CN101982469A - Method for removing bacterial endotoxins in cephalosporin antibiotics by utilizing macroporous adsorption resins - Google Patents
Method for removing bacterial endotoxins in cephalosporin antibiotics by utilizing macroporous adsorption resins Download PDFInfo
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- CN101982469A CN101982469A CN 201010517502 CN201010517502A CN101982469A CN 101982469 A CN101982469 A CN 101982469A CN 201010517502 CN201010517502 CN 201010517502 CN 201010517502 A CN201010517502 A CN 201010517502A CN 101982469 A CN101982469 A CN 101982469A
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- cephalosporins
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- resin
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- 239000002158 endotoxin Substances 0.000 title claims abstract description 54
- 239000011347 resin Substances 0.000 title claims abstract description 51
- 229920005989 resin Polymers 0.000 title claims abstract description 51
- 150000001780 cephalosporins Chemical class 0.000 title claims abstract description 48
- 229930186147 Cephalosporin Natural products 0.000 title claims abstract description 47
- 229940124587 cephalosporin Drugs 0.000 title claims abstract description 47
- 238000000034 method Methods 0.000 title claims abstract description 41
- 238000001179 sorption measurement Methods 0.000 title claims abstract description 30
- 239000003242 anti bacterial agent Substances 0.000 title abstract description 8
- 229940088710 antibiotic agent Drugs 0.000 title abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 14
- 239000007787 solid Substances 0.000 claims abstract description 11
- 230000003068 static effect Effects 0.000 claims abstract description 5
- 239000000243 solution Substances 0.000 claims description 37
- 239000003463 adsorbent Substances 0.000 claims description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- -1 cephalofruxin Chemical compound 0.000 claims description 11
- 238000002425 crystallisation Methods 0.000 claims description 11
- 230000008025 crystallization Effects 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 7
- GNWUOVJNSFPWDD-XMZRARIVSA-M Cefoxitin sodium Chemical compound [Na+].N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)CC1=CC=CS1 GNWUOVJNSFPWDD-XMZRARIVSA-M 0.000 claims description 6
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 6
- 229940083608 sodium hydroxide Drugs 0.000 claims description 6
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 claims description 5
- 229960002682 cefoxitin Drugs 0.000 claims description 5
- 229960004366 ceftezole Drugs 0.000 claims description 5
- 229960004261 cefotaxime Drugs 0.000 claims description 4
- DZMVCVMFETWNIU-LDYMZIIASA-N ceftezole Chemical compound O=C([C@@H](NC(=O)CN1N=NN=C1)[C@H]1SC2)N1C(C(=O)O)=C2CSC1=NN=CS1 DZMVCVMFETWNIU-LDYMZIIASA-N 0.000 claims description 4
- 238000010306 acid treatment Methods 0.000 claims description 3
- 239000012984 antibiotic solution Substances 0.000 claims description 3
- 230000031018 biological processes and functions Effects 0.000 claims description 3
- 229960001242 cefotiam Drugs 0.000 claims description 3
- 229960004755 ceftriaxone Drugs 0.000 claims description 3
- MMRINLZOZVAPDZ-LSGRDSQZSA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(1-methylpyrrolidin-1-ium-1-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;chloride Chemical compound Cl.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 MMRINLZOZVAPDZ-LSGRDSQZSA-N 0.000 claims description 2
- QYQDKDWGWDOFFU-IUODEOHRSA-N Cefotiam Chemical compound CN(C)CCN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC=3N=C(N)SC=3)[C@H]2SC1 QYQDKDWGWDOFFU-IUODEOHRSA-N 0.000 claims description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 2
- 229960001139 cefazolin Drugs 0.000 claims description 2
- FLKYBGKDCCEQQM-WYUVZMMLSA-M cefazolin sodium Chemical compound [Na+].S1C(C)=NN=C1SCC1=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 FLKYBGKDCCEQQM-WYUVZMMLSA-M 0.000 claims description 2
- 229960002100 cefepime Drugs 0.000 claims description 2
- 229960002025 cefminox Drugs 0.000 claims description 2
- 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 claims description 2
- 229960004489 cefonicid Drugs 0.000 claims description 2
- DYAIAHUQIPBDIP-AXAPSJFSSA-N cefonicid Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)[C@H](O)C=2C=CC=CC=2)CC=1CSC1=NN=NN1CS(O)(=O)=O DYAIAHUQIPBDIP-AXAPSJFSSA-N 0.000 claims description 2
- 229960004682 cefoperazone Drugs 0.000 claims description 2
