CN114805639A - Preparation method and application of high-purity sugammadex sodium - Google Patents
Preparation method and application of high-purity sugammadex sodium Download PDFInfo
- Publication number
- CN114805639A CN114805639A CN202110125319.7A CN202110125319A CN114805639A CN 114805639 A CN114805639 A CN 114805639A CN 202110125319 A CN202110125319 A CN 202110125319A CN 114805639 A CN114805639 A CN 114805639A
- Authority
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- China
- Prior art keywords
- sugammadex sodium
- sodium
- prepared
- acid
- cyclodextrin
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- Granted
Links
- 229940041622 sugammadex sodium Drugs 0.000 title claims abstract description 77
- KMGKABOMYQLLDJ-VKHHSAQNSA-F sugammadex sodium Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].O([C@@H]([C@@H]([C@H]1O)O)O[C@H]2[C@H](O)[C@H]([C@@H](O[C@@H]3[C@@H](CSCCC([O-])=O)O[C@@H]([C@@H]([C@H]3O)O)O[C@@H]3[C@@H](CSCCC([O-])=O)O[C@@H]([C@@H]([C@H]3O)O)O[C@@H]3[C@@H](CSCCC([O-])=O)O[C@@H]([C@@H]([C@H]3O)O)O[C@@H]3[C@@H](CSCCC([O-])=O)O[C@@H]([C@@H]([C@H]3O)O)O[C@@H]3[C@@H](CSCCC([O-])=O)O[C@@H]([C@@H]([C@H]3O)O)O3)O[C@@H]2CSCCC([O-])=O)O)[C@H](CSCCC([O-])=O)[C@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H]3[C@@H](CSCCC([O-])=O)O1 KMGKABOMYQLLDJ-VKHHSAQNSA-F 0.000 title claims abstract description 76
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 47
- 238000003756 stirring Methods 0.000 claims abstract description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 17
- 239000003960 organic solvent Substances 0.000 claims abstract description 16
- 229940079593 drug Drugs 0.000 claims abstract description 13
- 239000002253 acid Substances 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 66
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 29
- 238000001035 drying Methods 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- 229920000858 Cyclodextrin Polymers 0.000 claims description 13
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical class OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 claims description 13
- -1 iodo γ -cyclodextrin Chemical compound 0.000 claims description 13
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- DKIDEFUBRARXTE-UHFFFAOYSA-N 3-mercaptopropanoic acid Chemical compound OC(=O)CCS DKIDEFUBRARXTE-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 206010029315 Neuromuscular blockade Diseases 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000012670 alkaline solution Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- YXSLJKQTIDHPOT-UHFFFAOYSA-N Atracurium Dibesylate Chemical compound C1=C(OC)C(OC)=CC=C1CC1[N+](CCC(=O)OCCCCCOC(=O)CC[N+]2(C)C(C3=CC(OC)=C(OC)C=C3CC2)CC=2C=C(OC)C(OC)=CC=2)(C)CCC2=CC(OC)=C(OC)C=C21 YXSLJKQTIDHPOT-UHFFFAOYSA-N 0.000 claims description 3
- 239000005557 antagonist Substances 0.000 claims description 3
- 229960001862 atracurium Drugs 0.000 claims description 3
- 229960000358 cisatracurium Drugs 0.000 claims description 3
- YXSLJKQTIDHPOT-LJCJQEJUSA-N cisatracurium Chemical compound C1=C(OC)C(OC)=CC=C1C[C@H]1[N@+](CCC(=O)OCCCCCOC(=O)CC[N@+]2(C)[C@@H](C3=CC(OC)=C(OC)C=C3CC2)CC=2C=C(OC)C(OC)=CC=2)(C)CCC2=CC(OC)=C(OC)C=C21 YXSLJKQTIDHPOT-LJCJQEJUSA-N 0.000 claims description 3
- 229940032712 succinylcholine Drugs 0.000 claims description 3
- AXOIZCJOOAYSMI-UHFFFAOYSA-N succinylcholine Chemical compound C[N+](C)(C)CCOC(=O)CCC(=O)OCC[N+](C)(C)C AXOIZCJOOAYSMI-UHFFFAOYSA-N 0.000 claims description 3
- 229960001844 tubocurarine Drugs 0.000 claims description 3
- JFJZZMVDLULRGK-URLMMPGGSA-O tubocurarine Chemical compound C([C@H]1[N+](C)(C)CCC=2C=C(C(=C(OC3=CC=C(C=C3)C[C@H]3C=4C=C(C(=CC=4CCN3C)OC)O3)C=21)O)OC)C1=CC=C(O)C3=C1 JFJZZMVDLULRGK-URLMMPGGSA-O 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 239000003929 acidic solution Substances 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- YXRDKMPIGHSVRX-OOJCLDBCSA-N rocuronium Chemical compound N1([C@@H]2[C@@H](O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(CC=C)CCCC2)CCOCC1 YXRDKMPIGHSVRX-OOJCLDBCSA-N 0.000 claims 2
- 229960000491 rocuronium Drugs 0.000 claims 2
- 229960005457 pancuronium Drugs 0.000 claims 1
- GVEAYVLWDAFXET-XGHATYIMSA-N pancuronium Chemical compound C[N+]1([C@@H]2[C@@H](OC(C)=O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(C)CCCCC2)CCCCC1 GVEAYVLWDAFXET-XGHATYIMSA-N 0.000 claims 1
- 229960003819 vecuronium Drugs 0.000 claims 1
- BGSZAXLLHYERSY-XQIGCQGXSA-N vecuronium Chemical compound N1([C@@H]2[C@@H](OC(C)=O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(C)CCCCC2)CCCCC1 BGSZAXLLHYERSY-XQIGCQGXSA-N 0.000 claims 1
