CN110003240A - A kind of Cefminox sodium raw materials and preparation method thereof and preparation - Google Patents
A kind of Cefminox sodium raw materials and preparation method thereof and preparation Download PDFInfo
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- CN110003240A CN110003240A CN201910370340.6A CN201910370340A CN110003240A CN 110003240 A CN110003240 A CN 110003240A CN 201910370340 A CN201910370340 A CN 201910370340A CN 110003240 A CN110003240 A CN 110003240A
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- Prior art keywords
- cefminox sodium
- sodium
- cefminox
- raw materials
- preparation
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- JSDXOWVAHXDYCU-VXSYNFHWSA-N cefminox Chemical compound S([C@@H]1[C@@](C(N1C=1C(O)=O)=O)(NC(=O)CSC[C@@H](N)C(O)=O)OC)CC=1CSC1=NN=NN1C JSDXOWVAHXDYCU-VXSYNFHWSA-N 0.000 title claims abstract description 108
- 239000002994 raw material Substances 0.000 title claims abstract description 58
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 239000007924 injection Substances 0.000 claims abstract description 27
- 238000002347 injection Methods 0.000 claims abstract description 27
- 239000001509 sodium citrate Substances 0.000 claims abstract description 17
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims abstract description 17
- 239000000463 material Substances 0.000 claims abstract description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- 239000012043 crude product Substances 0.000 claims description 23
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 18
- 239000000126 substance Substances 0.000 claims description 11
- 238000002425 crystallisation Methods 0.000 claims description 9
- 230000008025 crystallization Effects 0.000 claims description 9
- 239000012065 filter cake Substances 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 9
- 229910052708 sodium Inorganic materials 0.000 claims description 9
- 239000011734 sodium Substances 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 238000010792 warming Methods 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- 208000015181 infectious disease Diseases 0.000 claims description 4
- 235000007164 Oryza sativa Nutrition 0.000 claims description 3
- 230000001580 bacterial effect Effects 0.000 claims description 3
- 235000009566 rice Nutrition 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 2
- 240000007594 Oryza sativa Species 0.000 claims 1
- 229940090044 injection Drugs 0.000 abstract description 19
- 238000012360 testing method Methods 0.000 abstract description 15
- 239000003814 drug Substances 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 8
- 238000009472 formulation Methods 0.000 abstract description 6
- 239000000203 mixture Substances 0.000 abstract description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 abstract description 5
- 239000013078 crystal Substances 0.000 abstract description 4
- 239000013618 particulate matter Substances 0.000 abstract description 4
- 229940093181 glucose injection Drugs 0.000 abstract description 3
- 239000008354 sodium chloride injection Substances 0.000 abstract description 3
- 230000007774 longterm Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 30
- 239000012535 impurity Substances 0.000 description 17
- 229960002025 cefminox Drugs 0.000 description 12
- 230000014759 maintenance of location Effects 0.000 description 10
- 239000012085 test solution Substances 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 9
- 239000007788 liquid Substances 0.000 description 8
- 229920000642 polymer Polymers 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 238000011049 filling Methods 0.000 description 6
- 230000035945 sensitivity Effects 0.000 description 6
- 229930186147 Cephalosporin Natural products 0.000 description 5
- 229940124587 cephalosporin Drugs 0.000 description 5
- 150000001780 cephalosporins Chemical class 0.000 description 5
- -1 2- amino -2- carboxylethylthio Chemical group 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 4
- GRTOGORTSDXSFK-XJTZBENFSA-N ajmalicine Chemical compound C1=CC=C2C(CCN3C[C@@H]4[C@H](C)OC=C([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 GRTOGORTSDXSFK-XJTZBENFSA-N 0.000 description 4
- 150000008064 anhydrides Chemical class 0.000 description 4
- 238000007689 inspection Methods 0.000 description 4
- 238000013112 stability test Methods 0.000 description 4
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000356 contaminant Substances 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000013557 residual solvent Substances 0.000 description 3
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000001433 sodium tartrate Substances 0.000 description 3
- 229960002167 sodium tartrate Drugs 0.000 description 3
- 235000011004 sodium tartrates Nutrition 0.000 description 3
- 108090000204 Dipeptidase 1 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000209094 Oryza Species 0.000 description 2
