JPH04247089A - Crystallization of alkali metal salt of cephalosporin compound - Google Patents
Crystallization of alkali metal salt of cephalosporin compoundInfo
- Publication number
- JPH04247089A JPH04247089A JP9839191A JP9839191A JPH04247089A JP H04247089 A JPH04247089 A JP H04247089A JP 9839191 A JP9839191 A JP 9839191A JP 9839191 A JP9839191 A JP 9839191A JP H04247089 A JPH04247089 A JP H04247089A
- Authority
- JP
- Japan
- Prior art keywords
- alkali metal
- metal salt
- compound
- cephalosporin compound
- cephalosporin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 alkali metal salt Chemical class 0.000 title claims abstract description 60
- 229930186147 Cephalosporin Natural products 0.000 title claims abstract description 36
- 229940124587 cephalosporin Drugs 0.000 title claims abstract description 36
- 229910052783 alkali metal Inorganic materials 0.000 title claims abstract description 22
- 238000002425 crystallisation Methods 0.000 title claims abstract description 22
- 230000008025 crystallization Effects 0.000 title claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- 150000001413 amino acids Chemical class 0.000 claims abstract description 10
- 125000003277 amino group Chemical group 0.000 claims abstract description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 10
- 239000007864 aqueous solution Substances 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims description 5
- 150000001780 cephalosporins Chemical group 0.000 claims description 2
- 239000013078 crystal Substances 0.000 abstract description 21
- FLKYBGKDCCEQQM-WYUVZMMLSA-M cefazolin sodium Chemical compound [Na+].S1C(C)=NN=C1SCC1=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 FLKYBGKDCCEQQM-WYUVZMMLSA-M 0.000 description 14
- 229960003408 cefazolin sodium Drugs 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000012153 distilled water Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 239000003960 organic solvent Substances 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 235000001014 amino acid Nutrition 0.000 description 7
- 229940024606 amino acid Drugs 0.000 description 7
- 229960001139 cefazolin Drugs 0.000 description 7
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 3
- 229930064664 L-arginine Natural products 0.000 description 3
- 235000014852 L-arginine Nutrition 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 159000000001 potassium salts Chemical class 0.000 description 2
- 238000010079 rubber tapping Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 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
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- RRYMAQUWDLIUPV-BXKDBHETSA-N cefacetrile Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC#N)[C@@H]12 RRYMAQUWDLIUPV-BXKDBHETSA-N 0.000 description 1
- OLVCFLKTBJRLHI-AXAPSJFSSA-N cefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](O)C=3C=CC=CC=3)[C@H]2SC1 OLVCFLKTBJRLHI-AXAPSJFSSA-N 0.000 description 1
- 229960003012 cefamandole Drugs 0.000 description 1
- SNBUBQHDYVFSQF-HIFRSBDPSA-N cefmetazole Chemical compound S([C@@H]1[C@@](C(N1C=1C(O)=O)=O)(NC(=O)CSCC#N)OC)CC=1CSC1=NN=NN1C SNBUBQHDYVFSQF-HIFRSBDPSA-N 0.000 description 1
- 229960003585 cefmetazole Drugs 0.000 description 1
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 description 1
- 229960004682 cefoperazone Drugs 0.000 description 1
- 229960004261 cefotaxime Drugs 0.000 description 1
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 description 1
