CN110437260B - Cefuroxime sodium raw material, injection and preparation method thereof - Google Patents

Cefuroxime sodium raw material, injection and preparation method thereof Download PDF

Info

Publication number
CN110437260B
CN110437260B CN201910793868.4A CN201910793868A CN110437260B CN 110437260 B CN110437260 B CN 110437260B CN 201910793868 A CN201910793868 A CN 201910793868A CN 110437260 B CN110437260 B CN 110437260B
Authority
CN
China
Prior art keywords
cefuroxime
tank
controlling
temperature
stirring
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201910793868.4A
Other languages
Chinese (zh)
Other versions
CN110437260A (en
Inventor
王杰
马慧丽
王晨光
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shijiazhuang Pharma Group Zhongnuo Pharmaceutical Shijiazhuang Co Ltd
Original Assignee
Shijiazhuang Pharma Group Zhongnuo Pharmaceutical Shijiazhuang Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shijiazhuang Pharma Group Zhongnuo Pharmaceutical Shijiazhuang Co Ltd filed Critical Shijiazhuang Pharma Group Zhongnuo Pharmaceutical Shijiazhuang Co Ltd
Priority to CN201910793868.4A priority Critical patent/CN110437260B/en
Publication of CN110437260A publication Critical patent/CN110437260A/en
Application granted granted Critical
Publication of CN110437260B publication Critical patent/CN110437260B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic 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; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/02—Preparation
    • C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic 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; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
    • C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Engineering & Computer Science (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

The invention relates to a cefuroxime sodium raw material, an injection and a preparation method thereof, and belongs to the technical field of medicines. The cefuroxime sodium raw material is prepared by dripping cefuroxime acid solution and 95% ethanol solution of sodium acetate trihydrate prepared according to a specific mixed solvent ratio and a specific concentration at a specific dripping speed in a specific solvent environment. The cefuroxime sodium for injection prepared from the raw materials by special process control has the advantages of obviously improved quality and stability, reduced generation of related substances 2, and strictly controlled product quality, thereby ensuring the safety and effectiveness of medication.

