CN113876723A - Preparation process of cefotaxime sodium for injection - Google Patents
Preparation process of cefotaxime sodium for injection Download PDFInfo
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- CN113876723A CN113876723A CN202111331259.0A CN202111331259A CN113876723A CN 113876723 A CN113876723 A CN 113876723A CN 202111331259 A CN202111331259 A CN 202111331259A CN 113876723 A CN113876723 A CN 113876723A
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- cefotaxime
- sodium
- cefotaxime sodium
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- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 title claims abstract description 121
- 229960002727 cefotaxime sodium Drugs 0.000 title claims abstract description 121
- 238000002347 injection Methods 0.000 title claims abstract description 35
- 239000007924 injection Substances 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 76
- 239000000243 solution Substances 0.000 claims abstract description 68
- GPRBEKHLDVQUJE-VINNURBNSA-N cefotaxime Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1 GPRBEKHLDVQUJE-VINNURBNSA-N 0.000 claims abstract description 63
- 238000003756 stirring Methods 0.000 claims abstract description 47
- 239000013078 crystal Substances 0.000 claims abstract description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 33
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims abstract description 24
- 235000017281 sodium acetate Nutrition 0.000 claims abstract description 24
- 239000001632 sodium acetate Substances 0.000 claims abstract description 24
- 239000000843 powder Substances 0.000 claims abstract description 20
- 239000012046 mixed solvent Substances 0.000 claims abstract description 17
- 238000002156 mixing Methods 0.000 claims abstract description 15
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000001914 filtration Methods 0.000 claims abstract description 8
- 238000004108 freeze drying Methods 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 6
- 239000007788 liquid Substances 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 11
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 8
- 239000012528 membrane Substances 0.000 claims description 7
- 238000004659 sterilization and disinfection Methods 0.000 claims description 7
- 239000002131 composite material Substances 0.000 claims description 6
- LTGPFZWZZNUIIK-LURJTMIESA-N Lysol Chemical compound NCCCC[C@H](N)CO LTGPFZWZZNUIIK-LURJTMIESA-N 0.000 claims description 5
- 238000011049 filling Methods 0.000 claims description 5
- 238000007789 sealing Methods 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 4
- 239000007921 spray Substances 0.000 claims description 4
- 238000004042 decolorization Methods 0.000 claims description 2
- 230000001954 sterilising effect Effects 0.000 claims description 2
- 229960004261 cefotaxime Drugs 0.000 abstract description 15
- 238000001556 precipitation Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 239000012535 impurity Substances 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 238000002835 absorbance Methods 0.000 description 4
- 238000013461 design Methods 0.000 description 4
- 238000007086 side reaction Methods 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 206010005940 Bone and joint infections Diseases 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 241000588923 Citrobacter Species 0.000 description 1
- 241000588921 Enterobacteriaceae Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- YGBFLZPYDUKSPT-MRVPVSSYSA-N cephalosporanic acid Chemical class S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C[C@H]21 YGBFLZPYDUKSPT-MRVPVSSYSA-N 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000002270 exclusion chromatography Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- 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
-
- 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
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- 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
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
-
- 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
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation process of cefotaxime sodium for injection, which comprises the following steps: s1 mixing ethanol and n-propanol at a volume ratio of 7:2, and adding water to obtain a mixed solvent; s2, adding sodium acetate into the mixed solvent according to the material-to-liquid ratio of 50-80 mg/mL at 25-35 ℃ to obtain a sodium acetate solution; s3, adding cefotaxime acid into the sodium acetate solution according to the mass ratio of 1 (0.3-0.4), and stirring at constant temperature for reaction to obtain a cefotaxime-containing solution; s4 filtering and purifying; s5 sterile cefotaxime sodium seed crystals are added, ethanol is added dropwise while stirring, stirring and crystal growing are stopped after the dropwise adding is finished, the filtration and the freeze drying are carried out, cefotaxime sodium freeze-dried powder is obtained, and the cefotaxime sodium is bottled and sealed to obtain cefotaxime sodium for injection.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, and particularly relates to a preparation process of cefotaxime sodium for injection.