- 229960005495 cefotetan Drugs 0.000 description 1
- SRZNHPXWXCNNDU-RHBCBLIFSA-N cefotetan Chemical compound N([C@]1(OC)C(N2C(=C(CSC=3N(N=NN=3)C)CS[C@@H]21)C(O)=O)=O)C(=O)C1SC(=C(C(N)=O)C(O)=O)S1 SRZNHPXWXCNNDU-RHBCBLIFSA-N 0.000 description 1
- PWAUCHMQEXVFJR-PMAPCBKXSA-N cefpiramide Chemical compound C1=NC(C)=CC(O)=C1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 PWAUCHMQEXVFJR-PMAPCBKXSA-N 0.000 description 1
- 229960005446 cefpiramide Drugs 0.000 description 1
- 229960003202 cefsulodin Drugs 0.000 description 1
- SYLKGLMBLAAGSC-QLVMHMETSA-N cefsulodin Chemical compound C1=CC(C(=O)N)=CC=[N+]1CC1=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)[C@@H](C=3C=CC=CC=3)S(O)(=O)=O)[C@H]2SC1 SYLKGLMBLAAGSC-QLVMHMETSA-N 0.000 description 1
- 229960001991 ceftizoxime Drugs 0.000 description 1
- NNULBSISHYWZJU-LLKWHZGFSA-N ceftizoxime Chemical compound N([C@@H]1C(N2C(=CCS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 NNULBSISHYWZJU-LLKWHZGFSA-N 0.000 description 1
- JFPVXVDWJQMJEE-IZRZKJBUSA-N cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 JFPVXVDWJQMJEE-IZRZKJBUSA-N 0.000 description 1
- 229960001668 cefuroxime Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 229960003067 cystine Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000002763 monocarboxylic acids Chemical class 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
【０００１】0001
【産業上の利用分野】この発明はセファロスポリン化合
物のアルカリ金属塩の晶析方法に関するものであり、医
療の分野で利用される。FIELD OF INDUSTRIAL APPLICATION This invention relates to a method for crystallizing an alkali metal salt of a cephalosporin compound, and is used in the medical field.
【０００２】0002
【従来技術】従来セファロスポリン化合物のアルカリ金
属塩の晶析においては、加温した蒸留水にセファロスポ
リン化合物および炭酸水素ナトリウムなどの塩基を加え
て、セファロスポリン化合物のアルカリ金属塩の過飽和
水溶液を調製し、この過飽和水溶液を加温した有機溶媒
中に一定時間を要して滴下するという方法が用いられて
いた。[Prior Art] Conventionally, in crystallization of an alkali metal salt of a cephalosporin compound, the cephalosporin compound and a base such as sodium hydrogen carbonate are added to heated distilled water to supersaturate the alkali metal salt of the cephalosporin compound. A method has been used in which an aqueous solution is prepared and this supersaturated aqueous solution is dropped into a heated organic solvent over a certain period of time.
【０００３】一方、晶析操作において、晶析しようとす
る化合物と構造が類似する化合物を少量添加することに
より結晶形や結晶粒径を変える技術が知られている。
（薬学雑誌９９，７４５〜７５１（１９７９））On the other hand, a technique is known in which the crystal shape and grain size are changed by adding a small amount of a compound having a similar structure to the compound to be crystallized in the crystallization operation. (Pharmaceutical Journal 99, 745-751 (1979))
【００
０４】00
04]
【発明が解決しようとする課題】従来の晶析方法により
得られるセファロスポリン化合物のアルカリ金属塩の結
晶は、粉体特性のうち圧縮率が大きい、すなわちタッピ
ング前後のかさ密度の変化が大きいため、流動性が悪く
バイアルへの充填性が悪いという問題点があった。[Problems to be Solved by the Invention] Crystals of alkali metal salts of cephalosporin compounds obtained by conventional crystallization methods have a high compressibility among powder characteristics, that is, a large change in bulk density before and after tapping. However, there were problems in that it had poor fluidity and poor filling into vials.
【０００５】[0005]
【課題を解決するための手段】この発明は上記の問題点
を解決し、圧縮率が小さく、バイアルへの充填性が良い
セファロスポリン化合物のアルカリ金属塩の結晶を得る
ための晶析方法を提供するものである。[Means for Solving the Problems] The present invention solves the above problems and provides a crystallization method for obtaining crystals of alkali metal salts of cephalosporin compounds that have a low compressibility and good filling properties into vials. This is what we provide.