Description

Cefuroxime sodium raw material, injection and preparation method thereof
Technical Field
The invention relates to a cefuroxime sodium raw material, an injection and a preparation method thereof, and belongs to the technical field of medicines.
Background
Cefuroxime sodium was first marketed in 1978 in Germany, Ireland, England, Italy (trade name Curoxim), developed by GlaxoSmithKline, UK. The trade name "Zinacef" was marketed in japan by Shin Nihon Jitsugyo corporation in 1980, and there were only oral dosage forms. U.S. FDA approval was obtained by Teligent corporation at 10 months 1983 under the tradename Zinacef. The injection is marketed in China in 1987 under the trade name of West Lixin, and the tablet is marketed in China in 1989. Cefuroxime sodium has been on the market for many years at home and abroad, and has been collected and loaded in Chinese, British, American and European pharmacopoeias, and has definite safety and effectiveness.
Cefuroxime sodium belongs to the second generation of cephalosporins, which inhibit cell division and growth by binding to Penicillin Binding Proteins (PBPs) on the bacterial cell membrane, and finally, dissolve and die the bacteria. Has broad-spectrum antibacterial effect, wide application range, high antibacterial effect on Staphylococcus aureus, Streptococcus, meningococcus, influenzae, etc., stronger effect on gram-negative bacteria than first generation cephalosporins, and can resist beta-lactamase and penicillin-resistant Staphylococcus aureus. The traditional Chinese medicine composition is mainly used for treating respiratory tract infection, ear infection, nose infection, throat infection, urinary tract infection, skin and soft tissue infection, bone and joint infection, gonorrhea, septicemia, meningitis and other infections caused by sensitive bacteria in clinic. When the traditional Chinese medicine composition is used for treating meningitis, enough medicine can enter cerebrospinal fluid, and the traditional Chinese medicine composition has a remarkable curative effect on meningitis caused by meningococcus.
The chemical name of cefuroxime sodium is (6R, 7R) -7- [2- (furan-2-yl) -2- (methoxyimino) acetamido ] -3-carbamoyloxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid sodium salt. It is white to yellowish powder or crystalline powder, odorless, hygroscopic, soluble in water, slightly soluble in methanol, and insoluble in ethanol, and has specific rotation degree of +55 ° to +65 °.
Chinese patent document CN101906109B provides a method for preparing cefuroxime sodium, which comprises the step of reacting cefuroxime acid with a mixed sodium salt to generate cefuroxime sodium, wherein the mixed sodium salt comprises two or three of sodium acetate, sodium lactate and sodium isooctanoate. The product prepared by the method has the advantages of uniform crystal dispersion, good fluidity, good solubility and better performance on indexes such as color grade, content, impurities and the like. Chinese patent document CN104771372B discloses a cefuroxime sodium powder injection preparation for injection, which is prepared by the following steps: (1) dissolving sodium acetate in solvent to obtain sodium acetate solution; (2) adding solvent and water, stirring and adding cefuroxime acid until the cefuroxime acid is dissolved; adding active carbon, decolorizing, filtering, washing the filter residue with mixed solvent, filtering with a filter flask, and putting the filtrate into a crystallizing tank; (3) the molecular assembly and form optimization technology of crystal products in the particle process is applied by limited responsibility company of pharmaceutical industry of north China, Hebei China, China and drug industry, the temperature is controlled, the stirring speed is controlled, and sodium acetate solution is dripped; adding a dissolving agent according to the feeding rate; (4) performing suction filtration, washing, vacuum drying, weighing and subpackaging; (5) and subpackaging the preparations with different specifications to obtain the cefuroxime sodium for injection. The cefuroxime sodium powder prepared by the preparation method achieves excellent hydrodynamic properties, uniform particle size distribution and improved color grade, clarity and purity. Chinese patent document CN106565748B discloses a preparation method of cefuroxime sodium and a preparation thereof, which comprises three steps of preparation of 3-deacetylation-7-aminocephalosporanic acid, preparation of cefuroxime acid and preparation of cefuroxime sodium.
In the prior art, the related substance 2 is rarely researched, the country requires strict control on the impurity, and researches show that the product of the patent technology is not good in controlling the related substance 2 and can quickly increase in the process of an accelerated test. Therefore, the product quality needs to be further improved, and the content of the related substance 2 is strictly controlled by optimizing the process, so that the cefuroxime sodium for injection with more stable quality and lower adverse reaction is developed.
Disclosure of Invention
The invention aims to provide a cefuroxime sodium raw material and an injection with more reliable quality aiming at the defects of the prior art, the cefuroxime sodium raw material is prepared by dripping a cefuroxime acid solution and a 95% ethanol solution of sodium acetate trihydrate, which are prepared according to a specific mixed solvent ratio and a specific concentration, at a specific dripping speed in a specific solvent environment. The cefuroxime sodium for injection prepared from the raw materials by special process control has the advantages of obviously improved quality and stability, reduced generation of related substances 2, and strictly controlled product quality, thereby ensuring the safety and effectiveness of medication.
In order to realize the purpose of the invention, the following technical scheme is adopted:
the invention provides a preparation method of a cefuroxime sodium raw material, which specifically comprises the following steps:
(1) preparing a cefuroxime acid solution: respectively adding a mixed solvent of methanol, absolute ethanol and water into a material preparation tank A, stirring, controlling the temperature to be 10-15 ℃, then adding cefuroxime acid, controlling the temperature to be 10-15 ℃ and completely dissolving to obtain a cefuroxime acid solution for later use;
(2) preparing a salt forming agent solution: adding 95% ethanol into the material preparing tank B, stirring, controlling the temperature to 10-15 ℃, then adding sodium acetate trihydrate, controlling the temperature to 10-15 ℃ and completely dissolving to obtain a salt forming agent solution for later use;
(3) salt forming reaction: adding the methanol, the absolute ethyl alcohol, the water and the 95% ethyl alcohol which are 20% in volume respectively in the step (1) and the step (2) into a mixing tank C, uniformly stirring, pressurizing to 0.2MPa by using nitrogen, filtering a mixed solvent into an aseptic reaction tank by three-level sterilizing filtration (0.45um, 0.22um and 0.22um), stirring, controlling the temperature to be 10-15 ℃, adding sterile cefuroxime sodium seed crystals, dropwise adding the solutions in the mixing tank A and the mixing tank B into the aseptic reaction tank by three-level sterilizing filtration (0.45um, 0.22um and 0.22um) according to a dropwise adding scheme in the following table, continuously stirring after dropwise adding is finished, and cooling the obtained mixture to 5-10 ℃; and (3) carrying out solid-liquid separation in a sterile environment, washing the solid product with absolute ethyl alcohol for three times, and carrying out vacuum drying for 5-10 hours to obtain the sterile cefuroxime sodium raw material medicine.
In the step (1), the preferable solvent ratio for preparing the cefuroxime acid solution is methanol: anhydrous ethanol: water 5.5:10.8: 0.2. in the step (1), the preferable preparation concentration of the cefuroxime acid solution is 7-11% (kg/L). In the step (1) and the step (2), the feeding molar ratio of the cefuroxime acid to the sodium acetate trihydrate is preferably 1: 1.1. in the step (2), the preparation concentration of the preferable salt forming agent solution is 2.5-4.0% (kg/L). In the step (3), the addition amount of the seed crystal is 1 per mill of the cefuroxime acid. In the step (3), the total volume (L) of the absolute ethanol used for washing the solid product is 4 times of the weight (kg) of the cefuroxime acid. In the step (3), the vacuum drying condition is that the drying is carried out under the vacuum degree of 35-45 ℃ and less than or equal to-0.095 Mpa. In step (3), the dropping protocol is shown in the following table:
Figure BDA0002180310830000031
further, the preparation method of the cefuroxime sodium raw material specifically comprises the following steps:
(1) preparing a cefuroxime acid solution: respectively adding methanol (55L), absolute ethyl alcohol (108L) and water (2L) into a clean stainless steel batching tank A in a metering manner, stirring, controlling the temperature of liquid in the stainless steel tank A to be 10-15 ℃, then adding cefuroxime acid (15kg) weighed in advance, controlling the temperature to be 10-15 ℃, and obtaining a cefuroxime acid solution for later use after complete dissolution;
(2) preparing a salt forming agent solution: respectively adding 95% ethanol (165L) into a clean stainless steel batching tank B, stirring, controlling the temperature of liquid in the stainless steel batching tank B to 10-15 ℃, then adding sodium acetate trihydrate (5.29kg) weighed in advance, controlling the temperature to 10-15 ℃, and completely dissolving to obtain a salt forming agent solution for later use;
(3) salt forming reaction: respectively metering methanol (11L), absolute ethyl alcohol (21.6L), water (0.4L) and 95% ethyl alcohol (33L) into a clean stainless steel batching tank C, uniformly stirring, pressurizing to 0.2MPa by using nitrogen, filtering a mixed solvent into an aseptic reaction tank through three-level sterilizing filtration (0.45um, 0.22um and 0.22um), stirring, controlling the temperature of liquid in the aseptic reaction tank to 10-15 ℃, adding sterile cefuroxime sodium seed crystals (15g) weighed in advance, dropwise adding the solutions in the batching tank A and the batching tank B into the aseptic reaction tank through three-level sterilizing filtration (0.45um, 0.22um and 0.22um) according to a dropwise adding scheme in the following table, continuously stirring after the dropwise adding is finished, and cooling the obtained mixture to 5-10 ℃; performing solid-liquid separation in a sterile environment, washing the solid product with anhydrous ethanol (60L) for three times, and drying at 35-45 deg.C and vacuum degree of-0.095 Mpa for 8 hr to obtain sterile cefuroxime sodium raw material.
Time (min) Speed of addition (ml/min) of cefuroxime acid solution Addition rate of salt forming agent solution (ml/min)
0-10 200 280
10-30 500 500
30-complete addition of material 1200 1200
Further, the preparation method of the cefuroxime sodium raw material specifically comprises the following steps:
(1) preparing a cefuroxime acid solution: respectively adding methanol (275L), absolute ethyl alcohol (540L) and water (10L) into a clean stainless steel batching tank A, stirring, controlling the temperature of liquid in the stainless steel tank A to be 10-15 ℃, then adding cefuroxime acid (75kg) weighed in advance, controlling the temperature to be 10-15 ℃, and obtaining a cefuroxime acid solution for later use after complete dissolution;
(2) preparing a salt forming agent solution: respectively adding 95% ethanol (825L) into a clean stainless steel batching tank B, stirring, controlling the temperature of liquid in the stainless steel batching tank B to 10-15 ℃, then adding sodium acetate trihydrate (26.45kg) weighed in advance, controlling the temperature to 10-15 ℃, and completely dissolving to obtain a salt forming agent solution for later use;
(3) salt forming reaction: respectively metering methanol (55L), absolute ethyl alcohol (108L), water (2L) and 95% ethyl alcohol (165L) into a clean stainless steel batching tank C, uniformly stirring, pressurizing to 0.2MPa by using nitrogen, filtering a mixed solvent into an aseptic reaction tank through three-level sterilizing filtration (0.45um, 0.22um and 0.22um), stirring, controlling the temperature of liquid in the aseptic reaction tank to 10-15 ℃, adding sterile cefuroxime sodium seed crystals (75g) weighed in advance, then respectively performing three-level sterilizing filtration (0.45um, 0.22um and 0.22um) on solutions in the batching tank A and the batching tank B according to a dropping scheme in the following table, dropping the solutions into the aseptic reaction tank, continuously stirring after dropping, and cooling an obtained mixture to 5-10 ℃; performing solid-liquid separation in a sterile environment, washing the solid product with anhydrous ethanol (300L) for three times, and drying at 35-45 deg.C and vacuum degree of-0.095 Mpa for 8 hr to obtain sterile cefuroxime sodium raw material.
Time (min) Speed of addition (ml/min) of cefuroxime acid solution Addition rate of salt forming agent solution (ml/min)
0-10 1000 1400
10-30 2500 2500
30-complete addition of material 6000 6000