- 206010035664 Pneumonia Diseases 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000002924 anti-infective effect Effects 0.000 description 2
- 102000006635 beta-lactamase Human genes 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 235000013339 cereals Nutrition 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940126678 chinese medicines Drugs 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 206010034674 peritonitis Diseases 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 241000606125 Bacteroides Species 0.000 description 1
- 241000606124 Bacteroides fragilis Species 0.000 description 1
- 208000014085 Chronic respiratory disease Diseases 0.000 description 1
- 208000003322 Coinfection Diseases 0.000 description 1
- 241000194033 Enterococcus Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010056254 Intrauterine infection Diseases 0.000 description 1
- 208000032376 Lung infection Diseases 0.000 description 1
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 206010049677 Salpingo-oophoritis Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 206010044302 Tracheitis Diseases 0.000 description 1
- 206010000269 abscess Diseases 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 208000003167 cholangitis Diseases 0.000 description 1
- 201000001352 cholecystitis Diseases 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002270 exclusion chromatography Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229940126680 traditional chinese medicines Drugs 0.000 description 1
- 210000004291 uterus Anatomy 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
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- 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
- C07D501/12—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
- C07D501/57—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with a further substituent in position 7, e.g. cephamycines
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)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to biomedicine technical fields, and in particular to a kind of Cefminox sodium raw materials and preparation method thereof and preparation；Applicant is by test creative for many years, obtain a kind of new Cefminox sodium crystal, the crystal form drug is prepared into new powder-injection after combining with auxiliary material sodium citrate, after being mixed with sodium chloride injection or glucose injection, maintaining a long-term stability property, particulate matter etc. hardly increases, and further illustrates that invention formulation has better stability.
Description
Technical field
The invention belongs to biomedicine technical fields, and in particular to a kind of Cefminox sodium raw materials and preparation method thereof and system
Agent.
Background technique
Cefminox is the forth generation cephalosporin analog antibiotic (trade name developed by Japanese Mingzhi's pharmacy), the 7 α-methoxy based structures of Cefminox are lacked by other cephalosporins, by conjunction with penicillin
The 1A of albumen (PBP), 1B and 3 have very strong compatibility, inhibit the synthesis of bacteria cell wall, and are incorporated into peptide polysaccharide, peptide for inhibiting
Polysaccharide promotes bacteriolyze in conjunction with ester gp, can show powerful disinfection vitality in a short time, to play strong bactericidal effect.
This product has a broad spectrum antibiotic activity to Grain-positive and gram-negative bacteria, especially to streptococcus (except enterococcus),
The primary liver bacterium of Escherichia coli, kerekou pneumonia, Proteus, haemophilus influenzae, Bacteroides have very strong antibacterial action.This product
The beta lactamase that various bacterial strains generate is stablized, the beta-lactamase enzyme generated to bacteroides fragilis is especially stable.
The medicine is mainly used for septicemia caused by sensitive bacteria, circumtonsillar abscess, tracheitis, capillary bronchitis, branch gas
Enlargement of pipe infection or the secondary infection of chronic respiratory disease, pneumonia, the change of pulmonary suppuration venereal disease, nephropyelitis, cystitis, gall-bladder
Inflammation, cholangitis, peritonitis, pelvic peritonitis, adnexitis, intra-uterine infection, pelvic cavity class, uterus side inflammation of connective tissue etc..
Monitoring after Japan's listing in 4 years by a definite date shows do not have special side effect in the crowd for including old man and pregnant woman,
Using similar to other cephalosporins medicines.
Currently, the whole world, which expects medical market sales volume in 2018, is up to 500,000,000,000~606,000,000,000 dollars, wherein resisting
The 15% of the infection total share of medication Zhan, about 60,000,000,000 dollars.Cephalosporins occupy always anti-infective medication in the past 10 years
First.It is reported according to foreign countries, 45% for selling volume and accounting for all anti-infective medications of Cephalosporins, annual sales amount is about
23000000000 dollars.