【０００６】この発明のセファロスポリン化合物のアル
カリ金属塩の晶析方法は、セファロスポリン化合物のア
ルカリ金属塩の晶析工程において、セファロスポリン化
合物のアル力リ金属塩の過飽和水溶液を調製する際に、
アミノ酸または該セファロスポリン化合物と構造類似で
あって分子中にアミノ基およびカルボキシル基を有する
化合物を添加することを特徴とするものである。The method for crystallizing an alkali metal salt of a cephalosporin compound of the present invention includes preparing a supersaturated aqueous solution of an alkali metal salt of a cephalosporin compound in the step of crystallizing an alkali metal salt of a cephalosporin compound. Occasionally,
It is characterized by adding an amino acid or a compound having a structure similar to the cephalosporin compound and having an amino group and a carboxyl group in the molecule.
【０００７】この発明の晶析方法に用いられるセファロ
スポリン化合物としては、例えば、セファゾリン、セフ
チゾキシム、セファセトリル、セファマンドーレ、セフ
ォタキシム、セフォテタン、セフォペラゾン、セフスロ
ジン、セフテゾール、セフピラミド、セフメタゾール、
セフロキシムなどが挙げられる。The cephalosporin compounds used in the crystallization method of the present invention include, for example, cefazolin, ceftizoxime, cefacetril, cefamandole, cefotaxime, cefotetan, cefoperazone, cefsulodin, ceftesol, cefpiramide, cefmetazole,
Examples include cefuroxime.
【０００８】この発明の晶析方法に用いられるアミノ酸
としては、例えばモノアミノモノカルボン酸（例えばグ
リシン、アラニン、バリン、ロイシン、イソロイシンな
ど）、オキシアミノ酸（例えばセリン、トレオニンなど
）、イオウを含むアミノ酸（例えばシステイン、シスチ
ン、メチオニンなど）、モノアミノジカルボン酸（例え
ばアスパラギン酸、グルタミン酸など）、ジアミノモノ
カルボン酸（例えばリジン、アルギニンなど）、芳香環
をもつアミノ酸（例えばフェニルアラニン、チロシンな
ど）、複素環をもつアミノ酸（例えばヒスチジン、トリ
プトファン、プロリン、オキシプロリンなど）などが挙
げられるが、ジアミノモノカルボン酸が好ましい[0008] Amino acids used in the crystallization method of the present invention include, for example, monoamino monocarboxylic acids (eg, glycine, alanine, valine, leucine, isoleucine, etc.), oxyamino acids (eg, serine, threonine, etc.), and sulfur-containing amino acids. (e.g. cysteine, cystine, methionine, etc.), monoaminodicarboxylic acids (e.g. aspartic acid, glutamic acid, etc.), diaminomonocarboxylic acids (e.g. lysine, arginine, etc.), amino acids with aromatic rings (e.g. phenylalanine, tyrosine, etc.), heterocycles (e.g., histidine, tryptophan, proline, oxyproline, etc.), but diaminomonocarboxylic acids are preferred.
【００
０９】この発明の晶析方法に用いられるセファロスポリ
ン化合物と構造類似であって分子中にアミノ基およびカ
ルボキシル基を有する化合物としては、セファロスポリ
ン骨格の７位にアミノ基およびカルボキシル基を有する
化合物が好ましく、そのような化合物としては、例えば
７−（Ｄ−５−アミノアジピンアミド）−３−アセトキ
シメチル−３−セフェム−４−カルボン酸、７−（Ｄ−
５−アミノアジピンアミド）−３−（５−メチル−１，
３，４−チアジアゾール−２−イル）チオメチル−３−
セフェム−４−カルボン酸またはその塩類が挙げられる
。塩類としては、ナトリウム塩、カリウム塩などのアル
カリ金属塩、カルシウム塩、マグネシウム塩などのアル
カリ土類金属塩、塩酸塩、硫酸塩などの無機酸との塩な
どが挙げられる。00
09 Compounds having an amino group and a carboxyl group in the molecule that are structurally similar to the cephalosporin compound used in the crystallization method of the present invention include compounds having an amino group and a carboxyl group at the 7-position of the cephalosporin skeleton. Compounds are preferred, such as 7-(D-5-aminoadipinamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid, 7-(D-
5-aminoadipinamide)-3-(5-methyl-1,
3,4-thiadiazol-2-yl)thiomethyl-3-
Cephem-4-carboxylic acid or its salts can be mentioned. Examples of the salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, and salts with inorganic acids such as hydrochlorides and sulfates.