Background
The cefotaxime is the third-generation semi-synthesized cephalosporin, has wide antibacterial spectrum, and has strong activity on gram-negative bacteria such as Enterobacteriaceae bacteria such as Escherichia coli, Klebsiella, Citrobacter, Salmonella and the like. Because cefotaxime is a derivative of cephalosporanic acid, and free acid of cefotaxime is insoluble in water, the cefotaxime sodium salt injection is clinically applied to pneumonia, respiratory tract infection, urinary tract infection, meningitis, skin soft tissue infection, bone and joint infection and the like caused by various sensitive bacteria.
In order to improve the effect and safety of the medicine, strict control is generally required from two aspects of the medicine safety of the prescription design and the medicine quality safety of the production process. In the production and preparation process of cefotaxime sodium for injection, the cefotaxime sodium has high acid-base and stability sensitivity, so that the problems of impurity generation, low purity of the product, poor stability and the like easily occur due to degradation or side reaction of different degrees in the preparation process of cefotaxime sodium for injection. Therefore, how to control the occurrence of side reactions in the preparation process of cefotaxime sodium is still one of the major research hotspots at present. Therefore, a novel preparation process of cefotaxime sodium for injection is found to ensure the quality of cefotaxime sodium salt injection formulations and is beneficial to ensuring and improving the safety of clinical application of cefotaxime.
Disclosure of Invention
Therefore, the invention provides a preparation process of cefotaxime sodium for injection.
The technical scheme of the invention is realized as follows:
a preparation process of cefotaxime sodium for injection comprises the following steps:
s1, preparing a mixed solvent: mixing ethanol and n-propanol according to a volume ratio of 7 (1-2) to obtain a composite organic solvent, and adding water to prepare a mixed solvent with an organic solvent volume fraction of 50-70% for later use;
s2, under the condition that the temperature is controlled to be 25-35 ℃, adding sodium acetate into the mixed solvent prepared in the step 1 according to the material-liquid ratio of 50-80 mg/mL, and mixing and dissolving to obtain a sodium acetate solution;
s3, adding cefotaxime acid into a sodium acetate solution step by step according to the mass ratio of (0.3-0.4) 1, wherein the addition amount of the cefotaxime acid for the first time is 1/5 of the prescription amount of the cefotaxime acid, then adding the cefotaxime acid in an equivalent incremental manner according to the prescription amount of 1/10-1/15 of the cefotaxime acid, and stirring at constant temperature for reaction to obtain a solution containing cefotaxime sodium;
s4, adding activated carbon into the solution containing cefotaxime sodium for decolorization, and filtering by using an aseptic membrane to obtain a purified solution containing cefotaxime sodium;
s5, adding sterile cefotaxime sodium seed crystals into the cefotaxime sodium-containing purified solution obtained in the step 4, transferring the solution into a water bath at the temperature of 12-14 ℃, stirring the solution for 3-5 min at the speed of 80-90 r/min, dropwise adding ethanol while keeping stirring, cooling the water bath temperature to 1-5 ℃ at the speed of 0.5 ℃/min when dropwise adding ethanol, keeping the temperature constant until the dropwise adding is finished after the index temperature is reached, and stopping stirring and crystal growing for 60-120 min; carrying out suction filtration and freeze drying to obtain cefotaxime sodium freeze-dried powder;
s6, bottling the freeze-dried cefotaxime sodium powder, filling the freeze-dried cefotaxime sodium powder into a reagent bottle subjected to multi-stage sterilization according to the specification, and sealing to obtain cefotaxime sodium for injection.
Further, in the step S3, the stirring time is 40-60 min, and the temperature is controlled to be 40-50 ℃ during stirring.
Further, in S3, the first amount of cefotaxime acid was 1/5 of the amount prescribed for cefotaxime acid, and then added incrementally in equal amounts of 1/10.
Further, in the step S5, after adding the purified solution containing cefotaxime sodium into sterile cefotaxime sodium seed crystal, transferring the solution into a water bath at 13 ℃, stirring the solution at 85r/min for 4min, dropwise adding ethanol while keeping stirring, cooling the water bath to 3 ℃ at 0.5 ℃/min when dropwise adding ethanol, and keeping the temperature constant until the dropwise adding is completed after the target temperature is reached.
Further, in the S5, the volume ratio of the ethanol to the purified solution containing cefotaxime sodium is (5-8): 1, and the dropping speed is 3-5 mL/min.