The Cefminox preparation of sodium of present above-mentioned sale is powder-injection, but the powder-injection faces after matching in clinical use,
It needs to inject in 4 hours and finish, and the nurse of many hospitals is clinically, faces the drug workload matched and injects medicine to patient
The workload of object is all very big, and therefore, completion cannot be injected in 4 hours by causing to face the cefminox sodium matched, and brings to patient
Therefore certain risk studies new cefminox sodium and its preparation, is of great significance.
Summary of the invention
For these reasons, in order to solve the deficiencies in the prior art, applicant obtains one by test creative for many years
The new Cefminox sodium crystal of kind, which is prepared into new powder-injection after combining with auxiliary material sodium citrate, with sodium chloride
After injection or glucose injection mixing, maintaining a long-term stability property, particulate matter etc. hardly increases.
The present invention is after test of many times, and in multi-drug auxiliary material of comforming, screening obtains sodium citrate, is prepared into powder-injection.
To achieve the above object, technical scheme is as follows:
A kind of Cefminox sodium raw materials, the Cefminox sodium raw materials are prepared by the following method: taking cefminox sodium thick
Product are added tetrahydrofuran dissolution completely, after acetone is added, are crystallized, obtain cefminox sodium bulk pharmaceutical chemicals.
Wherein the weight grams of cefminox sodium crude product and the volume ml of tetrahydrofuran in the preparation method of the raw material
Than for 1:3.5-5.
Wherein cefminox sodium crude product weight grams and acetone volume ml ratio are 1 in the preparation method of the raw material:
4.5-6。
Wherein raw material the preparation method comprises the following steps:
Cefminox sodium crude product is taken, tetrahydrofuran is added, is warming up to 40-50 DEG C, acetone is added, stirs evenly, 5 DEG C -10
It DEG C stands, crystallization is precipitated, filtering, filter cake acetone washing is dry, obtains Cefminox sodium raw materials.
A kind of Cefminox sodium injection is prepared by Cefminox sodium raw materials described above with sodium citrate.
Wherein the weight ratio of Cefminox sodium raw materials and sodium citrate raw material is 1:0.04-0.06.
Wherein the weight ratio of Cefminox sodium raw materials and sodium citrate raw material is 1:0.05.
The Cefminox sodium raw materials the preparation method comprises the following steps: take cefminox sodium crude product, tetrahydrofuran is added, is warming up to
40-50 DEG C, acetone is added, stirs evenly, crystallization is precipitated in 5 DEG C of -10 DEG C of standings, and filtering, filter cake acetone washing is dry, obtains
Cefminox sodium raw materials；The weight grams of cefminox sodium crude product and the volume ml of tetrahydrofuran are than being 1:3.5-5；Cephalo
Minot sodium crude product weight grams and acetone volume ml are than being 1:4.5-6.
A kind of Cefminox sodium injection, preferred Cefminox sodium raw materials the preparation method comprises the following steps: taking cephalo rice
Tetrahydrofuran is added in promise sodium crude product, is warming up to 45 DEG C, and acetone is added, stirs evenly, and crystallization, mistake is precipitated in 5 DEG C of -10 DEG C of standings
Filter, filter cake acetone washing is dry, obtains Cefminox sodium raw materials；The weight grams and tetrahydrofuran of cefminox sodium crude product
Volume ml than be 1:4.5；Cefminox sodium crude product weight grams and acetone volume ml are than being 1:5.5.
The powder-injection infects caused by treating sensitive bacterial in preparation.
Cefminox sodium crude product of the present invention: being provided by Harbin Yu Heng pharmaceutical Co. Ltd, buys the date 2018
On March 25, in.
It is calculated in cefminox sodium crude product of the present invention by anhydride, (the C containing Cefminox16H21N7O7S3) content is
85.9%.
Of the present invention and preparation method obtains: Cefminox sodium raw materials are as follows: is (+)-(6R, 7S) -7- [(S) -2-
(2- amino -2- carboxylethylthio) acetylamino] -7- methoxyl group -3- [[(l- methyl-1 H- tetrazole -5- base) sulfenyl] first
Base] -8 oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid sodium heptahydrates, meet Chinese Pharmacopoeia 2015 editions
About all standard under cefminox sodium item.
Tetrahydrofuran of the present invention, acetone and other organic solvent, are purchased from the limited public affairs in Chinese medicines group chemical reagent Beijing
Department buys January 11 2018 date.