【００１０】この発明の晶析方法は、まず蒸留水にセフ
ァロスポリン化合物を懸濁し、例えば炭酸水素ナトリウ
ム、水酸化ナトリウム、炭酸ナトリウム、炭酸水素カリ
ウム、水酸化カリウム、炭酸カリウムなどの塩基を加え
てセファロスポリン化合物を溶解し、次いで上記アミノ
酸または該セファロスポリン化合物と構造類似であって
分子中にアミノ基およびカルボキシ基を有する化合物を
加えて溶解する。アミノ酸および該セファロスポリン化
合物と構造類似であって分子中にアミノ基およびカルボ
キシ基を有する化合物は、セファロスポリン化合物と同
時に蒸留水に加えて溶解してもよい。蒸留水はセファロ
スポリン化合物のアルカリ金属塩の溶解性を高めるため
に、４０〜５０℃に加温することが好ましい。[0010] In the crystallization method of the present invention, a cephalosporin compound is first suspended in distilled water, and a base such as sodium hydrogen carbonate, sodium hydroxide, sodium carbonate, potassium hydrogen carbonate, potassium hydroxide, potassium carbonate, etc. is added. The cephalosporin compound is dissolved therein, and then the above amino acid or a compound having a structure similar to the cephalosporin compound and having an amino group and a carboxy group in the molecule is added and dissolved. An amino acid and a compound having a structure similar to the cephalosporin compound and having an amino group and a carboxy group in the molecule may be added and dissolved in distilled water at the same time as the cephalosporin compound. The distilled water is preferably heated to 40 to 50°C in order to increase the solubility of the alkali metal salt of the cephalosporin compound.
【００１１】この発明の晶析方法における上記アミノ酸
およびセファロスポリン化合物と構造類似であって分子
中にアミノ基およびカルボキシル基を有する化合物の添
加量は、重量比でセファロスポリン化合物の０．１〜５
％、好ましくは０．５〜２％である。[0011] In the crystallization method of the present invention, the amount of the compound having a similar structure to the amino acid and the cephalosporin compound and having an amino group and a carboxyl group in the molecule is added in a weight ratio of 0.1 to that of the cephalosporin compound. ~5
%, preferably 0.5-2%.
【００１２】このようにして得られたセファロスポリン
化合物のアルカリ金属塩の過飽和水溶液を、常法に従っ
て一定温度に加温した有機溶媒中に一定時間を要して徐
々に滴下し、セファロスポリン化合物のアルカリ金属塩
の結晶を晶析する。セファロスポリン化合物のアルカリ
金属塩としては、先に例示したセファロスポリン化合物
のナトリウム塩、カリウム塩などが挙げられる。有機溶
媒としては例えば、メタノール、エタノール、アセトン
、イソプロピルアルコールなどおよびこれらの２種以上
の混合溶媒が用いられ、セファロスポリン化合物の種類
によって適宜選択される。この有機溶媒およびその混合
溶媒には少量の蒸留水を加えてもよい。晶析温度は４０
〜５０℃が好ましい。The thus obtained supersaturated aqueous solution of the alkali metal salt of the cephalosporin compound is gradually dropped over a certain period of time into an organic solvent heated to a certain temperature according to a conventional method. Crystallizing the alkali metal salt of the compound. Examples of the alkali metal salts of cephalosporin compounds include the sodium salts and potassium salts of the cephalosporin compounds listed above. As the organic solvent, for example, methanol, ethanol, acetone, isopropyl alcohol, etc., and a mixed solvent of two or more thereof are used, and are appropriately selected depending on the type of cephalosporin compound. A small amount of distilled water may be added to this organic solvent and its mixed solvent. Crystallization temperature is 40
~50°C is preferred.
