CN105560194A - High-purity ceftazidime powder injection and preparation method thereof - Google Patents
High-purity ceftazidime powder injection and preparation method thereof Download PDFInfo
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- CN105560194A CN105560194A CN201410553446.7A CN201410553446A CN105560194A CN 105560194 A CN105560194 A CN 105560194A CN 201410553446 A CN201410553446 A CN 201410553446A CN 105560194 A CN105560194 A CN 105560194A
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- 229960000484 ceftazidime Drugs 0.000 title claims abstract description 154
- 239000000843 powder Substances 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- NMVPEQXCMGEDNH-TZVUEUGBSA-N ceftazidime pentahydrate Chemical compound O.O.O.O.O.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 NMVPEQXCMGEDNH-TZVUEUGBSA-N 0.000 title claims abstract 40
- 238000002347 injection Methods 0.000 title abstract description 10
- 239000007924 injection Substances 0.000 title abstract description 10
- 239000012535 impurity Substances 0.000 claims abstract description 69
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 55
- 239000003814 drug Substances 0.000 claims abstract description 42
- 229940079593 drug Drugs 0.000 claims abstract description 32
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229920000642 polymer Polymers 0.000 claims abstract description 20
- SQQLCFFMLJEMPT-CDOVDWRASA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-(1-methoxy-2-methyl-1-oxopropan-2-yl)oxyiminoacetyl]amino]-8-oxo-3-(pyridin-1-ium-1-ylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(=O)OC)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 SQQLCFFMLJEMPT-CDOVDWRASA-N 0.000 claims abstract description 14
- 239000000243 solution Substances 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 22
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 21
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 239000000706 filtrate Substances 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 14
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- 239000013078 crystal Substances 0.000 claims description 10
- 239000011148 porous material Substances 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- 238000009298 carbon filtering Methods 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- 239000006184 cosolvent Substances 0.000 claims description 5
- 238000001291 vacuum drying Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 238000013019 agitation Methods 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 239000004475 Arginine Substances 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims 1
- 235000011167 hydrochloric acid Nutrition 0.000 claims 1
- 235000011007 phosphoric acid Nutrition 0.000 claims 1
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 11
- ORFOPKXBNMVMKC-DWVKKRMSSA-N ceftazidime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 ORFOPKXBNMVMKC-DWVKKRMSSA-N 0.000 description 112
- 238000012360 testing method Methods 0.000 description 15
- 239000000047 product Substances 0.000 description 13
- 230000000694 effects Effects 0.000 description 12
- 239000013558 reference substance Substances 0.000 description 6
- 239000003643 water by type Substances 0.000 description 6
- 241000588724 Escherichia coli Species 0.000 description 5
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 5
- 208000003455 anaphylaxis Diseases 0.000 description 5
- 229940023064 escherichia coli Drugs 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- 206010002198 Anaphylactic reaction Diseases 0.000 description 4
- 229920002307 Dextran Polymers 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 4
- 230000036783 anaphylactic response Effects 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 3
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 3
- KRTGQDGIPNXUGP-UHFFFAOYSA-N 7-[[2-(2-amino-1,3-thiazol-4-yl)-2-[2-methyl-1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]oxyiminoacetyl]amino]-8-oxo-3-(pyridin-1-ium-1-ylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C=1SC(N)=NC=1C(=NOC(C)(C)C(=O)OC(C)(C)C)C(=O)NC(C(N1C=2C([O-])=O)=O)C1SCC=2C[N+]1=CC=CC=C1 KRTGQDGIPNXUGP-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- LRKHKETXQNDOKF-IODBXWCGSA-N CC(C)(O\N=C(\C(=O)N[C@H]1[C@H]2SC=C(C[n+]3ccccc3)C(N2C1=O)C([O-])=O)c1csc(N)n1)C(O)=O Chemical compound CC(C)(O\N=C(\C(=O)N[C@H]1[C@H]2SC=C(C[n+]3ccccc3)C(N2C1=O)C([O-])=O)c1csc(N)n1)C(O)=O LRKHKETXQNDOKF-IODBXWCGSA-N 0.000 description 3
- 229930186147 Cephalosporin Natural products 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- 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 3
- 238000003556 assay Methods 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 229940124587 cephalosporin Drugs 0.000 description 3
- 150000001780 cephalosporins Chemical class 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 238000004811 liquid chromatography Methods 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 241000193830 Bacillus <bacterium> Species 0.000 description 2
- 241000191940 Staphylococcus Species 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- FGDQGIKMWOAFIK-UHFFFAOYSA-N acetonitrile;phosphoric acid Chemical compound CC#N.OP(O)(O)=O FGDQGIKMWOAFIK-UHFFFAOYSA-N 0.000 description 2