The invention also provides a preparation method of the cefuroxime sodium powder injection for injection, which comprises the following steps:
the sterile cefuroxime sodium raw material medicine prepared by the method is delivered to a sterile preparation workshop, is subpackaged by adopting a screw rod under the layer A flow, is filled with high-purity sterile nitrogen, is directly subpackaged according to different specifications to prepare cefuroxime sodium for injection (0.25g, 0.5g, 0.75g, 1.5g, 2.25g and 2.5g), and the residual oxygen content is controlled to be less than or equal to 2 percent.
Compared with the prior art, the cefuroxime sodium raw material and the injection thereof prepared by the method have better impurity control and better stability, the retention time of 0.82-1.0 in the related substance 2 is only 0.3% -0.4% after the acceleration of 6 months and is far lower than the standard limit of 0.6%, and the product index in the prior art is already over 0.6% in the acceleration process.
In the preparation process of the cefuroxime sodium raw material, sodium acetate trihydrate is preferably selected as a salt forming agent, 95% ethanol is selected as a salt forming agent solvent, and the concentration range of the salt forming agent solution is ensured to be 2.5% -4.0%; preferably, the feeding molar ratio of the cefuroxime acid to the sodium acetate trihydrate is 1: 1.1; the optimal solvent composition and the optimal mixture ratio of the cefuroxime acid solution are preferably methanol: anhydrous ethanol: water 5.5:10.8: 0.2.
in addition, the multi-aspect research is carried out on the dropping mode and the dropping speed in particular, and the discovery that the addition of the salt forming agent solution or the addition of the cefuroxime acid solution at first is not good, the color grade of the prepared product is unstable, the moisture content is higher, the purity is lower, the related objects are higher, the mode of adding the two solutions at the same time is better, the conditions of various dropping speeds are further compared, the uniform dropping, the sectional acceleration first and the deceleration dropping are carried out, finally, the optimal dropping scheme is found, wherein the optimal dropping scheme is that the 0-10min cefuroxime acid solution and the salt forming agent solution are slowly added at the speeds of 20ml/min and 25-30ml/min respectively, the 10min-30min two solutions are added at the speed of 50ml/min at the same time, and the 30 min-after the dropping is finished, the two solutions are added at the speed of 120ml/min at the same time. Cefuroxime sodium is most unstable in dissolution state and is easy to deteriorate, so that impurities are increased. The salt forming agent is added into the reaction kettle in an excessive amount, so that the reaction is ensured to be full, other side reactions are prevented, impurities are avoided, the whole reaction system achieves a stable state balance under the conditions of the specific flow rate and the dropping mode, cefuroxime sodium can be quickly generated by the cefuroxime acid through reaction, crystals are immediately separated out, and the impurities are greatly reduced.
Under the combined action of all the process optimization conditions, the product with excellent indexes such as low water content, good color grade, high purity, low related substances and the like is finally obtained.
The preparation process of cefuroxime sodium for injection further ensures that the stability of the preparation product is better by controlling the residual oxygen content of the powder injection to be less than or equal to 2 percent.
Detailed Description
The following detailed description of the invention is provided to facilitate an understanding of the invention and to enable any person skilled in the art to make or use the invention without limiting it.
Comparative example 1 preparation of cefuroxime sodium for injection in patent CN200910203295.1
Comparative example 1 of the present invention is a cefuroxime sodium raw material sample prepared according to the method of "example 1" in patent CN200910203295.1, and then a cefuroxime sodium sample for injection is prepared according to the method of preparing powder injection of "example 1-1" in the present invention.
Comparative example 2 preparation of cefuroxime sodium for injection in patent CN201510104252.3
Comparative example 2 of the present invention is a sample of cefuroxime sodium for injection prepared according to the method of "example 3" in patent CN 201510104252.3.
Comparative example 3 preparation of cefuroxime sodium for injection in patent CN201610871443.7
Comparative example 3 of the present invention is a sample of cefuroxime sodium for injection prepared according to the method of "example 1" in patent CN 201610871443.7.
EXAMPLE 1 preparation of a cefuroxime sodium starting material according to the invention
(1) Preparing a cefuroxime acid solution: respectively metering methanol (50L), absolute ethyl alcohol (98L) and water (2L) into a clean stainless steel batching tank A, stirring, controlling the temperature of liquid in the stainless steel batching tank A to be 10-15 ℃, then adding cefuroxime acid (15kg) weighed in advance, controlling the temperature to be 10-15 ℃, and obtaining a cefuroxime acid solution for later use after complete dissolution;
(2) preparing a salt forming agent solution: respectively adding 95% ethanol (150L) into a clean stainless steel batching tank B, stirring, controlling the temperature of liquid in the stainless steel batching tank B to 10-15 ℃, then adding sodium acetate trihydrate (5.29kg) weighed in advance, controlling the temperature to 10-15 ℃, and completely dissolving to obtain a salt forming agent solution for later use;
(3) salt forming reaction: respectively metering methanol (10L), absolute ethyl alcohol (19.6L), water (0.4L) and 95% ethyl alcohol (30L) into a clean stainless steel batching tank C, uniformly stirring, pressurizing to 0.2MPa by using nitrogen, filtering a mixed solvent into a sterile reaction tank through three-level sterilizing filtration (0.45um, 0.22um and 0.22um), stirring, controlling the liquid temperature in the sterile reaction tank to 10-15 ℃, adding sterile cefuroxime sodium seed crystals (15g) weighed in advance, dropwise adding the two prepared feed liquids into the sterile reaction tank through three-level sterilizing filtration (0.45um, 0.22um and 0.22um) according to a dropwise adding scheme in the following table, continuously stirring after dropwise adding is finished, and cooling the obtained mixture to 5-10 ℃; performing solid-liquid separation in a sterile environment, washing the solid product with anhydrous ethanol (60L) for three times, and drying at 35-45 deg.C and vacuum degree of-0.095 Mpa for 7 hr to obtain sterile cefuroxime sodium raw material.
Time (min) Speed of addition (ml/min) of cefuroxime acid solution Addition rate of salt forming agent solution (ml/min)
0-10 200 250
10-30 500 500
30-complete addition of material 1200 1200
Example 2 preparation of a cefuroxime sodium starting material according to the invention
(1) Preparing a cefuroxime acid solution: respectively metering methanol (55L), absolute ethyl alcohol (108L) and water (2L) into a clean stainless steel batching tank, stirring, controlling the temperature of liquid in the stainless steel tank to be 10-15 ℃, then adding cefuroxime acid (15kg) weighed in advance, controlling the temperature to be 10-15 ℃, and obtaining a cefuroxime acid solution for later use after complete dissolution;
(2) preparing a salt forming agent solution: respectively adding 95% ethanol (165L) into a clean stainless steel batching tank, stirring, controlling the temperature of liquid in the stainless steel batching tank to 10-15 ℃, then adding sodium acetate trihydrate (5.29kg) weighed in advance, controlling the temperature to 10-15 ℃, and completely dissolving to obtain a salt forming agent solution for later use;
(3) salt forming reaction: respectively metering methanol (11L), absolute ethyl alcohol (21.6L), water (0.4L) and 95% ethyl alcohol (33L) into a clean stainless steel batching tank C, uniformly stirring, pressurizing to 0.2MPa by using nitrogen, filtering a mixed solvent into a sterile reaction tank through three-level sterilizing filtration (0.45um, 0.22um and 0.22um), stirring, controlling the liquid temperature in the sterile reaction tank to 10-15 ℃, adding sterile cefuroxime sodium seed crystals (15g) weighed in advance, dropwise adding the two prepared feed liquids into the sterile reaction tank through three-level sterilizing filtration (0.45um, 0.22um and 0.22um) according to a dropwise adding scheme in the following table, continuously stirring after dropwise adding is finished, and cooling the obtained mixture to 5-10 ℃; performing solid-liquid separation in a sterile environment, washing the solid product with anhydrous ethanol (60L) for three times, and drying at 35-45 deg.C and vacuum degree of-0.095 Mpa for 8 hr to obtain sterile cefuroxime sodium raw material.
Time (min) Cefuroxime acid solution is added rapidlyDegree (ml/min) Addition rate of salt forming agent solution (ml/min)
0-10 200 280
10-30 500 500
30-complete addition of material 1200 1200
Example 3 preparation of a cefuroxime sodium starting material according to the invention
(1) Preparing a cefuroxime acid solution: respectively metering methanol (60L), absolute ethyl alcohol (118L) and water (2L) into a clean stainless steel batching tank A, stirring, controlling the temperature of liquid in the stainless steel batching tank A to be 10-15 ℃, then adding cefuroxime acid (15kg) weighed in advance, controlling the temperature to be 10-15 ℃, and obtaining a cefuroxime acid solution for later use after complete dissolution;
(2) preparing a salt forming agent solution: respectively adding 95% ethanol (180L) into a clean stainless steel batching tank B, stirring, controlling the temperature of liquid in the stainless steel batching tank B to 10-15 ℃, then adding sodium acetate trihydrate (5.29kg) weighed in advance, controlling the temperature to 10-15 ℃, and completely dissolving to obtain a salt forming agent solution for later use;
(3) and salt forming reaction: respectively metering methanol (12L), absolute ethyl alcohol (23.6L), water (0.4L) and 95% ethyl alcohol (36L) into a clean stainless steel batching tank C, uniformly stirring, pressurizing to 0.2MPa by using nitrogen, filtering a mixed solvent into a sterile reaction tank through three-level sterilizing filtration (0.45um, 0.22um and 0.22um), stirring, controlling the liquid temperature in the sterile reaction tank to 10-15 ℃, adding sterile cefuroxime sodium seed crystals (15g) weighed in advance, dropwise adding the two prepared feed liquids into the sterile reaction tank through three-level sterilizing filtration (0.45um, 0.22um and 0.22um) according to a dropwise adding scheme in the following table, continuously stirring after dropwise adding is finished, and cooling the obtained mixture to 5-10 ℃; performing solid-liquid separation in a sterile environment, washing the solid product with anhydrous ethanol (60L) for three times, and drying at 35-45 deg.C and vacuum degree of-0.095 Mpa for 9 hr to obtain sterile cefuroxime sodium raw material.
Time (min) Speed of addition (ml/min) of cefuroxime acid solution Addition rate of salt forming agent solution (ml/min)
0-10 200 300
10-30 500 500
30-complete addition of material 1200 1200
EXAMPLE 1' preparation of cefuroxime sodium raw material according to the invention
(1) Preparing a cefuroxime acid solution: methanol (250L), absolute ethyl alcohol (490L) and water (10L) are respectively metered into a clean stainless steel batching tank A, stirred, the temperature of the liquid in the stainless steel batching tank A is controlled to be 10-15 ℃, and then cefuroxime acid (75kg) weighed in advance is added, the temperature is controlled to be 10-15 ℃, and after complete dissolution, a cefuroxime acid solution is obtained for standby.
(2) Preparing a salt forming agent solution: respectively adding 95% ethanol (750L) into a clean stainless steel batching tank B, stirring, controlling the temperature of liquid in the stainless steel batching tank B to 10-15 ℃, then adding sodium acetate trihydrate (26.45kg) weighed in advance, controlling the temperature to 10-15 ℃, and forming a salt solution for later use after complete dissolution.
(3) Salt forming reaction: respectively metering methanol (50L), absolute ethyl alcohol (98L), water (2L) and 95% ethyl alcohol (150L) into a clean stainless steel batching tank C, uniformly stirring, pressurizing to 0.2MPa by using nitrogen, filtering a mixed solvent into an aseptic reaction tank through three-stage sterilization filtration (0.45um, 0.22um and 0.22um), stirring, controlling the temperature of liquid in the aseptic reaction tank to 10-15 ℃, adding sterile cefuroxime sodium seed crystals (75g) weighed in advance, dropwise adding the two prepared feed liquids into the aseptic reaction tank through three-stage sterilization filtration (0.45um, 0.22um and 0.22um) according to a dropwise adding scheme in the following table, continuously stirring after dropwise adding is finished, and cooling the obtained mixture to 5-10 ℃; performing solid-liquid separation in a sterile environment, washing the solid product with anhydrous ethanol (300L) for three times, and drying at 35-45 deg.C and vacuum degree of-0.095 Mpa for 7 hr to obtain sterile cefuroxime sodium raw material.