- DKOQGJHPHLTOJR-WHRDSVKCSA-N cefpirome Chemical compound N([C@@H]1C(N2C(=C(C[N+]=3C=4CCCC=4C=CC=3)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 DKOQGJHPHLTOJR-WHRDSVKCSA-N 0.000 claims description 2
- 229960000466 cefpirome Drugs 0.000 claims description 2
- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 claims description 2
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 claims 1
- 238000001914 filtration Methods 0.000 abstract description 9
- 239000012530 fluid Substances 0.000 abstract description 3
- 238000003795 desorption Methods 0.000 abstract 1
- 238000000227 grinding Methods 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 239000000706 filtrate Substances 0.000 description 15
- 239000002585 base Substances 0.000 description 10
- 238000010298 pulverizing process Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- GPRBEKHLDVQUJE-VINNURBNSA-N cefotaxime Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1 GPRBEKHLDVQUJE-VINNURBNSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 230000001105 regulatory effect Effects 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 239000012266 salt solution Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 238000000108 ultra-filtration Methods 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- 229960000479 ceftriaxone sodium Drugs 0.000 description 3
- FDRNWTJTHBSPMW-GNXCPKRQSA-L disodium;(6r,7r)-7-[[(2e)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(2-methyl-6-oxido-5-oxo-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound [Na+].[Na+].S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)/C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C([O-])=NN1C FDRNWTJTHBSPMW-GNXCPKRQSA-L 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000088 plastic resin Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- BWRRTAXZCKVRON-DGPOFWGLSA-N cefotiam dihydrochloride Chemical compound Cl.Cl.CN(C)CCN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC=3N=C(N)SC=3)[C@H]2SC1 BWRRTAXZCKVRON-DGPOFWGLSA-N 0.000 description 2
- 229960001668 cefuroxime Drugs 0.000 description 2
- JFPVXVDWJQMJEE-IZRZKJBUSA-N cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 JFPVXVDWJQMJEE-IZRZKJBUSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 229920006008 lipopolysaccharide Polymers 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000002203 pretreatment Methods 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 description 1
- 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 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 230000000274 adsorptive effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229960003016 cefoxitin sodium Drugs 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000011013 endotoxin removal Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000009967 tasteless effect Effects 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical class CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical class CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a method for removing bacterial endotoxins in cephalosporin antibiotics by utilizing macroporous adsorption resins, comprising the following steps: firstly filtering the cephalosporin antibiotics solution containing the bacterial endotoxins and removing solid insoluble matters; then utilizing the pretreated macroporous adsorption resins to carry out static adsorption or dynamic adsorption on the cephalosporin antibiotics solution; and finally crystallizing, drying and grinding the solution after adsorption treatment, thus obtaining the product with bacterial endotoxins in accordance with the quality standard. The method has the advantages of high bacterial endotoxins removal rate, good selectivity, easy desorption, repeated use, low fluid resistance and easy magnification.
Description
Technical field
The invention belongs to separation technology field, be specifically related to the method that a kind of macroporous adsorbent resin is removed bacterial endotoxin in the cephalosporins.
Background technology
Bacterial endotoxin is the peculiar structure on the gram-negative bacteria cell wall adventitia, and its essence is lipopolysaccharides, mainly is made up of the two parts on chemical structure, i.e. polysaccharide and lipoid A.Lipoid A is the active centre of lipopolysaccharides, mainly is made up of the length fatty acids of glucosamine, phosphatase 11 0～18 carbon, under cynnematin salts solution condition, has hydrophobicity and electronegativity.The intracellular toxin of denier enters human body will cause high heat, diarrhoea, and vasodilation, even faint or death.