【００１３】晶析終了後５℃前後まで冷却し、その温度
で１〜２時間熟成させたのち、結晶を濾取し、上記有機
溶媒で洗浄する。このようにして得られる結晶を常法に
より加温下で真空乾燥する。After the crystallization is completed, the mixture is cooled to around 5° C. and aged for 1 to 2 hours at that temperature, and then the crystals are collected by filtration and washed with the above-mentioned organic solvent. The crystals thus obtained are vacuum dried under heating in a conventional manner.
【００１４】[0014]
【効果】後記実施例１〜４および製造例１で得られたβ
型セファゾリンナトリウム結晶について、タッピング前
とタッピング後のかさ密度を測定し、次式により圧縮率
を求めた。[Effect] β obtained in Examples 1 to 4 and Production Example 1 described later
The bulk density of the type cefazolin sodium crystal before and after tapping was measured, and the compressibility was determined using the following formula.
【００１５】結果を表１に示す。The results are shown in Table 1.
【表１】[Table 1]
【００１６】表１から明らかなように、この発明の晶析
方法で得られた実施例１〜４のβ型セファゾリンナトリ
ウム結晶は、従来の晶析方法で得られた製造例１のβ型
セファゾリンナトリウム結晶に比べて圧縮率が小さいこ
とがわかる。そのため、流動性に優れておりバイアルへ
の充填性が良い。As is clear from Table 1, the β-type cefazolin sodium crystals of Examples 1 to 4 obtained by the crystallization method of the present invention are different from the β-type cefazolin sodium crystals of Production Example 1 obtained by the conventional crystallization method. It can be seen that the compressibility is smaller than that of sodium crystals. Therefore, it has excellent fluidity and is easy to fill into vials.
【００１７】製造例１
４０℃に加温した蒸留水（３６ｍｌ）中に、セファ
ゾリン（２０ｇ）及び炭酸水素ナトリウム（３．７ｇ）
を発泡に注意して加え、セファゾリンを溶解する。溶解
液のｐＨが６．０〜６．４であることを確認し、０．２
μのメンブランフィルターで清澄濾過し、次いで蒸留水
（４ｍｌ）にて洗浄する。別に５００ｍｌの３頸コルベ
ンに混合有機溶媒（組成比：エタノール８５．５％、ア
セトン９．６％、イソプロピルアルコール４．９％）２
００ｍｌ）及び蒸留水（３ｍｌ）を加え４５℃に保温し
ておく。これに先に調製したセファゾリンナトリウムの
過飽和水溶液を晶析温度４０〜４５℃の範囲で４０分要
して滴下し、β型セファゾリンナトリウムを晶析させる
。晶析終了後、５℃まで冷却し同温下１時間熟成後、結
晶を濾取し、結晶を上記混合有機溶媒（６６．６ｍｌ）
で洗浄する。濾取した結晶を３５℃で１５時間真空乾燥
させ、β型セファゾリンナトリウム結晶（１８．９６ｇ
）を得る。Production Example 1 Cefazolin (20 g) and sodium hydrogen carbonate (3.7 g) were added to distilled water (36 ml) heated to 40°C.
to dissolve the cefazolin. Confirm that the pH of the solution is 6.0 to 6.4, and
It is clarified by filtration using a μ membrane filter, and then washed with distilled water (4 ml). Separately, mix organic solvent (composition ratio: ethanol 85.5%, acetone 9.6%, isopropyl alcohol 4.9%) in 500 ml of three-necked colben.
00 ml) and distilled water (3 ml) and keep warm at 45°C. The previously prepared supersaturated aqueous solution of cefazolin sodium is added dropwise over a period of 40 minutes at a crystallization temperature of 40 to 45°C to crystallize β-type cefazolin sodium. After crystallization, the crystals were cooled to 5°C and aged for 1 hour at the same temperature.
Wash with water. The filtered crystals were vacuum dried at 35°C for 15 hours to obtain β-type cefazolin sodium crystals (18.96g
).