Time (min) Speed of addition (ml/min) of cefuroxime acid solution Addition rate of salt forming agent solution (ml/min)
0-10 1000 1250
10-30 2500 2500
30-complete addition of material 6000 6000
Example 2' preparation of a cefuroxime sodium starting Material according to the invention
(1) Preparing a cefuroxime acid solution: methanol (275L), absolute ethyl alcohol (540L) and water (10L) are respectively metered into a clean stainless steel batching tank A, stirred, the temperature of liquid in the stainless steel batching tank A is controlled to be 10-15 ℃, and then cefuroxime acid (75kg) weighed in advance is added, the temperature is controlled to be 10-15 ℃, and the cefuroxime acid is completely dissolved for later use.
(2) Preparing a salt forming agent solution: respectively adding 95% ethanol (825L) into a clean stainless steel batching tank B, stirring, controlling the temperature of the liquid in the stainless steel batching tank B to 10-15 ℃, then adding sodium acetate trihydrate (26.45kg) weighed in advance, controlling the temperature to 10-15 ℃, and completely dissolving for later use.
(3) Salt forming reaction: respectively metering methanol (55L), absolute ethyl alcohol (108L), water (2L) and 95% ethyl alcohol (165L) into a clean stainless steel batching tank C, uniformly stirring, pressurizing to 0.2MPa by using nitrogen, filtering a mixed solvent into an aseptic reaction tank through three-stage sterilization filtration (0.45um, 0.22um and 0.22um), stirring, controlling the temperature of liquid in the aseptic reaction tank to 10-15 ℃, adding sterile cefuroxime sodium seed crystals (75g) weighed in advance, dropwise adding the two prepared feed liquids into the aseptic reaction tank through three-stage sterilization filtration (0.45um, 0.22um and 0.22um) according to a dropwise adding scheme in the following table, continuously stirring after dropwise adding is finished, and cooling the obtained mixture to 5-10 ℃; performing solid-liquid separation in a sterile environment, washing the solid product with anhydrous ethanol (300L) for three times, and drying at 35-45 deg.C and vacuum degree of-0.095 Mpa for 8 hr to obtain sterile cefuroxime sodium raw material.
Time (min) Speed of addition (ml/min) of cefuroxime acid solution Addition rate of salt forming agent solution (ml/min)
0-10 1000 1400
10-30 2500 2500
30-complete addition of material 6000 6000
Example 3' preparation of a cefuroxime sodium starting Material according to the invention
(1) Preparing a cefuroxime acid solution: respectively adding methanol (300L), absolute ethyl alcohol (590L) and water (10L) into a clean stainless steel batching tank A, stirring, controlling the temperature of liquid in the stainless steel tank A to be 10-15 ℃, then adding cefuroxime acid (75kg) weighed in advance, controlling the temperature to be 10-15 ℃, and obtaining a cefuroxime acid solution for later use after complete dissolution;
(2) preparing a salt forming agent solution: respectively adding 95% ethanol (900L) into a clean stainless steel batching tank B, stirring, controlling the temperature of liquid in the stainless steel batching tank B to 10-15 ℃, then adding sodium acetate trihydrate (26.45kg) weighed in advance, controlling the temperature to 10-15 ℃, and completely dissolving to obtain a salt forming agent solution for later use;
(3) salt forming reaction: respectively metering methanol (60L), absolute ethyl alcohol (118L), water (2L) and 95% ethyl alcohol (180L) into a clean stainless steel batching tank C, uniformly stirring, pressurizing to 0.2MPa by using nitrogen, filtering a mixed solvent into an aseptic reaction tank through three-stage sterilization filtration (0.45um, 0.22um and 0.22um), stirring, controlling the temperature of liquid in the aseptic reaction tank to 10-15 ℃, adding sterile cefuroxime sodium seed crystals (75g) weighed in advance, dropwise adding the two prepared feed liquids into the aseptic reaction tank through three-stage sterilization filtration (0.45um, 0.22um and 0.22um) according to a dropwise adding scheme in the following table, continuously stirring after dropwise adding is finished, and cooling the obtained mixture to 5-10 ℃; performing solid-liquid separation in a sterile environment, washing the solid product with anhydrous ethanol (300L) for three times, and drying at 35-45 deg.C and vacuum degree of-0.095 Mpa for 9 hr to obtain sterile cefuroxime sodium raw material.
Time (min) Speed of addition (ml/min) of cefuroxime acid solution Addition rate of salt forming agent solution (ml/min)
0-10 1000 1500
10-30 2500 2500
30-complete addition of material 6000 6000
Example 4' preparation of a cefuroxime sodium starting Material according to the invention
(1) Preparing a cefuroxime acid solution: respectively metering methanol (225L), absolute ethyl alcohol (440L) and water (10L) into a clean stainless steel batching tank, stirring, controlling the temperature of liquid in the stainless steel tank to 10-15 ℃, then adding cefuroxime acid (75kg) weighed in advance, controlling the temperature to 10-15 ℃, and obtaining a cefuroxime acid solution for later use after complete dissolution;
(2) preparing a salt forming agent solution: respectively metering 95% ethanol (675L) into a clean stainless steel batching tank, stirring, controlling the temperature of liquid in the stainless steel batching tank to 10-15 ℃, then adding sodium acetate trihydrate (26.45kg) weighed in advance, controlling the temperature to 10-15 ℃, and completely dissolving to obtain a salt forming agent solution for later use;
(3) salt forming reaction: respectively metering methanol (45L), absolute ethyl alcohol (88L), water (2L) and 95% ethyl alcohol (135L) into a clean stainless steel batching tank C, uniformly stirring, pressurizing to 0.2MPa by using nitrogen, filtering a mixed solvent into an aseptic reaction tank through three-stage sterilization filtration (0.45um, 0.22um and 0.22um), stirring, controlling the temperature of liquid in the aseptic reaction tank to 10-15 ℃, adding sterile cefuroxime sodium seed crystals (75g) weighed in advance, dropwise adding the two prepared feed liquids into the aseptic reaction tank through three-stage sterilization filtration (0.45um, 0.22um and 0.22um) according to a dropwise adding scheme in the following table, continuously stirring after dropwise adding is finished, and cooling the obtained mixture to 5-10 ℃; performing solid-liquid separation in a sterile environment, washing the solid product with anhydrous ethanol (300L) for three times, and drying at 35-45 deg.C and vacuum degree of-0.095 Mpa for 5 hr to obtain sterile cefuroxime sodium raw material.
Time (min) Speed of addition (ml/min) of cefuroxime acid solution Addition rate of salt forming agent solution (ml/min)
0-10 1000 1150
10-30 2500 2500
30-complete addition of material 6000 6000
EXAMPLE 5' preparation of cefuroxime sodium starting Material according to the invention
(1) Preparing a cefuroxime acid solution: respectively adding methanol (360L), absolute ethyl alcohol (705L) and water (10L) into a clean stainless steel batching tank A, stirring, controlling the temperature of liquid in the stainless steel batching tank A to be 10-15 ℃, then adding cefuroxime acid (75kg) weighed in advance, controlling the temperature to be 10-15 ℃, and completely dissolving for later use;
(2) preparing a salt forming agent solution: respectively adding 95% ethanol (1075L) into a clean stainless steel batching tank B, stirring, controlling the temperature of liquid in the stainless steel batching tank B to 10-15 ℃, then adding sodium acetate trihydrate (26.45kg) weighed in advance, controlling the temperature to 10-15 ℃, and completely dissolving for later use;
(3) salt forming reaction: respectively metering methanol (72L), absolute ethyl alcohol (141L), water (2L) and 95% ethyl alcohol (215L) into a clean stainless steel batching tank C, uniformly stirring, pressurizing to 0.2MPa by using nitrogen, filtering a mixed solvent into an aseptic reaction tank through three-stage sterilization filtration (0.45um, 0.22um and 0.22um), stirring, controlling the temperature of liquid in the aseptic reaction tank to 10-15 ℃, adding sterile cefuroxime sodium seed crystals (75g) weighed in advance, dropwise adding the two prepared feed liquids into the aseptic reaction tank through three-stage sterilization filtration (0.45um, 0.22um and 0.22um) according to a dropwise adding scheme in the following table, continuously stirring after dropwise adding is finished, and cooling the obtained mixture to 5-10 ℃; performing solid-liquid separation in a sterile environment, washing the solid product with anhydrous ethanol (300L) for three times, and drying at 35-45 deg.C and vacuum degree of-0.095 Mpa for 10 hr to obtain sterile cefuroxime sodium raw material.
Time (min) Speed of addition (ml/min) of cefuroxime acid solution Addition rate of salt forming agent solution (ml/min)
0-10 1000 1500
10-30 2500 2500
30-complete addition of material 6000 6000
Example 1-1 preparation of cefuroxime sodium for injection
Sterile cefuroxime sodium raw material medicine prepared in the example 1 is delivered to a sterile preparation workshop, is subpackaged by a screw rod under the grade A laminar flow, is filled with high-purity sterile nitrogen, and is directly subpackaged according to different specifications to prepare cefuroxime sodium for injection (0.25g, 0.5g, 0.75g, 1.5g, 2.25g and 2.5 g). The residual oxygen amount is 1.2-1.6%.
Example 2-1 preparation of cefuroxime sodium for injection
Sterile cefuroxime sodium raw material medicine prepared in the example 2 is delivered to a sterile preparation workshop, is subpackaged by adopting a screw rod under the grade A laminar flow, is filled with high-purity sterile nitrogen, and is directly subpackaged according to different specifications to prepare cefuroxime sodium for injection (0.25g, 0.5g, 0.75g, 1.5g, 2.25g and 2.5 g). The residual oxygen amount is 1.3-1.7%.
Example 3-1 preparation of cefuroxime sodium for injection
Sterile cefuroxime sodium raw material medicine prepared in the example 3 is delivered to a sterile preparation workshop, is subpackaged by a screw rod under the grade A laminar flow, is filled with high-purity sterile nitrogen, and is directly subpackaged according to different specifications to prepare cefuroxime sodium for injection (0.25g, 0.5g, 0.75g, 1.5g, 2.25g and 2.5 g). The residual oxygen amount is 1.1-1.4%.
EXAMPLE 1' -1 preparation of cefuroxime sodium for injection
The sterile cefuroxime sodium raw material drug prepared in the example 1' is delivered to a sterile preparation workshop, and is subpackaged by a screw rod under the grade A laminar flow, and is filled with high-purity sterile nitrogen, and is directly subpackaged according to different specifications to prepare cefuroxime sodium for injection (0.25g, 0.5g, 0.75g, 1.5g, 2.25g and 2.5 g). The residual oxygen amount is 1.3-1.6%.
Example 2' -1 preparation of cefuroxime sodium for injection
The sterile cefuroxime sodium raw material drug prepared in the example 2' is delivered to a sterile preparation workshop, and is subpackaged by adopting a screw rod under the A-grade laminar flow, and is filled with high-purity sterile nitrogen, and is directly subpackaged according to different specifications to prepare cefuroxime sodium for injection (0.25g, 0.5g, 0.75g, 1.5g, 2.25g and 2.5 g). The residual oxygen amount is 1.2-1.5%.
EXAMPLE 3' -1 preparation of cefuroxime sodium for injection
The sterile cefuroxime sodium raw material drug prepared in the example 3' is delivered to a sterile preparation workshop, and is subpackaged by adopting a screw rod under the grade A laminar flow, and is filled with high-purity sterile nitrogen, and is directly subpackaged according to different specifications to prepare cefuroxime sodium for injection (0.25g, 0.5g, 0.75g, 1.5g, 2.25g and 2.5 g). The residual oxygen amount is 1.2-1.7%.
EXAMPLE 4' -1 preparation of cefuroxime sodium for injection
The sterile cefuroxime sodium raw material drug prepared in the example 4' is delivered to a sterile preparation workshop, and is subpackaged by adopting a screw rod under the grade A laminar flow, and is filled with high-purity sterile nitrogen, and is directly subpackaged according to different specifications to prepare cefuroxime sodium for injection (0.25g, 0.5g, 0.75g, 1.5g, 2.25g and 2.5 g). The residual oxygen amount is 1.2-1.4%.
EXAMPLE 5' -1 preparation of cefuroxime sodium for injection
The sterile cefuroxime sodium raw material drug prepared in the example 5' is delivered to a sterile preparation workshop, and is subpackaged by adopting a screw rod under the grade A laminar flow, and is filled with high-purity sterile nitrogen, and cefuroxime sodium for injection (0.25g, 0.5g, 0.75g, 1.5g, 2.25g and 2.5g) is directly subpackaged according to different specifications. The residual oxygen amount is 1.3-1.6%.
Test example 1 salt-forming agent and selection test for the kind and amount of solvent used