- 230000003385 bacteriostatic effect Effects 0.000 description 2
- 239000008366 buffered solution Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 239000003684 drug solvent Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000010812 external standard method Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- WFIYPADYPQQLNN-UHFFFAOYSA-N 2-[2-(4-bromopyrazol-1-yl)ethyl]isoindole-1,3-dione Chemical compound C1=C(Br)C=NN1CCN1C(=O)C2=CC=CC=C2C1=O WFIYPADYPQQLNN-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 241000588986 Alcaligenes Species 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010002199 Anaphylactic shock Diseases 0.000 description 1
- 241000606124 Bacteroides fragilis Species 0.000 description 1
- 241001478240 Coccus Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000588921 Enterobacteriaceae Species 0.000 description 1
- 241000194033 Enterococcus Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- 241000191992 Peptostreptococcus Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000002828 disc diffusion antibiotic sensitivity testing Methods 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
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- 230000000857 drug effect Effects 0.000 description 1
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- 230000002949 hemolytic effect Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
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- 210000003734 kidney Anatomy 0.000 description 1
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- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000019837 monoammonium phosphate Nutrition 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
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- 210000002345 respiratory system Anatomy 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
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- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the field of medicinal chemistry, and particularly relates to a high-purity ceftazidime powder injection and a preparation method thereof. The high-purity ceftazidime powder injection can have the dosage of 0.5g, 1g or 2g, and contains ceftazidime crude drug, wherein in the ceftazidime crude drug, the content of ceftazidime with the structural formula (I) is 99.70-99.95wt%, the content of impurity pyridine is 0.001-0.05wt%, the content of impurity ceftazidime polymer is 0.001-0.05wt%, the content of impurity ceftazidime methyl ester is lower than 0.05wt%, and the total content of other impurities is 0.03-0.30wt%. The high-purity ceftazidime powder injection has extremely high stability, high safety and high antibacterial activity, and the lifetime thereof is longer than that of existing ceftazidime powder injection by 50% or above. Furthermore, the preparation method of the high-purity ceftazidime powder injection, provided by the invention, is easy and convenient to operate, low in cost and high in safety.
Description
Technical field
The invention belongs to medicinal chemistry art, more specifically, relate to a kind of highly purified ceftazidime injectable powder and preparation method thereof.
Background technology
Ceftazidime applies a very wide range of third generation cephalosporin clinically, within 1984, developed by Ge Lansu company of Britain.Ceftazidime has a broad antifungal spectrum, to most gram positive bacteria and negative bacterium effective.Such as, height antibacterial activity is had to the enterobacteriaceae lactobacteriaceae such as escherichia coli, pneumobacillus and hemophilus influenza, Pseudomonas aeruginosa etc.; Also good antibacterial action is had to nitrate-negative bacillus, Bacillus alcaligenes etc.; The gram positive coccus such as streptococcus pneumoniae, Hemolytic streptococcus is extremely sensitive to this product.But this product only has a moderate activity to staphylococcus, and enterococcus and methicillin-resistant Staphylococcus are then often to this product drug resistance.This product is to the certain antibacterial activity of the anaerobe such as dyspepsiacoccus and peptostreptococcus tool, but poor to bacteroides fragilis antibacterial action.
The medicinal ceftazidime raw material that pharmacopeia (such as European Pharmacopoeia, Chinese Pharmacopoeia) specifies is: the content of the ceftazidime of structural formula (I) is not less than 95%, impurity pyridine content is not higher than 0.12%, impurity ceftazidime polymer content is not higher than 0.30%, and other content of impurities is not higher than 2.0%.Therefore, can say, medicinal ceftazidime is in fact containing active component (ceftazidime of structural formula (I)) and related impurities.
The structural formula (I) of ceftazidime
Medicine out until use to patient, needs a process from plant produced.Medicine is in put procedure, and active component lost efficacy gradually, and content reduces, and impurity content raises.In order to ensure effectiveness and the safety of medicine, pharmacopeia all has strict effect phase regulation and storage condition regulation to medicine.The medicine of good stability, its effect phase is long, stable curative effect, and safety is very high.