Further, in the step S5, the mass ratio of the sterile cefotaxime sodium seed crystal to the added cefotaxime acid is 0.5: 100.
Further, in the S4, the adding amount of the activated carbon is 0.02-0.03 g/mL; the decoloring temperature is 40-50 ℃, the time is 30-40 min, and the aperture of the sterile membrane is 0.1-0.2 μm.
Further, in the S6, the freeze-dried powder of cefotaxime sodium is bottled at the room temperature of 10-20 ℃ and the humidity of less than or equal to 60%.
Further, in the S6, the reagent bottle is sterilized by spraying with lysol having a mass concentration of 0.2 to 0.3% and peracetic acid having a mass concentration of 1 to 1.5% in sequence.
Compared with the prior art, the invention has the beneficial effects that:
1) according to the preparation method of cefotaxime sodium for injection, provided by the invention, the combination of ethanol and n-propanol is used as a composite organic solvent, and the mixing condition between cefotaxime acid and a sodium acetate solution is strictly controlled in a stepwise increasing manner, so that the stable reaction rate is enhanced, and the reaction stability is improved.
2) On the basis of primary adsorption, filtration and purification of a solution containing cefotaxime sodium, sterile cefotaxime sodium seed crystals and ethanol are used as a elution agent, so that the agglomeration phenomenon is reduced, and full crystallization and precipitation of cefotaxime sodium are facilitated.
3) According to the method, the crystallization precipitation of cefotaxime sodium is controlled under the condition of water bath, the crystal granularity is uniform, meanwhile, the precipitation rate of cefotaxime sodium is controlled in a combined mode of short-time constant-temperature water bath seed crystal mixing and gradual water bath cooling, the degradation or side reaction of cefotaxime sodium in the precipitation process is reduced, and the yield and the purity are improved.
Detailed Description
In order to better understand the technical content of the invention, specific examples are provided below to further illustrate the invention.
The experimental methods used in the examples of the present invention are all conventional methods unless otherwise specified.
The materials, reagents and the like used in the examples of the present invention can be obtained commercially without specific description.
Example 1
A preparation process of cefotaxime sodium for injection comprises the following steps:
s1, preparing a mixed solvent: mixing ethanol and n-propanol at a volume ratio of 7:1 to obtain a composite organic solvent, and adding water to obtain a mixed solvent with an organic solvent volume fraction of 50% for later use;
s2, under the condition of controlling the temperature at 25 ℃, adding sodium acetate into the mixed solvent prepared in the step 1 according to the material-liquid ratio of 50mg/mL, and mixing and dissolving to obtain a sodium acetate solution;
s3, under the stirring state of 110r/min, adding cefotaxime acid into a sodium acetate solution step by step according to the mass ratio of 0.3:1, wherein the addition amount of the cefotaxime acid for the first time is 1/5 of the prescription amount of the cefotaxime acid, then adding the cefotaxime acid in an equivalent increasing mode of increasing the prescription amount of 1/10 of the cefotaxime acid each time in an increasing mode, keeping the constant temperature of 40 ℃ at an interval of 100S, and stirring for reacting for 40min to obtain a solution containing cefotaxime sodium;
s4, adding 0.02g/mL activated carbon into the solution containing cefotaxime sodium, decoloring at 40 ℃ for 30min, and filtering through a sterile membrane with the aperture of 0.1 mu m to obtain a purified solution containing cefotaxime sodium;
s5, adding sterile cefotaxime sodium seed crystals into the cefotaxime sodium-containing purified solution obtained in the step 4, wherein the mass ratio of the sterile cefotaxime sodium seed crystals to the added cefotaxime acid is 0.5:100, transferring the solution into a water bath at the temperature of 12 ℃, stirring the solution for 3min at the speed of 80r/min, dropwise adding ethanol while keeping stirring, wherein the volume ratio of the ethanol to the cefotaxime-containing purified solution is 5:1, the dropwise adding speed is 3mL/min, cooling the water bath to 1 ℃ at the speed of 0.5 ℃/min when dropwise adding ethanol, keeping the temperature of the water bath to be constant after the dropwise adding is finished, and stopping stirring and growing crystals for 60min after the dropwise adding is finished; carrying out suction filtration and freeze drying to obtain cefotaxime sodium freeze-dried powder;
s6, bottling the freeze-dried powder of cefotaxime sodium at the room temperature of 10 ℃ and the humidity of less than or equal to 60%, sequentially adopting 0.2% by mass of lysol and 1% by mass of peracetic acid to perform spray disinfection treatment on reagent bottles, filling the freeze-dried powder of cefotaxime sodium into the multistage disinfected reagent bottles according to the design specification, and sealing to obtain the cefotaxime sodium for injection.