【００１８】[0018]
【実施例】この発明を以下の実施例についてさらに詳細
に説明する。EXAMPLES The present invention will be explained in more detail with reference to the following examples.
【００１９】実施例１
４０℃に加温した蒸留水（４４．７ｍｌ）中に、セ
ファゾリン（２４．８３ｇ）を加えて懸濁し、次いで炭
酸水素ナトリウム（５．０５ｇ）を加えてセファゾリン
を溶解し、次いでＬ−アルギニン（０．２４８ｇ）を加
える。溶解液のｐＨが６．０〜６．４であることを確認
し、０．２μのメンブランフィルターで清澄濾過し、次
いで蒸留水（５ｍｌ）に洗浄する。別に５００ｍｌの３
頸コルベンに混合有機溶媒（組成比：エタノール８５．
５％、アセトン９．６％、イソプロピルアルコール４．
９％）（２４８．３ｍｌ）及び蒸留水（３．７２ｍｌ）
を加え、４５℃に保温しておく。これに先に調製したセ
ファゾリンナトリウムの過飽和水溶液を晶析温度４０−
４５℃の範囲で４０分要して滴下し、β型セファゾリン
ナトリウムを晶析させる。晶析終了後、５℃まで冷却し
同温下で１時間熟成後、結晶を濾取し、結晶を上記混合
有機溶媒（８２．７ｍｌ）で洗浄する。濾取した結晶を
３５℃で１５時間真空乾燥させ、β型セファゾリンナト
リウム結晶（２１．８２ｇ）を得る。Example 1 Cefazolin (24.83 g) was added and suspended in distilled water (44.7 ml) heated to 40°C, and then sodium hydrogen carbonate (5.05 g) was added to dissolve the cefazolin. , then add L-arginine (0.248 g). After confirming that the pH of the solution is 6.0 to 6.4, it is clarified and filtered using a 0.2μ membrane filter, and then washed with distilled water (5 ml). Separately 500ml 3
Mixed organic solvent (composition ratio: ethanol 85.
5%, acetone 9.6%, isopropyl alcohol4.
9%) (248.3ml) and distilled water (3.72ml)
Add and keep warm at 45℃. To this, a supersaturated aqueous solution of cefazolin sodium prepared previously was added at a crystallization temperature of 40-
The mixture is added dropwise over a period of 40 minutes at 45° C. to crystallize β-type cefazolin sodium. After completion of crystallization, the mixture was cooled to 5° C. and aged for 1 hour at the same temperature, and then the crystals were collected by filtration and washed with the above mixed organic solvent (82.7 ml). The filtered crystals are vacuum dried at 35° C. for 15 hours to obtain β-type cefazolin sodium crystals (21.82 g).
【００２０】実施例２
実施例１のＬ−アルギニン（０．２４８ｇ）をＬ−
リジン（０．２４８ｇ）に替えて、実施例１と同様にし
てβ型セファゾリンナトリウム結晶（２０．９２ｇ）を
得る。Example 2 L-arginine (0.248g) from Example 1 was converted into L-arginine (0.248g).
β-type cefazolin sodium crystals (20.92 g) were obtained in the same manner as in Example 1 except for using lysine (0.248 g).
【００２１】実施例３
４０〜４５℃に加温した蒸留水（５４ｍｌ）中に、セフ
ァゾリン（３０ｇ）を加えて懸濁し、次いで炭酸水素ナ
トリウム（６．１ｇ）を加えてセファゾリンを溶解し、
次いで７−（Ｄ−５−アミノアジピンアミド）−３−（
５−メチル−１，３，４−チアジアゾール−２−イル）
チオメチル−３−セフェム−４−カルボン酸のナトリウ
ム塩（３００ｍｇ）を加えて溶解する。別に５００ｍｌ
の３頸コルベンに混合有機溶媒（組成比：エタノール８
５．５％、アセトン９．６％、イソプロピルアルコール
４．９％）（３００ｍｌ）及び蒸留水（４．５ｍｌ）を
加え、４５゜Ｃに保温しておく。これに先に調製したセ
ファゾリンナトリウムの過飽和水溶液を晶析温度４０−
４５℃の範囲で４０分要して滴下し、β型セファゾリン
ナトリウムを晶析させる。晶析終了後、５℃まで冷却し
同温下１時間熟成後、結晶を濾取し、結晶を上記混合有
機溶媒（１００ｍｌ）で洗浄する。濾取した結晶を３５
℃で１５時間真空乾燥させ、β型セファゾリンナトリウ
ム結晶（２８．２ｇ）を得る。Example 3 Cefazolin (30 g) was added and suspended in distilled water (54 ml) heated to 40-45°C, and then sodium hydrogen carbonate (6.1 g) was added to dissolve cefazolin.