In order to examine the influence of different salt-forming agents and the dosage thereof, and the kind and dosage of the used solvent on cefuroxime sodium, 21 prescriptions under different conditions were designed, as shown in table 1. In table 1, 3 formulations of the same salt-forming agent and the same solvent are a control group, such as: prescription 1-3. The simultaneous adjustment of the salt forming agent amount and the solvent amount is selected in a control group, the main purpose is to ensure that the molar concentrations of the solutions of the salt forming agents dissolved in the solvents are the same, and the optimal salt forming agent type and the optimal salt forming agent amount (i.e. the optimal molar ratio of the salt forming agent amount to 1.5kg of cefuroxime acid) are preferably selected by comparing different formulas.
The preparation method of cefuroxime sodium comprises the following steps:
1. preparing a cefuroxime acid solution: dissolving cefuroxime acid (1.5kg) in a mixed solvent of methanol (5.5L), acetone (10.8L) and water (0.2L) at 10-15 ℃;
2. preparing a salt forming agent solution: according to the formula in the table 1, the preparation is carried out at the temperature of 10-15 ℃;
3. salt forming reaction: taking 20% of the amount of each solvent used in the preparation of the cefuroxime acid solution and the salt forming agent solution to prepare a crystallized solvent base material, stirring, keeping the temperature at 10-15 ℃, adding cefuroxime sodium (1.5g), then simultaneously dropwise adding the cefuroxime acid solution and the salt forming agent solution, dropwise adding the cefuroxime acid solution at the flow rate of 100mL/min, then adjusting the dropwise adding rate of the salt forming agent solution according to different prescriptions in the table 1, finishing the dropwise adding of the two solutions at the constant speed and at the same time as much as possible, then continuously stirring, cooling the obtained mixture to 5 ℃, filtering, washing the product by absolute ethyl alcohol (6L) for three times, and drying for 8 hours at the vacuum degree of 40 ℃ and less than or equal to-0.095 Mpa.
TABLE 1 formulation of different salt-forming agents and their amounts
Figure BDA0002180310830000111
Figure BDA0002180310830000121
The cefuroxime sodium is prepared by adopting the method for preparing the salt forming agent prepared by the prescription 1-the prescription 21. The samples were then subjected to mass detection analysis and the results are shown in table 2. The detection methods of moisture, pH, color grade and polymer are according to the second part of the Chinese pharmacopoeia 2015 edition, the high performance liquid chromatography method is adopted to detect the purity of cefuroxime sodium, and the detection methods of related substances 1 and 2 are shown below.
The detection method of cefuroxime sodium related substance 1 comprises the following steps:
is used newly. Taking a proper amount of the product, adding water to dissolve and dilute the product to prepare a solution containing 0.5mg per 1ml, taking 1ml of the sample solution as a sample solution, precisely measuring 1ml of the sample solution, putting the sample solution into a 100ml measuring flask, diluting the sample solution to a scale with water, shaking up the sample solution to serve as a reference solution, measuring the reference solution by high performance liquid chromatography (general rule 0512), and taking octyl silane bonded silica gel as a filler: taking 50mmol/L ammonium formate solution as a mobile phase A, acetonitrile as a mobile phase B, and carrying out linear gradient elution according to the following table, wherein the flow rate is 1.5ml per minute; the detection wavelength is 273nm, the cefuroxime reference substance is about 10mg, the cefuroxime reference substance is placed into a 20ml measuring flask, 1ml of 0.1mol/L sodium hydroxide solution is added for dissolution, after the cefuroxime reference substance is placed for 15 minutes, 0.1mol/L hydrochloric acid solution is added for neutralization, the cefuroxime reference substance is diluted to a scale mark by water to serve as a system applicability solution, 20 mu L of the cefuroxime reference substance is injected into a liquid chromatograph, a chromatogram is recorded, and the separation degree between the cefuroxime and the adjacent impurity peak (the relative retention time is about 1.1) is more than 3.0.
Time (minutes) Mobile phase A (%) Mobile phase B (%)
0 95 5
60 80 20
100 60 40
110 60 40
110.1 95 5
120 95 5
Precisely measuring 20 μ l of each of the test solution and the reference solution, respectively injecting into a liquid chromatograph, and recording chromatogram. If there is impurity peak in the chromatogram of the sample solution, the content of the impurity is calculated according to the main component self-contrast method multiplied by the correction factor, which is all in accordance with the corresponding limit regulation in the following table.
Figure BDA0002180310830000122
Figure BDA0002180310830000131
The detection method of cefuroxime sodium related substance 2 comprises the following steps:
is used newly. Taking a proper amount of the cefuroxime axetil powder, adding water to dissolve and dilute the cefuroxime axetil powder to prepare a solution containing 0.5mg per 1ml, taking a sample solution, taking another proper amount of cefuroxime axetil reference substance, precisely weighing 1ml of the reference solution, adding water to dissolve and quantitatively dilute the cefuroxime axetil powder to prepare a solution containing 1 mu g per 1ml, taking the solution as the reference solution, precisely weighing 1ml of the reference solution, placing the solution in a 10ml measuring flask, diluting the solution to scale with water, shaking the solution uniformly to obtain a sensitive solution, and measuring the solution by using molecular exclusion chromatography (general rule 0514). Using spherical hydrophilic modified silica GEL as filler (TSK-GEL G2000swxl, 7.8mm multiplied by 30cm, 5 μm or chromatographic column with equivalent efficiency); 5mmol/L ammonium acetate solution-acetonitrile (95:5) is used as a mobile phase, the flow rate is 0.6ml per minute, and the detection wavelength is 273 nm. Taking about 10mg of cefuroxime reference substance, placing the cefuroxime reference substance in a 20ml measuring flask, adding 1ml of 0.1mol/L sodium hydroxide solution to dissolve the cefuroxime reference substance, placing the cefuroxime reference substance for 15 minutes, adding 0.1mol/L hydrochloric acid solution to neutralize the cefuroxime reference substance, diluting the cefuroxime reference substance with water to a scale mark to obtain a system applicability solution, taking 20 mu L of the system applicability solution, injecting the system applicability solution into a liquid chromatograph, recording a chromatogram, wherein the retention time of a cefuroxime peak is about 14.5 minutes, and the separation degree of the cefuroxime peak and the time of the adjacent degraded impurity peak before the cefuroxime peak meets the requirement. And (3) injecting 20 mu l of the sensitivity solution into a liquid chromatograph, and recording a chromatogram, wherein the signal-to-noise ratio of the peak height of the main component is greater than 10. Precisely measuring 20 mu l of each of the test solution and the control solution, respectively injecting into a liquid chromatograph, recording a chromatogram, wherein if an impurity peak exists in the chromatogram of the test solution, the area of the impurity peak with the relative retention time of less than 0.82 is within 0.2 percent of the area of the main peak of the control solution, and the area of the impurity peak with the relative retention time of 0.82-1.0 is within 3 times (0.6 percent) of the area of the main branch of the control solution.
TABLE 2 quality test results for samples of recipe 1-recipe 21
Figure BDA0002180310830000132
Figure BDA0002180310830000141
The reason for selecting the three salt-forming agents is that the three salt-forming agents have better solubility in organic solvents. The solubility of sodium isooctanoate is the best, but a by-product isooctanoate after salt forming reaction can remain in the product in a small amount, because the water insolubility of isooctanoate can cause the risk of increasing insoluble small particles in a sterile product; sodium lactate generally exists in the form of an aqueous solution, and can only be stably dissolved in 95% ethanol or a solvent with higher water content, and the possibility of separating out oily sodium lactate exists in the solvent with low water content, which can cause the content of a finished product to be reduced; the sodium acetate trihydrate has good solubility in a solvent and water, and the acetic acid which is a byproduct after reaction has good solubility in the solvent and water, so that the sodium acetate trihydrate which does not participate in the reaction and the acetic acid after the reaction can be ensured to be dissolved in the solvent, and the residual trace amount of acetic acid or sodium acetate cannot influence the solubility of the product and visible foreign matters.
The formula 1-6 adopts sodium lactate (60%) as a salt forming agent, and the obtained product has high water content, low yield, poor color grade, low purity, high related substances 1 and 2, high polymer content and poor product quality; the formula 7-15 adopts sodium isooctanoate as a salt forming agent, the obtained product has low water content, high yield and good color grade, but related substances 1 and 2 are higher, and the product quality is not ideal enough; the formula 16-21 adopts sodium acetate trihydrate as a salt forming agent, the obtained product has low water content and high purity, wherein the formula 19-21 adopts 95% ethanol as a salt forming agent solvent, the obtained product has lower water content, higher yield, better color grade, higher purity, lower related substances 1 and 2, particularly related substances with retention time of less than 0.82 in the related substances 2 are not detected, and the related substances with retention time of 0.82-1.0 are only 0.14% -0.16%. The final preferable salt forming agent is sodium acetate trihydrate, the solvent of the salt forming agent is 95% ethanol, and the dosage of the salt forming agent is 529g, namely the molar ratio of cefuroxime acid to sodium acetate trihydrate is 1: 1.1.
test example 2 screening test for concentration of salt-forming agent solution
On the basis of test example 1, the effect of the concentration of the salt forming agent solution on the preparation of cefuroxime sodium was further examined. 529g of 95% ethanol solution of sodium acetate trihydrate with different concentrations was prepared according to the recipe 1-7 in Table 3, and cefuroxime sodium was prepared by the following method. And the samples are subjected to quality detection and analysis, and the detection methods of moisture, pH, color grade, polymer, purity, related substances 1 and related substances 2 are the same as the above, and the results are shown in Table 4.
The preparation method of cefuroxime sodium comprises the following steps:
1. preparing a cefuroxime acid solution: dissolving cefuroxime acid (1.5kg) in a mixed solvent of methanol (5.5L), acetone (10.8L) and water (0.2L) at 10-15 ℃;
2. preparing a salt forming agent solution: according to the formula in the table 3, the preparation is carried out at the temperature of 10-15 ℃;
3. salt forming reaction: taking 20% of the amount of each solvent used in the preparation of the cefuroxime acid solution and the salt forming agent solution to prepare a crystallized solvent base material, stirring, keeping the temperature at 10-15 ℃, adding cefuroxime sodium (1.5g), then simultaneously dropwise adding the cefuroxime acid solution and the salt forming agent solution, dropwise adding the cefuroxime acid solution at the flow rate of 100mL/min, then adjusting the dropwise adding rate of the salt forming agent solution according to different prescriptions in Table 3, finishing the dropwise adding of the two solutions at the constant speed and at the same time as much as possible, then continuously stirring, cooling the obtained mixture to 5 ℃, filtering, washing the product by absolute ethyl alcohol (6L) for three times, and drying for 8 hours at the vacuum degree of 40 ℃ and less than or equal to-0.095 Mpa.
TABLE 3 recipe for different concentrations of salt forming agent solution
Figure BDA0002180310830000151
TABLE 4 quality test results for samples of prescriptions 1-7
Figure BDA0002180310830000161
As can be seen from Table 4, the yield and pH of cefuroxime sodium gradually increase with the increase of the concentration of the salt-forming agent, the influence on the moisture, color grade and purity of cefuroxime sodium is less obvious, the influence on related substances 1 and 2 of cefuroxime sodium is more obvious, especially related substances with retention time of less than 0.82 in related substances 2, the prescriptions 3 to 5 are all undetected, the prescriptions 1, 2, 6 and 7 are all 0.02%, while related substances with retention time of 0.82 to 1.0 in related substances 2, the prescriptions 3 to 5 are all less than 0.2%, and the prescriptions 1, 2, 6 and 7 are respectively 0.36%, 0.31%, 0.30% and 0.32%, so the final concentration range of the salt-forming agent is preferably 2.5% -4.0%.
Test example 3 screening test of solvent formulation for cefuroxime acid solution
