CN112538123B - 一种舒更葡糖钠晶型m - Google Patents
一种舒更葡糖钠晶型m Download PDFInfo
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- CN112538123B CN112538123B CN201910894050.1A CN201910894050A CN112538123B CN 112538123 B CN112538123 B CN 112538123B CN 201910894050 A CN201910894050 A CN 201910894050A CN 112538123 B CN112538123 B CN 112538123B
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- Prior art keywords
- sodium
- sulmore
- gluconate
- stirring
- crystal form
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- 239000011734 sodium Substances 0.000 title claims abstract description 114
- 229910052708 sodium Inorganic materials 0.000 title claims abstract description 114
- 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 title claims abstract description 112
- 239000013078 crystal Substances 0.000 title claims abstract description 45
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 21
- 239000008103 glucose Substances 0.000 claims abstract description 19
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- 229920002370 Sugammadex Polymers 0.000 claims abstract description 13
- 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 claims abstract description 13
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- 238000000034 method Methods 0.000 claims abstract description 8
- 230000005855 radiation Effects 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 69
- 238000003756 stirring Methods 0.000 claims description 52
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 claims description 40
- 229940050410 gluconate Drugs 0.000 claims description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 25
- 239000008213 purified water Substances 0.000 claims description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 238000002425 crystallisation Methods 0.000 claims description 23
- 230000008025 crystallization Effects 0.000 claims description 23