Then 7-(D-5-aminoadipinamide)-3-(
5-methyl-1,3,4-thiadiazol-2-yl)
Add and dissolve the sodium salt of thiomethyl-3-cephem-4-carboxylic acid (300 mg). Separately 500ml
Mixed organic solvent (composition ratio: ethanol 8
5.5%, acetone 9.6%, isopropyl alcohol 4.9%) (300 ml) and distilled water (4.5 ml) were added and kept warm at 45°C. To this, a supersaturated aqueous solution of cefazolin sodium prepared previously was added at a crystallization temperature of 40-
The mixture is added dropwise over a period of 40 minutes at 45° C. to crystallize β-type cefazolin sodium. After completion of crystallization, the mixture was cooled to 5° C. and aged for 1 hour at the same temperature, and then the crystals were collected by filtration and washed with the above mixed organic solvent (100 ml). 35% of the filtered crystals
Vacuum drying was carried out at ℃ for 15 hours to obtain β-type cefazolin sodium crystals (28.2 g).
【００２２】実施例４
実施例３の７−（Ｄ−５−アミノアジピンアミド）
−３−（５−メチル−１，３，４−チアジアゾール−２
−イル）チオメチル−３−セフェム−４−カルボン酸の
ナトリウム塩（３００ｍｇ）を、７−（Ｄ−５−アミノ
アジピンアミド）−３−アセトキシメチル−３−セフェ
ム−４−カルボン酸のナトリウム塩（３００ｍｇ）に替
えて、実施例３と同様にしてβ型セファゾリンナトリウ
ム結晶（２８．５ｇ）を得る。Example 4 7-(D-5-aminoadipinamide) of Example 3
-3-(5-methyl-1,3,4-thiadiazole-2
-yl)thiomethyl-3-cephem-4-carboxylic acid sodium salt (300 mg) was mixed with 7-(D-5-aminoadipinamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid sodium salt (300 mg). (300 mg), β-type cefazolin sodium crystals (28.5 g) were obtained in the same manner as in Example 3.
Claims (3)
属塩の晶析工程において、セファロスポリン化合物のア
ルカリ金属塩の過飽和水溶液を調製する際に、アミノ酸
または該セファロスポリン化合物と構造類似であって分
子中にアミノ基およびカルボキシル基を有する化合物を
添加することを特徴とするセファロスポリン化合物のア
ルカリ金属塩の晶析方法。Claim 1: In the crystallization step of an alkali metal salt of a cephalosporin compound, when preparing a supersaturated aqueous solution of an alkali metal salt of a cephalosporin compound, an amino acid or a molecule structurally similar to the cephalosporin compound is used. A method for crystallizing an alkali metal salt of a cephalosporin compound, the method comprising adding a compound having an amino group and a carboxyl group therein.
ある請求項１に記載のセファロスポリン化合物のアルカ
リ金属塩の晶析方法。2. The method for crystallizing an alkali metal salt of a cephalosporin compound according to claim 1, wherein the amino acid is a diaminomonocarboxylic acid.