It is reported at present, the ceftazidime crude drug produced, impurity pyridine content is generally at 0.08 ~ 0.12wt%, impurity ceftazidime polymer content is at 0.08 ~ 0.3wt%, other content of impurities is 0.8 ~ 2.0wt%, ceftazidime purity is 98.0 ~ 99.0wt%, and particularly impurity ceftazidime methyl ester content is at about 0.5wt%.Now on the market as the ceftazidime preparation of medicine sales, in order to ensure the safety of medicine within the effect phase and curative effect, the effect phase of States Pharmacopoeia specifications ceftazidime preparation is 2 years, and storage condition is shady and cool storehouse, and namely less than 20 DEG C, this brings inconvenience in the majority to drug flow.Now ceftazidime raw material on the market and preparation; all there is the problems such as impurity content is higher, stability deviation; depositing in process; the change of its impurity is very fast; when particularly exceeding condition of storage; impurity content often understands overrun requirement; as ceftazidime polymer reaches more than 0.3wt%; impurity pyridine is more than 0.12wt%; other total impurities is more than 2.0wt%, and these contain more polymictic ceftazidime, has considerable influence to the efficacy and saferry of medicine; as easily there is anaphylaxis, drug effect reduces, safety reduces.
US4,659,813 purification process disclosing a kind of ceftazidime, the method is, at the temperature of about 5 ~ 15 DEG C, pH is the ceftazidime aqueous solution of about 5.5 ~ about 6.5, its pH is regulated to be about 4.0 ~ about 4.7 with acid, and by controlling adding of acid in crystallization process, make pH be maintained at about 4.0 ~ about 4.7, thus separate out ceftazidime.Although this method has certain help to raising product purity, in this way, to circulate common ceftazidime by market, even if according to said method refining more than 10 times, still can not get the ceftazidime that purity reaches more than 99.5%.
Summary of the invention
Therefore, one object of the present invention there are provided a kind of highly purified ceftazidime injectable powder, its excellent stability, and safety is good, and the effect phase of medicine extends more than 50% than existing ceftazidime injectable powder.First production of the present invention has gone out this highly purified ceftazidime injectable powder, and its antibacterial activity is high, and stability substantially increases, and the effect phase extends more than 1 year, and safety is more reliable.
Another object of the present invention is to the preparation method that a kind of above-mentioned highly purified ceftazidime injectable powder is provided.
According to the present invention, highly purified ceftazidime injectable powder provided by the invention, it is characterized in that, often propping up dosage can be 0.5g, 1g or 2g, it comprises ceftazidime crude drug, the ceftazidime content of the structural formula (I) of this ceftazidime crude drug is 99.70wt% ~ 99.95wt%, impurity pyridine content is 0.001wt% ~ 0.05wt%, impurity ceftazidime polymer content is 0.001wt% ~ 0.05wt%, impurity ceftazidime methyl ester content is below 0.05wt%, and other content of impurities are 0.03wt% ~ 0.30wt%.
Described impurity ceftazidime methyl ester:
Other described impurity comprise: impurity A (σ
2-ceftazidime), impurity B (E-ceftazidime), impurity C (7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid) and impurity D (the ceftazidime tert-butyl ester etc.,
Impurity A (σ
2-ceftazidime):
Impurity B (E-ceftazidime):
Impurity C (7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid):
Impurity D (the ceftazidime tert-butyl ester):
This highly purified ceftazidime injectable powder can only comprise ceftazidime crude drug, can also comprise cosolvent further, such as sodium carbonate or arginine.When ceftazidime injectable powder comprises ceftazidime crude drug and cosolvent, the weight ratio between ceftazidime crude drug and cosolvent can be 10:1 ~ 1:1 (w/w).
Described ceftazidime crude drug, by the assay method of Chinese Pharmacopoeia 2010 editions regulation, by weight, the ceftazidime content of structural formula (I) is preferably 99.80wt% ~ 99.95wt%, impurity pyridine content is 0.001wt% ~ 0.02wt%, impurity ceftazidime polymer content is 0.001wt% ~ 0.02wt%, and impurity ceftazidime methyl ester content is below 0.05wt%, and other content of impurities are 0.03wt% ~ 0.20wt%.