The auxiliary materials such as sodium citrate of the present invention are purchased from Chinese medicines group chemical reagent Beijing Co., Ltd, buy the date
On January 11st, 2018.
This hair has following beneficial technical effects:
1, feed preparation process is simple, is suitble to industrialized production.
2, preparation method of the present invention obtains raw material and is prepared into powder-injection, and solubility is good, and impurity content variation is small, insoluble micro-
Grain incrementss are small.
3, sodium citrate is added in invention formulation, helps to redissolve, invention formulation is in sodium chloride solution and glucose
Stability is high in solution.
Detailed description of the invention
Fig. 1 embodiment 3 obtains Cefminox sodium raw materials crystal form map.It is surveyed by grand reputation wing Yao (Beijing) Science and Technology Ltd.
It is fixed.
Specific embodiment
The following describes the present invention further through the description of specific embodiments, but it is to limit of the invention that this, which is not,
System, those skilled in the art's basic thought according to the present invention can make various modifications or improvements, but without departing from this
The basic thought of invention, is all within the scope of the present invention.
The present invention following test commissions Shen Yao (Xianghe) Science and Technology Ltd. completes.
Prepare embodiment
Embodiment 1
Cefminox sodium crude product 100g is taken, tetrahydrofuran 350mL is added, is warming up to 40 DEG C, acetone 450mL, stirring is added
Uniformly, crystallization is precipitated in 5 DEG C of -10 DEG C of standings, and filtering, filter cake acetone washing is dry, obtains Cefminox sodium raw materials 78.2g；
After testing, residual solvent meets standards of pharmacopoeia in Cefminox sodium raw materials.Through detecting: for (+)-(6R, 7S) -7- [(S) -
2- (2- amino -2- carboxylethylthio) acetylamino] -7- methoxyl group -3- [[(l- methyl-1 H- tetrazole -5- base) sulfenyl] first
Base] -8 oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid sodium heptahydrates.It is calculated by anhydride, contains head
Spore minot (C16H21N7O7S3) 99.7%.Related substance I: single maximum contaminant is 0.014%, total impurities 0.078%；It is related
Substance II: impurity of the relative retention time between 0.82~0.10 is 0.011%, and impurity of the relative retention time less than 0.82 is
It is not detected.
Embodiment 2
Cefminox sodium crude product 100g is taken, tetrahydrofuran 500mL is added, is warming up to 45 DEG C, acetone 600mL, stirring is added
Uniformly, crystallization is precipitated in 5 DEG C of -10 DEG C of standings, and filtering, filter cake acetone washing is dry, obtains Cefminox sodium raw materials 79.4g；
After testing, residual solvent meets States Pharmacopoeia specifications in Cefminox sodium raw materials.Through detecting: for (+)-(6R, 7S) -7- [(S) -
2- (2- amino -2- carboxylethylthio) acetylamino] -7- methoxyl group -3- [[(l- methyl-1 H- tetrazole -5- base) sulfenyl] first
Base] -8 oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid sodium heptahydrates.It is calculated by anhydride, contains head
Spore minot (C16H21N7O7S3) 99.5%.Related substance I: single maximum contaminant is 0.016%, total impurities 0.124%；It is related
Substance II: impurity of the relative retention time between 0.82~0.10 is 0.014%, and impurity of the relative retention time less than 0.82 is
It is not detected.
Embodiment 3
Cefminox sodium crude product 100g is taken, tetrahydrofuran 450mL is added, is warming up to 50 DEG C, acetone 550mL, stirring is added
Uniformly, crystallization is precipitated in 5 DEG C of -10 DEG C of standings, and filtering, filter cake acetone washing is dry, obtains Cefminox sodium raw materials 81.5g；
After testing, residual solvent meets States Pharmacopoeia specifications in Cefminox sodium raw materials.Through detecting: for (+)-(6R, 7S) -7- [(S) -
2- (2- amino -2- carboxylethylthio) acetylamino] -7- methoxyl group -3- [[(l- methyl-1 H- tetrazole -5- base) sulfenyl] first
Base] -8 oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid sodium heptahydrates.It is calculated by anhydride, contains head
Spore minot (C16H21N7O7S3) 99.8%.Related substance I: single maximum contaminant is 0.010%, total impurities 0.065%；It is related
Substance II: impurity of the relative retention time between 0.82~0.10 is 0.011%, and impurity of the relative retention time less than 0.82 is
It is not detected.