Example 2
A preparation process of cefotaxime sodium for injection comprises the following steps:
s1, preparing a mixed solvent: mixing ethanol and n-propanol at a volume ratio of 7:2 to obtain a composite organic solvent, and adding water to obtain a mixed solvent with an organic solvent volume fraction of 70% for later use;
s2, under the condition of controlling the temperature at 35 ℃, adding sodium acetate into the mixed solvent prepared in the step 1 according to the material-liquid ratio of 80mg/mL, and mixing and dissolving to obtain a sodium acetate solution;
s3, under the stirring state of 130r/min, adding cefotaxime acid into a sodium acetate solution step by step according to the mass ratio of 0.4:1, wherein the addition amount of the cefotaxime acid for the first time is 1/5 of the prescription amount of the cefotaxime acid, then adding the cefotaxime acid in an equivalent increasing mode of increasing the prescription amount of 1/15 of the cefotaxime acid each time in an increasing mode, keeping the constant temperature of 50 ℃ at intervals of 120S, stirring and reacting for 60min to obtain a solution containing cefotaxime sodium;
s4, adding 0.03g/mL of activated carbon into the solution containing cefotaxime sodium, decoloring at 50 ℃ for 40min, and filtering through a sterile membrane with the aperture of 0.2 mu m to obtain a purified solution containing cefotaxime sodium;
s5, adding sterile cefotaxime sodium seed crystals into the cefotaxime sodium-containing purified solution obtained in the step 4, wherein the mass ratio of the sterile cefotaxime sodium seed crystals to the added cefotaxime acid is 0.5:100, transferring the solution into a water bath at 14 ℃, stirring the solution for 5min at the speed of 90r/min, dropwise adding ethanol while keeping stirring, wherein the volume ratio of the ethanol to the cefotaxime sodium-containing purified solution is 8:1, the dropwise adding speed is 5mL/min, cooling the water bath to 5 ℃ at the speed of 0.6 ℃/min when dropwise adding ethanol, keeping the temperature of the water bath to be constant after the dropwise adding is finished, and stopping stirring and growing crystals for 120min after the dropwise adding is finished; carrying out suction filtration and freeze drying to obtain cefotaxime sodium freeze-dried powder;
s6, bottling the freeze-dried powder of cefotaxime sodium at the room temperature of 20 ℃ and the humidity of less than or equal to 60%, sequentially adopting 0.3% by mass of lysol and 1.5% by mass of peracetic acid to perform spray disinfection treatment on reagent bottles, filling the freeze-dried powder of cefotaxime sodium into the multistage disinfected reagent bottles according to the design specification, and sealing to obtain the cefotaxime sodium for injection.