あって分子中にアミノ基およびカルボキシル基を有する
化合物が、セファロスポリン骨格の７位にアミノ基およ
びカルボキシル基を有する化合物である請求項１に記載
のセファロスポリン化合物のアルカリ金属塩の晶析方法
。3. The compound having a structure similar to a cephalosporin compound and having an amino group and a carboxyl group in the molecule is a compound having an amino group and a carboxyl group at the 7-position of the cephalosporin skeleton. A method for crystallizing an alkali metal salt of a cephalosporin compound as described.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9839191A JPH04247089A (en) | 1991-01-31 | 1991-01-31 | Crystallization of alkali metal salt of cephalosporin compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9839191A JPH04247089A (en) | 1991-01-31 | 1991-01-31 | Crystallization of alkali metal salt of cephalosporin compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH04247089A true JPH04247089A (en) | 1992-09-03 |
Family
ID=14218549
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP9839191A Pending JPH04247089A (en) | 1991-01-31 | 1991-01-31 | Crystallization of alkali metal salt of cephalosporin compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH04247089A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2015074618A (en) * | 2013-10-08 | 2015-04-20 | 協和発酵バイオ株式会社 | Method for producing amino acid |
-
1991
- 1991-01-31 JP JP9839191A patent/JPH04247089A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2015074618A (en) * | 2013-10-08 | 2015-04-20 | 協和発酵バイオ株式会社 | Method for producing amino acid |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU617347B2 (en) | Novel crystalline 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido) -3-vinyl-3-cephem-4-carboxylic acid (syn isomer) | |
| KR950003612B1 (en) | Cephalosporin salts | |
| KR900001422B1 (en) | Anhydrous crystalline sodium salt of 5-chloro-3-(2-rhenoyl)-2-oxindole-1-carboxamide | |
| WO1995029913A1 (en) | Crystal of pyrrolidylthiocarbapenem derivative, lyophilized preparation containing said crystal, and process for producing the same | |
| JPH045038B2 (en) | ||
| AU597262B2 (en) | Cephalosporin salts and injectable compositions | |
| JPH04247089A (en) | Crystallization of alkali metal salt of cephalosporin compound | |
| JP2958567B2 (en) | Freeze-dried BMY-28142 dihydrochloride for parenteral use | |
| JPH10511377A (en) | Manufacture of cefotaxime | |
| JPS61180789A (en) | Crystalline triethylamine salt of cephbperazone | |
| WO2006106529A1 (en) | A co-spray dried composition of cefepime with base and process for preparation thereof | |
| JPH0689024B2 (en) | Method for producing polypeptides | |
| WO2005094800A2 (en) | A co-precipitated cefepime composition and process for preparation thereof | |
| JPS624393B2 (en) | ||
| DK167319B1 (en) | STABLE HYDRATE OF A PENICILLIN DERIVATIVE AND PROCEDURE FOR PREPARING THEREOF | |
| JPH0150225B2 (en) | ||
| JP3755908B2 (en) | Crystallization of cephalosporin compounds | |
| SU925251A3 (en) | Process for producing d-configuration crystalline form of sesquisalt of sodium 7beta-[alpha-carboxy-alpha-(n-oxyphenyl) acetamido-7-alpha-methoxy-3-(1-methyl-tetrazol-5-yl) thiomethyl-2-oxadethia-3-cefem-4-carboxyate | |
| WO2006109324A2 (en) | Processes for preparation of amorphous cefepime acid addition salts | |
| SU860705A3 (en) | Method of preparing crystalline form of d-configuration of diammonium salt of 7-beta-/-alpha-carboxy-alpha-p-oxyphenyl acetamido /-7-alpha-methoxy-3-(1-methyltetrazol-5-yl)-thiomethyl-1-oxydethia-3-cephem-4-carboxalic acid | |
| JPH0157115B2 (en) | ||
| FI73976C (en) | Process for distributing the racemate S- (carboxymethyl) - (R, S) -cysteine in isomers | |
| JPH085898B2 (en) | Ceforanide derivative | |
| KR840002143B1 (en) | A process for preparing n-carboxy cefadroxil disodium salt | |
| JPH06247974A (en) | Cephalosporin salt and its preparation |