[related substance I]
It takes this product appropriate, adds flowing phased soln and dilute and be made in every lml containing about the solution of Cefminox 1.0mg, as
Test solution；Precision measures in right amount, is quantitatively diluted and is made in every lml containing about the solution of Cefminox 10mg with mobile phase, made
For contrast solution；Precision measures contrast solution lml, is quantitatively diluted and is made in every lm l containing about Cefminox 0.5mg with mobile phase
Solution, as sensitivity solution.According to the chromatographic condition under content determination item, 100 μ l liquid chromatograph of sensitivity solution is taken, it is main
The signal-to-noise ratio of ingredient peak height should be greater than 10.Precision measures test solution and each 10 μ l of contrast solution, is injected separately into liquid chromatogram
Instrument, 3.5 times of record chromatogram to principal component peak retention time.If any impurity peaks, single impurity in test solution chromatogram
Peak area is not greater than 0.5 times (0.5%) of contrast solution main peak area, and the sum of each impurity peak area is not greater than contrast solution
1.5 times (1.5%) of main peak area.It ignores at peak in test solution chromatogram less than sensitivity solution main peak area.
[related substance II]
Face and uses brand-new.Take this product appropriate, accurately weighed, being dissolved in water and quantifying dilution is made in every lm l containing about cephalo rice
The solution of promise 1.0mg, as test solution；Separately take Cefminox reference substance appropriate, it is accurately weighed, it is dissolved in water and quantitative dilute
It releases and is made containing about the solution of 5 μ g in every lm l, as contrast solution；Precision measures contrast solution 1ml, is quantitatively diluted with mobile phase
It is made containing about the solution of 0.2 μ g in every lml, as sensitivity solution.It is measured according to molecular exclusion chromatography (general rule 0514).Use ball
Shape hydrophilic modifying silica gel (the molecular weight scope of application is polymer 500~15000) be filler (TSK-GEL G2000swxl,
7.8mm × 30cm, 5 μm or the comparable chromatographic column of efficiency are with phosphate buffer (pH 7.0) [0.005mol/L disodium hydrogen phosphate
Solution -0.005mol/L sodium dihydrogen phosphate (61:39)]-acetonitrile (95:5) be mobile phase, flow velocity be 0.8ml per minute, inspection
Survey wavelength is 254nm.Test solution 10ml is taken, 0.lmol/L sodium hydroxide solution 1ml is added, is placed at room temperature for 1 minute, then plus
0.lmol/L hydrochloric acid solution 1ml, shakes up, as system suitability solution.It takes 10 μ l to inject liquid chromatograph, records chromatogram；
Cefminox peak retention time is about 12 minutes, and the Cefminox peak separating degree peak-to-peak with adjacent degradation impurity before it should conform to
It asks.It takes 10 μ l of sensitivity solution to infuse people's liquid chromatograph, records chromatogram, the signal-to-noise ratio of principal component peak height should be greater than 10.It is accurate
Test solution and each 10 μ l of contrast solution are measured, liquid chromatograph is injected separately into, records chromatogram；Test solution chromatogram
In if any impurity peaks, impurity peak area of the relative retention time between 0.82~0.10 is not greater than contrast solution main peak area
(0.5%), the sum of impurity peak area of the relative retention time less than 0.82 is not greater than 0.6 times of contrast solution main peak area
(0.3%), the peak in test solution chromatogram less than sensitivity solution main peak area is ignored.
According to " measurement of cefminox sodium the high molecular polymer " [survey of Gao Danling cefminox sodium high molecular polymer
Fixed (J), Strait Pharmaceutical Journal, 2006,18 (6): 45-47] content of high molecular polymer in measurement each sample.
[assay] is measured according to high performance liquid chromatography (general rule 0512).