In order to examine the influence of different solvents and the amounts thereof used in the cefuroxime acid solution on cefuroxime sodium, 9 formulations under different conditions were designed, as shown in table 5. In table 5, each 3 formulations using the same solvents were a control group, such as: prescription 1-prescription 3. The total amount 1650L of solvent in a control group is kept constant, and different prescriptions are formed by adjusting the ratio of each solvent. The main purpose is to ensure that the molar concentrations of solvent solutions formed by dissolving cefuroxime acid in different prescriptions are the same, and an optimal solvent ratio prescription is preferably selected through comparison of different prescriptions.
The preparation method of cefuroxime sodium comprises the following steps:
1. preparing a cefuroxime acid solution: according to the recipe in Table 5, cefuroxime acid (1.5kg) was dissolved in different mixed solvents at 10-15 ℃;
2. preparing a salt forming agent solution: sodium acetate trihydrate (529g) was dissolved in 95% ethanol (16.5L) at 10-15 deg.C;
3. salt forming reaction: taking 20% of the amount of each solvent used in the preparation of the cefuroxime acid solution and the salt forming agent solution to prepare a crystallized solvent base material, stirring, keeping the temperature at 10-15 ℃, adding cefuroxime sodium (1.5g), simultaneously dropwise adding the cefuroxime acid solution and the salt forming agent solution at a flow rate of 100mL/min at a constant speed, continuing stirring after dropwise adding is finished, cooling the obtained mixture to 5 ℃, filtering, washing the product by absolute ethyl alcohol (6L) for three times, and drying for 8 hours at a vacuum degree of 40 ℃ and less than or equal to-0.095 Mpa.
TABLE 5 formulation of various solvents and their amounts
Figure BDA0002180310830000171
Different mixed solvents are prepared according to the prescriptions 1-9 in the table 5, and the cefuroxime sodium is prepared by the method. And the samples are subjected to quality detection and analysis, and the detection methods of moisture, pH, color grade, polymer, purity, related substances 1 and related substances 2 are the same as the above, and the results are shown in Table 6.
TABLE 6 quality test results for samples of recipe 1 to recipe 9
Figure BDA0002180310830000172
Figure BDA0002180310830000181
As can be seen from the data in Table 6, the product obtained in the formula 5 has low moisture, good color grade, high purity, lower related substances 1 and 2 and better product quality, so that the optimal solvent composition and the mixture ratio of the cefuroxime acid solution are preferably methanol: anhydrous ethanol: water 5.5:10.8: 0.2.
test example 4 cefuroxime acid solution, salt-forming agent solution addition method and addition rate screening test
In order to examine the influence of the addition modes and the addition rates of the cefuroxime acid solution and the salt forming agent solution on the cefuroxime sodium, the formulas under different addition conditions were designed as shown in table 7.
The preparation method of cefuroxime sodium comprises the following steps:
1. preparing a cefuroxime acid solution: dissolving cefuroxime acid (1.5kg) in a mixed solvent of methanol (5.5L), absolute ethanol (10.8L) and water (0.2L) at 10-15 ℃;
2. preparing a salt forming agent solution: sodium acetate trihydrate (529g) was dissolved in 95% ethanol (16.5L) at 15 ℃;
3. salt forming reaction: taking 20% of the amount of each solvent used in the preparation of the cefuroxime acid solution and the salt forming agent solution to prepare a crystallized solvent base material, stirring, keeping the temperature at 10-15 ℃, adding cefuroxime sodium (1.5g), then dropwise adding according to the scheme in Table 9, continuing to stir after the dropwise adding is finished, cooling the obtained mixture to 5 ℃, filtering, washing the product by absolute ethyl alcohol (6L) for three times, and drying for 8 hours at the vacuum degree of 40 ℃ and less than or equal to-0.095 Mpa.
TABLE 7 screening test for the modes of addition and rates of addition of different cefuroxime acid solutions and salt-forming agent solutions I
Figure BDA0002180310830000182
Figure BDA0002180310830000191
Cefuroxime acid solution and salt forming agent solution are added according to the scheme of the prescription 1-22 in the table 7, cefuroxime sodium is prepared by the method, and then quality detection and analysis are carried out on a sample, wherein the detection methods of moisture, pH, color grade, polymer, purity, related substances 1 and related substances 2 are the same as the above, and the results are shown in the table 8.
Table 8: prescription 1-prescription 22 sample quality detection results
Figure BDA0002180310830000201
Figure BDA0002180310830000211
According to the detection result, the quality index of the prescription 18 is superior to that of all other prescriptions, and through comparison analysis of the prescription 1-the prescription 6 of the comparison group with a part of the solution of the salt forming agent added firstly, the prescription 7 of the comparison group with a part of the solution of the cefuroxime acid added firstly, and the prescription 13-the prescription 22 of the comparison group added simultaneously, the product prepared by adding one of the solutions firstly is unstable in color grade, higher in moisture, lower in purity and higher in related substances, the mode of adding the solution simultaneously is better, and the conditions under different rates are further compared by adding the solution simultaneously.
The formula 13-15 is that two solutions are dripped at constant speed simultaneously, wherein the dripping speed of the formula 14 is 100ml/min, and the prepared product has low related substances and good quality; the formula 16-19 is that two solutions are dripped simultaneously, and after 30min, the dripping speed is increased simultaneously until the dripping is finished, wherein the product prepared by the formula 18 has higher purity, lower water content and lower related substances, and the product quality is better than that of the product prepared by the formula 14; in the formulas 20 to 22, the two solutions are simultaneously dripped, the dripping speed is increased after 30min, and further the dripping speed is increased after 90min until the dripping is finished, so that the quality of the prepared product is inferior to that of the product prepared in the formula 18. Through the comparison study of the prescriptions 1-22, the better dropping mode and rate condition are preferably the case of the prescription 18, two solutions are dropped at the rate of 50ml/min at the same time in 0-30min, and two solutions are dropped at the rate of 120ml/min at the same time after 30 min-dropping.
The protocol was further optimized based on prescription 18 and the screening tests of prescriptions 23-28 in Table 9 were performed. Cefuroxime acid solution and salt forming agent solution are added according to the scheme of the prescription 23-28 in the table 9, the method is adopted to prepare cefuroxime sodium, and the quality detection and analysis are carried out on the sample, wherein the detection methods of the moisture, the pH, the color grade, the polymer, the purity, the related substances 1 and the related substances 2 are the same as the above, and the results are shown in the table 10.
TABLE 9 screening test II for the addition modes and rates of different cefuroxime acid solutions and salt-forming agent solutions
Figure BDA0002180310830000221
Table 10: prescription 23-prescription 28 sample quality detection results
Figure BDA0002180310830000222
As can be seen from the test results, the quality indexes of the prescriptions 26 and 27 are better than those of all other prescriptions.
On the basis of the dripping scheme of the prescription 18, the two solutions are firstly dripped slowly within 0-10min, the product quality is found to be slightly improved, if the product quality prepared by the prescription 23 and the prescription 26-28 is better than that prepared by the prescription 18, the necessity of firstly dripping slowly in the first 10min is seen, and the full reaction is facilitated.
However, if the addition rate after 90min is changed, either faster or slower, such as prescription 24 or prescription 25, the quality of the product obtained is not ideal, and is not as good as that of the product obtained by prescription 18.
Then, the comparison between the prescriptions 23 and 26-28 shows that the quality of the products prepared by the prescriptions 26 and 27 is improved more remarkably, and the flow rate ratio of slowly dripping the cefuroxime acid solution and the salt forming agent solution in the first 10 minutes is also important, so that the optimal dripping scheme is determined to be that the cefuroxime acid solution and the salt forming agent solution are slowly dripped at the rates of 20ml/min and 25-30ml/min respectively in 0-10min, the two solutions are dripped at the rate of 50ml/min simultaneously in 10min-30min, and the two solutions are dripped at the rate of 120ml/min simultaneously after 30 min-dripping is finished.
Test example 5 stability examination
The 0.75g cefuroxime sodium for injection prepared in the above examples 1-1, 2-1, 3-1, 1 ' -1, 2 ' -1, 3 ' -1, 4 ' -1, 5 ' -1 and comparative examples 1, 2, 3 was packed on the market in a simulated manner, and left at 40 ℃ and 75% relative humidity for 6 months, and the moisture, pH, color grade, content, related 1, related 2, polymer and the like were examined, and the results are shown in Table 11. The detection method of all the detection items except the content is the same as above.
The content detection method comprises the following steps: measured by high performance liquid chromatography (general rule 0512).
The chromatographic condition and the system applicability test use octyl silane bonded silica gel as a filling agent; acetate buffer (0.68 g sodium acetate, 5.8g glacial acetic acid, water diluted to 1000ml, adjusting pH to 3.4 with glacial acetic acid) -acetonitrile (85:15) is used as mobile phase. The detection wavelength was 273 nm. Taking a proper amount of the product, adding water to dissolve and dilute the product to prepare a solution containing 0.5mg per 1ml, placing the solution in a water bath at 60 ℃ for 30 minutes, cooling the solution to convert the cefuroxime part into the descarbamoyl cefuroxime, taking 20 mu l of the solution as a system applicable solution, injecting the solution into a liquid chromatograph, and recording a chromatogram map, wherein the separation degree of the cefuroxime peak and the descarbamoyl cefuroxime peak is more than 3.0. The separation between the cefuroxime peak and the impurity peak with a relative retention time of about 1.1 is satisfactory.
The determination method comprises precisely weighing appropriate amount of the product, dissolving in water, quantitatively diluting to obtain solution containing 0.1mg per 1ml, using as test solution (prepared or stored at 2-8 deg.C), precisely weighing 20 μ l, injecting into liquid chromatograph, and recording chromatogram; taking another appropriate amount of cefuroxime reference substance, measuring by the same method, and calculating C in the sample according to the peak area of the external standard16H16N4O8The content of S.
TABLE 110.75 g Specification cefuroxime sodium stability test results for injection
Figure BDA0002180310830000231
Figure BDA0002180310830000241
Figure BDA0002180310830000251
Figure BDA0002180310830000261
Figure BDA0002180310830000271
The 1.5g cefuroxime sodium for injection prepared in the above examples 1-1, 2-1, 3-1, 1 ' -1, 2 ' -1, 3 ' -1, 4 ' -1, 5 ' -1 and comparative examples 1, 2, 3 was packed on the market in a simulated manner, and left at 40 ℃ and 75% relative humidity for 6 months, and the moisture, pH, color grade, content, related 1, related 2, polymer and the like were examined, and the results are shown in Table 12. The detection method of all the detection items is the same as above.
TABLE 121.5 g Specification cefuroxime sodium stability test results for injection
Figure BDA0002180310830000281
Figure BDA0002180310830000291
Figure BDA0002180310830000301
Figure BDA0002180310830000311
As seen from the results in tables 11 and 12, the products prepared in the examples of the present invention are superior in quality and stability to those prepared in the comparative examples 1 to 3, and after accelerated for 6 months, the retention time of the related substance 2 of the comparative examples 1 to 3 was 0.07 to 0.09% and the retention time of the related substance 2 of the comparative examples 1 to 3 was 0.01 to 0.04%; the retention times of 0.82 to 1.0 in each of the related matters 2 of comparative examples 1 to 3 exceeded 0.6%, while each of the examples was 0.30% to 0.39%. The invention strictly controls the generation of the related substance 2 through a special process, simultaneously has better control on impurities H, single impurities and total impurities in the related substance 1, further improves the product quality, and provides better selection for clinical medication.
The above is only a preferred embodiment of the present invention, and it should be understood that the present invention is not limited thereto, and those skilled in the art can make various modifications, decorations and equivalents without departing from the principle of the present invention, and therefore, the present invention is to be covered within the protection scope of the present invention.