Because cephalosporins upstream raw material producer adopts enzyme method technique production one after another, make that the bacterial endotoxin index of upstream raw material and corresponding intermediate is extremely unstable, and then have influence on the quality product of cephalosporins.Simultaneously because the influence of production environment, production unit and production operation also may be brought a certain amount of bacterial endotoxin into.In order to obtain the cephalosporins product of constant product quality, safety, study that a kind of production cost is low, to remove the method for bacterial endotoxin efficiently more and more important.
Removal bacterial endotoxin method commonly used has activated carbon method, ion-exchange-resin process, soda acid method of chemical treatment, ultrafiltration process.Wherein ion-exchange-resin process and soda acid method of chemical treatment are not suitable for cephalosporins removal bacterial endotoxin.Activated carbon method is widely used in the removal of bacterial endotoxin at present aborning.But because its absorption to material is not optionally, thereby other materials in the adsorbent solution inevitably.Because activated carbon adsorptive capacity is strong, be difficult for desorb simultaneously, can not reuse.Ultra-filtration membrane used in the ultrafiltration process cleans difficulty, replacement charge is high, resistance to flow is very big, should not handle thick liquid, so the use of ultrafiltration process limits to some extent.
Removing intracellular toxin based on the affinity adsorption of affinity media, have clearance height, advantage that selectivity is high, be the focus of research at present, but it is not suitable for industrialized production to affinity media material requirements height.
Macroporous adsorbent resin is generally white granular, and granularity mostly is the 20-60 order, is the novel non-ionic macromolecule compound of a class, physico-chemical property is stable, be insoluble in acid, alkali and the organic solvent, good to the organism selectivity, be not subjected to the influence of inorganic salt plasma and low molecular compound.Macroporous adsorbent resin is not also having report aspect the microbiotic removal bacterial endotoxin.
Summary of the invention
The objective of the invention is in order to overcome the shortcoming and defect of prior art, the method that provides a kind of macroporous resin to remove bacterial endotoxin in the cephalosporins, the advantage that this method has bacterial endotoxin clearance height, selectivity is good, desorb is easy, can use repeatedly, fluid resistance is little, be easy to amplify.
Purpose of the present invention can reach by following measure:
A kind of method that adopts macroporous adsorbent resin to remove bacterial endotoxin in the cephalosporins comprises the steps:
(1) the cephalosporins solution that will contain bacterial endotoxin filters, and removes solid insoluble;
(2) with pretreated macroporous adsorbent resin the cephalosporins antibiotic solution is carried out Static Adsorption processing or dynamic adsorption processing;
(3) solution after the adsorption treatment is carried out crystallization, drying is pulverized.After the pulverizing promptly to bacterial endotoxin meets the cephalosporin antibiotics of industry or enterprise-quality standard, particularly meet the cephalosporin antibiotics of 2010 editions standards of pharmacopoeia.
Cephalosporins solution described in the step (1) is for obtaining the cephalosporins solution of pH value 4～10 by chemical method or biological process reaction.
Generally (bacteria endotoxin content of raw material is as greater than 10EU/mg greater than 0.3EU/mg and less than the raw material of 10EU/mg by bacteria endotoxin content for this cephalosporins solution, particularly then belonging to defective raw material greater than 15EU/mg need handle in advance), obtain by chemical method or biological process reaction, if wherein contained cephalosporins is without macroporous resin treatment, and its bacterial endotoxin of the product of gained is greater than standards of pharmacopoeia or company standard behind crystallizing and drying.The bacteria endotoxin content of the cephalosporins solution that general preceding method obtains is greater than 0.05EU/mg.
Present method is very low to the requirement of antibiotic concentration in the solution, and scope is wider, can be 10～300g/L, and this concentration depends primarily on difference, producer not equal of preparation feedback technology, product.
