CN1279045C - 头孢硫脒复盐及其制造方法 - Google Patents
头孢硫脒复盐及其制造方法 Download PDFInfo
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- CN1279045C CN1279045C CN 200410050902 CN200410050902A CN1279045C CN 1279045 C CN1279045 C CN 1279045C CN 200410050902 CN200410050902 CN 200410050902 CN 200410050902 A CN200410050902 A CN 200410050902A CN 1279045 C CN1279045 C CN 1279045C
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- cefathiamidine
- salt
- double salt
- cephalothin
- sulfur
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- 150000003839 salts Chemical class 0.000 title claims abstract description 71
- JYXACOFERDBGGQ-RHSMWYFYSA-N cefathiamidine Chemical compound S1CC(COC(C)=O)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CSC(NC(C)C)=NC(C)C)[C@H]21 JYXACOFERDBGGQ-RHSMWYFYSA-N 0.000 title claims description 74
- 229950005040 cefathiamidine Drugs 0.000 title claims description 74
- 238000004519 manufacturing process Methods 0.000 title claims description 12
- -1 cephalothin sulfur amidine Chemical class 0.000 claims abstract description 20
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000012046 mixed solvent Substances 0.000 claims abstract description 3
- 239000000126 substance Substances 0.000 claims abstract 2
- 150000002500 ions Chemical class 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 229910052700 potassium Inorganic materials 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- OEOIWYCWCDBOPA-UHFFFAOYSA-N 6-methyl-heptanoic acid Chemical compound CC(C)CCCCC(O)=O OEOIWYCWCDBOPA-UHFFFAOYSA-N 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 3
- 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 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 claims description 3
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 230000008020 evaporation Effects 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 239000001103 potassium chloride Substances 0.000 claims description 3
- 235000011164 potassium chloride Nutrition 0.000 claims description 3
- 159000000000 sodium salts Chemical class 0.000 claims description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims 2
- 125000002091 cationic group Chemical group 0.000 claims 2
- 150000007522 mineralic acids Chemical class 0.000 claims 2
- 150000007524 organic acids Chemical class 0.000 claims 2
- 239000000203 mixture Substances 0.000 abstract description 12
- 231100000252 nontoxic Toxicity 0.000 abstract description 4
- 230000003000 nontoxic effect Effects 0.000 abstract description 4
- 230000003647 oxidation Effects 0.000 abstract description 3
- 238000007254 oxidation reaction Methods 0.000 abstract description 3
- 229960000603 cefalotin Drugs 0.000 abstract 10
- 229910052717 sulfur Inorganic materials 0.000 abstract 10
- 239000011593 sulfur Substances 0.000 abstract 10
- 238000002360 preparation method Methods 0.000 abstract 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract 1
- 150000001450 anions Chemical group 0.000 abstract 1
- 150000001768 cations Chemical group 0.000 abstract 1
- VUFGUVLLDPOSBC-XRZFDKQNSA-M cephalothin sodium Chemical compound [Na+].N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C([O-])=O)C(=O)CC1=CC=CS1 VUFGUVLLDPOSBC-XRZFDKQNSA-M 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 51
- 239000002932 luster Substances 0.000 description 21
- 239000000243 solution Substances 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000009413 insulation Methods 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 238000005352 clarification Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000000354 decomposition reaction Methods 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000005286 illumination Methods 0.000 description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 229960004249 sodium acetate Drugs 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 3
- 239000004299 sodium benzoate Substances 0.000 description 3
- 235000010234 sodium benzoate Nutrition 0.000 description 3
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 206010059866 Drug resistance Diseases 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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- YGBFLZPYDUKSPT-MRVPVSSYSA-N cephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C[C@H]21 YGBFLZPYDUKSPT-MRVPVSSYSA-N 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- DGLRDKLJZLEJCY-UHFFFAOYSA-L disodium hydrogenphosphate dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O DGLRDKLJZLEJCY-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 239000011833 salt mixture Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 229960000999 sodium citrate dihydrate Drugs 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及头孢硫脒复盐及其制造方法，它公开了一种头孢硫脒复盐的化学结构通式，其制造方法是以溶液中具有阴、阳离子结构的无毒、或者是可药用的单盐与头孢硫脒在水或有机溶剂或有机溶剂与水的混合溶剂中溶解后，用与头孢硫脒复盐不溶的有机溶剂析出或低温蒸发析出；其中单盐与头孢硫脒的当量比为0.2～5∶1。本发明的头孢硫脒复盐在外界温度、水分、pH、光照以及氧化等因素影响下，色泽比头孢硫脒稳定。
Description
技术领域
本发明涉及药品及其制造，进一步说是抗生素药品及制造。
背景技术
头孢硫脒是半合成头孢菌素类化合物，化学名为7-[2-(N，N′-二异丙基脒硫基)乙酰胺基]头孢烷酸内盐，它具有与烷基季铵盐相似的表面活性作用，亲水性比较强，头孢硫脒作为抗生素类药品早已用于临床，主要用于注射剂。在头孢硫脒上市之前，许多抗生素类药品因长期使用导致了细菌的耐药性增长。头孢硫脒对细菌的抑杀作用强，特别是对肠球菌疗效显著，因此一经上市即在临床上受到广泛欢迎和应用。头孢硫脒为内盐结构，这种内盐结构易受外界条件影响，如温度、水分、pH、光照及氧化等因素而导致色泽变深。药品的质量标准中对色泽稳定性要求严格，须保证药品在贮藏期内色泽质量符合药品法定标准。而头孢硫脒的色泽稳定性不理想，早已成为制药商长期来期望解决但没很好解决的课题。
发明内容
本发明的目的之一是提供一种稳定性好的头孢硫脒复盐的化合物。
本发明的另一个目的是提供一种制造头孢硫脒复盐的方法。
本发明的技术解决方案是：
一种头孢硫脒复盐，其化合物结构式为
其中M为Na、K等阳离子，B代表相应的酸根。
本发明所述Na、K等阳离子是来自无机或有机的可药用的单盐；酸根是来自所指无机或者是有机可药用的单盐，其含有如苯甲酸根、醋酸根、磷酸氢根、磷酸二氢根、碳酸根、碳酸氢根、柠檬酸根、异辛酸根、卤族离子、亚硫酸根、亚硫酸氢根、硫代硫酸根、硫酸根、葡萄糖酸根、乳糖酸根等。
本发明所述的头孢硫脒复盐的干品含量(以头孢硫脒计)与理论干品含量相近；本发明所述的头孢硫脒复盐的钠、钾离子含量与理论值相符；热分析结果表明头孢硫脒复盐与头孢硫脒的分解点基本一致，头孢硫脒与单盐的混合物的分解点低于头孢硫脒、或者是头孢硫脒复盐。如：
| 头孢硫脒复盐 | HPLC(头孢硫脒) | 离子色谱 | 热分析 | |||
| 干品含量％ | 理论干品含量％ | 含量％ | 理论含量％ | 复盐分解点 | 混合物分解点 | |
| 醋酸钠复盐 | 84.80 | 85.21 | 3.97 | 4.14 | 163.8 | 153.0 |
| 苯甲酸钠复盐 | 79.16 | 76.65 | 3.69 | 3.73 | 167.8 | 158.9 |
| 亚硫酸氢钠复盐 | 78.21 | 81.96 | 4.03 | 3.99 | 171.2 | 162.2 |
本发明头孢硫脒复盐的制造方法是，以溶液中具有阴、阳离子结构的无毒、或者是可药用的单盐，与头孢硫脒在水中，或有机溶剂或有机溶剂与水的混合溶剂中溶解后，用头孢硫脒复盐不溶的有机溶剂析出或低温蒸发析出，经重结晶，成为组成稳定的复盐，其中单盐与头孢硫脒的当量比为0.2～5∶1。
以上所述以溶液中具有阴、阳离子结构的无毒、或者是可药用的单盐是无机、或者是有机的钠盐、钾盐。
本发明的制造方法所述有机溶剂水溶液是指0～100％的甲醇、乙醇、二甲基甲酰胺、或者是乙腈水溶液。
以上本发明的制造方法所述的头孢硫脒与单盐的其最佳当量比是0.8～1.5∶1。
本发明所述的与复盐不溶的溶剂如酮类、醇类、醚类、酯类、烷烃。
可药用的单盐与头孢硫脒可成复盐，这是因为具有阴阳离子结构的盐与头孢硫脒在水溶液中混合使其达到离子平衡状态，通常是加入的阳离子与头孢硫脒中4-位羧酸根的阴离子结合，加入的阴离子与7-位的类季铵阳离子结合，析出而形成的是组成稳定的复盐。
复盐的稳定性可从以下表格数据看出
稳定性试验结果：
强光照射试验(照度4500lx±500lx)
| 0天 | 5天 | 10天 | |
| 头孢硫脒 | 色泽＜YG4 | Y7≤色泽＜Y8 | 色泽＜Y8 |
| 头孢硫脒复盐 | 色泽＜YG4 | 色泽＜YG4 | 色泽＜Y5 |
高湿度试验(25，相对湿度90％±5％)
| 0天 | 5天 | 10天 | |
| 头孢硫脒 | 色泽＜YG4 | Y7＜YG7 | 色泽＜YG8 |
| 头孢硫脒复盐 | 色泽＜YG4 | 色泽＜YG4 | 色泽＜Y5 |
高温试验(60℃)
| 0天 | 5天 | 10天 | |
| 头孢硫脒 | 色泽＜YG4 | Y7＜Y8 | 色泽＜Y10 |
| 头孢硫脒复盐 | 色泽＜YG4 | 色泽＜Y8 | 色泽＜Y10 |
结论：在光照和高湿条件下头孢硫脒复盐色泽比头孢硫脒稳定，高温条件二者变化一致；在上述各条件下头孢硫脒复盐含量变化与头孢硫脒相似，但在溶液状态下结果与已发表的稳定性研究结果相一致，即头孢硫脒的氯化钠溶液24小时内效价降低为0，而蒸馏水溶液24小时内降21％。(医药工业，1978，11，24)。
热分析结果表明：头孢硫脒复盐与头孢硫脒的分解点基本一致；头孢硫脒与单盐的混合物的分解点低于头孢硫脒、或者是头孢硫脒复盐。这说明复盐已形成，且热稳定性高于两单盐混合物。
本发明以内盐头孢硫脒为底物，与其它无毒或可药用的无机或有机的钠盐、钾盐在水或有机溶剂或有机溶剂水溶液中共同溶解，再析出形成复盐目标物。此复盐是两种单盐按固定组成结合而形成的盐。在水溶液中以简单离子存在，不含配离子。
本发明的优点是头孢硫脒复盐在外界温度、水分、pH、光照以及氧化等因素影响下，色泽比头孢硫脒稳定。
具体实施方式
实例一
将1.80g(22mmol)醋酸钠投入40ml 80％乙腈溶液中，搅拌溶解，冰水浴降温，内温＜10℃时加入9.45g(20mmol)头孢硫脒，保温搅拌20min，溶液澄清透明，加入35ml丙酮，保温养晶30min，继续滴加50ml丙酮，保温养晶2hr，过滤，用丙酮洗涤，＜45℃、750mmHg真空下干燥6hr，得头孢硫脒醋酸钠复合物，干品含量84.8％。理论干品含量85.21％。
实例二
将1.17g(20mmol)氯化钠投入8ml水中，冰水浴降温，内温＜10℃时加入9.45g(20mmol)头孢硫脒，滴加32ml乙醇，保温搅拌30min，溶液澄清，加入35ml乙酸乙酯，保温养晶60min，继续滴加45ml乙酸乙酯，保温养晶2hr，过滤，用乙酸乙酯洗涤，＜45℃、750mmHg真空下干燥6hr，得头孢硫脒氯化钠复合物，干品含量90.87％。理论干品含量88.98％。
实例三
将2.88g(20mmol)苯甲酸钠投入40ml80％乙醇溶液中，冰水浴降温，内温＜5℃时加入9.45g(20mmol)头孢硫脒，搅拌5min，溶液澄清，抽真空蒸发析出过滤，用丙酮洗涤，＜45℃、750mmHg真空下干燥6hr，得头孢硫脒苯甲酸钠复合物，干品含量78.23％。理论干品含量76.65％。
实例四
将2.02g(6.88mmol)枸橼酸钠二水合物投入40ml水中，冰水浴降温，内温＜10℃时加入9.45g(20mmol)头孢硫脒，保温搅拌30min，溶液澄清，加入50ml丙酮，保温养晶30min，继续滴加70ml丙酮，保温养晶2hr，过滤，用丙酮洗涤，＜45℃、750mmHg真空下干燥6hr，得头孢硫脒枸橼酸钠复合物，干品含量82.69％。理论干品含量84.60％。
实例五
将2.72g(20mmol)磷酸二氢钾投入50％乙醇溶液中，冰水浴降温，内温＜10℃时加入9.45g(20mmol)头孢硫脒，保温搅拌10min，溶液澄清，加入130ml异丙醇，保温养晶过夜，过滤，用丙酮洗涤，＜45℃、750mmHg真空下干燥6hr，得头孢硫脒磷酸二氢钾复合物，干品含量79.98％。理论干品含量77.65％。
实例六
将3.58g(10mmol)磷酸氢二钠十二水合物投入40ml30％DMF水溶液中，冰水浴降温，内温＜10℃时加入9.45g(20mmol)头孢硫脒，保温搅拌30min，溶液澄清，加入200ml丙酮，保温养晶30min，继续滴加320ml丙酮，过滤，用丙酮洗涤，＜45℃、750mmHg真空下干燥6hr，得头孢硫脒磷酸氢二钠复合物，干品含量85.64％。理论干品含量86.93％。
实例七
将3.49g(16mmol)葡萄糖酸钠投入50％甲醇溶液中，冰水浴降温，内温＜10℃时加入9.45g(20mmol)头孢硫脒，保温搅拌30min，溶液澄清，加入10ml丙酮，保温养晶30min，继续滴加20ml丙酮，冷藏过夜，次日继续滴加50ml丙酮，过滤，用丙酮洗涤，＜45℃、750mmHg真空下干燥6hr，得头孢硫脒葡萄糖酸钠复合物，干品含量65.43％。理论干品含量68.39％。
实例八
将2.08g(20mmol)亚硫酸氢钠，投入30ml水中，冰水浴降温，内温＜10℃时加入9.45g(20mmol)头孢硫脒，保温搅拌30min，溶液澄清，加入250ml丙酮，有晶析出，放冰箱冷藏过夜，次日过滤，用丙酮洗涤，＜45℃、750mmHg真空下干燥6hr，得头孢硫脒亚硫酸氢钠复合物，干品含量78.21％。理论干品含量81.96％。
Claims (6)
1、头孢硫脒复盐，其特征是化学结构通式为
其中M为来自可药用单盐的阳离子；B代表所指可药用单盐的酸根，选自苯甲酸根、醋酸根、磷酸氢根、磷酸二氢根、碳酸根、碳酸氢根、柠檬酸根、异辛酸根、卤族离子、亚硫酸根、亚硫酸氢根、硫代硫酸根、硫酸根、葡萄糖酸根或乳糖酸根。
2、根据权利要求1所述的头孢硫脒复盐，其中阳离子M为Na或K离子。
3、头孢硫脒复盐的制造方法，其特征是溶液中具有阴或阳离子结构的可药用的单盐与头孢硫脒在水或有机溶剂或有机溶剂与水的混合溶剂中溶解后，用与头孢硫脒复盐不溶的有机溶剂析出或低温蒸发析出；其中单盐与头孢硫脒的当量比为0.2～5∶1。
4、根据权利要求3所述的头孢硫脒复盐的制造方法，其特征是溶液中具有阴或阳离子结构的可药用的单盐是无机或者是有机的钠盐或钾盐。
5、根据权利要求4所述的头孢硫脒复盐的制造方法，其中单盐是由Na或K阳离子和无机或有机酸根所组成，其无机或有机酸根为苯甲酸根、醋酸根、磷酸氢根、磷酸二氢根、碳酸根、碳酸氢根、柠檬酸根、异辛酸根、卤族离子、亚硫酸根、亚硫酸氢根、硫代硫酸根、硫酸根、葡萄糖酸根或乳糖酸根。
6、根据权利要求3所述的头孢硫脒复盐的制造方法，其特征是头孢硫脒∶单盐的当量比为0.8～1.5∶1。
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