- 239000012065 filter cake Substances 0.000 claims description 21
- 238000001914 filtration Methods 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- AEQDJSLRWYMAQI-UHFFFAOYSA-N 2,3,9,10-tetramethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline Chemical compound C1CN2CC(C(=C(OC)C=C3)OC)=C3CC2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-UHFFFAOYSA-N 0.000 claims description 15
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- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 9
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 8
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 239000003158 myorelaxant agent Substances 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 3
- 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 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 229940041622 sugammadex sodium Drugs 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 26
- 239000000243 solution Substances 0.000 abstract description 22
- 229940079593 drug Drugs 0.000 abstract description 17
- 238000002347 injection Methods 0.000 abstract description 10
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- 229940090044 injection Drugs 0.000 abstract description 9
- 229910017488 Cu K Inorganic materials 0.000 abstract description 4
- 229910017541 Cu-K Inorganic materials 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000002441 X-ray diffraction Methods 0.000 abstract description 3
- 229940093181 glucose injection Drugs 0.000 abstract description 2
- 238000001228 spectrum Methods 0.000 abstract 1
- 229940083542 sodium Drugs 0.000 description 96
- 235000015424 sodium Nutrition 0.000 description 96
- 230000000052 comparative effect Effects 0.000 description 26
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 24
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 17
- 229960001031 glucose Drugs 0.000 description 17