Cephalosporins among the present invention can be all injection class cephalosporins compounds, and corresponding intermediates, or its salt or acid, and it comprises a generation, two generations, three generations, the related products in four generations.Salt wherein can be any one in sodium salt, sylvite, ammonium salt, the organic amine salt; Described organic amine salt can be triethylamine salt, Tri-n-Propylamine salt, tri-n-butylamine salt, diethylamine, arginine, Methionin, any one in the thanomin.
Above-mentioned cephalosporins further can be selected ceftezole, Cephazolin, cephalofruxin, cefotiam, ceftriaxone, cefotaxime, cefoperazone, ceftazime, cefonicid, cefoxitin, cefminox, cefepime or cefpirome, or its intermediate, or its salt or acid.
Cephalosporin antibiotics solution can adopt the mixing solutions of the aqueous solution or water and organic solvent, and it is mainly determined by the preparation process of cephalosporin antibiotics.
Macroporous adsorbent resin need carry out pre-treatment earlier before use, and this pretreatment process is to adopt acetone treatment earlier, is washed till neutrality, adopts sodium-hydroxide treatment again, is washed till neutrality, adopts the salt acid treatment at last, is washed till neutrality.Wherein the consumption of acetone is generally 1～3 times of resin volume; Sodium hydroxide can adopt 2～10% the sodium hydroxide solution of 1～3BV, and hydrochloric acid can adopt 2～10% the hydrochloric acid soln of 1～3BV.When regenerating, can adopt back two steps of pretreatment process, promptly adopt sodium-hydroxide treatment earlier, be washed till neutrality, adopt the salt acid treatment again, be washed till neutrality adsorbing saturated macroporous adsorbent resin.
Described in the step (2) in the weight in wet base of macroporous adsorbent resin and the cephalosporins solution mass ratio of cephalosporins be 1: 1～1: 10, be preferably 1: 2～1: 5, further preferred 1: 2～1: 4.
Above-mentioned Static Adsorption is treated to pretreated macroporous adsorbent resin with after cephalosporins solution mixes whip attachment, filters, and obtains the solution after the adsorption treatment.
Above-mentioned dynamic adsorption is treated to packs pretreated macroporous adsorbent resin in the packed column into, under 1～5 normal atmosphere cephalosporins solution is adsorbed by packed column, obtains the solution after the adsorption treatment.
It is the nonpolar adsorption resin of skeleton that macroporous adsorbent resin of the present invention adopts with vinylbenzene, preferred DM1180 resin or DM825 resin.
Solution after the adsorption treatment is carried out the crystalline process can be handled by existing method, as transfers to suitable pH value, adding crystallization reagent etc.
In intermittent type adsorption treatment step, adopt macroporous adsorbent resin that the cephalosporins antibiotic solution is handled after, water or water and the organic solvent mixed solvent small volume of solution of simply cleaning resin remnants more also.If the continous way adsorption treatment, this step can not adopt yet.
The present invention makes full use of on the basis of macroporous adsorbent resin characteristic, macroporous resin is applied to the removal of bacterial endotoxin in the cephalosporins, substitute existing bacterial endotoxin removal method, thereby obtain the cephalosporins that bacterial endotoxin meets 2010 editions standards of pharmacopoeia.
The present invention have bacterial endotoxin clearance height, selectivity good, to cephalosporins absorption less, desorb easily, can use repeatedly, fluid resistance is little, the advantage that is easy to amplify.
Embodiment
Further explain content of the present invention by following examples, but the embodiment that is provided should not be understood that protection domain of the present invention is construed as limiting.
The macroporous adsorbent resin that uses is available from the DM1180 and the DM825 of Shandong Lukang Record Pharmaceuticals Co., Ltd..The cephalosporins that exists bacterial endotoxin to represent in the preparation process to use bacterial endotoxin to obtain in the solution greater than the raw material reaction of 0.3EU/mg, without macroporous resin treatment, its bacterial endotoxin of the product of gained is greater than standards of pharmacopoeia or company standard behind crystallizing and drying, and promptly this index of product is defective.
Macroporous resin passes through pre-treatment before use earlier, and method is as follows:
(1) DM1180 or DM825 resin are packed into dress post with the acetone treatment of 2 times of resin volumes (BV), is washed till tasteless then with pure water;
(2) sodium hydroxide solution with 2BV5% advances post, and flow velocity 2BV/h finishes the back and soaked 2 hours, is washed till neutrality with pure water;
(3) hydrochloric acid soln with 2BV5% advances post, and flow velocity 2BV/h finishes the back and soaked 2 hours, is washed till neutrality with pure water, can use.
The regeneration of macroporous resin only needs to adopt step (2) and (3) two steps in the pretreatment process to get final product.
Embodiment 1
Obtain the cefotaxime triethylamine salt solution of 1200L bacterial endotoxin by reaction greater than 0.05EU/mg, pH value 8.0 is with pressure (2 normal atmosphere) to enter the packed column that contains 100kg (weight in wet base) DM1180 macroporous adsorbent resin behind plate-and-frame filter press solids removed by filtration insolubles and is carried out the dynamic adsorption processing.Can also further wash resin with water after disposing.Filtrate through plastic resin treatment is regulated pH to 3.5 with hydrochloric acid, and crystallization obtains cefotaxime acid, obtains the cefotaxime acid of 240kg bacterial endotoxin less than 0.05EU/mg after drying, the pulverizing, and the rate of loss of cefotaxime acid is lower than 0.5%.
Embodiment 2
Obtain the cefotaxime triethylamine salt solution of 40L bacterial endotoxin by reaction greater than 0.05EU/mg, pH8.0, behind plate-and-frame filter press solids removed by filtration insolubles, enter the packed column that contains 3.5kg (weight in wet base) DM1180 macroporous adsorbent resin under the normal pressure and carry out the dynamic adsorption processing.Filtrate through plastic resin treatment is regulated pH to 3.5 with hydrochloric acid, and crystallization obtains cefotaxime acid, obtains 8kg after drying, the pulverizing, and bacterial endotoxin is less than the cefotaxime acid of 0.05EU/mg, and the rate of loss of cefotaxime acid is lower than 1%.
Embodiment 3
Obtain the ceftriaxone triethylamine salt solution of 100L bacterial endotoxin by reaction greater than 0.15EU/mg, pH8.0 is with pressure (2 normal atmosphere) to enter the packed column that contains 3.5Kg (weight in wet base) DM1180 macroporous adsorbent resin behind plate-and-frame filter press solids removed by filtration insolubles and carries out the dynamic adsorption processing.The mixing solutions washing resin of water and organic solvent after disposing.Filtrate is added sodium acetate soln, and adds acetone, and crystallization obtains ceftriaxone sodium, obtains 15kg after drying, the pulverizing, and bacterial endotoxin is less than the ceftriaxone sodium of 0.15EU/mg, and the rate of loss of ceftriaxone sodium is lower than 1%.
Embodiment 4
Obtain the ceftezole triethylamine salt solution of 150mL bacterial endotoxin greater than 0.075EU/mg by reaction, organic phase is removed in layering, and water pH7.2 filters, and filtrate adds 8g (weight in wet base) DM825 macroporous adsorbent resin and stirs 30min.Filter, filtrate is regulated pH to 2.0 with hydrochloric acid, and crystallization obtains cefotaxime acid, obtains 25g after drying, the pulverizing, and bacterial endotoxin is less than the ceftezole acid of 0.075EU/mg, and the rate of loss of ceftezole acid is lower than 1%.
Embodiment 5
Obtain the ceftazime triethylamine salt solution of 150mL bacterial endotoxin greater than 0.1EU/mg, pH8.0, solids removed by filtration insolubles by reaction.Filtrate adds 10g (weight in wet base) DM1180 macroporous adsorbent resin and stirs 30min.Filter, filtrate obtains the ceftazime dihydrochloride with acid crystal, obtains 25g after drying, the pulverizing, and bacterial endotoxin is less than the ceftazime acid dihydrochloride of 0.1EU/mg, and the rate of loss of ceftazime acid dihydrochloride is lower than 1%.