Example 3
A preparation process of cefotaxime sodium for injection comprises the following steps:
s1, preparing a mixed solvent: mixing ethanol and n-propanol at a volume ratio of 7:2 to obtain a composite organic solvent, and adding water to obtain a mixed solvent with an organic solvent volume fraction of 55% for later use;
s2, under the condition of controlling the temperature at 30 ℃, adding sodium acetate into the mixed solvent prepared in the step 1 according to the material-to-liquid ratio of 65mg/mL, and mixing and dissolving to obtain a sodium acetate solution;
s3, under the stirring state of 120r/min, adding cefotaxime acid into a sodium acetate solution step by step according to the mass ratio of 0.35:1, wherein the addition amount of the cefotaxime acid for the first time is 1/5 of the prescription amount of the cefotaxime acid, then adding the cefotaxime acid in an equivalent increasing mode of increasing the prescription amount of 1/10 of the cefotaxime acid each time in an increasing mode, keeping constant temperature of 45 ℃ at intervals of 120S, stirring and reacting for 50min to obtain a solution containing cefotaxime sodium;
s4, adding 0.03g/mL of activated carbon into the solution containing cefotaxime sodium, decoloring at 45 ℃ for 38min, and filtering through a sterile membrane with the aperture of 0.1 mu m to obtain a purified solution containing cefotaxime sodium;
s5, adding sterile cefotaxime sodium seed crystals into the cefotaxime sodium-containing purified solution obtained in the step 4, wherein the mass ratio of the sterile cefotaxime sodium seed crystals to the added cefotaxime acid is 0.5:100, firstly transferring the solution into a water bath at the temperature of 12 ℃, stirring the solution at the speed of 90r/min for 5min, dropwise adding ethanol at the dropwise adding speed of 3mL/min while keeping stirring, wherein the volume ratio of the ethanol to the cefotaxime sodium-containing purified solution is 6:1, in the process of dropwise adding the ethanol, reducing the temperature of the water bath to 3 ℃ at the speed of 0.5 ℃/min, keeping the temperature until the dropwise adding is finished, stopping stirring and growing crystals for 100min, dropwise adding the ethanol at the normal temperature of 85r/min while stirring, wherein the volume ratio of the ethanol to the cefotaxime-containing purified solution is 6:1, the dropwise adding speed is 4mL/min, and stopping stirring and growing crystals for 90min after the dropwise adding is finished; carrying out suction filtration and freeze drying to obtain cefotaxime sodium freeze-dried powder;
s6, bottling the freeze-dried powder of cefotaxime sodium at the room temperature of 18 ℃ and the humidity of less than or equal to 60%, sequentially adopting 0.25% by mass of lysol and 1.6% by mass of peracetic acid to perform spray disinfection treatment on reagent bottles, filling the freeze-dried powder of cefotaxime sodium into the multistage disinfected reagent bottles according to the design specification, and sealing to obtain the cefotaxime sodium for injection.
Example 4
Referring to the preparation steps of example 3, in step S5, according to the mass ratio of sterile cefotaxime sodium seed crystals to the added cefotaxime acid being 0.5:100, after adding a purified solution containing cefotaxime sodium into sterile cefotaxime sodium seed crystals, firstly transferring into a water bath at 13 ℃, stirring at a speed of 85r/min for 4min, dropwise adding ethanol at a dropwise adding speed of 3mL/min while keeping stirring, wherein the volume ratio of ethanol to the purified solution containing cefotaxime sodium is 6:1, in the process of dropwise adding ethanol, reducing the water bath temperature to 3 ℃ at 0.6 ℃/min, keeping the temperature until the dropwise adding is finished, stopping stirring and growing crystals for 100min after the dropwise adding is finished, and the rest steps are the same as those of example 3.
Example 5
Referring to the preparation steps of example 3, in step S5, according to the mass ratio of sterile cefotaxime sodium seed crystals to the added cefotaxime acid being 0.5:100, after adding a purified solution containing cefotaxime sodium into sterile cefotaxime sodium seed crystals, firstly transferring into a water bath at 13 ℃, stirring at a speed of 85r/min for 4min, dropwise adding ethanol at a dropwise adding speed of 4mL/min while keeping stirring, wherein the volume ratio of ethanol to the purified solution containing cefotaxime sodium is 6:1, in the process of dropwise adding ethanol, reducing the water bath temperature to 3 ℃ at 0.5 ℃/min, keeping the temperature until the dropwise adding is finished, stopping stirring and growing crystals for 100min after the dropwise adding is finished, and the rest steps are the same as those of example 3.
Example 6
A preparation process of cefotaxime sodium for injection is carried out according to the preparation steps of example 3, and the difference is that in step S5, according to the mass ratio of sterile cefotaxime sodium seed crystal to cefotaxime acid which is added in is 0.5:100, a purified solution containing cefotaxime sodium is added into the sterile cefotaxime sodium seed crystal, the mixture is transferred into a freezing chamber for 12 ℃, ethanol is dropwise added at the dropwise adding speed of 3mL/min under the stirring at the speed of 90r/min, in the process of dropwise adding ethanol, the temperature is reduced to 3 ℃ at the speed of 1 ℃/min, after the dropwise adding is finished, the stirring is stopped for growing crystals for 100min, and the rest steps are the same as those in example 3.