By the assay method that Chinese Pharmacopoeia specifies, (namely impurity ceftazidime methyl ester and other impurity, comprise impurity A (σ for the ceftazidime purity of mensuration structural formula (I) and related substance
2-ceftazidime), impurity B (E-ceftazidime), impurity C (7-amino-3-picolyl-3-cephalosporin-4-carboxyl acid) and impurity D (the ceftazidime tert-butyl ester etc.)), impurity pyridine, impurity ceftazidime polymer content, assay method is summarized as follows:
(1) ceftazidime purity and determination of related substances method: get product to be tested, accurately weighed, dissolve by mobile phase A and be diluted to every 1ml about containing the solution of ceftazidime 1mg, as need testing solution; Precision measures need testing solution 1ml, puts in 100ml measuring bottle, is diluted to scale by mobile phase A, in contrast solution.Measuring according to high performance liquid chromatography (China's coastal port two annex V D), is filler with octadecylsilane chemically bonded silica; Mobile phase A is acetonitrile-phosphate buffered solution (getting 22.6g Ammonium biphosphate be dissolved in water and be diluted to 1000ml, the phosphoric acid solution adjust ph to 3.9 with 10%) (7:93); Mobile phase B is acetonitrile-phosphate buffered solution (getting 22.6g Ammonium biphosphate be dissolved in water and be diluted to 1000ml, the phosphoric acid solution adjust ph to 3.9 with 10%) (14:86); Column temperature: 35 DEG C; Flow velocity is 1.0ml per minute; Determined wavelength is 255nm.Press as following table 1 linear gradient elution.Theoretical cam curve calculates by ceftazidime peak and is not less than 5000, and ceftazidime is adjacent impurity peaks and the peak-to-peak separating degree of each other impurities all should be not less than 1.5, otherwise suitably should adjust ratio and detector sensitivity that mobile phase respectively forms.Get contrast solution 10 μ l injection liquid chromatography, regulate detection sensitivity, make the peak height of main constituent chromatographic peak be about 20% of full scale.Precision measures need testing solution and each 10 μ l of contrast solution, respectively injection liquid chromatography, and record chromatogram, calculates the purity of single impurity and total impurities content and ceftazidime by Self-control method.
Table 1 gradient elution program table
| Retention time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 00 | 100 | 0 |
| 14 | 100 | 0 |
| 29 | 0 | 100 |
| 45 | 0 | 100 |
| 50 | 100 | 0 |
| 65 | 100 | 0 |
(2) impurity pyridine algoscopy measures according to high performance liquid chromatography (Chinese Pharmacopoeia two annex VD).
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; With acetonitrile-0.25mol/L ammonium dihydrogen phosphate (get Ammonium biphosphate 57.5158g, with water dissolution and be diluted to 2000ml)-water (300:100:600) by ammonia solution adjust ph to 7.0 for mobile phase; Flow velocity is 1.0m1 per minute; Inspection side wave is long is 254nm.Theoretical cam curve should be not less than 3000.Get pyridine reference substance solution 20 μ l injection liquid chromatography, calculate sample introduction result for several times, its relative standard deviation must not more than 3.0%.
The preparation precision of pyridine reference substance solution takes pyridine and is about lg, puts in 100m1 measuring bottle, and be dissolved in water and be diluted to scale, shaking up, precision measures l0ml, puts in another l00ml measuring bottle, is diluted with water to scale, shakes up, in less than 15 DEG C storages.Precision measures 2ml before use, puts in 200ml measuring bottle, adds pH7.0 phosphate buffer (take disodium hydrogen phosphate,anhydrous 5.68g, potassium dihydrogen phosphate 3.63g, be dissolved in water and be diluted to 1000m1) and is diluted to scale, shake up, in contrast product solution.
Algoscopy precision takes product to be tested and is about 660mg, puts in 100m1 measuring bottle, adds above-mentioned pH7.0 phosphate buffer and dissolves and be diluted to scale (in less than 15 DEG C storages, in 1 hour, sample introduction is complete), shake up, precision measures 20 μ l and notes people's chromatograph of liquid, record chromatogram; Separately get pyridine reference substance solution, be measured in the same method.The content of pyridine in product to be tested is calculated by external standard method.
(3) ceftazidime polymer determination method measures according to molecular exclusion chromatography (Chinese Pharmacopoeia two annex VH).
Chromatographic condition and system suitability sephadex G-10 (40 ~ 120 μMs) are filler, glass column internal diameter 1.3 ~ 1.6cm, post height 30 ~ 40cm.With the 0.lmol/L phosphate buffer [0.lmol/L disodium phosphate soln-0.lmol/L sodium dihydrogen phosphate (61:39)] of the pH7.0 containing 3.5% ammonium sulfate for mobile phase A, take water as Mobile phase B, flow velocity is about 0.8ml per minute, and determined wavelength is 254nm.Respectively with mobile phase A, B for mobile phase, get 0.1mg/ml blue dextran 2000 solution 200 μ l, note people chromatograph of liquid, theoretical cam curve calculates with blue dextran 2000 peak and is all not less than 600, and tailing factor all should be less than 2.0.In two kinds of flow phase system, the ratio of blue dextran 2000 peak retention time should between 0.93 ~ 1.07, and in contrast solution main peak and need testing solution, in polymer peak and corresponding chromatographic system, the ratio of the retention time at blue dextran 2000 peak all should between 0.93 ~ 1.07.Another is mobile phase with Mobile phase B, and precision measures contrast solution 200 μ l, continuous sample introduction 5 times, and the relative standard deviation of peak area should be not more than 5.0%.