Claims (5)

1. A preparation method of cefuroxime sodium raw material medicine is characterized by comprising the following steps:
(1) preparing a cefuroxime acid solution: respectively adding a mixed solvent of methanol, absolute ethyl alcohol and water into a material preparation tank A, stirring, controlling the temperature to 10-15 ℃, then adding cefuroxime acid, controlling the temperature to 10-15 ℃ and completely dissolving to obtain a cefuroxime acid solution with the concentration kg/L of 7-11% for later use;
(2) preparing a salt forming agent solution: adding 95% ethanol into the material preparing tank B, stirring, controlling the temperature to 10-15 ℃, then adding sodium acetate trihydrate, controlling the temperature to 10-15 ℃ and completely dissolving to obtain a salt forming agent solution with the concentration kg/L of 2.5% -4.0% for later use; the feeding molar ratio of the cefuroxime acid to the sodium acetate trihydrate is 1: 1.1;
(3) salt forming reaction: adding the methanol, the absolute ethyl alcohol, the water and the 95% ethyl alcohol which are 20% in volume respectively in the step (1) and the step (2) into a mixing tank C, stirring uniformly, pressurizing to 0.2MPa by using nitrogen, filtering the mixed solvent into an aseptic reaction tank by three-level sterilizing filtration of 0.45um, 0.22um and 0.22um, stirring, controlling the temperature to 10-15 ℃, adding sterile cefuroxime sodium seed crystal, then respectively performing three-level sterilizing filtration of 0.45um, 0.22um and 0.22um on the solutions in the mixing tank A and the mixing tank B according to a dropping scheme, dropping into the aseptic reaction tank, continuously stirring after dropping is finished, and cooling the obtained mixture to 5-10 ℃; performing solid-liquid separation in a sterile environment, washing the solid product with absolute ethyl alcohol for three times, and performing vacuum drying for 5-10 hours to obtain a sterile cefuroxime sodium raw material medicine; the addition amount of the seed crystal is 1 per mill of the cefuroxime acid; the dropping scheme is as follows:
Figure FDA0003159145840000011
2. the method for preparing cefuroxime sodium raw material drug according to claim 1, wherein in the step (3); the total volume L of the absolute ethyl alcohol used for washing the solid product is 4 times of the weight kg of the cefuroxime acid; the vacuum drying condition is drying at 35-45 deg.C and vacuum degree of-0.095 Mpa or less.
3. The method for preparing cefuroxime sodium raw material drug according to claim 1, which comprises the following steps:
(1) preparing a cefuroxime acid solution: respectively adding 55L of methanol, 108L of absolute ethyl alcohol and 2L of water into a clean stainless steel batching tank A, stirring, controlling the temperature of liquid in the stainless steel batching tank A to be 10-15 ℃, then adding 15kg of cefuroxime acid weighed in advance, controlling the temperature to be 10-15 ℃, and obtaining a cefuroxime acid solution for later use after complete dissolution;
(2) preparing a salt forming agent solution: respectively adding 165L of 95% ethanol into a clean stainless steel batching tank B, stirring, controlling the temperature of liquid in the stainless steel batching tank B to 10-15 ℃, then adding 5.29kg of sodium acetate trihydrate weighed in advance, controlling the temperature to 10-15 ℃, and completely dissolving to obtain a salt forming agent solution for later use;
(3) salt forming reaction: respectively adding 11L of methanol, 21.6L of absolute ethyl alcohol, 0.4L of water and 33L of 95% ethanol into a clean stainless steel batching tank C, uniformly stirring, pressurizing to 0.2MPa by using nitrogen, filtering a mixed solvent into an aseptic reaction tank through three-level sterilizing filtration of 0.45um, 0.22um and 0.22um, stirring, controlling the temperature of liquid in the aseptic reaction tank to 10-15 ℃, adding 15g of sterile cefuroxime sodium seed crystal weighed in advance, then respectively performing three-level sterilizing filtration of 0.45um, 0.22um and 0.22um on solutions in the batching tank A and the batching tank B according to a dropping scheme, dropping into the aseptic reaction tank, continuously stirring after dropping is finished, and cooling the obtained mixture to 5-10 ℃; performing solid-liquid separation in a sterile environment, washing the solid product with 60L of absolute ethyl alcohol for three times, and drying for 8 hours at 35-45 ℃ and a vacuum degree of less than or equal to-0.095 Mpa to obtain a sterile cefuroxime sodium raw material medicine;
wherein, the dropping scheme is as follows:
Figure FDA0003159145840000021
4. the method for preparing cefuroxime sodium raw material drug according to claim 1, which comprises the following steps:
(1) preparing a cefuroxime acid solution: respectively adding 275L of methanol, 540L of absolute ethyl alcohol and 10L of water into a clean stainless steel batching tank A, stirring, controlling the temperature of liquid in the stainless steel batching tank A to be 10-15 ℃, then adding 75kg of cefuroxime acid weighed in advance, controlling the temperature to be 10-15 ℃, and obtaining a cefuroxime acid solution for later use after complete dissolution;
(2) preparing a salt forming agent solution: respectively adding 825L 95% ethanol into a clean stainless steel mixing tank B, stirring, controlling the temperature of the liquid in the stainless steel tank B to 10-15 ℃, adding 26.45kg sodium acetate trihydrate weighed in advance, controlling the temperature to 10-15 ℃, and completely dissolving to obtain a salt forming agent solution for later use;
(3) salt forming reaction: respectively adding 55L of methanol, 108L of absolute ethyl alcohol, 2L of water and 165L of 95% ethanol into a clean stainless steel batching tank C, uniformly stirring, pressurizing to 0.2MPa by using nitrogen, filtering a mixed solvent into an aseptic reaction tank through three-level sterilizing filtration of 0.45um, 0.22um and 0.22um, stirring, controlling the temperature of liquid in the aseptic reaction tank to 10-15 ℃, adding 75g of sterile cefuroxime sodium seed crystals weighed in advance, then respectively performing three-level sterilizing filtration of 0.45um, 0.22um and 0.22um on solutions in the batching tank A and the batching tank B according to a dropping scheme, dropping into the aseptic reaction tank, continuously stirring after dropping is finished, and cooling the obtained mixture to 5-10 ℃; performing solid-liquid separation in a sterile environment, washing the solid product with 300L of absolute ethyl alcohol for three times, and drying at 35-45 ℃ and a vacuum degree of less than or equal to-0.095 Mpa for 8 hours to obtain a sterile cefuroxime sodium raw material medicine;
wherein, the dropping scheme is as follows:
Figure FDA0003159145840000031
5. a preparation method of cefuroxime sodium powder injection for injection is characterized by comprising the following steps:
the sterile cefuroxime sodium raw material drug prepared by the method according to any one of claims 1 to 4 is delivered to a sterile preparation workshop, is subpackaged by a screw rod under the grade A laminar flow, is filled with high-purity sterile nitrogen, is directly subpackaged according to different specifications to prepare cefuroxime sodium for injection with the specifications of 0.25g, 0.5g, 0.75g, 1.5g, 2.25g and 2.5g respectively, and the residual oxygen is controlled to be less than or equal to 2 percent.
CN201910793868.4A 2019-08-27 2019-08-27 Cefuroxime sodium raw material, injection and preparation method thereof Active CN110437260B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201910793868.4A CN110437260B (en) 2019-08-27 2019-08-27 Cefuroxime sodium raw material, injection and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910793868.4A CN110437260B (en) 2019-08-27 2019-08-27 Cefuroxime sodium raw material, injection and preparation method thereof