- 238000000746 purification Methods 0.000 abstract description 12
- 239000012535 impurity Substances 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000007787 solid Substances 0.000 description 17
- 238000001816 cooling Methods 0.000 description 16
- 235000019441 ethanol Nutrition 0.000 description 16
- 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 15
- 238000006243 chemical reaction Methods 0.000 description 15
- 238000002425 crystallisation Methods 0.000 description 15
- 230000008025 crystallization Effects 0.000 description 15
- 239000011734 sodium Substances 0.000 description 15
- 229910052708 sodium Inorganic materials 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- 239000012065 filter cake Substances 0.000 description 10
- 229920002370 Sugammadex Polymers 0.000 description 7
- 229960002257 sugammadex Drugs 0.000 description 7
- WHRODDIHRRDWEW-VTHZAVIASA-N sugammadex Chemical compound O([C@@H]([C@@H]([C@H]1O)O)O[C@H]2[C@H](O)[C@H]([C@@H](O[C@@H]3[C@@H](CSCCC(O)=O)O[C@@H]([C@@H]([C@H]3O)O)O[C@@H]3[C@@H](CSCCC(O)=O)O[C@@H]([C@@H]([C@H]3O)O)O[C@@H]3[C@@H](CSCCC(O)=O)O[C@@H]([C@@H]([C@H]3O)O)O[C@@H]3[C@@H](CSCCC(O)=O)O[C@@H]([C@@H]([C@H]3O)O)O[C@@H]3[C@@H](CSCCC(O)=O)O[C@@H]([C@@H]([C@H]3O)O)O3)O[C@@H]2CSCCC(O)=O)O)[C@H](CSCCC(O)=O)[C@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H]3[C@@H](CSCCC(O)=O)O1 WHRODDIHRRDWEW-VTHZAVIASA-N 0.000 description 7
- 238000001291 vacuum drying Methods 0.000 description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 238000002386 leaching Methods 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 229960003682 rocuronium bromide Drugs 0.000 description 6
- OYTJKRAYGYRUJK-FMCCZJBLSA-M rocuronium bromide Chemical compound [Br-].N1([C@@H]2[C@@H](O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(CC=C)CCCC2)CCOCC1 OYTJKRAYGYRUJK-FMCCZJBLSA-M 0.000 description 6
- 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 5
- 239000007788 liquid Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000007670 refining Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 229960004298 vecuronium bromide Drugs 0.000 description 4
- VEPSYABRBFXYIB-PWXDFCLTSA-M vecuronium bromide Chemical compound [Br-].N1([C@@H]2[C@@H](OC(C)=O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(C)CCCCC2)CCCCC1 VEPSYABRBFXYIB-PWXDFCLTSA-M 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 239000012982 microporous membrane Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000001694 spray drying Methods 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000002826 coolant Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000002232 neuromuscular Effects 0.000 description 2
- 229960003379 pancuronium bromide Drugs 0.000 description 2
- NPIJXCQZLFKBMV-YTGGZNJNSA-L pancuronium bromide Chemical compound [Br-].[Br-].C[N+]1([C@@H]2[C@@H](OC(C)=O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(C)CCCCC2)CCCCC1 NPIJXCQZLFKBMV-YTGGZNJNSA-L 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000011034 membrane dialysis Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical group CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000011895 specific detection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/724—Cyclodextrins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0003—General processes for their isolation or fractionation, e.g. purification or extraction from biomass
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Abstract
The invention relates to a preparation method and application of high-purity sugammadex sodium, wherein the method comprises the following steps: 1) dissolving sugammadex sodium to be purified in water, adding an organic solvent into the prepared sugammadex sodium water solution, adjusting the pH value to 2-3 with acid, and stirring; 2) adding alkali to adjust the pH value to 8-9, and stirring; 3) adding small molecular alcohol, crystallizing, and separating. The high-purity sugammadex sodium prepared by the invention effectively solves the problem of purification of the sugammadex sodium, and ensures the quality of medicines and the safety of clinical medication.
Description
Technical Field
The invention relates to the field of medicinal chemistry, and in particular relates to a preparation method and application of high-purity sugammadex sodium.
Background
Sugammadex sodium (trade name: brimstin) is the first and only selective relaxation antagonist worldwide and is clinically used for reversing the neuromuscular anesthesia effect induced by the conventionally used neuromuscular blocking drugs rocuronium bromide and vecuronium bromide.
