75 percent plus or minus 5 percent, the acceleration time is 3 months, and the quality of each sample after the acceleration test is finished is checked.
Table 2: accelerated test data for samples of examples and comparative examples
Figure GDA0004077865450000091
According to the experimental data in the table 2, it can be seen that the absorbance and impurity quality of the product are stable through an accelerated experiment, all indexes meet the quality requirements of pharmacopoeia of EP10.0 edition, and the preparation method provided by the invention has a good effect on the stability of the product. The test methods of the above examples and comparative examples were carried out according to the methods prescribed in the pharmacopoeia of EP version 10.0.

Claims (5)

1. A preparation method of cefotaxime sodium for injection takes cefotaxime acid as a starting raw material, and is characterized by comprising the following operation steps:
(a) Taking a mixed solution of a sodium chloride solution and cefotaxime sodium seed crystals as an initial base material, wherein the mass fraction of sodium chloride in the sodium chloride solution is 26.5%, and the volume-weight ratio mL/g of the sodium chloride solution to the cefotaxime acid is 2-3:4;
(b) Adding cefotaxime acid into the alcohol reagent, and uniformly stirring to obtain a first mixed solution;
(c) Adding sodium acetate trihydrate into the alcohol aqueous solution, and uniformly stirring to obtain a second mixed solution;
(d) Simultaneously adding the first mixed solution and the second mixed solution obtained in the steps (b) and (c) into the initial base material obtained in the step (a) to obtain a crystallization solution;
(e) Adding an acetone reagent into the crystallization liquid in the step (d) in a flowing mode, and growing crystals;
(f) After the feeding is finished, filtering, and washing a filter cake by using an atomized alcohol reagent;
(g) Washing the filter cake obtained in the step (f) with acetone, and drying;
(h) Subpackaging the preparation to obtain a cefotaxime sodium hydrochloride product for injection; the alcohol reagent or the alcohol in the alcohol aqueous solution in the steps b, c and f is one of methanol, ethanol and isopropanol; step b, the volume-weight ratio mL/g of the alcohol reagent to the cefotaxime acid is 2-3:4; the alcohol reagent atomized in the step f adopts a high-speed gasification nozzle, the diameter of the formed atomized liquid drop is 1-2 mu m, the volume-weight ratio mL/g of the washing dosage to the cefotaxime acid is 1-2: 20.
2. the method for preparing cefotaxime sodium for injection according to claim 1, wherein the method comprises the following steps: in the step a, the cefotaxime sodium seed crystal accounts for 0.5-1% of the weight of the cefotaxime acid.
3. The method for preparing cefotaxime sodium for injection according to claim 1, wherein the method comprises the following steps: the molar ratio of the sodium acetate trihydrate to the cefotaxime acid in the step c is 1.05-1.1; the volume-weight ratio mL/g of the alcohol reagent, water and sodium acetate trihydrate is 10-15.
4. The method for preparing cefotaxime sodium for injection according to claim 1, wherein the method comprises the following steps: and d, finishing adding the first mixed solution and the second mixed solution at a constant speed within 30 min.
5. The method for preparing cefotaxime sodium for injection according to claim 1, wherein the method comprises the following steps: in the step e, the volume-weight ratio mL/g of acetone to cefotaxime acid is 10-15.
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CN101486719A (en) * 2009-02-17 2009-07-22 福建省福抗药业股份有限公司 Method for converting cefotaxime acid into sodium salt crystal
CN103275101B (en) * 2013-05-17 2015-08-05 天津大学 Prepare the method for cefotaxime sodium crystal
CN103319504A (en) * 2013-06-28 2013-09-25 华北制药河北华民药业有限责任公司 Crystallization method for cefotaxime sodium
CN104086569B (en) * 2014-07-29 2016-10-26 石药集团中诺药业（石家庄）有限公司 A kind of preparation method of cefotaxime sodium
CN107049958A (en) * 2017-04-26 2017-08-18 四川制药制剂有限公司 The preparation technology of cefotaxime sodium for injection powder-injection

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