Example 7
A process for preparing cefotaxime sodium for injection, according to the preparation steps of example 3, in step S3, under the stirring condition of 120r/min, according to the mass ratio of 0.35:1, adding cefotaxime acid into the sodium acetate solution by 2 times of equal amount, wherein the addition amount of the cefotaxime acid for 2 times is 1/2 of the prescription amount of the cefotaxime acid, and stirring and reacting for 50min at constant temperature of 45 ℃ to obtain a solution containing cefotaxime sodium.
Comparative example 1
A process for preparing cefotaxime sodium for injection, which is different from the process of example 3 in that: in step S3, adding cefotaxime acid into the sodium acetate solution at a mass ratio of 0.4:1 once under the stirring condition of 120r/min, and stirring and reacting at a constant temperature of 45 ℃ for 50min to obtain a cefotaxime-containing solution.
According to the preparation process of cefotaxime sodium for injection in the embodiments 3-7 and the comparative example 1, cefotaxime acid in each group is equal, cefotaxime sodium freeze-dried powder is obtained by freeze drying in the same environment as the experiment groups 1-6, the yield of the cefotaxime sodium freeze-dried powder is counted, and equal sampling is carried out.
Measurement of absorbance of the sample: measuring absorbance by ultraviolet spectrophotometry, accurately weighing the sample to be tested, preparing into 0.1g/mL solution, measuring at the specified wavelength (430nm) by ultraviolet-visible spectrophotometry (general rule 0401), and determining according to the specification of 'Chinese pharmacopoeia' 2020 edition that the absorbance should not exceed 0.20.
And (3) determining the content of related substances in the sample: measuring by high performance liquid chromatography (general rule 0512), and measuring and inspecting the main component and impurity content of cefotaxime sodium by using an octadecylsilane chemically bonded silica chromatographic column (4.6mm multiplied by 200mm,5 mu m) according to a method for measuring related substances of cefotaxime sodium in 'Chinese pharmacopoeia' 2020 edition;
assay sample cefotaxime polymer: the content of the cefotaxime polymer is not over marked by 1 percent according to the regulation of China pharmacopoeia 2020 edition by measuring according to a molecular exclusion chromatography (general rule 0514), and the results are shown in the following table 1:
TABLE 1
As can be seen from the above table, in embodiments 3 to 5 of the present invention, the yield of the cefotaxime sodium finished product for injection is increased, the absorbance is not more than 0.05, the purity of the cefotaxime sodium product is high, the content of the main component is more than 99.0%, wherein the yield of embodiment 5 can reach as high as 91.5, the content of impurities is significantly reduced, and the content of the cefotaxime polymer can be less than 0.05%; the yield of the cefotaxime sodium product prepared in the embodiment 6 is reduced, the impurity content is improved, wherein the content of a cefotaxime polymer is obviously increased, which indicates that byproducts are easily generated in the crystallization precipitation process of the cefotaxime sodium, and indicates that the cefotaxime sodium is crystallized and precipitated by controlling the water bath temperature condition, and compared with the traditional single cooling mode for precipitation, the method can better control the precipitation rate of the cefotaxime sodium, reduce the degradation or side reaction of the cefotaxime sodium in the precipitation process and improve the yield and the purity by utilizing a combination mode of short-time constant-temperature water bath seed crystal mixing and gradual water bath cooling; example 7 changes the mixing conditions of cefotaxime acid and sodium acetate solution, and the purity of the product is reduced, which indicates that the impurity content is higher in the reaction process of cefotaxime acid and sodium acetate solution; in the comparative example 1, the ratio of the sodium acetate solution to the cefotaxime acid is changed, the yield of the product is reduced, the purity of the product is obviously reduced, and the content of the cefotaxime polymer is increased.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (9)
1. A preparation process of cefotaxime sodium for injection is characterized by comprising the following steps: the method comprises the following steps:
s1, preparing a mixed solvent: mixing ethanol and n-propanol according to a volume ratio of 7 (1-2) to obtain a composite organic solvent, and adding water to prepare a mixed solvent with an organic solvent volume fraction of 50-70% for later use;