Embodiment 6
Obtain the cephalofruxin acid solution by reaction, use NaHCO
3Regulate pH to 6.5, remove organic phase, obtain the cephalofruxin sodium solution of 3L bacterial endotoxin, the solids removed by filtration insolubles greater than 0.1EU/mg.Filtrate pressurization enters and contains 80g (weight in wet base) DM825 macroporous absorption tree packed column and carry out dynamic adsorption and handle.Filtrate through plastic resin treatment is regulated pH to 2.0 with hydrochloric acid, and crystallization obtains cefuroxime acid, obtains the cefuroxime acid of 300g bacterial endotoxin less than 0.1EU/mg after drying, the pulverizing.
Embodiment 7
The cefoperazone acid crude of bacterial endotoxin greater than 0.05EU/mg added in the mixture of entry and solvent, add the sodium bicarbonate dissolving again, pH7.5, solids removed by filtration insolubles.Add 20g (weight in wet base) DM1180 macroporous adsorbent resin in the filtrate and stir 30min.Filter, filtrate is regulated pH to 2.0 with hydrochloric acid, and crystallization obtains cefoperazone acid, obtains the cefoperazone acid of 50g bacterial endotoxin less than 0.05EU/mg after drying, the pulverizing.
Embodiment 8
Obtain the cefoxitin acid solution by reaction, use NaHCO
3Regulate pH to 7, remove organic phase, obtain the cefoxitin sodium solution of 500mL bacterial endotoxin, the solids removed by filtration insolubles greater than 0.1EU/mg.Add 5g (weight in wet base) DM825 macroporous adsorbent resin in the filtrate and stir 30min.Filter, filtrate is regulated pH2.5 with hydrochloric acid, and crystallization obtains cefoxitin acid, obtains the cefoxitin acid of 20g bacterial endotoxin less than 0.1EU/mg after drying, the pulverizing.
Embodiment 9
Obtain the cefotiam triethylamine salt solution of 400mL bacterial endotoxin greater than 0.1EU/mg, pH8.0, solids removed by filtration insolubles by reaction.Add 15g (weight in wet base) DM1180 macroporous adsorbent resin in the filtrate and stir 30min.Filter.Add hydrochloric acid and methylene dichloride, stir, remove organic phase.Filtrate is regulated pH to 1.0 with hydrochloric acid, and adds acetone, and crystallization obtains the cefotiam dihydrochloride, obtains the cefotiam dihydrochloride of 50g bacterial endotoxin less than 0.1EU/mg after drying, the pulverizing.
Claims (10)
1. a method that adopts macroporous adsorbent resin to remove bacterial endotoxin in the cephalosporins is characterized in that comprising the steps:
(1) the cephalosporins solution that will contain bacterial endotoxin filters, and removes solid insoluble;
(2) with pretreated macroporous adsorbent resin the cephalosporins antibiotic solution is carried out Static Adsorption processing or dynamic adsorption processing;
(3) solution after the adsorption treatment is carried out crystallization, drying is pulverized.
2. method according to claim 1 is characterized in that cephalosporins solution described in the step (1) is for obtaining the cephalosporins solution of pH value 4～10 by chemical method or biological process reaction.
3. method according to claim 1, the bacteria endotoxin content that it is characterized in that cephalosporins solution described in the step (1) is greater than 0.05EU/mg.
4. method according to claim 1, the content that it is characterized in that cephalosporins in the described cephalosporins solution is 10～300g/L.
5. according to arbitrary described method in the claim 1～4, it is characterized in that described cephalosporins is ceftezole, Cephazolin, cephalofruxin, cefotiam, ceftriaxone, cefotaxime, cefoperazone, ceftazime, cefonicid, cefoxitin, cefminox, cefepime or cefpirome, or its intermediate, or its salt or acid.
6. method according to claim 1, the pretreatment process that it is characterized in that macroporous adsorbent resin described in the step (2) is washed till neutrality for adopting acetone treatment earlier, adopts sodium-hydroxide treatment again, is washed till neutrality, adopts the salt acid treatment at last, is washed till neutrality.