- 239000000203 mixture Substances 0.000 description 14
- 238000004090 dissolution Methods 0.000 description 13
- 239000012535 impurity Substances 0.000 description 13
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- 238000013112 stability test Methods 0.000 description 11
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- 238000012360 testing method Methods 0.000 description 10
- 238000001816 cooling Methods 0.000 description 9
- CGRKCGWEOIQFRD-UHFFFAOYSA-N sodium;(4-aminophenyl)sulfonylazanide Chemical compound [Na+].NC1=CC=C(S([NH-])(=O)=O)C=C1 CGRKCGWEOIQFRD-UHFFFAOYSA-N 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 7
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- FMRFEDNKAXLENR-XRDLMGPZSA-L disodium (2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Na+].[Na+].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O FMRFEDNKAXLENR-XRDLMGPZSA-L 0.000 description 5
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- -1 and among them Chemical compound 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- 239000004475 Arginine Substances 0.000 description 2
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- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
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- BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
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- 230000009466 transformation Effects 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
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- 229960004298 vecuronium bromide Drugs 0.000 description 1
- 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 1
- 235000019156 vitamin B Nutrition 0.000 description 1
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
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Abstract
本发明提供了一种舒更葡糖钠晶型M,涉及晶型药物分子技术领域。该舒更葡糖钠晶型M使用Cu‑Kα辐射,以2θ表示的X射线衍射谱图5.93±0.2°,7.47±0.2°,8.38±0.2°,17.80±0.2°,18.83±0.2°,20.05±0.2°,21.55±0.2°,22.39±0.2°,24.03±0.2°有特征峰;并提供了相关制备方法和应用。本发明的舒更葡糖钠晶型M稳定性好,其溶液澄清度与颜色符合注射液原料药标准,提高了舒更葡糖钠注射制剂的安全性和稳定性。
Description
技术领域
本发明涉及晶型药物分子技术领域,具体涉及一种舒更葡糖钠晶型。
背景技术
舒更葡糖钠(Sugammadex Sodium),化学名为八-6-全脱氧-6-全(2-羧基乙基)硫代-γ-环糊精钠盐,CAS号:343306-79-6,具体结构式如下所示:
舒更葡糖钠是一种新型肌松药逆转剂,最早由荷兰Organon公司研发的,用于逆转常规使用的神经肌肉阻断药罗库溴铵或维库溴铵的阻滞作用,可立即逆转成人使用过的罗库溴铵作用、常规逆转儿童和青少年(2~17岁)使用过的罗库溴铵作用。舒更葡糖钠是首个和唯一的选择性松弛结合剂(selective relaxant binding agent,SRBA),是20年来麻醉药领域第一个重大药物进展,被誉为里程碑式的肌松拮抗剂。
Akzo Nobel拥有6-巯基环糊精衍生物的专利权(公告号:CN1402737A),其旗下人类卫生保健部门荷兰欧加农公司2007年并入先灵葆雅,先灵葆雅随后开发出sugammadex,2009年随着先灵葆雅被默沙东收购,默沙东获得sugammadex。本品已于2008年和2010年分别在欧盟和日本获得批准。2015年12月15日FDA批准舒更葡糖钠注射液(商品名:Bridion)上市销售。
近些年研究发现,药物晶型不同,其理化性质(密度、硬度、溶解度、稳定性、光学性及电学性等)、溶出速率、生物效应等均能发生变化,因此药物晶型研究在医药学上具有重要实用价值。晶型药物分子包括药物分子的多晶型、水合物、溶剂化物和盐类等,通过药物结晶的途径,不仅可以明确晶型药物分子的晶体学参数,还可以确定晶型中溶剂分子的种类和个数(如:结晶水分子),对于理解和掌握药物分子的空间排布,及理化性质具有非常重要的作用。
目前舒更葡糖钠晶型研究报道中,CN107400182报道了一种向舒更葡糖钠水溶液中滴加甲醇、乙醇等醇类,制备得到舒更葡糖钠晶型A;专利IN201741012475报道了甲醇/水混合溶液中,滴加甲醇析晶得到一种舒更葡糖钠晶型;专利US9879096公开制备了一种舒更葡糖钠无定型;专利CN109053933报道了5种舒更葡糖钠晶型和一种舒更葡糖钠无定型,专利TW201912656公开了舒更葡糖钠晶型I和II,并且报道了通过加热晶型II使其发生转晶得到舒更葡糖钠晶型III。
众所周知,作为有效的肌松拮抗剂的舒更葡糖钠为注射剂原料药,注射制剂对原料药的各个方面要求较为严格,已知的舒更葡糖钠晶型,在澄清度、颜色、溶解度、热稳定性、光稳定性、溶出度、生物利用度等方面不能很好的满足药物制剂要求,因此需要开发更多的晶型,一方面为药物应用提供更多的舒更葡糖钠晶型,在化学纯度、流动性、溶解度、稳定性(如储存稳定性、脱水稳定性、多晶型转化稳定性、低吸湿性、低剩余溶剂含量)、澄清度等方面改善药物性能,开发出具有更加高效的药物;另一方面,也要开发更适合工业化生产的,经济效益高的舒更葡糖钠晶型。
发明内容
为了克服现有技术的缺点,本发明的一个目的是提供了一种舒更葡糖钠晶型M;本发明的另一目的是提供了该舒更葡糖钠晶型M的制备方法;本发明还有一个目的是提供一种舒更葡糖钠晶型M在制备肌松拮抗剂药物中的用途。
本发明具体技术方案如下:
一种舒更葡糖钠晶型M,使用Cu-Kα辐射,以2θ表示的X射线衍射谱图在5.93±0.2°,7.47±0.2°,8.38±0.2°,17.80±0.2°,18.83±0.2°有特征峰。
优选地,所述的舒更葡糖钠晶型M,使用Cu-Kα辐射,以2θ表示的X射线衍射谱图在5.93±0.2°,7.47±0.2°,8.38±0.2°,17.80±0.2°,18.83±0.2°,20.05±0.2°,21.55±0.2°,22.39±0.2°,24.03±0.2°有特征峰。
优选地,所述的舒更葡糖钠晶型M,使用Cu-Kα辐射,其特征峰符合如图1所示的X射线粉末衍射图谱。
上述的舒更葡糖钠晶型M的制备在超声下进行,其制备方法具体包括以下步骤:
惰性气体保护超声条件下,将舒更葡糖钠加入纯化水中,搅拌溶解得舒更葡糖钠水溶液;向舒更葡糖钠水溶液中加入有机溶剂A后,控温反应,反应结束;超声下控温滴加有机溶剂B,滴加完毕,保温搅拌析晶;析晶结束,过滤,滤饼干燥,得白色结晶舒更葡糖钠。
优选地,所述超声功率为30~60KHz;优选为40~50KHz。
优选地,所述舒更葡糖钠与纯化水的质量体积比为1:1~2g/ml。
优选地,所述有机溶剂A为甲醇、乙醇、异丙醇、乙腈、丙酮、N,N-二甲基甲酰胺中的一种或两种;优选甲醇。
优选地,所述舒更葡糖钠与有机溶剂A的质量体积比为1:1~3,g/ml。
优选地,所述控温反应温度为20~50℃,优选30~40℃。
优选地,所述控温反应时间为1~3小时。
优选地,所述有机溶剂B为甲醇、乙醇、乙腈、丙酮、N,N-二甲基甲酰胺、异丙醇、叔丁醇、四氢呋喃、1,4-二氧六环、乙二醇、丙二醇中的一种或两种;优选丙酮。
优选地,所述有机溶剂B的用量为可使舒更葡糖钠达到最大析出量的合适用量;其中舒更葡糖钠与有机溶剂B的质量体积比优选为1:8~20,g/ml。
优选地,所述控温滴加有机溶剂B及搅拌析晶的温度为20~30℃。
优选地,所述析晶时间为2~4小时。
本发明中,所述的惰性气体通常选择氮气、氩气,其中特别优选为氩气。
上述舒更葡糖钠晶型M作为活性成分制备肌松拮抗剂药物的应用。
一种注射制剂,该注射制剂含有本发明所述的舒更葡糖钠晶型M,并混有其它组分。
优选地,本发明的注射制剂的制备方法如下:使用标准和常规的技术,使本发明化合物与制剂学上可接受的固体或液体载体结合,以及使之任意地与制剂学上可接受的赋形剂结合制备成可用注射制剂。
优选地,所述制剂可以为即用型液体注射剂,也可以为冻干粉针剂。
优选地,所述制剂的其它组分包括可联合使用的其它活性成分、渗透压调节剂、pH值调节剂、增溶剂、助溶剂、抗氧剂、抑菌剂、乳化剂、络合剂等。
更加优选地,所述渗透压调节剂选自氯化钠、葡萄糖、果糖、甘油、山梨醇、木糖醇、氯化镁、磷酸盐、枸橼酸钠、甘露醇中的一种或几种;所述pH值调节剂选自盐酸、硫酸、乳酸、苹果酸、醋酸、枸橼酸、磷酸、氢氧化钠、碳酸钠、碳酸氢钠、磷酸氢二钠、磷酸二氢钠、柠檬酸钠、精氨酸中的一种或几种;所述增溶剂选自吐温80、吐温60、伯洛沙姆68、中的一种或几种;所述助溶剂选自苯基酸钠、水杨酸钠、对氨基苯甲酸钠、乌拉坦、尿素、芥酰胺、葡萄糖、葡甲胺、苹果酸、蛋氨酸、甘氨酸、精氨酸、烟酰胺、碳酸氢钠、苯丙氨酸、维生素B6中的一种或几种;所述的抗氧剂选自L-半胱氨酸盐酸盐、亚硫酸钠、亚硫酸氢钠、没食子酸丙酯、谷胱甘肽、硫代硫酸钠、硫脲、疏基乙酸、焦亚硫酸钠、维生素B中的一种或几种;所述的抑菌剂选自中的一种或几种;所述的乳化剂选自卵磷脂、豆磷脂、伯洛沙姆68、胆固醇、甘油单油酸酯中的一种或几种;所述的络合剂选自乙二胺四乙酸二钠、乙二胺四乙酸钙二钠盐中的一种或几种。
本发明的有益效果:
1.本发明舒更葡糖钠晶型制备方法简单,生产设备要求低,所得产品纯度和收率较高,适于大规模推广应用。
2.本发明的舒更葡糖钠晶型有较好的稳定性,利用本发明晶型制备的剂型,其利于药物储存的同时保证了药效。
3.本发明舒更葡糖钠晶型的溶液澄清度与颜色合格,提高了舒更葡糖钠注射制剂的安全性和稳定性。
附图说明
图1:舒更葡糖钠晶型X射线粉末衍射图谱。
图2:舒更葡糖钠晶型差示扫描量热曲线(DSC/TGA)图。
具体实施方式
下面通过实施例来进一步说明本发明。应该正确理解的是:本发明的实施例仅仅是用于说明本发明,而不是对本发明的限制,所以,在本发明的方法前提下对本发明的简单改进均属本发明要求保护的范围。
实验所用物料:舒更葡糖钠可购买,也可参照现有技术制备;其他实验所用物料未标明来源和规格的均为市售分析纯或化学纯。
本发明采用HPLC测定舒更葡糖钠的纯度,色谱条件如下:
色谱柱:Phenomenex,Aqua-C18(2.0mm×150mm,3.0μm);
流动相:流动相A:25.0mmol/L磷酸盐缓冲溶液(pH=3.0)(取一水磷酸二氢钠3.45g,置于1000ml容量瓶中,加水950ml,用1.5mol/L磷酸溶液调节pH至3.00±0.03,并用水稀释至刻度,摇匀)-乙腈(83:20);流动相B:乙腈;
柱温:40℃;
检测波长:200nm;
流速:0.27ml/min;
进样量:2.5μl;
洗脱梯度如表1所示,其中舒更葡糖钠(8-取代物)保留时间约在20.5min~23.0min之间,次要活性成分7-取代物约在0.65倍主峰保留时间,舒更葡糖钠纯度以7-取代物与8-取代物面积和计算。
表1 洗脱梯度表
实施例1
氩气保护下,将舒更葡糖钠(10.03g)加入纯化水(15ml)中,放入超声仪(45KHz)中搅拌溶解;向舒更葡糖钠水溶液中加入甲醇(20ml),控温35℃超声反应2小时;反应结束,反应液超声(45KHz)下控温25℃,边搅拌边滴加丙酮(150ml),滴加完毕,保温25℃搅拌析晶3小时;析晶结束,过滤,滤饼40℃减压干燥至恒重,得白色结晶舒更葡糖钠,收率98.8%,纯度99.91%。
实施例2
氩气保护下,将舒更葡糖钠(10.06g)加入纯化水(10ml)中,放入超声仪(50KHz)中搅拌溶解;向舒更葡糖钠水溶液中加入乙醇(10ml),控温30℃超声反应3小时;反应结束,反应液超声(50KHz)下控温25℃,边搅拌边滴加甲醇(100ml),滴加完毕,保温25℃搅拌析晶3小时;析晶结束,过滤,滤饼40℃减压干燥至恒重,得白色结晶舒更葡糖钠,收率97.4%,纯度99.85%。
实施例3
氩气保护下,将舒更葡糖钠(10.04g)加入纯化水(20ml)中,放入超声仪(45KHz)中搅拌溶解;向舒更葡糖钠水溶液中加入甲醇(25ml),控温40℃超声反应2小时;反应结束,反应液超声(45KHz)下控温20℃,边搅拌边滴加乙腈(200ml),滴加完毕,保温20℃搅拌析晶4小时;析晶结束,过滤,滤饼40℃减压干燥至恒重,得白色结晶舒更葡糖钠,收率97.6%,纯度99.82%。
实施例4
氩气保护下,将舒更葡糖钠(10.02g)加入纯化水(15ml)中,放入超声仪(40KHz)中搅拌溶解;向舒更葡糖钠水溶液中加入乙腈(20ml),控温20℃超声反应3小时;反应结束,反应液超声(40KHz)下控温30℃,边搅拌边滴加乙醇(150ml),滴加完毕,保温30℃搅拌析晶3小时;析晶结束,过滤,滤饼40℃减压干燥至恒重,得白色结晶舒更葡糖钠,收率97.2%,纯度99.80%。
实施例5
氩气保护下,将舒更葡糖钠(10.03g)加入纯化水(15ml)中,放入超声仪(45KHz)中搅拌溶解;向舒更葡糖钠水溶液中加入N,N-二甲基甲酰胺(15ml),控温50℃超声反应1小时;反应结束,反应液超声(45KHz)下控温25℃,边搅拌边滴加异丙醇(120ml),滴加完毕,保温25℃搅拌析晶3小时;析晶结束,过滤,滤饼40℃减压干燥至恒重,得白色结晶舒更葡糖钠,收率96.6%,纯度99.82%。
实施例6
氩气保护下,将舒更葡糖钠(10.08g)加入纯化水(15ml)中,放入超声仪(30KHz)中搅拌溶解;向舒更葡糖钠水溶液中加入异丙醇(20ml),控温35℃超声反应2小时;反应结束,反应液超声(30KHz)下控温30℃,边搅拌边滴加甲醇(100ml),滴加完毕,保温30℃搅拌析晶3小时;析晶结束,过滤,滤饼40℃减压干燥至恒重,得白色结晶舒更葡糖钠,收率96.4%,纯度99.78%。
实施例7
氩气保护下,将舒更葡糖钠(10.05g)加入纯化水(15ml)中,放入超声仪(45KHz)中搅拌溶解;向舒更葡糖钠水溶液中加入甲醇(20ml),控温40℃超声反应2小时;反应结束,反应液超声(45KHz)下控温25℃,边搅拌边滴加四氢呋喃(180ml),滴加完毕,保温25℃搅拌析晶3小时;析晶结束,过滤,滤饼40℃减压干燥至恒重,得白色结晶舒更葡糖钠,收率97.5%,纯度99.81%。
实施例8
氩气保护下,将舒更葡糖钠(10.06g)加入纯化水(20ml)中,放入超声仪(50KHz)中搅拌溶解;向舒更葡糖钠水溶液中加入乙腈(20ml),控温35℃超声反应2小时;反应结束,反应液超声(50KHz)下控温25℃,边搅拌边滴加叔丁醇(200ml),滴加完毕,保温25℃搅拌析晶2小时;析晶结束,过滤,滤饼40℃减压干燥至恒重,得白色结晶舒更葡糖钠,收率96.1%,纯度99.77%。
实施例9
氩气保护下,将舒更葡糖钠(10.02g)加入纯化水(15ml)中,放入超声仪(60KHz)中搅拌溶解;向舒更葡糖钠水溶液中加入丙酮(20ml),控温35℃超声反应2小时;反应结束,反应液超声(60KHz)下控温25℃,边搅拌边滴加1,4-环氧六环(100ml),滴加完毕,保温25℃搅拌析晶3小时;析晶结束,过滤,滤饼40℃减压干燥至恒重,得白色结晶舒更葡糖钠,收率96.3%,纯度99.75%。
实施例10
氩气保护下,将舒更葡糖钠(10.07g)加入纯化水(15ml)中,放入超声仪(40KHz)中搅拌溶解;向舒更葡糖钠水溶液中加入甲醇(20ml),控温30℃超声反应3小时;反应结束,反应液超声(40KHz)下控温25℃,边搅拌边滴加乙二醇(150ml),滴加完毕,保温25℃搅拌析晶4小时;析晶结束,过滤,滤饼40℃减压干燥至恒重,得白色结晶舒更葡糖钠,收率96.8%,纯度99.80%。