s2, under the condition that the temperature is controlled to be 25-35 ℃, adding sodium acetate into the mixed solvent prepared in the step 1 according to the material-liquid ratio of 50-80 mg/mL, and mixing and dissolving to obtain a sodium acetate solution;
s3, adding cefotaxime acid into a sodium acetate solution step by step according to the mass ratio of (0.3-0.4) 1, wherein the addition amount of the cefotaxime acid for the first time is 1/5 of the prescription amount of the cefotaxime acid, then adding the cefotaxime acid in an equivalent incremental manner according to the prescription amount of 1/10-1/15 of the cefotaxime acid, and stirring at constant temperature for reaction to obtain a solution containing cefotaxime sodium;
s4, adding activated carbon into the solution containing cefotaxime sodium for decolorization, and filtering by using an aseptic membrane to obtain a purified solution containing cefotaxime sodium;
s5, adding sterile cefotaxime sodium seed crystals into the cefotaxime sodium-containing purified solution obtained in the step 4, transferring the solution into a water bath at the temperature of 12-14 ℃, stirring the solution for 3-5 min at the speed of 80-90 r/min, dropwise adding ethanol while keeping stirring, cooling the water bath temperature to 1-5 ℃ at the speed of 0.5-0.6 ℃/min when dropwise adding ethanol, keeping the temperature constant until the dropwise adding is finished after the index temperature is reached, and stopping stirring and crystal growing for 60-120 min; carrying out suction filtration and freeze drying to obtain cefotaxime sodium freeze-dried powder;
s6, bottling the freeze-dried cefotaxime sodium powder, filling the freeze-dried cefotaxime sodium powder into a reagent bottle subjected to multi-stage sterilization according to the specification, and sealing to obtain cefotaxime sodium for injection.
2. A process for preparing cefotaxime sodium for injection according to claim 1, wherein: in the step S3, the stirring time is 40-60 min, and the temperature is controlled to be 40-50 ℃ during stirring.
3. A process for preparing cefotaxime sodium for injection according to claim 2, wherein: in S3, the first amount of cefotaxime acid was added 1/5 of the amount prescribed for cefotaxime acid, followed by an equal incremental addition of 1/10 of the amount prescribed for cefotaxime acid.
4. A process for preparing cefotaxime sodium for injection according to claim 1, wherein: in the step S5, the purified solution containing cefotaxime sodium is added into sterile cefotaxime sodium seed crystal, then the mixture is transferred into a water bath at the temperature of 13 ℃, the mixture is stirred for 4min at the speed of 85r/min, ethanol is dropwise added while the stirring is kept, the temperature of the water bath is reduced to 3 ℃ at the speed of 0.5 ℃/min when the ethanol is dropwise added, and the temperature is maintained until the dropwise addition is finished after the index temperature is reached.
5. A process according to claim 4 for the preparation of cefotaxime sodium for injection, wherein: in the S5, the volume ratio of the ethanol to the purified solution containing cefotaxime sodium is (5-8): 1, and the dropping speed is 3-5 mL/min.
6. A process according to claim 4 for the preparation of cefotaxime sodium for injection, wherein: in the step S5, the mass ratio of the sterile cefotaxime sodium seed crystal to the added cefotaxime acid is 0.5: 100.
7. A process for preparing cefotaxime sodium for injection according to claim 1, wherein: in the S4, the adding amount of the activated carbon is 0.02-0.03 g/mL; the decoloring temperature is 40-50 ℃, the time is 30-40 min, and the aperture of the sterile membrane is 0.1-0.2 μm.
8. A process for preparing cefotaxime sodium for injection according to claim 1, wherein: in the S6, the freeze-dried powder of cefotaxime sodium is bottled at the room temperature of 10-20 ℃ and the humidity of less than or equal to 60%.
9. A process for preparing cefotaxime sodium for injection according to claim 1, wherein: in the S6, the reagent bottle multi-stage disinfection method comprises the steps of sequentially carrying out spray disinfection treatment by adopting 0.2-0.3% by mass of lysol and 1-1.5% by mass of peracetic acid.
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| CN117323301A (en) * | 2023-11-08 | 2024-01-02 | 上海金城素智药业有限公司 | High-quality cefotaxime sodium preparation for injection and preparation method thereof |
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