7. method according to claim 1 is characterized in that the mass ratio of cephalosporins in the weight in wet base of macroporous adsorbent resin described in the step (2) and the cephalosporins solution is 1: 1～1: 10.
8. method according to claim 1 is characterized in that described Static Adsorption is treated to pretreated macroporous adsorbent resin with after cephalosporins solution mixes whip attachment, filters, and obtains the solution after the adsorption treatment.
9. method according to claim 1, it is characterized in that described dynamic adsorption is treated to packs pretreated macroporous adsorbent resin in the packed column into, conventional or be forced under 1～5 normal atmosphere cephalosporins solution is adsorbed by packed column, obtain the solution after the adsorption treatment.
10. method according to claim 1 is characterized in that described macroporous adsorbent resin for being the nonpolar adsorption resin of skeleton with vinylbenzene, preferably DM1180 resin or DM825 resin.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102295654A (en) * | 2011-08-10 | 2011-12-28 | 江西新先锋医药有限公司 | Cefoxitin compound and composition thereof |
| CN102617605A (en) * | 2012-02-29 | 2012-08-01 | 石药集团中诺药业（石家庄）有限公司 | Ceftriaxone sodium compound and preparation method thereof |
| CN104437339A (en) * | 2014-12-30 | 2015-03-25 | 北海万物盛生物技术开发有限公司 | Preprocessing method of eluting plant stains by using macroporous resin |
| CN104610282A (en) * | 2015-02-14 | 2015-05-13 | 石药集团中诺药业（石家庄）有限公司 | Method for purifying cefazolin acid |
| CN104667892A (en) * | 2015-02-11 | 2015-06-03 | 北海和思科技有限公司 | Macroporous resin pretreatment method |
| CN114601805A (en) * | 2022-01-13 | 2022-06-10 | 南昌立健药业有限公司 | Cefminox sodium powder for injection and preparation method thereof |
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| WO2005111059A2 (en) * | 2004-04-23 | 2005-11-24 | Sigma-Aldrich Co. | Process for the reduction of endotoxins |
| CN1970780A (en) * | 2006-12-06 | 2007-05-30 | 云南沃森生物技术有限公司 | Process for removing endotoxin in bacteria polysaccharide by using macroporous resin |
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| WO2005111059A2 (en) * | 2004-04-23 | 2005-11-24 | Sigma-Aldrich Co. | Process for the reduction of endotoxins |
| CN1970780A (en) * | 2006-12-06 | 2007-05-30 | 云南沃森生物技术有限公司 | Process for removing endotoxin in bacteria polysaccharide by using macroporous resin |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102295654A (en) * | 2011-08-10 | 2011-12-28 | 江西新先锋医药有限公司 | Cefoxitin compound and composition thereof |
| CN102617605A (en) * | 2012-02-29 | 2012-08-01 | 石药集团中诺药业（石家庄）有限公司 | Ceftriaxone sodium compound and preparation method thereof |
| CN102617605B (en) * | 2012-02-29 | 2014-11-05 | 石药集团中诺药业（石家庄）有限公司 | Ceftriaxone sodium compound and preparation method thereof |
| CN104437339A (en) * | 2014-12-30 | 2015-03-25 | 北海万物盛生物技术开发有限公司 | Preprocessing method of eluting plant stains by using macroporous resin |
| CN104437339B (en) * | 2014-12-30 | 2017-07-04 | 赖世权 | A kind of macroporous absorbent resin elutes the preprocess method of plant stain |
| CN104667892A (en) * | 2015-02-11 | 2015-06-03 | 北海和思科技有限公司 | Macroporous resin pretreatment method |
| CN104610282A (en) * | 2015-02-14 | 2015-05-13 | 石药集团中诺药业（石家庄）有限公司 | Method for purifying cefazolin acid |
| CN114601805A (en) * | 2022-01-13 | 2022-06-10 | 南昌立健药业有限公司 | Cefminox sodium powder for injection and preparation method thereof |
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