Chromatographic condition and system suitability are filler with octadecylsilane chemically bonded silica；With acetum (1 →
100)-methanol-tetrahydrofuran (990:5:5) is mobile phase, Detection wavelength 254nm.Cefminox system suitability is taken to compare
Appropriate product are dissolved in water and dilute the solution being made in every lm l containing about lmg, and 10 μ l is taken to inject liquid chromatograph, the color of record
Spectrogram should be consistent with standard diagram.
Measuring method takes this product appropriate, accurately weighed, and being dissolved in water and quantifying dilution is made in every lml containing about Cefminox
The solution of 1.0mg, as test solution, precision measures 10 μ l and infuses people's liquid chromatograph, records chromatogram；Separately take Cefminox
Appropriate reference substance is measured in the same method.By external standard method with C in calculated by peak area test sample16H21N7O7S3Content.
Embodiment 4
Preparation prescription are as follows: embodiment 2 Cefminox sodium raw materials 10g, sodium citrate 0.4g；
The preparation method comprises the following steps: sterile cefminox sodium is taken to mix with sterile sodium citrate completely, and it is filling, obtain powder-injection 100
Branch.
Embodiment 5
Preparation prescription are as follows: embodiment 2 Cefminox sodium raw materials 10g, sodium citrate 0.6g；
The preparation method comprises the following steps: sterile cefminox sodium is taken to mix with sterile sodium citrate completely, and it is filling, obtain powder-injection 100
Branch.
Embodiment 6
Preparation prescription are as follows: embodiment 2 Cefminox sodium raw materials 10g, sodium citrate 0.5g；
The preparation method comprises the following steps: sterile cefminox sodium is taken to mix with sterile sodium citrate completely, and it is filling, obtain powder-injection 100
Branch.
The above-mentioned preparation of the present invention meets Chinese Pharmacopoeia (2015 editions) about requirements under cefminox sodium for injection item, adds
Speed test and stability test also comply with requirement.
Comparative example 1
Commercially available Cefminox sodium raw materials (are purchased from Hainan Xinshitong Pharmaceutical Co., Ltd, national drug standard H20058078, purchase
March 3 2018 date)
Test 1
Raw material stability test
The chemical stability of Cefminox sodium raw materials and commercially available Cefminox sodium raw materials to embodiment 1-3 is ground
Study carefully, investigation condition is high temperature (60 DEG C ± 2 DEG C), strong illumination (4500Lx ± 500lx), high humidity (92.5%, RH) inspection target
For appearance, content and related substance.
Test result is shown in Table 1.
Conclusion (of pressure testing): it is above-mentioned experiments have shown that: (1) the related substance of Cefminox sodium raw materials of the present invention, high molecular polymer contain
Amount is lower than the material content of the cefminox sodium of comparative example 1, has more excellent product quality；
(2) show that the related substance of the present invention and high molecular polymer incrementss are small by stability test, and comparative example
The 1 related substance of Cefminox sodium raw materials, high molecular polymer changes of contents are big, absolutely prove Cefminox sodium raw materials of the present invention
With better stability.
Test 2
Preparation stability test
Comparative example 2: 2 Cefminox sodium raw materials 10g, sodium tartrate 0.5g of the embodiment of the present invention；
Formulation preparation method: taking sterile Cefminox sodium raw materials and sterile sodium tartrate to mix completely, filling, obtains powder needle
Agent 100.
Comparative example 3: 2 Cefminox sodium raw materials 10g, sodium carbonate 0.5g of the embodiment of the present invention；
Formulation preparation method: taking sterile Cefminox sodium raw materials and sterile sodium carbonate to mix completely, filling, obtains powder-injection
100.
Comparative example 4: 2 Cefminox sodium raw materials 10g of the embodiment of the present invention.
Formulation preparation method: taking sterile Cefminox sodium raw materials, filling, obtains powder-injection 100.
Test method: being respectively placed in 70 DEG C of high temperature for embodiment 4-6 and comparative example 2, comparative example 3, comparative example 4, relatively wet
Degree 95% and illumination every plus sodium chloride injection 250ml, add glucose to infuse according to preparation under the conditions of 6000Lx, was taken in the 10th day
Liquid 250ml is penetrated, container closure is placed under the conditions of conventional (room temperature, city conventional illumination), and particulate matter inspection is [according to middle traditional Chinese medicines
Allusion quotation annex particulate matter inspection technique light blockage method, every milliliter >=10 μm particles are no more than 25, and every milliliter >=25 μm particles are not
Can exceed that 5], test result is shown in Table 2, table 3.
Sodium chloride injection stability result is added in 2 preparation of table
Glucose injection stability result is added in 2 preparation of table
Conclusion (of pressure testing): it is placed by conventional, after of the invention Cefminox sodium injection 4 hours, 6 hours, 8 hours, no
Dissolubility particle still conforms to quality criteria requirements, and sodium tartrate or sodium carbonate is added or is added without the Cefminox sodium powder of auxiliary material
Injection did not met quality requirement at 4 hours, this is absolutely proved, Cefminox sodium injection of the present invention is prepared in clinic
Afterwards, it can be reused by placing for a long time.
Claims (10)
1. a kind of Cefminox sodium raw materials, it is characterised in that the Cefminox sodium raw materials are prepared by the following method: taking cephalo
Minot sodium crude product is added tetrahydrofuran dissolution completely, after acetone is added, is crystallized, obtains cefminox sodium bulk pharmaceutical chemicals.
2. a kind of Cefminox sodium raw materials according to claim 1.Wherein cefminox sodium in the preparation method of the raw material
The weight grams of crude product and the volume ml of tetrahydrofuran are than being 1:3.5-5.
3. a kind of Cefminox sodium raw materials according to claim 1, wherein cefminox sodium in the preparation method of the raw material
Crude product weight grams and acetone volume ml are than being 1:4.5-6.
4. a kind of Cefminox sodium raw materials according to claim 1-3, wherein raw material the preparation method comprises the following steps:
Cefminox sodium crude product is taken, tetrahydrofuran is added, is warming up to 40-50 DEG C, acetone is added, stirs evenly, 5 DEG C -10 DEG C quiet
It sets, crystallization is precipitated, filtering, filter cake acetone washing is dry, obtains Cefminox sodium raw materials.
5. a kind of Cefminox sodium injection, it is characterised in that: the powder-injection is by the described in any item cephalo rice of claim 1-4
Promise sodium raw materials are prepared with sodium citrate.
6. a kind of Cefminox sodium injection according to claim 5, wherein Cefminox sodium raw materials and sodium citrate are former
The weight ratio of material is 1:0.04-0.06.
7. a kind of Cefminox sodium injection according to claim 5, wherein Cefminox sodium raw materials and sodium citrate are former
The weight ratio of material is 1:0.05.
8. according to a kind of described in any item Cefminox sodium injections of claim 5-7, it is characterised in that cefminox sodium is former
It is expecting that the preparation method comprises the following steps: taking cefminox sodium crude product, addition tetrahydrofuran is warming up to 40-50 DEG C, acetone is added, stirs evenly,
Crystallization is precipitated in 5 DEG C of -10 DEG C of standings, and filtering, filter cake acetone washing is dry, obtains Cefminox sodium raw materials；Cefminox sodium
The weight grams of crude product and the volume ml of tetrahydrofuran are than being 1:3.5-5；Cefminox sodium crude product weight grams and acetone
Volume ml is than being 1:4.5-6.
9. according to a kind of described in any item Cefminox sodium injections of claim 5-7, it is characterised in that cefminox sodium is former
Material the preparation method comprises the following steps: take cefminox sodium crude product, tetrahydrofuran is added, is warming up to 45 DEG C, acetone is added, stirs evenly, 5
Crystallization is precipitated in DEG C of -10 DEG C standings, and filtering, filter cake acetone washing is dry, obtains Cefminox sodium raw materials；Cefminox sodium is thick
The weight grams of product and the volume ml of tetrahydrofuran are than being 1:4.5；Cefminox sodium crude product weight grams and acetone volume
Ml than be 1:5.5.
10. being characterized in that the powder-injection exists according to a kind of described in any item Cefminox sodium injections of claim 5-7
Infection caused by preparation treatment sensitive bacterial.
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| CN113219080A (en) * | 2021-03-26 | 2021-08-06 | 天圣制药集团股份有限公司 | HPLC (high Performance liquid chromatography) detection method for high-molecular impurities in cefepime and preparation thereof |
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