The sugammadex sodium structure contains 8 sugar rings, is a polysaccharide compound with multiple reaction sites, and each sugar ring is provided with 5 chiral centers, so that the preparation and purification difficulty of the compound is increased, and the intermediate and the raw material medicine with qualified quality can be prepared by strictly controlling reaction conditions and post-treatment conditions. The existing sugammadex sodium purification method comprises membrane dialysis purification or column chromatography purification, but is not beneficial to scale production.
CN1402737A discloses a preparation method of sugammadex sodium, which comprises the steps of reacting gamma-cyclodextrin with iodine and triphenylphosphine, reacting the prepared 6-per-deoxy-6-per-iodo-gamma-cyclodextrin with 3-mercaptopropionic acid and sodium hydride (NaH), crystallizing the prepared sugammadex sodium through ethanol, and purifying the obtained white solid through dialysis (MWCO 1000). The method has the following defects: firstly, NaH which is extremely easy to spontaneously combust when meeting moisture in the air is used in the preparation, and a large amount of hydrogen is generated in the reaction, so that the explosion risk exists; and secondly, the sugammadex sodium obtained by refining the ethanol still needs dialysis and purification, and has the defects of high cost, long time consumption, no contribution to industrial production and the like.
Document 1 (Liuyue et al, optimization of synthesis process of sugammadex sodium, chemical and biological engineering, 7 th 2019, page 54-58) discloses a preparation method of sugammadex sodium, which comprises the steps of bromizing gamma-cyclodextrin, reacting with mercaptopropionic acid, dissolving a prepared crude product of sugammadex sodium with water, filtering with a 0.45-micrometer microporous membrane, and performing acid and alkali regulation for multiple times to realize purification. The method has the following defects that firstly, the crude product solution needs to be filtered by a microporous membrane, the process is complex, the operation is complicated, and the cost is high; in the purification, a large amount of viscous solids are separated out after the acid is adjusted for the first time, absolute ethyl alcohol is not needed to be added for dispersion and then filtration, the viscous solids are easy to agglomerate to cause difficulty in subsequent treatment, the ethanol dispersion time is unpredictably prolonged, the production period is obviously prolonged, the loss is increased, and the method is not suitable for industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of high-purity sugammadex sodium, which comprises the following steps:
1) dissolving sugammadex sodium to be purified in water, adding an organic solvent into the prepared sugammadex sodium water solution, adding acid, adjusting the pH value to 2-3, and stirring to prepare an acid solution;
2) adding alkali into the acidic solution prepared in the step 1), adjusting the pH value to 8-9, and stirring to prepare an alkaline solution;
3) adding micromolecular alcohol into the alkaline solution prepared in the step 2), crystallizing, separating, washing and drying to obtain the product.
In a preferred technical scheme of the invention, the sugammadex sodium to be purified is prepared by reacting halogenated gamma-cyclodextrin with mercaptopropionic acid.
In a preferred technical scheme of the invention, the halogenated gamma-cyclodextrin is selected from any one of iodo gamma-cyclodextrin, bromo gamma-cyclodextrin and chloro gamma-cyclodextrin or a combination thereof.
In a preferred embodiment of the invention, the reaction temperature in steps 1) -2) is 5-45 ℃, preferably 15-25 ℃.
In a preferred embodiment of the present invention, the organic solvent in step 1) is selected from any one of methanol, ethanol, isopropanol, N' N-dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone, or a combination thereof.
In a preferred embodiment of the present invention, the weight ratio of sugammadex sodium to water to be purified in step 1) is 1:1-10, preferably 1:1-5.
In a preferred embodiment of the present invention, the weight ratio of sugammadex sodium to be purified in step 1) to the organic solvent is 1:1-50, preferably 1-1: 30.
In a preferred embodiment of the present invention, the acid in step 1) is selected from any one of hydrochloric acid, dilute sulfuric acid, nitric acid, carbonic acid, and phosphoric acid, or a combination thereof.
In the preferable technical scheme of the invention, the concentration of the acid is 1-8mol/L, and preferably 2-6 mol/L.
In a preferred embodiment of the invention, the stirring speed in step 1) or 2) is 60rpm to 100 rpm.
In the preferred technical scheme of the invention, the stirring time in the step 1) is 30-80min, preferably 40-60 min.
In a preferred technical scheme of the invention, the alkali in the step 2) is selected from any one of sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate and sodium bicarbonate or a combination thereof.
In the preferred technical scheme of the invention, the concentration of the alkali liquor is 10-40%, and the preferred concentration is 20-30%.
In a preferred technical scheme of the invention, the stirring time in the step 2) is 0.5-5h, preferably 1-2 h.
In a preferred embodiment of the present invention, the small molecule alcohol in step 3) is selected from any one of methanol, ethanol, isopropanol, or a combination thereof.
In a preferred embodiment of the present invention, in step 3), the weight ratio of sugammadex sodium to be purified to small molecule alcohol is 1:1-50, preferably 1: 10-40.
In a preferred technical scheme of the invention, the crystallization mode in the step 3) is selected from any one or a combination of standing crystallization and stirring crystallization.
In a preferred technical scheme of the invention, the crystallization time in the step 3) is 0.5-10h, preferably 1-5h, and more preferably 1-2 h.
In a preferred embodiment of the present invention, the separation in step 3) is selected from any one of filtration, centrifugation, and membrane treatment, or a combination thereof.
In a preferred technical scheme of the invention, the washing solvent is a small molecular alcohol, preferably any one of methanol, ethanol and isopropanol or a combination thereof.
In a preferred embodiment of the present invention, the drying is selected from any one or a combination of reduced pressure drying, vacuum drying, spray drying, atmospheric drying, and ebullient drying.
In the preferred technical scheme of the invention, the drying temperature is 25-80 ℃, preferably 35-65 ℃, and more preferably 50-60 ℃.
In a preferred technical scheme of the invention, the purity of the prepared sugammadex sodium is not less than 97%, 97.5%, 98%, 98.5%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% and 100%.
In the preferred technical scheme of the invention, the content of the mono-hydroxysugammadex sodium in the prepared sugammadex sodium is less than or equal to 5.0 percent, and the content of the mono-hydroxysugammadex sodium is preferably less than or equal to 3.0 percent.
In the preferred technical scheme of the invention, the content of single impurities except the mono-hydroxy sugammadex sodium in the prepared sugammadex sodium is less than or equal to 0.5 percent, and the content of total impurities is less than or equal to 3.0 percent.
In a preferred embodiment of the present invention, the single impurity is selected from any one of an oxidized impurity, a substituted incomplete impurity, or a combination thereof.
In a preferred embodiment of the present invention, the oxidized impurity is selected from any one of impurity a or impurity B, or a combination thereof.
In a preferred embodiment of the present invention, the incompletely substituted impurity is impurity C.
In the preferred technical scheme of the invention, the single unknown impurity in the prepared sugammadex sodium is less than or equal to 0.2 percent.
In the preferred technical scheme of the invention, the total impurity content of the prepared sugammadex sodium is less than or equal to 2.0%.
The invention aims to provide a refining method of high-purity sugammadex sodium, which comprises the following steps:
dissolving sulgamide sodium to be refined in a mixed solvent consisting of water and an organic solvent, adding activated carbon, decoloring, filtering, and collecting filtrate;
② heating the collected filtrate to 50-60 ℃, adding organic solvent, crystallizing, separating, washing and drying to obtain the final product.
In a preferred embodiment of the present invention, the organic solvent is selected from any one of methanol, ethanol, isopropanol, N' N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and acetone, or a combination thereof.
In a preferred technical scheme of the invention, in the step I, the weight ratio of the sugammadex sodium to be refined to water is 1:0.5-3, preferably 1: 1-2.
In a preferred technical scheme of the invention, in the step I, the weight ratio of the sugammadex sodium to be refined to the organic solvent is 1:0.5-3, preferably 1: 1-2.
In the preferred technical scheme of the invention, the decoloring temperature after the activated carbon is added in the step I is 15-30 ℃, and the decoloring time is 1-3 h.
In a preferred technical scheme of the invention, the activated carbon is selected from aigret A activated carbon.
In the preferable technical scheme of the invention, in the step II, the weight ratio of the sugammadex sodium to be refined to the organic solvent is 1:0.5-30, preferably 1: 1-15.
In the preferred technical scheme of the invention, after the organic solvent is added in the step two, the stirring time is 10-50min, the temperature is reduced to 15-25 ℃, the stirring is carried out for 1-3h, and the crystallization is carried out.
In a preferred embodiment of the present invention, the separation in step (c) is selected from any one of filtration, centrifugation, and membrane treatment, or a combination thereof.
In a preferred embodiment of the present invention, the washing solvent is selected from any one of methanol and ethanol, or a combination thereof.
In a preferred embodiment of the present invention, the drying is selected from any one or a combination of reduced pressure drying, vacuum drying, spray drying, atmospheric drying, and ebullient drying.
In the preferred technical scheme of the invention, the drying temperature is 25-80 ℃, preferably 35-65 ℃, and more preferably 50-60 ℃.
In a preferred technical scheme of the invention, the purity of the prepared sugammadex sodium is not less than 98%, 98.5%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% and 100%.
In the preferred technical scheme of the invention, the content of the mono-hydroxysugammadex sodium in the prepared sugammadex sodium is less than or equal to 5.0 percent, and the content of the mono-hydroxysugammadex sodium is preferably less than or equal to 3.0 percent.
In the preferred technical scheme of the invention, the content of single impurities except the mono-hydroxy sugammadex sodium in the prepared sugammadex sodium is less than or equal to 0.5 percent, and the content of total impurities is less than or equal to 3.0 percent.
In a preferred embodiment of the present invention, the single impurity is selected from any one of an oxidized impurity, a substituted incomplete impurity, or a combination thereof.
In a preferred embodiment of the present invention, the oxidized impurity is selected from any one of impurity a or impurity B, or a combination thereof.
In a preferred embodiment of the present invention, the incompletely substituted impurity is impurity C.
In the preferred technical scheme of the invention, the single unknown impurity in the prepared sugammadex sodium is less than or equal to 0.2 percent.
In the preferred technical scheme of the invention, the total impurity content of the prepared sugammadex sodium is less than or equal to 2.0%.
In a preferred embodiment of the present invention, the preparation method of the sugammadex sodium to be purified or the sugammadex sodium to be refined includes the following steps:
s1: dissolving 3-mercaptopropionic acid in an organic solvent, dropwise adding alkali liquor at the temperature of 10-35 ℃, and reacting for 10-50min after dropwise adding;
s2: dropwise adding organic solution of halogenated gamma-cyclodextrin into the mixture prepared in S1 at 15-50 ℃, reacting at 30-40 ℃ for 30-50min after dropwise adding, heating, and reacting for 2-20 h;
s3, cooling the mixture prepared in S2, adding water, stirring, cooling to-5-2 ℃ after completely clarifying, stirring for 1-10h, separating, washing and drying to obtain the compound,
in the preferred technical scheme of the invention, the molar ratio of the halogenated gamma-cyclodextrin to the 3-mercaptopropionic acid is 1:10-20, and preferably 1: 12-15.
In a preferred technical scheme of the invention, the halogenated gamma-cyclodextrin is selected from any one of iodo gamma-cyclodextrin, bromo gamma-cyclodextrin and chloro gamma-cyclodextrin.
In a preferred embodiment of the present invention, the organic solvent in S1 or S2 is selected from any one of methanol, ethanol, isopropanol, N' N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and acetone, or a combination thereof.
In a preferred embodiment of the present invention, the molar ratio of 3-mercaptopropionic acid to base in S1 is 1:1 to 5.0, preferably 1:1.5 to 3.0.
In a preferred embodiment of the present invention, the base in S1 is selected from any one of sodium hydride, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, and sodium bicarbonate, or a combination thereof.
In the preferred technical scheme of the invention, the concentration of the alkali liquor in the S1 is 10-40%, preferably 20-30%.
In the preferred technical scheme of the invention, the weight ratio of the 3-mercaptopropionic acid in S1 to the organic solvent is 1:2-10, preferably 1: 5-7.
In the preferred technical scheme of the invention, the reaction temperature in S1 is 20-30 ℃.
In the preferred technical scheme of the invention, the reaction time in S1 is 20-40 min.
In the preferred technical scheme of the invention, the reaction temperature in S2 is 25-40 ℃.
In the preferred technical scheme of the invention, the weight ratio of the halogenated gamma-cyclodextrin in the S2 to the organic solvent is 1:2-15, preferably 1: 5-8.
In the preferable technical scheme of the invention, the temperature in S2 is raised to 47-52 ℃ for reaction for 4-6 h.
In the preferable technical scheme of the invention, the temperature of the mixture prepared by the S2 in the S3 is reduced to 35-45 ℃.
In the preferred technical scheme of the invention, the weight ratio of the halogenated gamma-cyclodextrin in the S3 to the water is 1:3-15, preferably 1: 6-10.
In the preferred technical scheme of the invention, the reaction temperature of the S3 added with water is 40-50 ℃.
In the preferred technical scheme of the invention, the temperature in S3 is reduced to 20-30 ℃, and crystallization is carried out for 0.5-2 h.
In a preferred technical scheme of the invention, the cooling mode is selected from any one of natural cooling and forced cooling or a combination thereof.
In the preferred technical scheme of the invention, the forced cooling adopts a cooling medium to realize forced cooling on the crystallization system.
In a preferred embodiment of the present invention, the cooling medium is selected from any one of condensed water, ice water, brine ice, dry ice solvent, and liquid nitrogen solvent, or a combination thereof.
In a preferred embodiment of the present invention, the separation is selected from any one of filtration, centrifugation, and membrane treatment, or a combination thereof.
In a preferred embodiment of the present invention, the washing solvent is selected from any one of methanol, ethanol, isopropanol, N' N-dimethylformamide, dimethylsulfoxide, acetonitrile, and acetone, or a combination thereof.
In a preferred embodiment of the present invention, the drying is selected from any one of vacuum drying, reduced pressure drying, atmospheric drying, spray drying, and boiling drying, or a combination thereof.
In the preferred technical scheme of the invention, the drying temperature is 25-80 ℃, preferably 35-70 ℃, and more preferably 40-60 ℃.
In a preferred technical scheme of the invention, the purity of the prepared sugammadex sodium is not less than 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% and 100%.
Another object of the present invention is to provide a pharmaceutical composition consisting of sugammadex sodium with high purity and a pharmaceutically acceptable carrier.
In a preferable technical scheme of the invention, the content of the sugammadex sodium in the pharmaceutical composition is 20mg/ml-200 mg/ml.
Another object of the present invention is to provide the use of the high-purity sugammadex sodium or the pharmaceutical composition thereof for the preparation of a medicament for antagonist drug-induced neuromuscular blockade.
In a preferred technical scheme of the invention, the drug for inducing neuromuscular blockade is any one or combination of rocuronium bromide and vecuronium bromide.
Another object of the present invention is to provide a pharmaceutical composition comprising high purity sugammadex sodium or a pharmaceutical composition thereof and other drugs.
In a preferred technical scheme of the invention, the other medicament is selected from any one of rocuronium bromide, vecuronium bromide, pancuronium bromide, rocuronium bromide, mivajmmonium, atracurium, cis-atracurium, tubocurarine or succinylcholine or a combination thereof.
The invention also aims to provide application of a pharmaceutical composition prepared from high-purity sugammadex sodium or a pharmaceutical composition thereof and other medicines in preparation of medicines for resisting drug-induced neuromuscular blockade.
In a preferred technical scheme of the invention, the other medicament is selected from any one of rocuronium bromide, vecuronium bromide, pancuronium bromide, rocuronium bromide, mivajmmonium, atracurium, cis-atracurium, tubocurarine or succinylcholine or a combination thereof.
Unless otherwise indicated, when the present invention relates to percentages between liquids, said percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentages between solid and liquid, said percentages being weight/volume percentages; the balance being weight/weight percent.
Compared with the prior art, the invention has the following beneficial technical effects:
1. the preparation method of the high-purity sugammadex sodium scientifically selects the halogenated gamma-cyclodextrin to carry out condensation reaction with the 3-mercaptopropionic acid, and prepares the high-purity sugammadex sodium by separation by adjusting the acidity and alkalinity of reaction liquid, thereby effectively solving the purification problem of the sugammadex sodium and ensuring the medicine quality and the clinical medication safety.
2. The preparation method provided by the invention improves the product yield and purity, has the advantages of simple operation, short production period, high cost, less three wastes, less pollution and the like, and is suitable for industrial production.
Drawings
FIG. 1 HPLC chromatogram of sugammadex sodium prepared by purification of example 1;
FIG. 2 example 5 HPLC chromatogram of refined sugammadex.
Detailed Description
The present invention is illustrated by the following examples, which should be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Other insubstantial modifications and adaptations of the present invention can be made without departing from the scope of the present invention.
In a specific embodiment, the purity of sugammadex sodium is determined by high performance liquid chromatography (chinese pharmacopoeia 2015 edition of rules 0512 for the four kingdoms). The specific detection conditions were as follows:
a chromatographic column: octadecylsilane bonded silica gel column (Phenomenex, Aqua C18,3 μm, 150mm × 2.0 mm);
mobile phase: 0.025mol/L phosphate buffer (pH3.0) -acetonitrile (83:20) as mobile phase A, acetonitrile as mobile phase B, and gradient eluting;
detection wavelength: 200 nm;
column temperature: 35-45 ℃;
flow rate: 0.2-0.35 ml/min.
Gradient elution conditions: see table 1.
TABLE 1
Time (min) | Mobile phase A (%) | Mobile phase B (%) |
0 | 100 | 0 |
21 | 100 | 0 |
35 | 98 | 2 |
50 | 92 | 8 |
55 | 75 | 25 |
60 | 50 | 50 |
65 | 30 | 70 |
The halogenated gamma-cyclodextrin of the invention is prepared according to the prior art.
Example 1Preparation of high-purity sugammadex sodium
The preparation method of the high-purity sugammadex sodium comprises the following steps:
1) under the protection of nitrogen, adding 90Kg of purified water and 45Kg of sodium sugammadex into a reaction kettle, stirring and dissolving, adding 45Kg of dimethyl sulfoxide, adjusting the pH of the solution to 2-3 by 3M hydrochloric acid at the temperature of 15-25 ℃, and stirring for 50min at 85 rpm;
2) dropwise adding a 25% NaOH solution into the mixed solution prepared in the step 1) at 15-25 ℃, adjusting the pH to 8-9, and stirring at 85rpm for 1.0 h;
3) slowly adding 360Kg of methanol into the mixed solution prepared in the step 2) for crystallization, separating out solids, stirring for 0.5 hour, continuously dropwise adding 990Kg of methanol, dropwise adding the methanol, stirring for crystallization for 1.0 hour at 15-25 ℃, centrifuging, collecting filter cakes, leaching the filter cakes with methanol, and vacuum drying for 12 hours at 50-60 ℃ to obtain 37.3Kg of white powdery sodium sugammadex, the purity of which is 98.78 percent, the content of the sodium mono-hydroxysugammadex is 0.94 percent, the impurities A and B are not detected, and the content of the impurities C is 0.16 percent.
Example 2Preparation of high-purity sugammadex sodium
The preparation method of the high-purity sugammadex sodium comprises the following steps:
1) adding 40g of purified water and 10g of sodium sugammadex under the protection of nitrogen, stirring for dissolving, adding 10g of dimethyl sulfoxide, adjusting the pH value of the solution to 2-3 by 3M hydrochloric acid at the temperature of 15-25 ℃, and continuously stirring for 50 min;
2) dripping 25% NaOH solution into the mixed solution prepared in the step 1) at 15-25 ℃, adjusting the pH value to 8-9, and stirring for 1.0 h;
3) slowly adding 80g of methanol into the mixed solution prepared in the step 2) for crystallization, separating out solids, stirring for 0.5 hour, continuously dropwise adding 220g of methanol, stirring for crystallization for 1.0 hour at 15-25 ℃, centrifuging, leaching a filter cake with methanol, collecting the filter cake, and vacuum drying for 12 hours at 50-60 ℃ to obtain 7.51g of white powdery sodium sugammadex, the purity of which is 99.0%, the content of sodium mono-hydroxysugammadex is 0.87%, the content of impurity A is 0.02%, the content of impurity B is not detected, and the content of impurity C is 0.03%.
Example 3Preparation of high-purity sugammadex sodium
The preparation method of the high-purity sugammadex sodium comprises the following steps:
1) adding 200g of purified water and 100g of sodium sugammadex under the protection of nitrogen, stirring for dissolving, adding 100g of dimethyl sulfoxide, adjusting the pH of the solution to 2-3 with 3M hydrochloric acid at the temperature of 15-25 ℃, and continuously stirring for 50 min;
2) dropwise adding a 25% NaOH solution into the mixed solution prepared in the step 1) at 15-25 ℃, adjusting the pH to 8-9, and stirring for 1.0 h;
3) slowly adding 800g of methanol into the mixed solution prepared in the step 2) for crystallization, separating out solids, stirring for 0.5 hour, continuously dropwise adding 4200g of methanol, stirring for crystallization for 1.0 hour at 15-25 ℃ after dropwise adding, centrifuging, leaching a filter cake with methanol, collecting the filter cake, and performing vacuum drying for 12 hours at 50-60 ℃ to obtain 90.5g of white powdery sodium sugammadex, the purity of which is 97.90 percent, the content of sodium mono-hydroxysugammadex is 1.75 percent, the content of impurity A is 0.05 percent, the content of impurity B is 0.05 percent, and the content of impurity C is 0.14 percent.
Example 4Preparation of sugammadex sodium
The preparation method of the sugammadex sodium comprises the following steps:
s1: under the protection of argon/nitrogen, 198Kg of dimethyl sulfoxide (DMSO) and 31.8Kg of 3-mercaptopropionic acid are added into a 1000L reaction kettle, 24Kg of 30 percent sodium hydroxide solution is slowly added into the reaction kettle, the temperature is controlled to be 20-30 ℃, after dripping, the reaction is carried out for 0.5 hour under the heat preservation;
s2: at the temperature of 25-40 ℃, 45Kg of perbrominated gamma is dripped into the mixed liquid prepared by S1
A DMSO solution of cyclodextrin, after dripping, keeping the temperature at 30-40 ℃ for 0.5 hour, and then heating to 47-52 ℃ for reaction for 5 hours;
s3: cooling the reaction system to 35-45 ℃, slowly dropwise adding 390Kg of purified water into the reaction kettle, controlling the solution to be 40-50 ℃, stirring at 70rpm until the solution is completely clear, cooling to 20-30 ℃, stirring for crystallization for 1 hour, cooling to-5-2 ℃, keeping the temperature and stirring for 2 hours, centrifuging, leaching the filter cake with DMSO, collecting the filter cake, and drying to obtain 45.15Kg of sugammadex sodium with the purity of 95.20%.
Example 5Refining of sugammadex sodium
The refining method of the sugammadex sodium comprises the following steps:
(1) under nitrogen protection, 100g of purified water and 50g of dimethyl sulfoxide (DMSO) were added, and 50g of sugammadex sodium obtained in example 3 was added with stirring, and after complete dissolution, 5g of Egret A activated carbon was added and decolorized at 15-30 ℃ for 2 hours. Filter pressing, removing the active carbon, and leaching the filter cake by purified water.
(2) Heating the filtrate to 50-60 ℃, slowly adding 650g of DMSO (dimethyl sulfoxide) for crystallization, keeping the temperature at 50-60 ℃ and stirring for 0.5h after adding, cooling the system to 15-25 ℃, keeping the temperature and stirring for 2h, centrifuging, leaching a filter cake with methanol, and vacuum drying at 50-60 ℃ for 16 h (the vacuum degree is more than or equal to 0.08MPa) to obtain the refined product of sugammadex sodium, wherein the yield is 88.5%, the purity is 99.3%, the content of mono-hydroxysugammadex sodium is 0.51%, the content of impurity A is 0.04%, the content of impurity B is 0.04%, and the content of impurity C is 0.10%.
Comparative example 1Purification of sugammadex sodium
A process for the purification of sugammadex sodium comprising the steps of:
(1) adjusting acid, adding distilled water into 50g crude sugammadex sodium, stirring or ultrasonic treating at room temperature until completely dissolving, and filtering with 0.45 μm microporous membrane. Cooling the filtrate to 2-5 ℃, stirring, dropwise adding 1mol/LHCl solution, adjusting the pH value to 2-3, separating out a large amount of viscous solid, adding 2ml of absolute ethyl alcohol, stirring for about 3 hours, completely dispersing the viscous solid into granular solid, filtering, and washing for 3 times by using 20% cold ethanol solution to obtain solid A;
(2) adding solid A into 4mL of methanol, magnetically stirring, uniformly dispersing, cooling to 2-5 ℃, dropwise adding about 1mL of 2mol/L NaOH solution, thickening and then thinning, heating to 55-60 ℃, completely dissolving the solid, naturally cooling the solution to 0 ℃ in an oil bath pot, crystallizing, and filtering to obtain solid B;
(3) adjusting the pH value to 30 ℃, adding 6 times of methanol, stirring for 30min, cooling to 0 ℃, crystallizing for 1h, and filtering to obtain a solid C;
(4) and (3) removing methanol, namely dissolving the solid C with 2 times of water, filtering, heating to 30 ℃, adding 2 times of ethanol, slowly cooling to-15 ℃, crystallizing for 3 hours, and filtering to obtain 28.5g of sugammadex sodium with the purity of 96.5%.