The preparation of contrast solution is got ceftazidime reference substance and is about 20mg, accurately weighed, is dissolved in water and quantitatively dilutes the solution made about containing l00 μ g in every 1ml.
Algoscopy is got product to be tested and is about 0.2g, accurately weighed, puts in l0ml measuring bottle, and adds sodium carbonate 20mg, is dissolved in water and is diluted to scale, shaking up, and precision measures 200 μ l and notes people's chromatograph of liquid immediately, is that mobile phase measures with mobile phase A, record chromatogram.Another precision measures contrast solution 200 μ l and notes people's chromatograph of liquid, is mobile phase, is measured in the same method with Mobile phase B.Go out the amount of ceftazidime polymer with calculated by peak area by external standard method.
The ceftazidime crude drug of existing market circulation, impurity pyridine content is generally 0.08 ~ 0.12%, impurity ceftazidime polymer is 0.08 ~ 0.3%, impurity ceftazidime methyl ester content is about 0.5%, other content of impurities is 0.8 ~ 2.0%, and particularly closely imitate the phase ceftazidime of (2 years) soon, impurity pyridine often exceeds 0.12% bound requirements, impurity ceftazidime polymer often exceeds 0.3% bound requirements, the bound requirements of other content of impurities more than 2.0%.
Pyridine is two class noxious substances, and pyridine can stimulate human eye, skin and respiratory tract, has impact to human central nervous system, liver, kidney, gastrointestinal, and consciousness of personality can be caused to reduce.If pyridine residual quantity is high, can produces human body and comparatively have a strong impact on.By the security test to ceftazidime medicine, the residual limit of pyridine safety in ceftazidime medicine can not more than 0.12%.Owing to containing pyridine groups in ceftazidime structure, medicine is in put procedure, and can decompose impurity pyridine out gradually, the particularly ceftazidime of poor stability, in put procedure, pyridine residual quantity can increase comparatively fast, and this has larger harm to human body.
Beta-Lactam antibiotic, as penicillin medicine and Cephalosporins, due to the less stable of parent nucleus, easily reset, decomposition and aggregation reaction, the polymer product formed and anaphylactic shock have close relationship.In penicillin, polymeric impurities is on average when 21.44 μ g/g, and anaphylaxis incidence rate is 0.2%; Polymeric impurities is on average when 51.24 μ g/g, and anaphylaxis incidence rate is 0.43%; During polymeric impurities average out to 76.7 μ g/g, irritated rate is 0.74%.Though cephalosporin anaphylaxis is so serious not as good as penicillin, during polymerization object height, human allergy can be caused equally to react.
In a word, during all kinds of impurity content height of ceftazidime crude drug, drug safety can significantly reduce, and toxicity increases, and curative effect can reduce.
The present inventor studies discovery, if ceftazidime crude drug purity reaches more than 99.7%, pyridine content is not higher than 0.05%, ceftazidime polymer content is not higher than 0.05%, and ceftazidime methyl ester content is below 0.05wt%, and other content of impurities are not higher than 0.30%, the injectable powder that this highly purified ceftazidime crude drug obtains, excellent stability, product deposits 2 years under normal temperature condition, and ceftazidime purity remains unchanged substantially.Place the ceftazidime after 2 years, its effect is still higher than existing ceftazidime on the market.
And the high-purity ceftazidime crude drug purity that the present invention is prepared first reaches 99.70%, more excellently reach 99.80%, optimum reaches 99.90%, even reaches 99.95%.
Highly purified ceftazidime injectable powder of the present invention, its preparation method comprises the following steps:
Step 1: active carbon is suspended in water, stir, to entering in column type funnel to filter, rinse active carbon with water, vacuum is drained, and forms the column type filter of active carbon filtering layer;
Step 2: be added to the water by ceftazidime crude drug, optionally adds alkali and makes it dissolve, obtain ceftazidime aqueous solution, pH value of solution 5.0 ~ 7.0, and wherein the concentration of ceftazidime is 5.0wt% ~ 40wt%; Obtained ceftazidime aqueous solution is slowly added in the active carbon filtering layer filter that step 1 formed, wash with water after adding, receive filtrate simultaneously;
Step 3: filtrate homoiothermic step 2 received is to 0 ~ 20 DEG C, and acid adding adjusts pH3.8 ~ 4.8, and highly purified ceftazidime crystal structure is separated out, and continues growing the grain 2 ~ 5 hours; The ceftazidime crystal of separating out is filtered, uses water and washing with acetone respectively, vacuum drying, obtain white highly purified ceftazidime crude drug; With
Step 4: ceftazidime crude drug step 3 obtained conventionally makes injectable powder.