Publications (2)

Publication Number Publication Date
CN110437260A CN110437260A (en) 2019-11-12
CN110437260B true CN110437260B (en) 2021-12-31

Family

ID=68437705

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910793868.4A Active CN110437260B (en) 2019-08-27 2019-08-27 Cefuroxime sodium raw material, injection and preparation method thereof

Country Status (1)

Country Link
CN (1) CN110437260B (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103102357A (en) * 2013-02-21 2013-05-15 广东立国制药有限公司 Synthesis method of cefuroxime sodium
CN103374019A (en) * 2012-04-12 2013-10-30 珠海保税区丽珠合成制药有限公司 Preparation method of cefuroxlme sodium
CN104771372A (en) * 2015-03-10 2015-07-15 华北制药河北华民药业有限责任公司 Cefuroxime sodium powder preparation for injection
CN106361706A (en) * 2016-09-30 2017-02-01 华北制药河北华民药业有限责任公司 Cefuroxime sodium powder preparation for injection
CN106565748A (en) * 2016-09-30 2017-04-19 华北制药河北华民药业有限责任公司 Preparation method for cefuroxime sodium and preparation thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103374019A (en) * 2012-04-12 2013-10-30 珠海保税区丽珠合成制药有限公司 Preparation method of cefuroxlme sodium
CN103102357A (en) * 2013-02-21 2013-05-15 广东立国制药有限公司 Synthesis method of cefuroxime sodium
CN104771372A (en) * 2015-03-10 2015-07-15 华北制药河北华民药业有限责任公司 Cefuroxime sodium powder preparation for injection
CN106361706A (en) * 2016-09-30 2017-02-01 华北制药河北华民药业有限责任公司 Cefuroxime sodium powder preparation for injection
CN106565748A (en) * 2016-09-30 2017-04-19 华北制药河北华民药业有限责任公司 Preparation method for cefuroxime sodium and preparation thereof

Also Published As

Publication number Publication date
CN110437260A (en) 2019-11-12

Similar Documents

Publication Publication Date Title
CN101584665B (en) Cefotiam hydrochloride medicament composition sterile powder injection and preparation method thereof
CN105560194B (en) Cefotaxime powder-injection of high-purity and preparation method thereof
CN101856356B (en) Cefazedone sodium composition powder injection
CN103417512B (en) A kind of Biomox and preparation method thereof
CN103830192A (en) Tenofovir disoproxil fumarate tablets allowing direct powder compression and preparation method thereof
CN104876947A (en) Cefetamet pivoxil hydrochloride hydrate crystals and dispersible tablet thereof
CN103524532B (en) Ceftizoxime sodium compound crystal form, and preparing method and pharmaceutical preparation thereof
CN110437260B (en) Cefuroxime sodium raw material, injection and preparation method thereof
CN108030924B (en) Preparation method of high-stability aprepitant composition
CN117379378A (en) Compound amoxicillin soluble powder for livestock and preparation process thereof
CN103833773A (en) Cefathiamidine compound
CN104926835B (en) A kind of cefotiam hydrochloride compound, its preparation method and its pharmaceutical composition
CN104873501A (en) Sulbactam sodium composition for treating infectious diseases
CN104095809A (en) Pharmaceutical composition of clindamycin phosphate injection and preparation method
CN101780052B (en) Ceftizoxime sodium liposome injection
CN110563748B (en) Cefazolin sodium injection and preparation method thereof
CN102936254B (en) Drug composition containing ceftizoxime sodium compound
CN110101670B (en) Aztreonam injection preparation and preparation method thereof
CN100415230C (en) Dispersion tablets of penicillin V potassium, and its preparing method
CN109620804B (en) Ceftriaxone sodium powder injection preparation for injection and preparation method thereof
CN106432279A (en) Method for preparing medicine ceftriaxone sodium crystal compound for treating surgical infection
CN106432278A (en) Crystalline compound of drug ceftriaxone sodium for treating surgical operation infections
CN106432274A (en) Crystalline compound of drug ceftriaxone sodium for treating surgical operation infections
CN103304580B (en) Cefepime dihydrochloride compound as well as preparation method and medicine composition thereof
CN103304604B (en) Clindamycin phosphate compound and preparation method and pharmaceutical composition thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant