CN101115792B - 稳定聚乙烯吡咯烷酮的方法 - Google Patents
稳定聚乙烯吡咯烷酮的方法 Download PDFInfo
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- CN101115792B CN101115792B CN2006800044709A CN200680004470A CN101115792B CN 101115792 B CN101115792 B CN 101115792B CN 2006800044709 A CN2006800044709 A CN 2006800044709A CN 200680004470 A CN200680004470 A CN 200680004470A CN 101115792 B CN101115792 B CN 101115792B
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- Prior art keywords
- polyvinylpyrrolidone
- acid
- methyl
- vinyl
- weight
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 title claims abstract description 57
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 title claims abstract description 57
- 238000000034 method Methods 0.000 title claims abstract description 31
- 230000006641 stabilisation Effects 0.000 title claims description 11
- 238000011105 stabilization Methods 0.000 title claims description 11
- -1 alkali metal sulfites Chemical class 0.000 claims abstract description 53
- 238000001035 drying Methods 0.000 claims abstract description 17
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 9
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 47
- 239000000243 solution Substances 0.000 claims description 27
- 239000000126 substance Substances 0.000 claims description 25
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 24
- 239000007864 aqueous solution Substances 0.000 claims description 21
- 239000002516 radical scavenger Substances 0.000 claims description 12
- 229940123457 Free radical scavenger Drugs 0.000 claims description 11
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 7
- 238000005507 spraying Methods 0.000 claims description 7
- 239000006185 dispersion Substances 0.000 claims description 6
- 229920001519 homopolymer Polymers 0.000 claims description 6
- 238000002036 drum drying Methods 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- 229920001577 copolymer Polymers 0.000 claims description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 abstract description 6
- 239000006096 absorbing agent Substances 0.000 abstract 1
- 230000000087 stabilizing effect Effects 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- 150000002978 peroxides Chemical class 0.000 description 19
- 229920000642 polymer Polymers 0.000 description 18
- 239000007789 gas Substances 0.000 description 15
- 239000000203 mixture Substances 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- OSSNTDFYBPYIEC-UHFFFAOYSA-N 1-ethenylimidazole Chemical compound C=CN1C=CN=C1 OSSNTDFYBPYIEC-UHFFFAOYSA-N 0.000 description 10
- 238000006116 polymerization reaction Methods 0.000 description 10
- WWYNJERNGUHSAO-XUDSTZEESA-N (+)-Norgestrel Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 WWYNJERNGUHSAO-XUDSTZEESA-N 0.000 description 9
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 9
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 9
- 229960004400 levonorgestrel Drugs 0.000 description 9
- 239000001301 oxygen Substances 0.000 description 9
- 229910052760 oxygen Inorganic materials 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 8
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 8
- FQPSGWSUVKBHSU-UHFFFAOYSA-N methacrylamide Chemical compound CC(=C)C(N)=O FQPSGWSUVKBHSU-UHFFFAOYSA-N 0.000 description 8
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 8
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 229960003910 promethazine Drugs 0.000 description 8
- 239000003963 antioxidant agent Substances 0.000 description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 6
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 6
- 229910052782 aluminium Inorganic materials 0.000 description 6
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 6
- 230000003078 antioxidant effect Effects 0.000 description 6
- 235000006708 antioxidants Nutrition 0.000 description 6
- 238000011049 filling Methods 0.000 description 6
- 239000011888 foil Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- HCZKYJDFEPMADG-TXEJJXNPSA-N masoprocol Chemical compound C([C@H](C)[C@H](C)CC=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-TXEJJXNPSA-N 0.000 description 6
- 239000000178 monomer Substances 0.000 description 6
- 238000010926 purge Methods 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 238000007789 sealing Methods 0.000 description 6
- 238000003860 storage Methods 0.000 description 6
- 229920002554 vinyl polymer Polymers 0.000 description 6
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 5
- WROUWQQRXUBECT-UHFFFAOYSA-N 2-ethylacrylic acid Chemical compound CCC(=C)C(O)=O WROUWQQRXUBECT-UHFFFAOYSA-N 0.000 description 5
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 5
- 229960005139 epinephrine Drugs 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 5
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 4
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 4
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 4
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000000743 anti-peroxide Effects 0.000 description 4
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 4
- 238000005660 chlorination reaction Methods 0.000 description 4
- UYMKPFRHYYNDTL-UHFFFAOYSA-N ethenamine Chemical compound NC=C UYMKPFRHYYNDTL-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- PNLUGRYDUHRLOF-UHFFFAOYSA-N n-ethenyl-n-methylacetamide Chemical compound C=CN(C)C(C)=O PNLUGRYDUHRLOF-UHFFFAOYSA-N 0.000 description 4
- ZQXSMRAEXCEDJD-UHFFFAOYSA-N n-ethenylformamide Chemical compound C=CNC=O ZQXSMRAEXCEDJD-UHFFFAOYSA-N 0.000 description 4
- YPHQUSNPXDGUHL-UHFFFAOYSA-N n-methylprop-2-enamide Chemical compound CNC(=O)C=C YPHQUSNPXDGUHL-UHFFFAOYSA-N 0.000 description 4
- 238000001694 spray drying Methods 0.000 description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 4
- WLWHLUQQCLCFNE-UHFFFAOYSA-N 1-ethenyl-3-methyl-2h-imidazole Chemical compound CN1CN(C=C)C=C1 WLWHLUQQCLCFNE-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 239000004258 Ethoxyquin Substances 0.000 description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 3
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 3
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 3
- NJSSICCENMLTKO-HRCBOCMUSA-N [(1r,2s,4r,5r)-3-hydroxy-4-(4-methylphenyl)sulfonyloxy-6,8-dioxabicyclo[3.2.1]octan-2-yl] 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)O[C@H]1C(O)[C@@H](OS(=O)(=O)C=2C=CC(C)=CC=2)[C@@H]2OC[C@H]1O2 NJSSICCENMLTKO-HRCBOCMUSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- NEHMKBQYUWJMIP-UHFFFAOYSA-N anhydrous methyl chloride Natural products ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 3
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000003795 chemical substances by application Substances 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
- 230000000052 comparative effect Effects 0.000 description 3
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- HCZKYJDFEPMADG-UHFFFAOYSA-N erythro-nordihydroguaiaretic acid Natural products C=1C=C(O)C(O)=CC=1CC(C)C(C)CC1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-UHFFFAOYSA-N 0.000 description 3
- 235000019285 ethoxyquin Nutrition 0.000 description 3
- DECIPOUIJURFOJ-UHFFFAOYSA-N ethoxyquin Chemical compound N1C(C)(C)C=C(C)C2=CC(OCC)=CC=C21 DECIPOUIJURFOJ-UHFFFAOYSA-N 0.000 description 3
- 229940093500 ethoxyquin Drugs 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
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- 229910001385 heavy metal Inorganic materials 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- COYVWKMZTCAFHO-UHFFFAOYSA-N n-methyl-n-propan-2-ylprop-2-enamide Chemical compound CC(C)N(C)C(=O)C=C COYVWKMZTCAFHO-UHFFFAOYSA-N 0.000 description 3
- AWGZKFQMWZYCHF-UHFFFAOYSA-N n-octylprop-2-enamide Chemical compound CCCCCCCCNC(=O)C=C AWGZKFQMWZYCHF-UHFFFAOYSA-N 0.000 description 3
- 238000012856 packing Methods 0.000 description 3
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 3
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 3
- AAYRWMCIKCRHIN-UHFFFAOYSA-N propane-1-sulfonic acid;prop-2-enamide Chemical compound NC(=O)C=C.CCCS(O)(=O)=O AAYRWMCIKCRHIN-UHFFFAOYSA-N 0.000 description 3
- 235000010378 sodium ascorbate Nutrition 0.000 description 3
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- LAYAKLSFVAPMEL-UHFFFAOYSA-N 1-ethenoxydodecane Chemical compound CCCCCCCCCCCCOC=C LAYAKLSFVAPMEL-UHFFFAOYSA-N 0.000 description 2
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- RUMACXVDVNRZJZ-UHFFFAOYSA-N 2-methylpropyl 2-methylprop-2-enoate Chemical compound CC(C)COC(=O)C(C)=C RUMACXVDVNRZJZ-UHFFFAOYSA-N 0.000 description 2
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- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
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- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 2
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- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 2
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- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K5/00—Use of organic ingredients
- C08K5/0008—Organic ingredients according to more than one of the "one dot" groups of C08K5/01 - C08K5/59
- C08K5/005—Stabilisers against oxidation, heat, light, ozone
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F6/00—Post-polymerisation treatments
- C08F6/06—Treatment of polymer solutions
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K3/00—Use of inorganic substances as compounding ingredients
- C08K3/30—Sulfur-, selenium- or tellurium-containing compounds
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K5/00—Use of organic ingredients
- C08K5/04—Oxygen-containing compounds
- C08K5/15—Heterocyclic compounds having oxygen in the ring
- C08K5/151—Heterocyclic compounds having oxygen in the ring having one oxygen atom in the ring
- C08K5/1535—Five-membered rings
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K3/00—Use of inorganic substances as compounding ingredients
- C08K3/30—Sulfur-, selenium- or tellurium-containing compounds
- C08K2003/309—Sulfur containing acids
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Abstract
公开了一种稳定聚乙烯吡咯烷酮的方法,包括用二氧化硫、亚硫酸或碱金属亚硫酸盐处理聚乙烯吡咯烷酮,然后用自由基清除剂处理该聚乙烯吡咯烷酮,并将处理过的溶液通过干燥转化为粉末状的聚乙烯吡咯烷酮。
Description
本发明涉及一种制备稳定的、抗过氧化物生成的聚乙烯吡咯烷酮的方法。
聚乙烯吡咯烷酮,例如N-乙烯吡咯烷酮的均聚物和共聚物,通常在其聚合之后通过喷雾干燥或转鼓式干燥或其它的热风干燥转化为自由流动的粉末。在这些过程中,由于与空气和热的充分接触,形成了微量的过氧化物,并且在随后的包装和储存过程中该过氧化物含量进一步增长。这种易于形成过氧化物的趋向在将聚乙烯吡咯烷酮用于药物制备中时可能产生问题。现行药典,例如Ph.Eur.3和JP XIII,将这些聚合物中过氧化物含量限制为最大400ppm。可通过隔绝空气进行干燥、在低温下储存或在真空或惰性气体中密封包装来减缓过氧化物的形成速度,但不能完全避免。还可首先通过在升高的温度和/或微碱性pH值下处理而降低过氧化物的含量。然而,该降低仅为短期性的;此后过氧化物含量又会快速增长。此外,这些方法涉及极高的费用,因此使用者的接受度低。
EP-B 873 130推荐将聚乙烯吡咯烷酮在氮气气氛下喷雾干燥并在气密容器中储存以防止过氧化物的形成。
抗氧化剂剂如酚类抗氧化剂、抗坏血酸、虎皮灵、叔丁基对甲酚、生育酚或去甲二氢愈创木酸(nordihydroguaraietic acid)用于防止有害的氧化过程的用途是公知的。同样已知由于酚类抗氧化剂缺乏生物可降解性,其适用性是有限的(参见-Chemie-Lexikon,第9版,Georg Thieme Verlag,斯图加特,1992)。
US 6,331,333公开了在氧清除剂的存在下在不透氧的包装中储存聚乙烯吡咯烷酮以避免储存期间过氧化物的生成。抗坏血酸、铁粉或铁盐可用作氧清除剂。这种情况下氧清除剂和聚乙烯吡咯烷酮在空间上是分离的。
US 6,498,231公开了为了在储存期间稳定,将聚乙烯吡咯烷酮与一种抗氧化剂混合并在含氧量不高于50,000ppm的气氛下储存。所用抗氧化剂为例如酚类或双酚类化合物,优选硫代酰胺或硫脲衍生物。 然而,所述抗氧化剂并非完全在生理上无害,因此在将该聚合物用于药物制剂时可能是个问题。
GB 836,831公开了一种稳定聚乙烯吡咯烷酮以抵抗褪色的方法,其中将该聚合物的溶液用二氧化硫、亚硫酸或碱金属亚硫酸盐处理。然而用此方法处理时,与未处理的聚合物相比,事实上储存后过氧化物的生成程度更大。
EP-B 1083 884记载了一种稳定聚乙烯吡咯烷酮以抵抗过氧化物生成的方法,其中该聚合物的水溶液与极少量的重金属或与分解过氧化物的酶混合。然而,由于可能在体内积聚,因而使用重金属是不利的。使用酶是不利的,特别是由于稳定性和费用问题。
本发明的一个目的为寻找一种稳定聚乙烯吡咯烷酮以抵抗过氧化物生成的改进方法,该方法有助于避免所述缺点。
相应地,发现了一种用于制备稳定的、抗过氧化物生成的聚乙烯吡咯烷酮的方法,所述方法包括首先用二氧化硫、亚硫酸或其碱金属盐并随后用自由基清除剂处理聚乙烯吡咯烷酮。
本发明中的聚乙烯吡咯烷酮为N-乙烯吡咯烷酮的均聚物和共聚物,尤其为水溶性聚乙烯吡咯烷酮。该方法同样也适用于交联的、水不溶性的聚乙烯吡咯烷酮(交联聚维酮(Crospovidone))。
合适的共聚物优选具有至少20重量%的乙烯吡咯烷酮含量。合适的共聚单体为所有的可与N-乙烯吡咯烷酮进行自由基共聚的单体。
聚合物中共聚单体的数目本身不受限制。然而,通常情况下该数目小于5。
合适的共聚单体的实例为N,N-二甲基氨基甲基(甲基)丙烯酸酯、N,N-二乙基氨基甲基(甲基)丙烯酸酯、N,N-二甲基氨基乙基(甲基)丙烯酸酯、N,N-二乙基氨基乙基(甲基)丙烯酸酯、N-[3-(二甲基氨基)丙基]甲基丙烯酰胺和N-[3-(二甲基氨基)丙基]丙烯酰胺。
同样可用的单体为取代的丙烯酸及其盐、酯和酰胺,其中取代基位于丙烯酸的2或3位的碳原子上,并且彼此独立地选自C1-C4烷基、-CN、COOH,特别优选为甲基丙烯酸、乙基丙烯酸和3-氰基丙烯酸。这些取代的丙烯酸的盐、酯和酰胺可如以上所述丙烯酸的盐、酯和酰胺 进行选择。
其它合适的单体为C1-C40直链、C3-C40支链或C3-C40碳环羧酸的烷基酯,乙烯基卤化物或者烯丙基卤化物——优选氯乙烯和烯丙基氯,乙烯醚——优选甲基、乙基、丁基或十二烷基乙烯基醚,乙烯基甲酰胺、乙烯基甲基乙酰胺、乙烯胺,乙烯内酰胺——优选乙烯吡咯烷酮和乙烯己内酰胺,乙烯基或烯丙基取代的杂环化合物——优选乙烯基吡啶、乙烯基噁唑啉和烯丙基吡啶。
合适的还有N-乙烯基咪唑,其中R9至R11彼此独立地为氢、C1-C4烷基或苯基:
合适的单体还有以下通式的二烯丙基胺,
其中
R12=C1至C24烷基。
合适的单体还有1,1-二氯乙烯;和含至少一个碳-碳双键的烃,优选苯乙烯、α-甲基苯乙烯、叔丁基苯乙烯、丁二烯、异戊二烯、环己二烯、乙烯、丙烯、1-丁烯、2-丁烯、异丁烯、乙烯基甲苯和这些单体的混合物。
特别合适的单体为丙烯酸、甲基丙烯酸、乙基丙烯酸、丙烯酸甲酯、丙烯酸乙酯、丙烯酸丙酯、丙烯酸正丁酯、丙烯酸异丁酯、丙烯酸叔丁酯、丙烯酸2-乙基己酯、丙烯酸癸酯、甲基丙烯酸甲酯、甲基丙烯酸乙酯、甲基丙烯酸丙酯、甲基丙烯酸正丁酯、甲基丙烯酸异丁酯、甲基丙烯酸叔丁酯、甲基丙烯酸2-乙基己酯、甲基丙烯酸癸酯、乙基丙烯酸甲酯、乙基丙烯酸乙酯、乙基丙烯酸正丁酯、乙基丙烯酸异丁酯、乙基丙烯酸叔丁酯、乙基丙烯酸2-乙基己酯、乙基丙烯酸癸酯、(甲基)丙烯酸十八酯、丙烯酸2,3-二羟基丙酯、甲基丙烯酸2,3-二羟基丙酯、丙烯酸2-羟基乙酯、丙烯酸羟基丙酯、甲基丙烯酸2-羟基 乙酯、乙基丙烯酸2-羟基乙酯、丙烯酸2-甲氧基乙酯、甲基丙烯酸2-甲氧基乙酯、乙基丙烯酸2-甲氧基乙酯、甲基丙烯酸2-乙氧基乙酯、乙基丙烯酸2-乙氧基乙酯、甲基丙烯酸羟基丙酯、单丙烯酸甘油酯、单甲基丙烯酸甘油酯、聚烷撑二醇(甲基)丙烯酸酯、不饱和的磺酸如丙烯酰胺丙磺酸;
丙烯酰胺、甲基丙烯酰胺、乙基丙烯酰胺、N-甲基丙烯酰胺,N,N-二甲基丙烯酰胺、N-乙基丙烯酰胺、N-异丙基丙烯酰胺、N-丁基丙烯酰胺、N-叔丁基丙烯酰胺、N-辛基丙烯酰胺、N-叔辛基丙烯酰胺、N-十八烷基丙烯酰胺、N-苯基丙烯酰胺、N-甲基甲基丙烯酰胺、N-乙基甲基丙烯酰胺、N-异丙基甲基丙烯酰胺、N-十二烷基甲基丙烯酰胺、1-乙烯基咪唑、1-乙烯基-2-甲基乙烯基咪唑、N,N-二甲基氨基甲基(甲基)丙烯酸酯、N,N-二乙基氨基甲基(甲基)丙烯酸酯、N,N-二甲基氨基乙基(甲基)丙烯酸酯、N,N-二乙基氨基乙基(甲基)丙烯酸酯、N,N-二甲基氨基丁基(甲基)丙烯酸酯、N,N-二乙基氨基丁基(甲基)丙烯酸酯、N,N-二甲基氨基己基(甲基)丙烯酸酯、N,N-二甲基氨基辛基(甲基)丙烯酸酯、N,N-二甲基氨基十二烷基(甲基)丙烯酸酯、N-[3-(二甲氨基)丙基]甲基丙烯酰胺、N-[3-(二甲氨基)丙基]丙烯酰胺、N-[3-(二甲氨基)丁基]甲基丙烯酰胺、N-[8-(二甲基氨基)辛基]甲基丙烯酰胺、N-[12-(二甲氨基)十二烷基]甲基丙烯酰胺、N-[3-(二乙氨基)丙基]甲基丙烯酰胺、N-[3-(二乙氨基)丙基]丙烯酰胺;特别优选N-异丙基甲基丙烯酰胺;
马来酸、富马酸、马来酐和其半酯,巴豆酸、衣康酸、二烯丙基二甲基氯化铵、乙烯醚(例如甲基、乙基、丁基或十二烷基乙烯醚)、乙烯基甲酰胺、N-乙烯基-N-甲基乙酰胺、乙烯胺;甲基乙烯酮、马来酰亚胺、乙烯基吡啶、乙烯基咪唑、乙烯基呋喃、苯乙烯、苯乙烯磺酸酯、烯丙基醇和其混合物。特别优选N-乙烯基-N-甲基乙酰胺。
其中,特别优选丙烯酸、甲基丙烯酸、马来酸、富马酸、巴豆酸、马来酐和其半酯,丙烯酸甲酯、甲基丙烯酸甲酯、丙烯酸乙酯、甲基丙烯酸乙酯、丙烯酸正丁酯、甲基丙烯酸正丁酯、丙烯酸正丁酯、甲基丙烯酸叔丁酯、丙烯酸异丁酯、甲基丙烯酸异丁酯、丙烯酸2-乙基己酯、丙烯酸十八酯、甲基丙烯酸十八酯、N-叔丁基丙烯酰胺、N-辛 基丙烯酰胺、丙烯酸2-羟基乙酯、丙烯酸羟基丙酯、甲基丙烯酸2-羟基乙酯、甲基丙烯酸羟基丙酯、烷撑二醇(甲基)丙烯酸酯、苯乙烯、不饱和的磺酸如丙烯酰胺丙磺酸、乙烯吡咯烷酮、乙烯己内酰胺、乙烯醚(例如:甲基、乙基、丁基或十二烷基乙烯醚)、乙烯基甲酰胺、N-乙烯基-N-甲基乙酰胺、乙烯胺、1-乙烯基咪唑、1-乙烯基-2-甲基咪唑、N,N-二甲基氨基甲基甲基丙烯酸酯和N-[3-(二甲基氨基)丙基]甲基丙烯酰胺;氯化3-甲基-1-乙烯基咪唑、3-甲基-1-乙烯基咪唑鎓甲基硫酸酯、N,N-二甲基氨基乙基甲基丙烯酸酯、N-异丙基甲基丙烯酰胺、用氯代甲烷季铵化的N-[3-(二甲氨基)-丙基]甲基丙烯酰胺。
VCAp、VI、氯化1-乙烯基-3-甲基咪唑(QVI)、VAC、(甲基)丙烯酰胺、二甲基氨基乙基(甲基)丙烯酸酯和二甲基氨基乙基(甲基)丙烯酰胺及其季铵化的类似物、二烯丙基二甲基氯化铵、乙烯醇(由乙酸乙烯酯聚合后通过水解制备)、VFA、乙烯胺(由VFA聚合后水解制备)、二甲基氨基丙基(甲基)丙烯酸酯、二甲基氨基丙基(甲基)丙烯酰胺、(甲基)丙烯酸、乙烯基哌啶酮、N,N-二甲基(甲基)丙烯酰胺、叔丁基(甲基)丙烯酰胺、N-叔辛基(甲基)丙烯酰胺、硬脂酰(甲基)丙烯酰胺、(甲基)丙烯酸甲酯、(甲基)丙烯酸乙酯、(甲基)丙烯酸丁酯、(甲基)丙烯酸叔丁酯、(甲基)丙烯酸2,3-二羟基丙酯、N-异丙基丙烯酰胺、丙酸乙烯酯、1-乙烯基-2-甲基咪唑、苯乙烯、乙烯基吡啶、链末端为甲氧基或羟基基团的具有总共2至200个EO或PO单元或EO/PO单元的聚环氧乙烷或环氧丙烷或者聚(环氧乙烷-共-环氧丙烷)与(甲基)丙烯酸的酯或与烯丙基醇的醚、马来酸、富马酸、甲基乙烯基醚、(甲基)丙烯酸羟基乙酯、(甲基)丙烯酸羟基丙酯、乙烯基己内酰胺、乙烯基噁唑啉类如乙烯基噁唑啉、乙烯基甲基噁唑啉、乙烯基乙基噁唑啉、丙烯酰胺丙磺酸、烯丙醇。
极特别优选的共聚单体为N-乙烯基内酰胺类如N-乙烯基己内酰胺(VCAp)、N-乙烯基甲酰胺,以及N-乙烯基咪唑(VI)、氯化1-乙烯基-3-甲基咪唑(QVI),脂族羧酸的乙烯酯如乙酸乙烯酯、丙酸乙烯酯、丁酸乙烯酯、月桂酸乙烯酯、硬脂酸乙烯酯,还有(甲基)丙烯酰胺、二甲基氨基乙基(甲基)丙烯酸酯和二甲基氨基乙基(甲基)丙烯酰胺以及其季铵化的类似物,二烯丙基二甲基氯化铵。
因此,极特别优选的共聚物为N-乙烯吡咯烷酮(VP)与乙酸乙烯酯的共聚物,该共聚物具有20:80至80:20的VP/VAc重量比,例如30:70、50:50、60:40、70:30,具有10至100、优选20至50的K值;还有VP和VI的共聚物,例如具有1:1的VP/VI重量比的共聚物;VP和VCap的共聚物,例如具有1:1重量比、具有10至100——优选20至60——的K值的共聚物。
优选的共聚物还有VP和氯化1-乙烯基-3-甲基咪唑(通过用氯甲烷对1-乙烯基咪唑季铵化获得)的具有20:80至99:1的VP/QVI重量比的共聚物,该共聚物可具有40,000至1,000,000以上道尔顿的分子量。
特别地,本发明还可稳定K值为1至150、优选K10至K90——例如K12、K15、K17、K25、K30、K60、K85、K90——的NVP均聚物的水溶液。
通过自由基聚合制备所述聚乙烯吡咯烷酮的方法本身是已知的。该聚合还可在常规交联剂的存在下发生。
聚合可以例如在合适溶剂中以溶液聚合的方式发生,所述合适溶剂如水、水和有机溶剂的混合物,例如乙醇/水或异丙醇/水混合物,或者纯有机溶剂如乙醇或异丙醇。
另外一种可能的聚合方法为产生一种交联的、不溶于水的聚合物的端聚合(popcorn polymerization)(Breitenbach等人IUPACInternational Symposium on macromolecular Chemistry,Budapest1969(第529-544页),Haff,Sanner,Straub,Polymer Journal Vol17,No.1第143-152页(1985))。
待处理的聚合物溶液通常具有5至60重量%、优选10-50重量%的固体含量。可使用直接从聚合物制备中获得的溶液,或者也可将粉末状聚合物溶于水中。
该处理通常在聚合后实施,优选在聚合反应的溶剂中实施。特别优选处理水溶液。
在有机溶剂中进行聚合的情况下,还可首先用水至少部分地或完全地取代有机溶剂,然后实施该处理。
当聚合物不溶于水或在水中溶解度低时,该处理还可在水分散体 或悬浮液中实施。
根据本发明,通过搅拌与二氧化硫、亚硫酸或者碱金属或碱土金属的亚硫酸盐溶液或分散体,对聚乙烯吡咯烷酮进行处理。所用碱金属亚硫酸盐为例如亚硫酸钾、亚硫酸氢钾、亚硫酸锂、亚硫酸氢锂,或者优选亚硫酸钠或亚硫酸氢钠。基于聚乙烯吡咯烷酮的量,亚硫酸或者亚硫酸盐或亚硫酸氢盐以0.005至1重量%、优选0.01至0.5重量%且特别优选0.03至0.20重量%的量使用。可直接通过将合适量的二氧化硫通入聚合物的水溶液或水分散体中获得合适浓度的亚硫酸。当在有机溶剂中对聚合物溶液进行处理时,同样可加入上述物质。
用上述过氧化物破坏剂(destroyer)进行处理时优选的pH范围为3-11,优选6-10,特别优选7-9。
根据本发明,还用自由基清除剂处理聚合物。所述自由基清除剂可以基于聚合物的0.01至1重量%、优选0.03至0.5重量%、特别优选0.05至0.25重量%的量使用。
合适的自由基清除剂为:抗坏血酸、去甲二氢愈创木酸、虎皮灵、防风根醇、棕榈酸抗坏血酸酯、BHT(“叔丁基对甲酚”:2,6-二-叔丁基-4-甲基苯酚)。
抗坏血酸优选作为自由基清除剂使用。还可使用抗坏血酸的铵盐、碱金属盐、碱土金属盐,例如抗坏血酸铵、抗坏血酸钠或抗坏血酸镁。合适的自由基清除剂还为抗坏血酸与无机酸或有机酸的酯如碳酸抗坏血酸酯、磷酸抗坏血酸酯、硫酸抗坏血酸酯、硬脂酸抗坏血酸酯或棕榈酸抗坏血酸酯,以及其铵盐、碱金属盐、碱土金属盐,例如磷酸抗坏血酸钠或棕榈酸抗坏血酸钠。
本发明方法通过在聚合后将二氧化硫或亚硫酸或其盐在升高的温度下加入到聚合溶液中进行实施。该处理可在10至100℃、优选40至90℃实施。该处理的持续时间取决于待处理的量。处理的持续时间可在1分钟至最高达4小时、优选10分钟至1小时的范围内。
然后用抗坏血酸处理该溶液或分散体。该处理在0至100℃、优选15至80℃、特别优选20至60℃的温度下实施。
该处理优选在搅拌下实施。该处理通常在大气压下实施,但也可在最高达1.6MPa的表压下实施。
用自由基清除剂进行的该第二次处理优选的pH范围为3-10,优选4-9。
然后将以此方式处理过的聚合物溶液或分散体通过干燥转化为自由流动的聚合物粉末。干燥可以例如喷雾干燥、转鼓式干燥或其它热风干燥的方式进行。喷雾干燥和转鼓式干燥为优选的干燥方法。
通常干燥后直接将粉末状的聚合物装入合适的包装材料中。原则上可使用所有容许用于药物、食品或化妆品用途的包装材料。有利的材料当然为具有较小或无氧气渗透性的材料。然而,令人惊奇地发现即使包装材料为氧渗透性的,而且聚乙烯吡咯烷酮存在于高氧气含量的气氛下,仍可获得极好的稳定性。这尤其表明本发明的稳定保护功能。
当然,也可在引入氮气或惰性气体的情况下进行包装。
本发明的方法令人惊奇地达到一种显著改善的抗过氧化物形成的长期稳定性。特别是,在热应力期间的稳定性和在含氧介质中的稳定性显著改善。
有利的还有,除了具有极好的生理容许性的抗坏血酸由于该处理而残留在聚合物粉末中之外,可以在不存在其它残留物的情况下获得稳定性。出乎意料的是,没有亚硫酸或其盐存在于聚合物粉末中,而且几个月后也没有抗坏血酸存在于聚合物粉末中,而抗过氧化物的稳定性却仍然很强。
因此以此方式稳定的聚乙烯吡咯烷酮特别有利地适用于在药物或化妆品制剂中使用,或者在食品和其它消费品技术中使用。可能由诸如其它抗氧化剂、重金属或酶引起的过敏性反应或其它不耐性完全被避免。
实施例
所有试样中的过氧化物含量通过滴定碘法测定。该数据基于以过氧化氢计算的ppm值(mg过氧化物/kg聚合物)。
实施例1
将K值为30(在1重量%的水溶液中测定)、浓度为20%的聚吡咯 烷酮水溶液在80℃下用聚合物的0.1重量%的二氧化硫(以6%SO2水溶液的形式)处理,并且搅拌该溶液1小时。然后将该溶液冷却至40℃,并且加入聚合物的0.1重量%的抗坏血酸。将以此方式处理的溶液喷雾干燥。然后将粉末状的聚乙烯吡咯烷酮密封入复合铝箔袋中,密封之前将填充后的袋用氮气吹扫两次,并储存于各种条件下。此外,还在空气中密封试样,然后在25℃下储存。刚处理完时以及储存3个月和6个月后测定过氧化物含量。结果列在以下表1中。
实施例1a
将K值为30(在1重量%的水溶液中测定)、浓度为20%的聚吡咯烷酮水溶液在80℃下用聚合物的0.2重量%的Na2SO3处理,并且搅拌该溶液1小时。然后将该溶液冷却至40℃,并且加入聚合物的0.1重量%的抗坏血酸。将以此方式处理的溶液喷雾干燥。然后将粉末状的聚乙烯吡咯烷酮密封入复合铝箔袋中,密封之前将填充后的袋用氮气吹扫两次,并储存于各种条件下。此外,还在空气中密封试样,然后在25℃下储存。刚处理完时以及储存3个月和6个月后测定过氧化物含量。结果列在下表中。
表1
实施例1 | 在空气中填充;在25℃下储存 | 在氮气中填充;在25℃/60%RH下储存 | 在氮气中填充;在40℃/75%RH下储存 |
初值 | <1 | <1 | <1 |
3个月 | 51 | 9 | 17 |
6个月 | 46 | 43 | 39 |
实施例1a | 在空气中填充;在25℃下储存 | 在氮气中填充;在25℃/60%RH下储存 | 在氮气中填充;在40℃/75%RH下储存 |
初值 | <1 | <1 | <1 |
3个月 | <1 | <10 | <10 |
6个月 | <1 | <20 | <20 |
实施例2(对比例)
聚合后不加入稳定剂,聚合物溶液在80℃下搅拌1小时,然后喷雾干燥(未处理试样)。
实施例3(对比例)
仅用二氧化硫处理
以类似于实施例1的方式用二氧化硫处理聚合物溶液,然后喷雾干燥。
实施例4(对比例)
仅用抗坏血酸处理
以类似于实施例1而不加入二氧化硫的方式处理聚合物溶液。
实施例5
用二氧化硫并进一步用其它自由剂清除剂处理
以类似于实施例1的方式处理聚合物溶液,但加入0.1重量%的其它自由基清除剂代替抗坏血酸。
5a)去甲二氢愈创木酸
5b)虎皮灵
5c)棕榈酸抗坏血酸酯
5d)BHT
5e)生育酚
5f)防风根醇
以类似于实施例1的方式包装实施例2至5的粉末并且测定其过氧化物含量。结果列在下表2中。
表2
实施例6
将K值为27(在1重量%的水溶液中测定)、浓度为20%的乙烯吡咯烷酮/乙酸乙烯酯(6:4)共聚物的水溶液在80℃下用0.1重量%的二氧化硫(基于聚合物;以6%SO2的水溶液的形式使用)处理,并且搅拌该溶液1小时。然后将该溶液冷却至40℃,并且加入0.1重量%(基于聚合物)的抗坏血酸。将以此方式处理的溶液喷雾干燥。然后将粉末状的共聚物密封入复合铝箔袋中,密封之前将填充后的袋用氮气吹扫两次,并储存于各种条件下。此外,还在空气中密封试样,然后在25℃下储存。刚处理完时以及储存3个月和6个月后测定过氧化物含量。结果列在表2中。
实施例6a
以类似于实施例6但不加入SO2和抗坏血酸的方式实施。
实施例7
将K值为12(在5重量%的水溶液中测定)、浓度为20%的聚乙烯吡咯烷酮均聚物的水溶液在80℃下用0.1重量%的二氧化硫(基于聚合物;以6%SO2的水溶液的形式使用)处理,并且搅拌该溶液1小时。然后将该溶液冷却至40℃,并且加入0.1重量%(基于聚合物)的抗坏血酸。将以此方式处理的溶液喷雾干燥。然后将粉末状的聚乙烯吡咯烷酮密封入复合铝箔袋中,密封之前将填充后的袋用氮气吹扫两次,并储存于各种条件下。此外,还在空气中密封试样,然后在25℃下储存。刚处理完时以及储存3个月和6个月后测定过氧化物含量。结果列在下表1中。
实施例7a
以类似于实施例7但不加入SO2和抗坏血酸的方式实施。
实施例8
将K值为90(在1重量%的水溶液中测定)、浓度为20%的聚乙烯吡咯烷酮均聚物的水溶液在80℃下用0.1重量%的二氧化硫(基于聚合物;以6%SO2的水溶液的形式使用)处理,并且搅拌该溶液1小时。然后将该溶液冷却至40℃,并且加入0.1重量%(基于聚合物)的抗坏血酸。将以此方式处理的溶液在一个转鼓式干燥器上干燥。然后将粉末状的聚乙烯吡咯烷酮密封入复合铝箔袋中,密封之前将填充后的袋用氮气吹扫两次,并储存于各种条件下。此外,还在空气中密封试样,然后在25℃下储存。刚处理完时以及储存3个月和6个月后测定过氧化物含量。结果列在下表1中。
实施例8a
以类似于实施例8但不加入SO2和抗坏血酸的方式实施。
实施例9
交联的聚乙烯吡咯烷酮(PVPP;PVP端聚物)
将浓度为15%的交联的聚乙烯吡咯烷酮的水性悬浮液在80℃下用 0.1重量%的二氧化硫(基于固体聚合物PVPP;以浓度为6%的水溶液的形式)处理,并且搅拌该溶液1小时。然后将该悬浮液过滤并洗涤。然后将PVPP与0.1重量%(基于聚合物)的抗坏血酸混合,然后将该聚合物干燥。接着将该PVPP粉末密封入复合铝箔袋中,密封之前将填充后的袋用氮气吹扫两次,并储存于各种条件下。此外,还在空气中密封试样,然后在25℃下储存。刚处理完时以及储存3个月和6个月后测定过氧化物含量。结果列在下表1中。
实施例9a
以类似于实施例9但不加入SO2和抗坏血酸的方式实施。
实施例10
β-胡萝卜素片
将100.0g10%的β-胡萝卜素干粉末与1000.0g磷酸氢钙和1110.0g微晶纤维素在Turbula混合器中混合。然后将该混合物在Diosna成粒机中用600.0gK值为30、浓度为25%的聚乙烯吡咯烷酮的水溶液润湿,其中所用聚乙烯吡咯烷酮为实施例1的聚乙烯吡咯烷酮;并将湿润的组合物通过0.8mm筛。在托盘中于30℃下进行干燥。然后再一次将干燥的颗粒通过0.8mm筛,并与15.0g硬脂酸镁、25.0g硅胶和100.0g实施例9中制备的交联聚乙烯吡咯烷酮混合,在旋转式压片机中10kN压力下压缩该混合物得到直径为8mm且重量为250mg的片。
将该片在玻璃容器中30℃下储存6个月,并测定β-胡萝卜素含量。
最初值:99.6%β-胡萝卜素6个月值:99.1%β-胡萝卜素
为了进行比较,以相同方法使用市售产品聚乙烯吡咯烷酮K30(过氧化物含量:320ppm)和交联聚维酮(过氧化物含量:250ppm)。
最初值:98.1%β-胡萝卜素6个月值:95.3%β-胡萝卜素
结果表明使用本发明的聚乙烯吡咯烷酮在刚制备完时和储存时对 β-胡萝卜素的显著稳定作用。
实施例11
左炔诺孕酮片
将7.5g的左炔诺孕酮(levonorgestrel)溶于500.0gK值为30、浓度为20%的聚乙烯吡咯烷酮的乙醇溶液,其中所用聚乙烯吡咯烷酮为实施例1的聚乙烯吡咯烷酮;并且将该溶液用于在Diosna成粒机中润湿1100.0g磷酸氢钙和1152.5g微晶纤维素的混合物,将湿润的组合物通过0.8mm筛。在托盘中于35℃下进行干燥。然后再次将干燥的颗粒通过0.8mm筛,并与15.0g硬脂酸镁、25.0g硅胶和100.0g实施例9中制备的交联聚乙烯吡咯烷酮混合,在旋转式压片机中15kN压力下压缩该混合物得到直径为8mm且重量为250mg的片。
将该片在玻璃容器中30℃下储存6个月,并测定左炔诺孕酮含量。
最初值:99.5%左炔诺孕酮 6个月值:99.2%左炔诺孕酮
为了进行比较,以相同方法使用市售产品聚乙烯吡咯烷酮K30(过氧化物含量:320ppm)和交联聚维酮(过氧化物含量:250ppm)。
最初值:98.5%左炔诺孕酮 6个月值:96.3%左炔诺孕酮
结果表明使用本发明的聚乙烯吡咯烷酮在刚制备完时和储存时对左炔诺孕酮的显著稳定作用。
实施例12
肾上腺素注射剂
将1.2g的盐酸肾上腺素、10.0g实施例7中制备的聚乙烯吡咯烷酮K12和7.5g氯化钠溶于998.0g的已煮沸并在氮气下冷却的注射用水中。通过在0.22μm过滤器过滤该溶液对其进行消毒,并在氮气下分配成1ml针剂。
25℃下储存该针剂3个月,并测定肾上腺素含量。
最初值:98.5%肾上腺素 3个月值:96.9%肾上腺素
为了进行比较,以相同方法使用市售产品聚乙烯吡咯烷酮K12(过氧化物含量:290ppm)。
最初值:96.4%肾上腺素 3个月值:89.3%肾上腺素
结果表明使用本发明的聚乙烯吡咯烷酮在刚制备完时和储存时对肾上腺素的显著稳定作用。
实施例13
异丙嗪溶液
50℃下将22.6g盐酸异丙嗪、25.0g实施例8中制备的聚乙烯吡咯烷酮K90、5.0g柠檬酸、2.0g山梨酸和60.0g蔗糖溶于975.0g软化水中,并将该溶液冷却至室温并分配至50ml琥珀色玻璃瓶中。
将该瓶在30℃下储存9个月,并测定异丙嗪含量。
最初值:99.8%异丙嗪9个月值:99.5%异丙嗪
为了进行比较,以相同方法使用市售产品聚乙烯吡咯烷酮K90(过氧化物含量:360ppm)。
最初值:98.4%异丙嗪 9个月值:95.3%异丙嗪
结果表明使用本发明的聚乙烯吡咯烷酮在刚制备完时和储存时对异丙嗪的显著稳定作用。
实施例14
硫酸特布他林薄膜片(film strip)
将100.0g实施例6中制备的乙烯吡咯烷酮/乙酸乙烯酯(6:4)共聚物和100.0g乙烯醇/聚乙二醇接枝共聚物(Kollicoat IR,BASFAG)通过搅拌溶于800.0g软化水中。然后将10.0g硫酸特布他林和2.0g糖精钠溶于该聚合物溶液中。用500μm小刀在Erichsen成膜器中制成薄膜。将薄膜在50℃下干燥,而后将该薄膜切成20x20mm 的片,装入塑料容器中。
将该容器在30℃下储存6个月,并测定硫酸特布他林含量。
最初值:99.6%硫酸特布他林
6个月值:99.8%硫酸特布他林
为了进行比较,以相同方法使用市售产品聚乙烯吡咯烷酮K90(过氧化物含量:360ppm)。
最初值:98.0%硫酸特布他林
6个月值:94.6%硫酸特布他林
结果表明使用本发明的聚乙烯吡咯烷酮在刚制备完时和储存时对异丙嗪的显著稳定作用。
实施例15
氢化泼尼松片
将100.0g氢化泼尼松(prednisolone)与适于直接成片的1100.0g乳糖和80.0g实施例1制备的聚乙烯吡咯烷酮K30、60.0g实施例9中制备的交联聚乙烯吡咯烷酮和15.0g硬脂酸镁在Turbula混合器中混合。然后在旋转式压片机中8kN压力下压缩该混合物得到直径为7mm且重量为135.0mg的片。
Claims (12)
1.一种稳定聚乙烯吡咯烷酮的方法,包括用二氧化硫、亚硫酸或碱金属亚硫酸盐处理聚乙烯吡咯烷酮,且随后用自由基清除剂处理该聚乙烯吡咯烷酮。
2.权利要求1的方法,其中二氧化硫、亚硫酸或碱金属亚硫酸盐以0.01至1重量%的量使用,所述量以聚乙烯吡咯烷酮的量计。
3.权利要求1或2的方法,其中自由基清除剂以0.01至1重量%的量使用,所述量以聚乙烯吡咯烷酮的量计。
4.权利要求1的方法,其中将抗坏血酸用作自由基清除剂。
5.权利要求1的方法,其中在聚合物的溶液中进行处理。
6.权利要求5的方法,其中在水溶液中进行处理。
7.权利要求1的方法,其中在水性悬浮液中进行处理。
8.权利要求1的方法,其中用二氧化硫、亚硫酸或碱金属亚硫酸盐的处理在10至100℃的温度下进行。
9.权利要求1的方法,其中用抗坏血酸的处理在0至100℃的温度下进行。
10.权利要求1的方法,其中处理的聚乙烯吡咯烷酮为均聚物或乙烯吡咯烷酮含量为至少5重量%的N-乙烯吡咯烷酮共聚物。
11.权利要求1的方法,其中以此方式处理的溶液或分散体通过干燥转化为粉末状的聚乙烯吡咯烷酮。
12.权利要求11的方法,其中干燥可通过喷雾干燥或转鼓式干燥进行。
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DE102005005974A DE102005005974A1 (de) | 2005-02-09 | 2005-02-09 | Verfahren zur Stabilisierung von Polyvinylpyrrolidonen |
DE102005005974.0 | 2005-02-09 | ||
PCT/EP2006/050737 WO2006084851A1 (de) | 2005-02-09 | 2006-02-08 | Verfahren zur stabilisierung von polyvinylpyrrolidonen |
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CN101115792B true CN101115792B (zh) | 2011-01-26 |
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EP (1) | EP1851269B1 (zh) |
JP (1) | JP4980933B2 (zh) |
CN (1) | CN101115792B (zh) |
AT (1) | ATE470689T1 (zh) |
DE (2) | DE102005005974A1 (zh) |
ES (1) | ES2346997T3 (zh) |
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HUE048873T2 (hu) * | 2006-07-21 | 2020-08-28 | Basf Se | Fertõtlenítõ és/vagy fehérítõ hatású poliuretán habok |
US8623978B2 (en) | 2010-11-23 | 2014-01-07 | Basf Se | Process for the preparation of low-peroxide crosslinked vinyllactam polymer |
CN103459480B (zh) * | 2011-04-12 | 2017-02-22 | 巴斯夫欧洲公司 | 包含至少一种无机磷化合物的氧化敏感性低过氧化物聚合物 |
EP2511331A1 (de) | 2011-04-12 | 2012-10-17 | Basf Se | Peroxidarmes Polymer enthaltend Phosphorverbindung |
DE202011005055U1 (de) | 2011-04-12 | 2011-09-12 | Basf Se | Peroxidarmes Polymer enthaltend Phosphorverbindung |
US9023931B2 (en) | 2011-04-12 | 2015-05-05 | Basf Se | Oxidation-sensitive, low-peroxide polymer comprising at least one inorganic phosphorus compound |
US9260546B2 (en) | 2012-08-08 | 2016-02-16 | Basf Se | Producing aqueous solutions of vinyllactam polymers and powders thereof |
WO2014023602A1 (de) | 2012-08-08 | 2014-02-13 | Basf Se | Verfahren zur herstellung wässriger lösungen von vinyllactam-polymeren und deren pulver |
CN103044596B (zh) * | 2012-12-13 | 2015-10-21 | 中盐安徽红四方股份有限公司 | 一种聚乙烯吡咯烷酮的聚合方法 |
CN106800616B (zh) * | 2016-12-22 | 2018-09-14 | 安徽山河药用辅料股份有限公司 | 一种高松密度交联聚维酮的制备方法 |
WO2018215136A1 (de) * | 2017-05-23 | 2018-11-29 | Basf Se | Verwendung bestimmter polymere zur herbeiführung eines anti-pollution-effekts |
JP6990559B2 (ja) * | 2017-10-30 | 2022-01-12 | 株式会社日本触媒 | N-ビニルラクタム系重合体の製造方法 |
DE102020205100A1 (de) | 2020-04-22 | 2021-10-28 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung eingetragener Verein | Additivzusammensetzung sowie deren verwendung, kondensationspolymerzusammensetzung, formmasse und hieraus hergestellte formmassen und formteile und deren verwendung |
DE102020205101A1 (de) | 2020-04-22 | 2021-10-28 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung eingetragener Verein | Verwendung von anorganischen Sulfiten und/oder Thiosulfaten zur Stabilisierung von thermoplastischen Kondensationspolymeren, stabilisierte Formmasse und hieraus hergestellte Formmassen und Formteile |
DE102021202103A1 (de) | 2021-03-04 | 2022-09-08 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung eingetragener Verein | Verwendung einer Stabilisatorzusammensetzung zur Stabilisierung von halogenfreien thermoplastischen Kunststoff-Recyclaten, eine Stabilisatorzusammensetzung, ein Masterbatch oder Konzentrat, eine stabilisierte Kunststoffzusammensetzung, hier ein Verfahren zur Stabilisierung von halogenfreien thermoplastischen Kunststoff-Recyclaten sowie Verwendung von Zusammensetzungen |
DE102022206466A1 (de) | 2022-06-27 | 2023-12-28 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung eingetragener Verein | Verwendung einer Stabilisatorzusammensetzung zur Stabilisierung von halogenfreier thermoplastischer Kunststoff-Neuware, Stabilisatorzusammensetzung, ein Masterbatch oder Konzentrat, eine stabilisierte Kunststoffzusammensetzung, Verfahren zur Stabilisierung von halogenfreien thermoplastischen Kunststoff-Neuware sowie Verwendung der Zusammensetzung |
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- 2006-02-08 EP EP06708084A patent/EP1851269B1/de active Active
- 2006-02-08 ES ES06708084T patent/ES2346997T3/es active Active
- 2006-02-08 US US11/815,478 patent/US8524827B2/en active Active
- 2006-02-08 WO PCT/EP2006/050737 patent/WO2006084851A1/de active Application Filing
- 2006-02-08 DE DE502006007163T patent/DE502006007163D1/de active Active
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US20080139724A1 (en) | 2008-06-12 |
DE502006007163D1 (de) | 2010-07-22 |
EP1851269B1 (de) | 2010-06-09 |
ATE470689T1 (de) | 2010-06-15 |
ES2346997T3 (es) | 2010-10-22 |
WO2006084851A1 (de) | 2006-08-17 |
JP2008530263A (ja) | 2008-08-07 |
JP4980933B2 (ja) | 2012-07-18 |
EP1851269A1 (de) | 2007-11-07 |
DE102005005974A1 (de) | 2006-08-10 |
CN101115792A (zh) | 2008-01-30 |
US8524827B2 (en) | 2013-09-03 |
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