In the method for the invention:
In step 1, the active carbon used, can use specific surface area to be 500 ~ 5000m
2/ g, pore volume are 0.1 ~ 10ml/g and average pore size is the active carbon of 0.1 ~ 10nm, and preferred specific surface area is 900 ~ 2000m
2/ g, pore volume are 0.2 ~ 2ml/g and average pore size is the active carbon of 1.0 ~ 5.0nm, such as, can be 767 type active carbons, ENO active carbon, egression A type active carbon or egression P type active carbon.
In step 2, be added to the water by ceftazidime crude drug, optionally add alkali and make it dissolve, the ceftazidime aqueous solution obtained, ceftazidime concentration is 5.0wt% ~ 40wt%, preferred 10wt% ~ 20wt%; This pH value of solution 5.0 ~ 7.0, preferred pH is 5.2 ~ 6.0.Activated carbon dosage and ceftazidime consumption, by weight, its ratio range 2:1 ~ 20:1, more excellent scope 4:1 ~ 10:1.Alkali used can be inorganic base or organic base, and wherein said inorganic base is sodium hydroxide solution, potassium hydroxide solution or ammonia etc., and described organic base is triethylamine or n-butylamine etc., and preferred sodium hydroxide solution, ammonia or triethylamine.The feed postition of described alkali, the mode that preferred employing under agitation drips.
In step 3, the acid used can be mineral acid or organic acid, and mineral acid can be hydrochloric acid, phosphoric acid or sulphuric acid, and organic acid can be formic acid or acetic acid, and preferred hydrochloric acid or phosphoric acid.The feed postition of described acid, the mode that preferred employing under agitation drips.
The filtrate received by the inventive method step 2, concentration range controls at 20mg/L ~ 300mg/L.Starting to receive concentration had better not lower than 30mg/L, and receiving liquid concentration raises gradually, and then declines, and treats that receipt of subsequent liquid concentration stops receiving lower than 20mg/L, merges these filtrate.
In the inventive method step 3, by the filtrate homoiothermic of the concentration range 20mg/L ~ 300mg/L (preferred 100mg/L ~ 300mg/L) of reception to 0 ~ 20 DEG C, best 0 ~ 5 DEG C, acid adding adjusts pH3.8 ~ 4.8 (preferably 4.0 ~ 4.5), highly purified ceftazidime crystal structure is separated out, continue growing the grain 2 ~ 5 hours, mixing speed 5 revs/min ~ 40 revs/min.The ceftazidime crystal of separating out is filtered, uses water and washing with acetone respectively, vacuum drying, obtain white highly purified ceftazidime crude drug.
The invention has the advantages that: prepared a kind of highly purified ceftazidime injectable powder, its excellent stability, safety is good, and antibacterial activity is high, the effect phase of medicine extends more than 50% than existing ceftazidime injectable powder.In addition, the preparation method of this high-purity ceftazidime injectable powder, easy and simple to handle, cost is low, and safety is good.
Detailed description of the invention
Embodiment 1
By active carbon (egression A type) (its specific surface 1020m
2/ g, pore volume 0.60ml/g, average pore size 2.35nm) 200 grams be suspended in 1000 ml waters, stir, being filled into diameter is in the column type funnel of 5cm, rinses active carbon with 1500 ml waters, vacuum is drained, and forms the column type filter that diameter is 5cm active carbon filtering layer.
The 50 grams of ceftazidimes circulated in market are added in 100 ml waters, drips 2N sodium hydroxide solution and make it dissolve, obtain ceftazidime aqueous solution, pH value of solution 6.3 ~ 7.0.Above ceftazidime solution is slowly added in the filter of active carbon filtering layer, within about 15 minutes, adds.Then 500 ml water eluting are used.Accept filtrate, front 100 milliliters of filtrates abandon it, treat that filter liquor concentration reaches 30mg/L and starts to collect, coutroi velocity 4 ~ 5mL/min, then stop collecting lower than 20mg/L to filter liquor concentration, collect filtrate 400 milliliters altogether.
By the filtrate homoiothermic of reception to 0 ~ 5 DEG C, add phosphoric acid and adjust pH4.0, highly purified ceftazidime crystal structure is separated out, and continues growing the grain 2 hours.The ceftazidime crystal of separating out is filtered, uses water and washing with acetone respectively, vacuum drying, obtain white highly purified ceftazidime 42 grams, yield 84%.
Ceftazidime purity 99.92%, pyridine 0.002%, ceftazidime polymer 0.01%, ceftazidime methyl ester 0.01%, other content of impurities 0.08%.
By pharmacopoeial requirements, stability test is carried out to product:
The ceftazidime (reference substance) that high-purity ceftazidime (sample) and market are bought is placed in Aluminum Drum, airtight package, in 15 ~ 20 DEG C and 25 ~ 30 DEG C, place under the condition of relative humidity 50% ~ 70%, detect respectively at sampling in 0 month, 6 months, 12 months, 18 months, 24 months, 30 months, 36 months, test event comprises outward appearance, impurity pyridine content, impurity ceftazidime polymer content, ceftazidime methyl ester content, other total impurities (related substance) and ceftazidime purity.Experimental data is as follows:
Test specimen is packed: experimental condition: 15 ~ 20 DEG C
Test specimen is packed: experimental condition: 25 ~ 30 DEG C
Embodiment 2
By active carbon (ENO active carbon (its specific surface 1430m
2/ g, pore volume 1.17ml/g, average pore size 3.27nm) mix with egression A type active carbon 1:1) 300 grams be suspended in 1000 ml waters, stir, being filled into diameter is in the column type funnel of 5cm, rinse active carbon with 2000 ml waters, vacuum is drained, and forms the column type filter that diameter is 5cm active carbon filtering layer.
The 50 grams of ceftazidimes circulated in market are added in 150 ml waters, drips triethylamine and make it dissolve, obtain ceftazidime aqueous solution, pH value of solution 5.5 ~ 6.0.Above ceftazidime solution is slowly added in the column type filter of active carbon filtering layer, within about 20 minutes, adds.Then 500 ml water eluting are used.Accept filtrate, front 100 milliliters of filtrates abandon it.Then start to receive filtrate 450 milliliters.
By the filtrate homoiothermic that receives containing product to 5 ~ 10 DEG C, add hydrochloric acid and adjust pH4.3, highly purified ceftazidime crystal structure is separated out, and continues growing the grain 5 hours.The ceftazidime crystal of separating out is filtered, uses water and washing with acetone respectively, vacuum drying, obtain white highly purified ceftazidime 39 grams, yield 78%.
Ceftazidime purity 99.91%, pyridine 0.001%, ceftazidime polymer 0.008%, ceftazidime methyl ester 0.02%, other content of impurities 0.09%.
The ceftazidime Antimicrobial test that high-purity ceftazidime of the present invention and market are bought
(1) experiment material
Test organisms is staphylococcus aureus (Staphylococcusaucreus) (ATCC6538), escherichia coli (Escherichiacoli) (8099), bacillus pyocyaneus (Pseudomonasaeruginosa) (ATCC4257).
(2) experimental technique
Antibacterial activity adopts disc diffusion method to measure.Reference substance ceftazidime (the purity 98.4% that test compound high-purity ceftazidime (prepared by the embodiment of the present invention 1) and market are bought, pyridine 0.07%, ceftazidime polymer 0.1%, ceftazidime methyl ester 0.4%,), respectively with distilled water be configured to 10,1,0.1mgL
-13 kinds of concentration.Experimental bacteria suspension 0.2mL is added, with T-shaped spreader uniform application in whole media surface in each culture dish.Get 20 μ L testing sample solutions on the filter paper of diameter 6mm, the agar plate surface having connect bacterium is attached to after slightly dry, each culture dish puts 4,3 repetitions are established in each process, cultivate 24h at 28 DEG C of calorstats, observe, record inhibition zone size, survey the diameter of inhibition zone by decussation method, get its meansigma methods as experimental result, evaluate the bacteriostatic activity of test compound according to this.
(3) experimental result
Antibacterial activity in vitro experiment finds (table 2), when drug concentration is to 1mgL
-1even high-purity ceftazidime houses the sample of 2 years, positive effect is still had to bacillus pyocyaneus (Pseudomonasaeruginosa), escherichia coli (Escherichiacoli) and staphylococcus aureus (Staphylococcusaucreus) antibacterial activity, and the ceftazidime that common market is bought does not manifest antibacterial effect.