晶型结构的确认
本发明中所涉及的X-射线粉末衍射测试仪器及测试条件:X-射线粉末衍射仪:PANalytical E;Cu-Kα;样品台:平板;入射光路:BBHD;衍射光路:PLXCEL;电压45kv,电流40mA;发散狭缝:1/4;防散射狭缝:1;索拉狭缝:0.04rad;步长:0.5s;扫描范围:3~50°。本发明舒更葡糖钠晶型对应的X射线粉末衍射图(Cu-Kα)中特征峰详见图1及表2。
表2 舒更葡糖钠晶型M PXRD峰
实施例1~10的样品都具有相同的X-射线粉末衍射图谱。
参照现有报道的舒更葡糖钠晶型的制备方法,制备对比实施例1~11舒更葡糖钠。
对比实施例1
将舒更葡糖钠(46g)加入纯化水(69ml)/甲醇(69ml)的混合溶液中,在25-35℃下搅拌溶解后,加入活性炭(11.5g),25-35℃下搅拌30min,过滤,滤饼用水(23ml)/甲醇(23ml)洗涤后,滤液控温25-35℃,加入甲醇(598ml)搅拌2小时,过滤,滤饼甲醇(184ml)洗涤,55-60℃下干燥14小时,得结晶舒更葡糖钠,收率55.3%,纯的99.62%。
对比实施例2
将舒更葡糖钠(10.9g)加入纯化水(15ml)/甲醇(15ml)的混合溶液中,加入活性炭(2g),过滤,滤饼纯化水(5ml)洗涤;将滤液控温50-55℃加入甲醇(135ml)后,在50-55℃下搅拌2小时,固体析出,过滤,滤饼用甲醇(20ml)洗涤,在70-75℃真空干燥24小时,得无定型舒更葡糖钠,收率62.4%,纯度99.53%。
对比实施例3
将舒更葡糖钠(5g)加入纯化水(10ml)中,搅拌溶解后,加热升温至50-60℃后,慢慢滴加甲醇(60ml),加完后析出固体,自然冷却至室温,再进一步冷却至0-5℃,再保温1小时,过滤,干燥得结晶舒更葡糖钠,收率86.2%,纯度99.64%。
对比实施例4
将舒更葡糖钠(10g)加入纯化水(20ml)中,搅拌溶清,加热升温至60℃,边搅拌边加入乙醇(120ml),有大量白色固体析出;自然冷却至室温,再进一步冷却至0℃,保温搅拌1小时,抽滤,滤饼干燥得结晶舒更葡糖钠,收率88.4%,纯度99.56%。
对比实施例5
将舒更葡糖钠(10g)加入纯化水(20ml)中,搅拌溶清,加热升温至75℃,边搅拌边加入DMF(60ml),有大量白色固体析出;自然冷却至室温,抽滤,滤饼干燥得结晶舒更葡糖钠,收率88.7%,纯度99.62%。
对比实施例6
将舒更葡糖钠(10g)加入纯化水(20ml)中,搅拌溶清,加热升温至50℃,边搅拌边加入丙酮(160ml),有大量白色固体析出;自然冷却至室温,再进一步冷却至0℃,保温搅拌1小时,抽滤,滤饼干燥得结晶舒更葡糖钠,收率87.3%,纯度99.58%。
对比实施例7
将舒更葡糖钠(10g)加入纯化水(20ml)中,搅拌溶清,溶液置入平底托盘中,放入冻干机,预冻至-80℃,再梯度升温,冻干过程24小时,得舒更结晶舒更葡糖钠,纯度99.34%。
对比实施例8
将舒更葡糖钠(10g)加入纯化水(50ml)中,搅拌溶清,搅拌下升温至75℃,搅拌转速200r/min,向溶液中滴加1,4-二氧六环(300ml),搅拌降至室温,有大量白色固体析出,抽滤,滤饼真空干燥至干,得无定型舒更葡糖钠,收率90.8%,纯度99.66%。
对比实施例9
将舒更葡糖钠(10g)加入纯化水(30ml)中,搅拌溶解得舒更葡糖钠水溶液;向舒更葡糖钠水溶液中加入DMF(75ml)进行结晶,在25℃下,搅拌析晶1小时,过滤,滤饼用水/DMF(20ml×2)混合溶液洗涤,得结晶舒更葡糖钠,收率86.7%,纯度99.58%。
对比实施例10
参照对比实施例9制备方法制备结晶舒更葡糖钠,取制备的结晶舒更葡糖钠(93g)加入纯化水(3ml)后,加入甲醇(480ml);将反应液加热至65℃,使反应液变澄清,缓慢降温;温度降至42-45℃,保温搅拌2小时,析晶;反应液继续降温至25℃,保持25℃下,搅拌析晶2小时,过滤,滤饼用水/甲醇(20ml×2)混合溶液洗涤,得结晶舒更葡糖钠,收率80.2%,纯度99.62%。
对比实施例11
取对比实施例10制备的结晶舒更葡糖钠(5g)在真空条件(15mmHg)加热至80-90℃干燥12小时,得结晶舒更葡糖钠,纯度99.64%。
热稳定性试验