The above description of the specific embodiments of the present invention is not intended to limit the present invention, and those skilled in the art may make various changes and modifications according to the present invention without departing from the spirit of the present invention, which is defined in the appended claims.
Claims (10)
1. A preparation method of high-purity sugammadex sodium comprises the following steps:
1) dissolving sugammadex sodium to be purified in water, adding an organic solvent into the prepared sugammadex sodium water solution, adding acid, adjusting the pH value to 2-3, and stirring to prepare an acid solution;
2) adding alkali into the acidic solution prepared in the step 1), adjusting the pH value to 8-9, and stirring to prepare an alkaline solution;
3) adding micromolecular alcohol into the alkaline solution prepared in the step 2), crystallizing, separating, washing and drying to obtain the product.
2. The method according to claim 1, wherein the sugammadex sodium to be purified is prepared by reacting a halogenated γ -cyclodextrin with mercaptopropionic acid.
3. The method according to claim 2, wherein the halogenated γ -cyclodextrin is selected from any one of iodo γ -cyclodextrin, bromo γ -cyclodextrin, chloro γ -cyclodextrin or a combination thereof.
4. The method according to claim 1, wherein the organic solvent in step 1) is selected from any one of methanol, ethanol, isopropanol, N' N-dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone or a combination thereof.
5. The method according to claim 1, wherein the acid in step 1) is selected from any one of hydrochloric acid, dilute sulfuric acid, nitric acid, carbonic acid, phosphoric acid, or a combination thereof.
6. The method according to any one of claims 1 to 6, wherein the sugammadex sodium produced has a purity of no less than any one of 97%, 97.5%, 98%, 98.5%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 100%.
7. A pharmaceutical composition, wherein the pharmaceutical composition consists of high purity sugammadex sodium and a pharmaceutically acceptable carrier.
8. Use of high purity sugammadex sodium prepared by the process of any one of claims 1 to 6 or the composition of claim 7 for the manufacture of a medicament for antagonist drug-induced neuromuscular blockade.
9. A pharmaceutical composition comprising the high purity sugammadex sodium prepared by the process of any one of claims 1-6 or a pharmaceutical composition thereof together with another drug.
10. The pharmaceutical composition according to claim 9, wherein the other drug is selected from any one of rocuronium, vecuronium, pancuronium, rocuronium, mivajjjjm, atracurium, cis-atracurium, tubocurarine or succinylcholine or a combination thereof.
Priority Applications (1)
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CN116606388A (en) * | 2023-06-09 | 2023-08-18 | 北京阳光诺和药物研究股份有限公司 | Alpha crystal form of sodium sugammadex and preparation method thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106749771A (en) * | 2015-11-23 | 2017-05-31 | 成都渊源生物科技有限公司 | A kind of easypro more glucose sodium preparation method of high-purity |
CN107892727A (en) * | 2017-11-27 | 2018-04-10 | 合肥博思科创医药科技有限公司 | A kind of purification process for the more glucose sodium that relaxes |
WO2019159191A1 (en) * | 2018-02-19 | 2019-08-22 | Extrovis Ag Extrovis Private Limited | An improved process for preparation of sugammadex sodium |
CN110627925A (en) * | 2018-06-22 | 2019-12-31 | 天津科伦药物研究有限公司 | Method for refining sugammadex sodium |
CN111040050A (en) * | 2019-12-26 | 2020-04-21 | 徐州工业职业技术学院 | Method for purifying sugammadex sodium |
-
2021
- 2021-01-29 CN CN202110125319.7A patent/CN114805639B/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106749771A (en) * | 2015-11-23 | 2017-05-31 | 成都渊源生物科技有限公司 | A kind of easypro more glucose sodium preparation method of high-purity |
CN107892727A (en) * | 2017-11-27 | 2018-04-10 | 合肥博思科创医药科技有限公司 | A kind of purification process for the more glucose sodium that relaxes |
WO2019159191A1 (en) * | 2018-02-19 | 2019-08-22 | Extrovis Ag Extrovis Private Limited | An improved process for preparation of sugammadex sodium |
CN110627925A (en) * | 2018-06-22 | 2019-12-31 | 天津科伦药物研究有限公司 | Method for refining sugammadex sodium |
CN111040050A (en) * | 2019-12-26 | 2020-04-21 | 徐州工业职业技术学院 | Method for purifying sugammadex sodium |
Non-Patent Citations (1)
Title |
---|
刘月 等: "舒更葡糖钠的合成工艺优化", 化学与生物工程, vol. 36, no. 7, pages 54 - 58 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116606388A (en) * | 2023-06-09 | 2023-08-18 | 北京阳光诺和药物研究股份有限公司 | Alpha crystal form of sodium sugammadex and preparation method thereof |
CN116606388B (en) * | 2023-06-09 | 2023-11-28 | 北京阳光诺和药物研究股份有限公司 | Alpha crystal form of sodium sugammadex and preparation method thereof |
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