Table 2 bacteriostatic test test result
Note: RSD% is relative standard deviation
Embodiment 3
The preparation of ceftazidime injectable powder
The ceftazidime aseptic powder crude drug 9kg obtained by method described in embodiment 1 and 1kg sodium carbonate aseptic powder, mix homogeneously, subpackage obtains sterile powder injection, specification 2.0g/ bottle.
Claims (10)
1. a highly purified ceftazidime injectable powder, often propping up dosage is 0.5g, 1g or 2g, it is characterized in that, it comprises ceftazidime crude drug, the ceftazidime content of the structural formula (I) of this ceftazidime crude drug is 99.70wt% ~ 99.95wt%, impurity pyridine content is 0.001wt% ~ 0.05wt%, impurity ceftazidime polymer content is 0.001wt% ~ 0.05wt%, impurity ceftazidime methyl ester content is below 0.05wt%, other content of impurities are 0.03wt% ~ 0.30wt%
2. highly purified ceftazidime injectable powder according to claim 1, it is characterized in that, the ceftazidime content of the structural formula (I) of described ceftazidime crude drug is 99.80wt% ~ 99.95wt%, impurity pyridine content is 0.001wt% ~ 0.02wt%, impurity ceftazidime polymer content is 0.001wt% ~ 0.02wt%, impurity ceftazidime methyl ester content is below 0.05wt%, and other content of impurities are 0.03wt% ~ 0.20wt%.
3. highly purified ceftazidime injectable powder according to claim 1 and 2, it is characterized in that, described injectable powder also comprises cosolvent, and this cosolvent is sodium carbonate or arginine.
4. a preparation method for highly purified ceftazidime injectable powder as claimed any one in claims 1 to 3, it is characterized in that, the method comprises the steps:
Step 1: active carbon is suspended in water, stir, to entering in column type funnel to filter, rinse active carbon with water, vacuum is drained, and forms the column type filter of active carbon filtering layer;
Step 2: be added to the water by ceftazidime crude drug, optionally adds alkali and makes it dissolve, obtain ceftazidime aqueous solution, pH value of solution 5.0 ~ 7.0, and wherein the concentration of ceftazidime is 5.0wt% ~ 40wt%; Obtained ceftazidime aqueous solution is slowly added in the active carbon filtering layer filter that step 1 formed, wash with water after adding, receive filtrate simultaneously;
Step 3: filtrate homoiothermic step 2 received is to 0 ~ 20 DEG C, and acid adding adjusts pH3.8 ~ 4.8, and highly purified ceftazidime crystal structure is separated out, and continues growing the grain 2 ~ 5 hours; The ceftazidime crystal of separating out is filtered, uses water and washing with acetone respectively, vacuum drying, obtain white highly purified ceftazidime crude drug; With
Step 4: ceftazidime crude drug step 3 obtained conventionally makes injectable powder.
5. the preparation method of highly purified ceftazidime injectable powder according to claim 4, is characterized in that, in described step 1, the specific surface area of described active carbon is 500 ~ 5000m
2/ g, pore volume is 0.1 ~ 10ml/g, and average pore size is 0.1 ~ 10nm.
6. the preparation method of the highly purified ceftazidime injectable powder according to claim 4 or 5, it is characterized in that, in described step 2, ceftazidime crude drug is added to the water, optionally adding alkali makes it dissolve, the ceftazidime aqueous solution obtained, ceftazidime concentration is 10wt% ~ 20wt%, pH is 5.2 ~ 6.0.
7. the preparation method of the highly purified ceftazidime injectable powder according to claim 4 or 5, is characterized in that, in described step 2, alkali used is sodium hydroxide solution, potassium hydroxide solution, ammonia, triethylamine or n-butylamine; The feed postition of described alkali, adopts the mode under agitation dripped.
8. the preparation method of the highly purified ceftazidime injectable powder according to claim 4 or 5, is characterized in that, activated carbon dosage and ceftazidime consumption, and by weight, its ratio range is 2:1 ~ 20:1.
9. the preparation method of the highly purified ceftazidime injectable powder according to claim 4 or 5, it is characterized in that, in described step 2, in the filtrate received, the concentration range of ceftazidime controls at 20mg/L ~ 300mg/L, start to receive concentration and be not less than 30mg/L, receiving liquid concentration raises gradually, and then declines, treat that receipt of subsequent liquid concentration stops receiving lower than 20mg/L, merge these filtrate.
10. the preparation method of highly purified ceftazidime injectable powder according to claim 4, is characterized in that, in described step 3, the acid used is hydrochloric acid, phosphoric acid, sulphuric acid, formic acid or acetic acid; The feed postition of described acid, adopts the mode under agitation dripped.
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