分别取实施例1和对比例1~11制备得到的舒更葡糖钠溶解于水中,之后在25℃于黑暗中储藏6个月,分别于1个月、3个月、6个月取样检测杂质含量,参照HPLC测定舒更葡糖钠的纯度测定法检测。结果见表3。
表3 舒更葡糖钠溶液状态下稳定性试验结果
如表3所示,在25℃于黑暗中储藏的舒更葡糖钠溶液稳定性试验结果显示,对比例2和对比例8无定型舒更葡糖钠的杂质明显增大,其经3个月稳定性考察后,杂质均超过了1%;其他对比实施例晶型,经过6个月考察后,结果显示杂质均大于0.5;本发明舒更葡糖钠晶型溶液稳定性试验结果显示,杂质变化不明显,基本稳定;考察发现本发明实施例1~10具有类似的稳定性试验结果。
分别取实施例1和对比例1~11制备得到的舒更葡糖钠,在40℃(RH45%)下于黑暗中经受加速测试6个月,分别于1个月、3个月、6个月取样检测杂质含量,参照HPLC测定舒更葡糖钠的纯度测定法检测。结果见表4。
表4 舒更葡糖钠固体状态下40℃经受加速测试结果
固体稳定性试验结果表明,对比例2和对比例8无定型舒更葡糖钠的杂质明显增大,其经3个月稳定性考察后,杂质均超过了1%;其他对比实施例晶型,经过6个月考察后,结果显示杂质均大于0.5;本发明舒更葡糖钠晶型固体稳定性试验结果显示,杂质变化不明显,基本稳定;考察发现本发明实施例1~10具有类似的稳定性试验结果。
光稳定性试验
分别取实施例1和对比例1~11制备得到的舒更葡糖钠,在强光照射(4500Lx±500Lx)下,于0、15、30天分别检测检测杂质含量,参照HPLC测定舒更葡糖钠的纯度测定法检测。结果见表5。
表5 舒更葡糖钠光稳定性测试结果
光稳定性试验结果表明,在强光照射条件下,本发明舒更葡糖钠晶型杂质变化不明显,光照稳定性较好,利用本发明晶型制备的剂型,其利于药物储存的同时保证了药效;对比例2和对比例8无定型舒更葡糖钠光照测试结果显示杂质显著增大,其光稳定较差;考察发现本发明实施例1~10具有类似的光稳定性试验结果。
澄清度与颜色试验
分别取实施例1和对比例1~11制备得到的舒更葡糖钠,在40℃下于黑暗中经受加速测试6个月,分别于初始阶段、1个月、3个月、6个月取样检测样品溶液澄清度和颜色。参照舒更葡糖钠注射液注册标注(JX20140183),样品溶液澄清度检测参考《中国药典2015年版四部通则0902》;样品溶液颜色检测,以超纯水为空白溶液,照紫外-可见分光光度法(中国药典2015年版四部通则0401),在350nm波长处测定吸光度(应小于0.75)。结果见表6。
表6 舒更葡糖钠固体状态下40℃经受加速测试结果
本发明舒更葡糖钠晶型经加速6个月考察后,澄清度<0.5号浊度,颜色检测吸光度<0.75,达到注射液原料药标准。考察发现本发明实施例1~10具有类似的澄清度和颜色测试结果。
Claims (8)
1.一种舒更葡糖钠晶型M,其特征在于,所述的舒更葡糖钠晶型使用Cu-Kα辐射,具有如图1所示的X-射线粉末衍射图谱,并且有且仅有表2的PXRD衍射峰。
2.一种制备权利要求1所述的舒更葡糖钠晶型M的方法,其特征在于,制备方法包括以下步骤:
惰性气体保护超声条件下,将舒更葡糖钠加入纯化水中,搅拌溶解得舒更葡糖钠水溶液;向舒更葡糖钠水溶液中加入有机溶剂A后,控温反应,反应结束;超声下控温滴加有机溶剂B,滴加完毕,保温搅拌析晶;析晶结束,过滤,滤饼干燥,得白色结晶舒更葡糖钠。
3.根据权利要求2所述的舒更葡糖钠晶型M的制备方法,其特征在于,所述超声功率为30-60KHz。
4.根据权利要求2所述的舒更葡糖钠晶型M的制备方法,其特征在于,所述有机溶剂A为甲醇、乙醇、异丙醇、乙腈、丙酮、N,N-二甲基甲酰胺中的一种或两种。
5.根据权利要求2所述的舒更葡糖钠晶型M的制备方法,其特征在于,所述舒更葡糖钠与纯化水的质量体积比为1:1~2,g/ml;所述舒更葡糖钠与有机溶剂A的质量体积比为1:1~3,g/ml。
6.根据权利要求2所述的舒更葡糖钠晶型M的制备方法,其特征在于,所述有机溶剂B为甲醇、乙醇、乙腈、丙酮、N,N-二甲基甲酰胺、异丙醇、叔丁醇、四氢呋喃、1,4-二氧六环、乙二醇、丙二醇中的一种或两种;所述舒更葡糖钠与有机溶剂B的质量体积比为1:8~20,g/ml。
7.根据权利要求2所述的舒更葡糖钠晶型M的制备方法,其特征在于,所述控温反应温度为20~50℃;所的控温滴加有机溶剂B及搅拌析晶的温度为20~30℃。
8.权利要求1所述的舒更葡糖钠晶型M作为活性成分制备肌松拮抗剂药物的应用。
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